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Volume 28, 42 Issues, 2021
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Special Issue Submission
Kinase Inhibitors In Drug Discovery
Guest Editor(s): Vikas Sharma
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I have a nice and meaningful experience with Bentham Science since my first trial of someone else's manuscript to the first time independent delivery of manuscript. I really learned a lot through this experience, and your patient and kind service impressed me a lot. Thank you very much for your serious and responsible attitude for all the manuscripts! Thanks to all the managers and editors!
109 Abstract Ahead of Print are available electronically
120 Articles Ahead of Print are available electronically
Breast cancer is the most frequently occurring malignant tumour in women worldwide. Unfortunately, despite
much research into this disease and advances in clinical care, breast cancer remains a leading cause of cancerrelated
deaths among females. Targeting molecular biomarkers of cancer is one of the main strategies in therapeutics
development. Improvements in the clinical outcome of breast cancer patients from the use of the selective oestrogen
receptor (ER) modulator tamoxifen for ER-positive breast tumours, or the Human Epidermal Growth Factor-
Receptor 2 (HER-2) targeting monoclonal antibody trastuzumab for HER-2 overexpressing breast cancers, are a
testament to the relevance and importance of this approach. The aim of this thematic issue is to collate updated reviews
on a selection of biomarkers and molecular targets that hold promise for novel therapeutics in breast cancer.
In this thematic issue, Tan et al.  reviewed information on the interferon-induced protein with tetratricopeptide
repeats (IFIT) family of proteins, which has been widely studied concerning the immune response in viral infection.
Recent studies discovered that members of this family regulate the aggressiveness of breast cancer and other
malignant tumours, and that they may prognosticate disease outcomes.
Matsumoto and Bay  presented current information on the complement component 1, q subcomponent binding
protein (C1QBP), a potential molecular chaperone molecule that can be found in different subcellular compartments.
They highlighted studies that demonstrated the roles of C1QBP in oncogenesis, cancer progression, and metastasis.
Sheta and Götte  described the involvement of Syndecan-1, a transmembrane heparan sulfate proteoglycan, in
various processes in breast carcinogenesis and progression. Additionally, they discussed various strategies that may
be used for targeting this molecule in breast cancer treatment.
Lee and Kim  focussed on the highly conserved HOX genes, which encode transcription factors, in breast
cancer. Additionally, they drew attention to the importance of long non-coding RNAs (lncRNAs) within the HOX
clusters in regulating the cellular behaviour of breast cancer cells.
The topic of lncRNAs was further examined by Tachiwana and Saitoh . Using several lncRNAs as examples,
they described how these molecules function as epigenetic regulators and thereby influence the development of malignant
tumours in the breast and other organs.
Song et al.  provided a comprehensive review on the potential use of RNA therapy for the treatment of breast
cancer. They also presented a summary of RNA-based drugs that are currently at different phases of clinical trials in
breast cancer treatment.
Shao et al.  reviewed the JAK/STAT signalling pathway, which has been well studied in breast and other
cancer types. Further, they highlighted studies that examined the effects of various inhibitors of JAK kinases and
STAT3 in breast cancer.
In their paper, Chen and Tan  emphasised the important relationship between breast cancer and the immune
system as well as the tumour microenvironment. They discussed the potential exploitation of lymphoid infiltrates in
immunotherapy of breast cancer.
The review by Feril et al.  provided background technical information on high-intensity focussed ultrasound
(HIFU). This was followed by a summary of clinical studies involving this technique in breast cancer treatment, as
well as a discussion on the advantages and challenges of HIFU.
There are many other potential leads for breast cancer therapeutics that are actively being investigated by researchers
around the world, and it would not be possible to cover all of them here. Nevertheless, we trust that readers
who are interested in breast cancer treatment will enjoy reading this issue and hope that it will inspire new ideas
that may translate into more effective therapeutic options for breast cancer in the future.
The aim of this special issue was to identify and review the latest achievements in the area of naturally occurring
bioactive compounds with antidiabetic potential, with articles from experts in the field, illustrating the possibilities
that these molecules and advanced strategies in the treatment of Diabetes mellitus can offer in respect of the health
Diabetes mellitus (DM) is one of the most common chronic diseases all over the world, with still increasing
prevalence. According to the latest data, about 463 million adult people (age 20-79 years) worldwide suffered from
diabetes in 2019, which is four times more than in the 1980s. If this trend continues, the number of diabetic people
will go over 600 million by 2040 . Diabetes mellitus is a complex metabolic disorder triggered by the deficiency
of insulin and manifested in a high level of blood glucose (hyperglycemia). The elevated glucose levels in the blood
can impede the metabolic pathways of proteins, carbohydrates, and fats in the organism and create grave complications
. There are several types of diabetes with two most prominent ones: type 1 diabetes mellitus (T1DM), previously
referred to as insulin-dependent DM, or "juvenile diabetes", an autoimmune disorder in which β-cells in the
pancreatic islets are rapidly destroyed which brings about impaired insulin secretion, further leading to insulin deficiency
in the organism. Type 2 diabetes mellitus (T2DM), previously recognized as non-insulin-dependent diabetes
mellitus, typically affects adults. There are a plethora of factors including behavior, genetics and socioeconomics
which greatly influence diabetes. Sadly, the more the standard of living rises, the more people suffer from both
types of diabetes around the globe .
At present, oral medicine and insulin cause side effects and cannot manage secondary complications which lead
to developing a combination therapy, which has been so far successful in controlling secondary complications and
glycemic index. New gene sequences responsible for diabetes have been identified and new tools such as PCRs,
DNA microarray and knocking out and silencing of genes in animals have been developed, all of which is contributing
to the breakthrough in developing effective medicine for battling, or even defeating, diabetes and its secondary
The diabetic drug market is growing rapidly, imposing very serious economic issues . Despite the fact that
many synthetic antidiabetics are available on the market, they cannot prevent the pathogenesis of this disease entirely
. In this respect, interest in new pharmacological targets is on the rise due to the high prevalence of DM. The
focus is mostly on natural products, among which plants and algae deserve a lot of attention, due to their notable
antidiabetic potential [1, 4, 5].
New drugs that do not have harmful effects found in standard antidiabetics have increased in demand and put
natural products, especially plant-based, at the center of scientific attention as their anti-diabetic potential is pronounced
through various mechanisms . Aumeeruddy and Mahomoodally presented, in their work, plants across
92 countries from 112 genera and 197 families that were recorded to manage diabetes. Leguminosae (105 genera
and 193 species), Compositae (97 genera and 188 species), and Lamiaceae (47 genera and 121 species) were noted
as the most significant . Also, many plants with antidiabetic effect come from the genus Acacia, Acalypha, Achillea,
Alisma, Allium, Aloe, Brassica, Calamus, Cassia, Citrus, Eucalyptus, Eugenia, Ficus, Gentiana, Lycium, Mangifera,
Marrubium, Mentha, Mimosa, Moringa, Piper, Plantago, Salvia, Solanum, Syzygium, Thymus, etc. .
An increasing number of studies suggest that classes of compounds such as flavonoids, alkaloids, and their essential
metabolites, are the ones that take credit for developing anti-diabetic drugs or decreasing diabetes risk factors
among susceptible individuals [1, 4, 6, 7]. Research has mostly been focused on three large groups of natural
products, flavonoids, alkaloids, and saponins because they possess compounds that decrease serum cholesterol, triglycerides,
urea, and creatinine levels in diabetic models, which lowers the risk of diabetic complications such as
cardiovascular diseases and diabetic nephropathy and while the conventional antidiabetics cause obesity, several
natural compounds reduce it in diabetic animals [6, 7]. These naturally occurring metabolites can regulate (or modulate)
various types of signaling pathways involved in diabetes. Treating T1DM relies on insulin replacement and
rehydration, whereas treating T2DM requires oral hypoglycaemic agents, some of which include biguanides (e.g.metformin), dipeptidyl peptidase IV inhibitors (e.g. sitagliptin), meglitinides (e.g. repaglinide), α-glucosidase inhibitors
(e.g. acarbose), sulfonylureas (e.g. glimepiride), thiazolidinediones (e.g. pioglitazone) and incretin mimetics
(e.g. exenatide), but not without adverse effects; hence, there is a need for finding alternatives [3, 4]. For example,
some plant extracts have a hypoglycemic effect due to their ability to inhibit α-amylase and α-glucosidase enzymes,
which helps to prevent postprandial blood glucose increase and chronic hyperglycaemia. Furthermore, α-amylase
and α-glucosidase inhibitors can slow down the digestion of carbohydrates and decrease the glucose absorption rate
from the gut. Dietary plant polyphenols and polyphenol-rich products have been recognized for lowering the risk of
T2DM. They regulate carbohydrate and lipid metabolism, reduce hyperglycaemia, dyslipidaemia and insulin resistance,
and stimulate insulin secretion .
Nowadays, algae studied by several authors have been considered as organisms not only of high ecological importance
but also of economic significance. The use of algae and their application in versatile areas (energy production,
agriculture, food science, cosmeceutical, and pharmacology) is notable. Due to the fact that algae are a good
source of bioactive compounds with prominent biological properties such as the prevention of T2DM, considerable
scientific attention has been given to these natural products. Many reports have demonstrated the beneficial properties
of extracts obtained from various algae and compounds such as polysaccharides, phenolic compounds or pigments,
in both in vitro and in vivo experiments .
Optimistically, the advanced research in this field may lead to the development of effective therapeutics for the
management of diabetes and its secondary complications.
This is the second part of our thematic issue about drug repurposing. Here, the topics focus on neurodegenerative
and cardiovascular diseases. Drugs discussed in this issue include antibiotics, anti-mycobacterials, antivirals, antifungals,
chelating agents, PPAR modulators, metformin, modulators of the renin-angiotensin system, including
angiotensin receptor blockers, and anticancer drugs. In addition, repurposing of andrographolide, edaravone,
cilostazol, sildenafil and sialidase inhibitors is also presented.
Repurposing drugs for neurodegenerative diseases is a major part of this issue. In their review, Rampa et al. discuss
the treatment of Alzheimer’s disease by recently repositioned drugs in various classes such antibiotics, antimycobacterials,
antivirals, antifungals, chelating agents, PPAR modulators, metformin, modulators of the reninangiotensin
system including angiotensin receptor blockers, and anticancer drugs . The authors then dissect new
hypotheses proposed regarding the pathogenesis of this disease. Such hypotheses, the authors argue, could unhide
previously overlooked therapeutic regimens. El Massry et al. reassess the mechanisms through which metformin
exerts its effects. and elegantly discuss how metabolic stress could be a powerful instigator of neural insults . In
particular, the authors discuss how metabolic stress contributes to the pathobiology of Alzheimer’s disease and depression.
The authors conclude with the therapeutic benefits of repurposing metformin for the reversal of brain injury
though they caution that further studies are warranted. Ren et al. discuss the potential repurposing of andrographolide
for use in the management of Alzheimer’s disease, Parkinson’s disease, as well as cancer, inflammation,
and cardiovascular disease . The authors then provide a perspective on pharmacological enhancement of andrographolide
such as derivatives, chemical modifications with potent biological activity and drug delivery. Traumatic
brain injury (TBI) is a debilitating disease that is putting a lot of financial and other burdens on different countries.
Shakkour et al. discuss how edaravone, is a potent free-radical scavenger that has been in the market for more than
30 years can be repositioned for TBI . In their review, the authors discuss the biochemical properties of edaravone
along with its effects on several neurological disorders in the hope that it can be adopted for treating TBI patients.
Anwar et al. present an interesting paper about targeting COVID-19 in Parkinson’s patients, and how drug
repurposing can help patients with COVID-19 who are already suffering from Parkinson disease . The authors
discuss how amantadine, a common drug possessing both antiviral and anti-Parkinson properties can be utilized.
Another section of this issue deals with drugs repurposed for cardiovascular disease. El-Hachem et al. discuss
how cilostazol, a selective inhibitor of phosphodiesterase-III, originally prescribed to treat intermittent claudication,
can be repurposed for the management of Raynaud’s phenomenon . This is largely due to this drug’s antiplatelet
and vasodilating properties. Poitras et al. present a very interesting paper about the chemistry and pharmacology of
PDE5 inhibitors . They also revisit sildenafil’s use for erectile dysfunction and pulmonary arterial hypertension.
The authors then end with a critical review of emerging evidence suggesting that sildenafil can be repurposed for
the treatment for persistent pulmonary hypertension of the newborn. Sobenin et al. present an exciting hypothesis
that decreasing LDL enzymatic desialylation reduces lipid accumulation in arterial wall, thus suppressing atherogenesis
. The authors then discuss the potential of repurposing sialidase inhibitors for use in the treatment or
management of atherosclerosis.
We hope readers enjoy both parts of the issue where we tried to cover leading causes of global death. We hope
that by discussing drug repositioning in metabolic, neurodegenerative, and cardiovascular diseases, as well as in
cancer, in addition to deep learning-based drug-target interactions (DTIs) prediction approaches and computational
approaches, our readers would benefit from this diverse array of topics.
Drug repurposing, also called drug repositioning, is an attractive approach that seeks to identify new targets or
treatments for existing drugs. This approach saves not only significant amounts of money, but also time invested in
drug design and development. This is especially so since pharmaceutical industry suffers from high attrition rates,
delay in the approval of new drugs as well as other regulatory requirements, all of which result in higher drug costs.
While serendipity played an initial role in sparking interest in drug repurposing, observational studies lend great
support for the garnered success of repositioning several drugs, such as sildenafil, metformin, or edaravone to name
a few. This repositioning offers new and big hopes for integrating already approved drugs, especially off-patent
ones, in the management/treatment of off-target diseases. This is the first of a two parts thematic issue dealing with
drug repurposing. Here, deep learning-based drug-target interactions (DTIs) prediction approaches are discussed,
along with drugs repurposed for cancer.
Schcolnik-Cabrera et al. discuss how drug repurposing helps patients meet their needs to access new treatments
. In their paper, the authors highlight the notion that drug repurposing approaches allow for faster preclinical
evaluation and clinical trials of the compound of interest, reduction in budgeting research and development costs, as
well as improvement of biosafety risks. The authors call upon increased advertising of repurposing in the health
community in order to reduce prescribing bias where appropriate.
Abbasi et al. write an elegant piece where they investigate the existing deep learning-based drug-target interactions
(DTIs) prediction approaches from multiple perspectives . They then explore these approaches in an attempt
to identify the deep network architectures that can be employed to extract valuable and relevant information
from drug compound and protein sequences. This paper also explores the process of how to combine descriptors for
drug and protein features, elements that may prove helpful in the race for drug discovery, especially when repurposing
is desired. Similarly, Falvo et al. discuss computational approaches, preclinical models and clinical trials that
are employed for repurposing drugs to treat different types of cancer, especially ones resistant to commonly used
anticancer drugs .
A central feature of this thematic issue revolves around combatting cancer with repurposed drugs that are
currently used for diseases other than cancer. Antoszczak et al. discuss how some antidepressants (citalopram,
fluoxetine, paroxetine, sertraline) and antipsychotics (chlorpromazine, pimozide, thioridazine, trifluoperazine) could
be repositioned for cancer treatment . Likewise, Zhang et al. discuss how pioglitazone, metformin, losartan, syrosingopine,
prazosin aspirin, celecoxib chloroquine, artemisinin, pyrimethamin, flubendazole, mebendazole, itraconazole,
rapamycin, sertraline, fluoxetine, paroxetine, as well as antibacterial drugs such as sulfisoxazole and
azithromycin can be intelligently employed for cancer therapy . Allegra et al. discuss how bromocriptine, chlorprothixene,
mebendazole, flubendazole, quinacrine, furazolidone, verteporfin, telmisartan, clarithromycin, or nelfinavir
among others can be repositioned for acute lymphoblastic leukemia, chronic myeloid leukemia (CML), and
lymphomas . Similarly, for CML, Nehme et al. elaborate the use of acriflavine (ACF) in blocking growth of
solid and and hematopoietic tumor cells . In this paper, the authors discuss how tyrosine kinase inhibitors (TKIs)
such as imatinib (IM) are effective in CML therapy; yet 15% of patients are refractory to IM. The authors then
move to suggest the repurposing of ACF in CML after IM failure or in combination with IM to improve the antitumor
effects of IM especially in resistant cancer populations. Paliogiannis et al. present a state of the art review on
repurposing anticancer drugs for use in idiopathic lung disease, and anti-fibrotic drugs for use in cancer therapy .
Iratni et al. discuss how sildenafil, commonly used for erectile dysfunction, can be reprofiled as a potential anticancer
drug . The authors discuss how the pro-apoptotic effect of Sildenafil lies in its ability to potentiate nitric
oxide (NO)/ phosphodiesterase type 5 (PDE5)-dependent mechanisms. In addition, the authors discuss sildenafil’s
ability to induce autophagy and potentiate anti-tumor immune responses. Alaaeddine et al. discuss in a rather elegant
way the value of designing multi-target directed ligands (MTDLs) modifying the activity of COX-2, 15-LOX,
and PPARγ in cancer and metabolic disorders . The authors then propose that concerted future effort to translate
these early results facilitating the adoption of these, and similar, molecules in clinical research.
We hope readers enjoy this part of the thematic issue. We invite them to read the second part which is primarily
dedicated to repositioning drugs for neurodegenerative and cardiovascular diseases.
Nitric Oxide (NO) is a well-known signaling molecule, which is involved in several functions in the respiratory
tract under physiological and pathogenic conditions . Published data indicate that NO, alone or with other molecules,
participates in the pathogenesis of the respiratory tract inflammation in humans and animal models. This special
issue provides an update on the role of this molecule in several biological processes, including its use as a biomarker
in some respiratory disorders.
NO activities are closely related to another gasotransmitter, hydrogen sulfide (H2S) , which presents similar
functions. NO and H2S can interfere with each other acting on the enzyme synthetic pathways, and synergistically
or antagonistically in the respiratory system as signals or damaging promoters. Fuschillo et al.  have described
the complex biological connections between NO and H2S, which involve multiple pathways, depending on the site
of action in the respiratory tract, and their concentrations.
In biological systems, an exaggerated production of NO in the presence of oxidative stress can promote the formation
of oxidizing reactive nitrogen species, such as peroxynitrite, leading to nitration and DNA damage, inhibition
of mitochondrial respiration, protein dysfunction, and cell damage. Di Stefano et al. have described the effect
and the balance between the reactive oxygen and nitrogen species production and the antioxidant protection of the
lung in chronic obstructive lung diseases .
In clinical practice, NO can be assessed in the exhaled air. It has been suggested as a biomarker for potentially
responder patients to corticosteroids and some biologicals drugs. Fractional Exhaled Nitric Oxide (FeNO) is a biomarker
of type 2 inflammation in asthma, signaling activation of interleukin (IL)-4/IL-13 pathway. FeNO could be
useful to assess treatment response or identify candidates for a specific drug that acts on type 2 inflammation
mechanisms linked to NO production, such as the IL-4/IL-13 pathway or upstream processes. Rolla et al.  have
discussed the FeNO values to be used as a predictive biomarker of responses to the biologics available for treating
severe asthma. Although based on data only from phase 3 studies, the authors suggested that FeNO can be used to
monitor the effects of several biological anti-inflammatory drugs, such as anti-IL-13, anti-IL-4 and anti-TSLP, and
can help in identifying candidates for anti-IL-4 and anti-IgE treatment. FeNO might also be an interesting biomarker
for future drugs, such as anti-IL-33, but at present, there are no published data on the role of FeNO in this
context. Lastly, FeNO has a role in assessing adherence to inhaled corticosteroids, and FeNO suppression test can
remotely evaluate non-adherent subjects that likely do not need a biological treatment.
Apart from asthma, NO can be involved in the pathophysiological mechanisms of other respiratory diseases and
can serve as a biomarker in other pulmonary diseases. The review by Lázár et al. summarizes the current knowledge
on the NO pathway involvement in the pathomechanism of pulmonary arterial hypertension (PAH), exploring novel
and easy-to-detect biomarkers of the pulmonary NO . In fact, several experimental and human studies prove the
crucial involvement of the attenuated endothelial NO signalling of the pulmonary vasculature in the pathomechanism
of PAH. This is also supported by circulating biomarkers such as the increased concentration of ADMA or the
reduced levels of NO metabolites. However, studies on exhaled NO (both bronchial and alveolar readouts), which
have the potential to more directly assess pulmonary vascular processes, show ambiguous results for differentiating
disease from health.
FeNO concentration measured at just one exhalation flow rate reliably reflects central airway inflammation, but
it is not sensitive to changes in the NO dynamics in the lung periphery. By measuring FeNO at several different
flow rates, one can estimate alveolar NO concentration, bronchial NO flux, bronchial wall NO concentration and
the bronchial diffusivity of NO. Lehtimäki et al. have performed a systematic review on the estimation of pulmonary
NO parameters to differentiate central and peripheral inflammation, also presenting a more precise analysis of
central airway NO output in several respiratory diseases . The authors discussed the use of extended NO analysis
in several pulmonary disorders such as asthma, COPD, parenchimal lung diseases and bronchiectasis, concluding
that it might serve as an interesting complement when judging the severity of lung disease.
FeNO might also be useful as biomarker after exposure to toxicant in occupational medicine. Iavicoli et al. have
explored the possibility of using FeNO as exposure marker in workers subjected to different kinds of metal- (silver
and gold), metal oxide- (titanium and silica dioxide), and carbon-based ENMs (carbon nanotubes) .
In the era of precision medicine, the topics discussed in the special issue: “The nitric oxide view: perspectives
and applications” will become very important to understand the pathophysiological processes of several respiratory
diseases, affording the possibility to select potential drug candidates for tailored treatments.
Medicinal plants and mushrooms are a valuable source of chemicals with potential therapeutic properties making
them uprising products of the 21st century. In recent years there are extensive studies on medicinal plants and edible
mushrooms dealing with their various pharmacological effects.
The need for this mini hot topic is necessary since this is an emerging scientific area with potential application in
medical and pharmaceutical industries. Focusing on chronic diseases and conditions that could be potentially treated
with products derived from nature, this mini hot topic covers three review papers. An up-to-date review on bioresource
therapeutics effective against bacterial species frequently associated with chronic sinusitis and tonsillitis is
focused on natural products that could be used to treat different bacteria linked to these chronic states. This review
updates current knowledge regarding medicinal plants and mushrooms which have been traditionally used in the
treatment of infections caused by chronic sinusitis and tonsillitis commonly linked bacteria – Staphylococcus
aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Fusobacterium nucleatum, Haemophilus influenzae
and Moraxella catarrhalis . Cytotoxicity and anticancer activity of genus Achillea are focused on Achillea spp.
with their potential anticancer properties. The anticancer properties of Achillea species were discussed, taking into
consideration ethnopharmacological data on their use in traditional medicine for the treatment of cancer . Role of
bioactive compounds and other metabolites from mushrooms against skin disorders- a systematic review assessing
their cosmeceutical and nutricosmetic outcomes is a review paper focusing on mushrooms and their products for the
treatment of skin disorders. This systematic review highlights that mushrooms contain diverse biomolecules that
can be sustainably used in the development of nutricosmetic and cosmeceutical formulations .
In the last few years, significant effort has been made to develop or improve data analytics platforms that could
be used to solve multidisciplinary problems within the cheminformatics and the nanoinformatics area [1, 2]. This
task is quite challenging as within these areas, various sources of information need to be integrated and explored,
and several data analysis and exploitation steps need to be encountered to provide validated and robust models.
Among other efforts, the Konstanz Information Miner (KNIME) platform, an open-source analytics platform,
has been explored and extended to address a wide range of demanding tasks, including data integration and processing,
as well as data exploitation and analysis. The visual creation of data flows (so-called pipelines), the selective
execution of specified analysis steps, and the presentation of the results via interactive views on models and data,
included within KNIME, offer significant advantages and stimulate efforts towards improved functionalities.
Within this collection of papers in the Special Issue entitled “Cheminformatics toolboxes and workflows within
KNIME Analytics”, recent advances in building KNIME workflows to address the challenges of cheminformatics
are discussed . The nodes and workflows presented will facilitate more applications in the field that is currently
expanding and growing.
Hemmerich et al.  discussed the multiple tools for accessing public data sources through the KNIME platform
for chem- and pharmacoinformatics data. Their review entitled “Accessing Public Compound Databases with
KNIME” discusses the valuable data offered by data sources and the necessary workflow to access them. Furthermore,
the authors highlighted the critical steps that should be taken with particular emphasis on curation, standardization
and merging of datasets.
In another paper, Mazanetz et al.  presented several paradigms for the ligand- and structure-based drug design
and optimization using KNIME. This review examined the recent developments within the KNIME to assist the
drug design of small molecules and provided a perspective on the challenges and future developments within this
field. This review includes the available tools for hit identification, hit to lead, and finally, lead optimization.
Gally et al.  focused on the virtual screening of molecular databases in an effort to identify potential bioactive
molecules and reviewed several toolkits used in different steps during the cleaning of molecular databases, integrated
within a KNIME workflow. Various steps considered included salts removal, splitting of mixtures, filtering
unwanted compounds, removing duplicate entries, and more. The workflow proposed has already been used for
drug design problems.
Contributions to the KNIME Community have also been highlighted by S.D. Roughley , in a paper reviewing
the Vernalis KNIME nodes that have significantly increased in recent years. Among the different nodes available,
nodes accessing publicly available information via web services, nodes providing cheminformatics functionality
without recourse to a cheminformatics toolkit, and nodes using one of the cheminformatics toolkits present in
KNIME, are specifically highlighted.
Afantitis et al.  presented Enalos Suite of Tools' collection to enhance Cheminformatics and Nanoinformatics
through KNIME. Enalos+ KNIME Nodes provide a broad range of important functionalities, including data mining
and retrieval from large available databases and tools for robust and predictive model development and validation as
well as the domain of applicability determination. Big data analysis and GPU calculations to accelerate time demanding
calculations have also been investigated and verified. Demonstration data sets, tutorial, and educational
videos allow the user to easily apprehend the nodes' functions that can be applied for in silico analysis of data.
The aforementioned efforts and KNIME workflows have significantly contributed towards reducing the time and
cost required within the drug discovery process and material design. More developments are underway and promise
to address more challenges in the field, specifically in the data exploitation and machine learning areas. Big data
analysis and GPU accelerated functionalities within KNIME are of significant interest, and additional life and material sciences applications within KNIME are anticipated to be developed as more tools are being integrated within
In this Thematic Issue, authors try to shed a light about the complexities to develop new knowledge in the field
of rare tumours. All the examples share some difficulties but also have their own particularities regarding their special
area of interest.
The main commonalities are related to the difficulties of obtaining sustainable funding for research in all the aspects
from clinical to translational. Charities around specific diseases and patient advocates play a key role to gain
awareness in these scenarios.
In the first review, Dr. Lamarca et al. focused on Biliary Tract Cancers . Biliary Tract Cancers (BTCs) have
been neglected by the wider cancer community, largely due to their relative rarity and the challenges of obtaining
sufficient patient numbers for adequately-powered studies and sustainable funding. National and international collaboration
is attempting to overcome these hurdles. BTCs are not a unique disease, but a mix of different malignancies
which differ not only in molecular aspects, but also in clinical and demographic characteristics. Tailored management,
smart clinical trial design, improved cross-sectional and functional imaging, and enhanced quality of life
assessments are required.
In their review, Dr. Heredia-Soto et al. explained how the development of high throughput techniques has
moved the biomarkers research field to a new scenario with large numbers of samples. Access to well annotated
patient derived models and high quality associated clinical data is paramount for effective translational research.
The establishment of new in vitro techniques alternative to the existing ones, such as, the refinement of 3D culture
allows for better modelling of the architectural conformation of the tumour . This is translated into more opportunities
for research in rare tumours.
Dr. Frizziero et al. made a thorough review about the aspects of research in Hepatocellular Carcinoma (HCC)
from clinical research to translational research . In HCC, it is difficult to establish universally recognisable standards
of care and clinical decision making is hampered by a number of areas of controversy and uncertainty in regard
to best practice. The clinical and biological heterogeneity of HCC mandates tailoring of treatment to individual
patients, at all disease stages, to achieve best outcomes. A stepwise construction of a personalised treatment plan
using both loco-regional and systemic therapies in varying sequence or combination along the disease course of a
single patient has become widespread in clinical practice.
Dr. Hernando et al. reviewed the state of research in thyroid cancers concluding that from translational research,
an improvement in the knowledge of the less common subtypes of the DTC and more aggressive variants like MTC
and ATC is urgently needed . The establishment of new molecular subtypes will allow to move forward in the
field of targeted therapies as well as to move from general multi-kinase inhibitors with multiple off-target toxicities
to developing new highly selective drugs. In the clinical field, we should optimize the inhibition of BRAF, exploring
combinations of drugs to overcome the resistance and adapting the data generated in other tumors such as melanoma
or colorectal cancer, but at the same time considering the different conditions of the TCs including different
sensibilities and resistances across tumors types.
The thematic issue also reviews the challenges of neuroendocrine tumour research from clinical trial design to
optimization of samples .
All these entities share two main problems, heterogeneity within low frequency (but, sometimes relatively higher
prevalence than expected) and limited resources. The scope of this thematic issue is raising awareness and help the
reader to understand what sort of hurdles a new and enthusiastic researcher needs to bear in mind when initiating a
research plan or a career in the field.
We expect that this thematic issue can be used as a tool to guide researchers through the most common problems
when approaching the study of rare cancers. The examples showed in this issue are common to other rare diseases
and rare cancers.
Jorge Barriuso received funding from the ENETS Centre of Excellence Fellowship Grant Award and Cancer Research
UK Accelerator Award C64263 / A29365.
Bio-based materials, including agricultural and forestry residues, e.g., the barks and branches of trees, residues
of industrial crops and bushes, as the plentiful and renewable resources for natural constituents that essential for
bio-medicinal and pharmaceutical applications, were not exploited adequately yet [1-3]. The major bio-polymers
(cellulose, chitosan, hemicellulose and lignin) and extractives as sustainable feedstock have been extensively investigated
for the manufacture of high value-added products, including bio-based bio-medicinal/ pharmaceutical products,
chemicals, and functional materials [4, 5]. This thematic issue presents a series of remarkable recent advances
on the bio-medicinal and pharmaceutical applications of bio-based materials, which covers 1) the technological development
of pretreatment, separation, purification, and structure identifications; 2) depolymerization, fractionation,
and evaluation of biologic and pharmacological activities; 3) design and fabrication the novel pharmaceutical molecules
and advanced bio-medical materials.
The first review, by Khan et al. , addresses the chitosan-nanocellulose composites for regenerative medicine
applications. The contributors summarized that regenerative medicine that represents an emerging multidisciplinary
field which brings together engineering methods and complexity of life sciences into a unified fundamental understanding
of structure-property relationship in micro/nano environment to develop next generation of scaffolds and
hydrogels to restore or improve tissue functions. Chitosan has several unique physico-chemical properties that make
it a highly desirable polysaccharide for various applications such as biomedical, food, nutraceutical, agriculture,
packaging, coating, etc. However, utilization of chitosan in regenerative medicine application is often limited due to
its inadequate mechanical, barrier and thermal properties. Cellulosic nanomaterials (CNs), owing to their exceptional
mechanical strength, ease of chemical modification, biocompatibility and favorable interaction with chitosan,
represent an attractive candidate for the fabrication of chitosan/CNs scaffolds and hydrogels. This contribution by
Avik Khan, Baobin Wang, and Yonghao Ni takes into consideration the preparation method, mechanical properties,
morphology, cytotoxicity/biocompatibility of chitosan/CNs nanocomposites for regenerative medicine applications,
which includes tissue engineering and wound dressing applications.
The work by Chang and co-workers  summarizes the application of cellulose based materials for the biomolecules
detection in medical diagnosis e.g. glucose, lactate, urea, gene, cell, amino acid, cholesterol, protein and
hydroquinone. Due to the properties of cellulose, it is an excellent carrier to immobilize bioactive molecules .
This contribution highlights the three forms of cellulose with unique properties: cellulose derivatives, bacterial cellulose
and nano-cellulose, and mainly clarifies the several kinds of cellulose-based biosensors: paper-based, membrane-
based and others biosensor. These cellulose-based biosensors possess accuracy, sensitivity, convenience, low
cost and fast response. The future focus will be to present on the design of miniaturized, multifunctional, intelligent
and integrated biosensors as well as low cost and environmentally friendly biosensor.
The review by Zhang and Too  discusses the recent progress in metabolic engineering and synthetic biology,
in valorizing renewable biomaterials, e.g., lignocellulose, to produce high value pharmaceuticals and nutraceuticals.
Briefly in the review, they discuss the recent systematic modular approach, multidimensional heuristic process or
MHP in the optimization of long and complex biosynthetic pathways, the flexible dynamic pathway regulation
strategy, microbial co-cultivation and efflux engineering in reducing product toxicity. The authors cite several recent
examples in these four strategies in which high titres, rates and yields of pharmaceutical and nutraceutical
products were achieved with high efficiency, demonstrating the wide applications of these strategies. Furthermore,
the authors discuss the necessity and advantages of synergistic applications of different strategies, such as combining
enzyme engineering strategies and pathway engineering strategies. The authors conclude a bright future in the
biosynthesis of pharmaceuticals and nutraceuticals in microbes from renewable biomaterials.
Cellulose nanofibrils (CNFs) are natural nanomaterials with nanometer dimensions. Compared with ordinary
cellulose, CNFs exhibit good mechanical properties, strong hydrophilicity, high Young's modulus, large specific surface areas and other distinguishing characteristics, which make them widely used in numerous fields . In the
review by Liu and co-authors , the contributors mainly discussed the recent findings in the preparation methods
of CNFs, the fabrication techniques of CNFs-based hydrogel and their recent progress in biomedical fields, focusing
on the application of CNFs-based hydrogel in scaffold materials and wound dressings. By summarizing the preparation
and application of CNFs-based hydrogels, this work has also analyzed and forecasted their development trends.
In the review, the contributors indicated that the research of CNFs-based hydrogels is still in the laboratory stage at
present, and it needs further exploration to be applied in practice. The authors of the work suggest that the development
of medical hydrogels with high mechanical properties and biocompatibility still poses significant challenges.
The contribution by Liu et al.  summarizes the three research hotspots on the hemicellulose-based hydrogels,
including intelligence, biodegradability and biocompatibility, and then overviews the progress in the fabrication and
applications of hemicellulose hydrogels in drug delivery system and tissue engineering (articular cartilage, cell immobilization,
and wound dressing). Their review presents the advantages of hemicellulose, which is the second
most abundant polysaccharide after cellulose in plants and a heterogeneous polysaccharide consisting of various
saccharide units. The unique physical and chemical properties of hemicellulose make it a promising material for
hydrogels. Furthermore, interpenetrating networking can endow desired mechanical properties to hydrogels. These
features make the hemicellulose-based hydrogels promising materials in biomedical applications. They also outlook
some areas that need further research and development in the future on the hemicellulose hydrogels for medical applications.
Such as, super water absorption hydrogels applied to baby diapers, mask, and feminine napkins in human
daily necessities. Customized fabrication of hydrogels using new molding means, such as 3D printing technology.
Along this line, in the contribution by Ma and co-authors , functional chitosan-based materials for biological
applications are addressed. In this context, they focus mainly on the chemical extraction and modification methods
of chitosan and provide recent progress of synthesis and use of chitosan-based materials in biological applications.
They first point out that extraction of chitin and chitosan from crustaceans has important practical significance, and
the chemical structures of chitosan obtained by different extraction methods exhibit not only excellent activities of
chitosan, but also show other appealing performance of combined materials, even endow it with the good synergistic
properties and its composite materials. Furthermore, broadening the practical application of chitosan by chemical
modification is also highlighted as the potential alternatives. By summarizing the preparation and application of chitosan-
based materials, this paper has also analyzed and prospected their development trends, and further studies are
needed to define the ideal physicochemical properties of chitosan for each type of biomedical applications. They
believe that the development of various functional chitosan-based materials for biological applications will be an
important field of research, and this kind of material has important commercial value.
It is well established that Cardiovascular Disease (CVD) is the leading cause of mortality in the modern societies.
Over the past decade, large amount of research has improved: i) Our understanding of mechanisms of CVD; ii)
Diagnosis; and iii) Treatment resulting to improved prognosis. In the present issue, we highlight the recent advances
in cardiovascular research from diagnosis to therapy.
The five review articles in this issue of the journal cover a broad range of topics from Cardiovascular risk factors,
such as Hyperlipidemia; manifestations of CVD such as Acute Coronary Syndromes (ACS) and Heart Failure
(HF); as well as to heart rhythm issues.
In an in-depth approach, it appears two clear topics emerge: a) the role of circulating biomarkers; and b) the role
of therapeutic strategies in different disease states.
ROLE OF BIOMARKERS
Zacharia et al.  have focused on the role of Microparticles (MPs) in acute coronary syndromes. Several studies
have examined the role of MPs as circulating biomarkers however with conflicting results. The authors have
provided a balanced critical approach of the role circulating MPs deriving from endothelial cells, platelets, red cells
and leukocytes as potential clinical tools.
Papageorgiou et al.  discussed the role of two common biomarkers NT-proBNP and BNP in Atrial Fibrillation
(AF). However, the focus is beyond their role in heart failure. Catheter ablation has been shown to be an effective
treatment strategy for AF and data suggest that these biomarkers can have a predictive role for long-term success
of ablation in non-heart failure patients.
Furthermore, Tsigkou et al.  reviewed the role of ST2 in acute coronary syndromes and heart failure. The
role of ST2 was recognised in the recently updated ACC/AHA HF guidelines. The authors have divided their paper
into clear subsections and provided an overview of ST2 either as a single or part of a multi-biomarker approach.
Statins are well known to lower cholesterol levels and also to reduce mortality of patients with CVD. PCSK-9
which further lower cholesterol levels have attracted recent research attention. Panagiotopoulou et al.  provide
an excellent summary of the clinical evidence covering both safety and efficacy.
Briasoulis et al.  come with an excellent review of the role of second and third generation left ventricular assist
devices and their role in clinical practice. Their paper also nicely focuses on the role of drugs such as Neprilisin
inhibitors and Empagliflozin in patients with heart failure.
The current evidence is promising and ongoing studies aim to evaluate the role of biomarkers and new therapeutic
approaches in CVD. We hope that this issue of the journal will provide valuable information and data which
will be of interest for the readers and could stimulate further research on the topic.
A Light on Natural Products of Relevance for Neurodegenerative Diseases
Molecular targeted therapy treats a specific molecule as a target by controlling its function. Lately, in the field of
anticancer treatment using cancer cells as a molecular target, many effective medications, such as immune checkpoint
inhibitors (nivolumab) and tyrosine kinase inhibitors (imatinib), have been developed. The field of nonmalignant
hematological disorders, in which we have been involved, is no exception.
I have been consistently engaged in pathological research for the field of nonmalignant hematological disorders,
especially Paroxysmal Nocturnal Hemoglobinuria (PNH). Eculizumab, a humanized monoclonal antibody against
complement component five (C5), was developed as a treatment for hemolysis in PNH, and displayed remarkable
suppression of hemolysis, along with enhancement in patients’ Quality of Life (QOL) and life prognosis . However,
unlike Caucasian patients, some Japanese patients exhibited resistance to eculizumab. We reported that the
poor response to eculizumab in a subset of Japanese patients could be explained by the inability of a subset of lysiscompetent
C5 in these patients to bind and undergo blockade by eculizumab, suggesting that polymorphisms in the
target proteins of antibody-based treatments, which are used for other diseases, must be considered in patients with
poor responses . Amid such trends, several companies aiming to develop new therapeutics could survive. Moreover,
the clinical research in this area has also become vigorous.
Here I would organize a special issue under the theme of “Innovative therapeutic strategies in the molecular targeting
era” and would introduce attractive and promising treatment strategies (involving recycling antibody, smallmolecule
reversible protease inhibitor, and RNA aptamer and its antidote) for nonmalignant hematological disorders.
The first review by Fukuzawa and Nezu addresses the “recycling antibody.” By introducing histidine residues
into the variable region of the antibody SKY59 to confer pH-dependent binding to the antigen, they develop a novel
recycling antibody that prolongs the plasma half-life of antibodies and decreases the drug dosage required for therapy
. This finding shattered the limit for dosing intervals of conventional antibodies, which require administration
every 2–3 weeks considering the half-life of previous antibodies, and offered several advantages such as improving
Wiles et al. review an update on the oral complement factor D inhibitor ACH-4471, which has evolved from irreversible
small molecules that exhibit poor selectivity to reversible small molecules and monoclonal antibodies that
demonstrate exceptional selectivity and potency . As factor D is not needed in the activation of either the classical
pathway or lectin pathway, selective factor D inhibition could be a favorable therapeutic approach for the treatment
of PNH by moderating the complement activity, thereby resulting in a lower risk of bacterial infection than
other complement-directed approaches.
In their review, Nimjee and Sullenger discuss the evolvement of therapeutic aptamers to determine clinical
niches . Short oligonucleotides, termed aptamers, can fold into three-dimensional structures, thereby enabling
them to bind and inhibit the activity of pathogenic proteins selectively. Although the affinities and activities of aptamers
have often been compared with those of antibodies, only a few of these agents have made it into clinical
studies compared with therapeutic antibodies. Of note, one therapeutic aptamer targeting VEGF has made it to the
market. They also understood the issues of aptamers and discussed their future prospects in a wide range of perspectives.
Hence, recycling antibody technology and bispecific antibody technology will usher in a new revolution in the
field of antibody therapy. Small-molecule compounds, such as factor D inhibitor, are critical approaches for developing
oral medicine. Nucleic acid medicines could potentially become the most inexpensive molecular targeted
drugs and are, in fact, considered the future of aptamer therapeutics. Together with these technologies, several specific
medicines will be developed against various diseases henceforth, thereby offering tremendous benefits to humanity.
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The natural polymers are extracted from the natural products or formed from the biochemical reaction or photosynthesis
in natural world, including the polymers derived from plants, animals, microbial fermentation, etc. They
are inexhaustible in supply and always available for use. Almost all of the natural polymers are biocompatibility,
biodegradability and environmental-friendly, and they are widely used in medicinal fields.
Hydrogels are crosslinked polymeric networks prepared from hydrophilic polymers, which can absorb and retain
high content of water while maintaining their three-dimensional integrity. As the diversified properties of the natural
polymers, they are the ideal skeleton for the preparation of the hydrogels. The hydrogels prepared from the natural
polymers could show interesting stimuli-responsiveness, good biodegradability, biocompatibility, and good
flexibility similar to natural tissue. Hydrogels are widely used in the medicinal fields with the above mentioned
properties. They can be used as wound dresser, the carrier for drug delivery, the substrate for cell culture and scaffold
for tissue engineering. They are also widely used as the critical materials for microfluidic chips, medical examination,
photodynamic therapy, and gene therapy etc.
Our research team has carried out research on hydrogels prepared from natural polymers and the corresponding
application as biomedical materials for a long time and has contacted and cooperated with many research teams. To
show the research achievements in this field, and to contribute to the celebration of the 80th anniversary of Beijing
Institute of Technology (BIT), we invited the team involved in medical hydrogels from natural polymers to contribute
to this thematic issue together. In this thematic issue, we will bring together several international scientists to
discuss the recent advances about the advancements of natural polymer-based hydrogels in synthetic pathways,
properties and applications in medicinal fields. The issue finally contains six reviews. Thanks for the contribution
and guidance of every expert to this special issue.
The paper by Zou et al.  reviewed the recent progress in the electrodeposition of different polysaccharides and
protein hydrogels. The strategies of pH induced assembly, Ca2+ crosslinking, metal ions induced assembly, oxidation
induced assembly derived from electrochemical methods were discussed. Pure, binary blend and ternary blend
polysaccharide and protein hydrogels with multiple functionalities prepared by electrodeposition were summarized.
In addition, the applications of these hydrogels in drug delivery, tissue engineering and wound dressing were also
The paper by Jiang et al.  presented some recent studies on natural polymer-based stimuli-responsive hydrogels,
including temperature-responsive hydrogel, pH-responsive hydrogel, light-responsive hydrogel, electricresponsive
hydrogel, redox-responsive hydrogel, enzyme-responsive hydrogel, magnetic-responsive hydrogel,
multi-responsive hydrogel, etc. The preparation methods, properties and applications of these hydrogels in medical
field were highlighted.
Hydrogels are extensively employed as scaffolds in tissue engineering. Specifically, hydrogels made of natural
polymers are efficient structures for tissue regeneration because of their mimic natural environment, which improves
the expression of cellular behavior. Taghipour et al.  presented a review focused on injectable hydrogels
scaffolds made of biocompatible natural polymers with particular features. These methods can be employed to engineer
injectable hydrogels and their latest applications in tissue regeneration.
Natural hydrogels can also be used with photosensitizers in photodynamic therapy for their excellent property of
sustained or controlled drug release, biodegradability, biocompatibility and other additional functions. In the review
of Feng et al. , the pertinent design variables were discussed along with a description of categories of natural hydrogels
available for photodynamic therapy.
To highlight recent studies of natural-based hydrogels and their applications for medical investigation, Tavakoli
et al.  presented recent studies of medical examination applications by using different natural-based hydrogels.
The application of natural-based hydrogels in the design and fabrication of biosensors, catheters and medical electrodes, detection of cancer, targeted delivery of imaging compounds (bioimaging) and fabrication of fluorescent
bioprobes was summarised.
In the review by Jose et al. , they presented an overview of various hydrogels based on natural polymers that
can be used for cell culture, irrespective of types of applications. They also explained how each hydrogel is made,
its source, its pros and cons in biological applications with special focus on regenerative engineering.
Oxidative Stress (OS) is involved in the development of many pathological conditions and diseases such as
cancer, neurodegenerative diseases and aging by effecting various important components of cells. Although the
multiple roles of OS in human biology and pathology have been intensely studied over the last decades, the problem
is still far beyond our full understanding. Therefore, in a rather short history of oxidative medicine, the roles of free
radicals and antioxidants have been entirely redefined.
Thiol-disulfide homeostasis is implicated in the pathogenesis of a wide variety of human diseases including cancer,
infection, inflammation, cardiovascular disease, neuronal disorders and diabetes mellitus, and so on. Therefore,
targeting the thiol-disulfide homeostasis emerges as a viable therapeutic approach in the treatment of these diseases.
The main topic of the proposed thematic issue is the importance of Carnosine metabolism for healthy organism
and in progression of different diseases. The special issue includes review articles which address the role of
carnosine in crosstalk between metabolic, cardiovascular, kidney and lung diseases. Carnosine (beta-alanyl-Lhistidine)
is a naturally synthesised dipeptide which is present in many animal/human tissues, like skeletal and heart
muscle, brain, lung and kidneys. Moreover, carnosine has a broad spectrum of activities and is engaged in different
metabolic pathways within particular tissues on one hand, and may not display the same functions in different tissues
on the other hand. In this special issue of Current Medicinal Chemistry entitled “Dysregulation of carnosine
metabolism in progression of diseases”, Tanaka and Kawahara , Gilardoni et al. , Menini et al. ,
Kilis-Pstrusinska , Caruso et al.  and Peters et al.  comprehensively reviewed the most recent literature
concerning various aspects of carnosine metabolism in different pathological conditions. We hope that the readers
will find this issue useful in their daily course of work.
The medical devices are increasingly used in medical practice. Catheters, stents and various tubes, needles and wires are
important tools in both therapy and diagnosis of various diseases, including cardiovascular and urological diseases, cancer,
haemorrhages, etc. The challenges in this field are both related to the medical aspect - especially the methodology of intervention
as well as the engineering of these devices, their composition and surface characteristics. This special issue analyses the
main advances in the field of engineering of these devices, including not only the development of new bulk materials but also
the surface modifications of these devices as many diseases are related to the surface and not to the bulk material. Most of the
existent materials have very good mechanical properties (which are consequences of the bulk material), but the failure mainly
occurs as a consequence of the surface - body fluids or surface - tissue interactions and due to this, nowadays, surface modification
is being considered as a challenge in improving these devices. The failure mostly occurs due to the long-term degradation
of the materials (and certainly this happen from the surface), the first biological response being inflammation; infections and
biofilm formation (in this case, some undesired microorganisms attach onto the surface followed by several steps which, finally
lead to biofilm formation) and even clogging of the tubular devices which means that different materials/substances slowly get
deposited onto the surface while decreasing the inner diameter until no fluid can pass through these devices (this can happen
not only as a consequence of infections and biofilm formation but also due to the protein, cells or salts deposition onto the inner
surface of these tubular devices).
Dutra G.V.S. et al.  highlight the manufacturing processes and the use of polymeric matrices for manufacturing implantable
medical devices. This review focuses on some additive manufacturing methods, such as 3D printing and hot melting
extrusion and presents the possibility of developing coatings as well as exploiting drug delivery in improving the performances
of these implantable medical devices.
Aramburu J. et al.  also focused on radioembolisation as a promising tool in the treatment of liver tumors. As an extensive
review, they highlight the role of the administration of the radioactive microspheres and the most important 10 parameters
which are influencing the outcome of the rodioembolisation.
Duta O.C. et al.  especially devoted this review to the PVC-based catheters - some of the most used catheters because of
their good accessibility. Taking into account the moderate performances, the surface modification is especially debated - both
physical and chemical methods are being considered.
Hung H.-S. and Hsu S.-H.  presented the main advances related to surface modification for vascular tissue engineering. It
is important to mention that restenosis is the major problem related to vascular implants, and due to this, the perspectives derived
from this review can be exploited in applying some of the proposed techniques in improving the nanotopography by using
During the past two decades, there have been marked increases in the frequency of drug-resistant (DR) “superbug”
pathogens and the threat of emerging and reemerging pathogens. Antimicrobial resistance has reached alarming
levels worldwide, resulting in a significant adverse impact on clinical outcomes and health care costs. The recently
published 2019 Antibiotic Resistance Threat Report by the Centers for Disease Control and Prevention
(CDC) states that, “There is no safe place from antibiotic resistance” . In contrast to standard antibiotics, antimicrobial
peptides (AMPs) do not require metabolic processing to cause antimicrobial activity, thus killing both metabolically
active and quiescent bacteria. AMPs, also known as host defense peptides (HDPs), are essential components
of host defense against infections. In addition to broad-spectrum antimicrobial activity, AMPs also have roles
in inflammation, immunity, and wound healing. The gold standard of AMPs is LL37, a cathelicidin that exhibits
broad-spectrum antimicrobial activity by rapidly destroying the lipoprotein membranes of microbes enveloped in
phagosomes. Serving as a front line of innate immunity in a wide spectrum of species, AMPs achieve their antimicrobial
activity through a number of mechanisms. The predominant mechanism is the physical disruption of bacterial
membranes, which is selectivity based on interactions with the relatively high density of negatively charged
phospholipids on the outer surface of bacterial membranes, in contrast to the more neutral surface charge presented
by eukaryotic cell membranes. AMPs have a low propensity for allowing the development of resistance, which generally
requires a fundamental change in bacterial membrane lipid composition.
Most natural AMPs are cationic peptides with an amphipathic structure. Substantial efforts have been devoted to
optimizing the structural design of AMPs in order to enhance their antibacterial activity. To obtain an ideal AMP
that will possess potent antimicrobial activity against bacteria while presenting minimal cytotoxicity to mammalian
cells, the number of hydrophobic residues in an AMP and the charge to hydrophobicity ratio of the peptide have to
be carefully considered. Biswas et al. (2020) , demonstrated the feasibility of using NMR-assisted AMP design
for yielding an optimized AMP (VG16KRKP) with enhanced antimicrobial activity due to structural modifications.
An in-depth review first describes various AMP studies that use high-resolution solution NMR spectroscopy, including
two-dimensional nuclear Overhauser effect spectroscopy (NOESY), total correlation spectroscopy
(TOCSY), and transferred NOESY (trNOESY) methods. The authors then used VG16KRKP
(VARGWKRKCPLFGKGG) as an example to discuss multiple rational approaches to improve the bioactive potential
of a prototypic AMP, VG16 (VDRGWGNGCGLFGKGG), a Dengue virus envelope protein. Additional strategies
to enhance the stability and antimicrobial properties, including dimerization, lipidation, and targeting intracellular
pathogens using gold nanoparticle-peptide conjugates, are also presented. These approaches and design techniques
provide a practical example to demonstrate the feasibility of optimized AMP drug development.
Frog skin is one of the richest natural reservoirs of AMPs: many peptides have been isolated from it, characterized,
and classified into several families encompassing temporins, brevinins, nigrocins and esculentins. Casciaro et
al. (2020) , reviewed the developmental approaches of anti-infective therapies using AMPs from the esculentin-1
AMP family derived from frog skin. Esculentin-1a(1-21)NH2 possesses broad-spectrum antimicrobial activity, especially
against the opportunistic Gram-negative bacterium Pseudomonas aeruginosa and fungal species such as
Candida albicans. Its antipseudomonal activity was further tested in vivo, in mouse models of acute Pseudomonasinduced
pneumonia for which intra-tracheal administrations of Esc(1-21) significantly prolonged the survival of
mice. The in vivo efficacy of this peptide was also successfully demonstrated in mouse models of Pseudomonasinduced
sepsis and keratitis. To enhance the therapeutic potential and to facilitate the antimicrobial drug development
for clinical applications, the peptide was optimized by changing the stereochemistry of two amino acids (from
L-to D-configuration) to reduce the peptide’s cytotoxicity. Covalent conjugation of the peptide to gold nanoparticles
or its encapsulation into poly(lactide-co-glycolide) nanoparticles further improved its half-life and stability in vitro
and in the host environment of animal models. Finally, the peptide was immobilized to biomedical devices (such as
silicon hydrogel contact lenses) to produce an antibacterial surface that reduces microbial growth and attachment.
Although AMPs/HDPs have been mostly evaluated for their antibacterial activity due to the emergence of DR
bacteria, these peptides also exhibit activity against a wide range of viruses. Many viral infections either still do not
have cures or treatments, or do not have effective vaccines or treatments. For example, coronavirus disease 2019
(COVID-19), also known as 2019-nCoV acute respiratory disease, caused the 2019-20 coronavirus outbreak.
COVID-19 is caused by SARS-CoV-2, a virus closely related to the SARS virus, and resulted in a significant loss in
human life and economic productivity. These unfortunate incidences highlight the need for new ways to treat viral
infections, or prepare for and prevent future emerging ones. Brice and Diamond (2020) , provide an excellent
review discussing the antiviral activities of human AMPs/HDPs, including alpha- and beta-defensins and the sole
human cathelicidin, LL-37, against both enveloped and non-enveloped viruses. AMPs/HDPs have shown to retain
antiviral activity against a large panel of diverse viruses, including but not limited to HSV1, HSV-2, HAdV, HPV,
BKV, JCV, SV40, HCV, Influenza A virus, RSV, and HIV-1. AMPs/HDPs seem to have a greater repertoire of
known activities against viruses beyond perturbing the membrane of the microorganisms; not only do they disrupt
viral envelopes, but they also directly affect host cells and specific steps of viral life cycles. The broad spectrum of
antiviral activities of these peptides, both in vitro and in vivo, suggests that they play an important role in innate defense
and warrants further examination in the context of activities against viruses. Moreover, the literature suggests
that AMPs/HDPs may be developed into viable antiviral therapeutic agents.
In the era of urgent threats heralding antimicrobial resistance, the topic tackled in this special issue “Antimicrobial
Peptides: from host defense against microbial pathogens to clinical development” will become more significant.
In particular, the focus is on optimizing the process of AMP development to be more efficient, and on the use of
AMPs to overcome drug resistance and microbial infection.
Cancer has emerged as one of the most significant medical issues of the modern world. Population growth and
ageing will soon render cancer as a leading health problem. Each year tens of millions of people are diagnosed with
cancer, among which lung, female breast and colorectal cancer are responsible for one-third of cancer incidence and
mortality. One of the five men and one of the six women worldwide develop cancer during their lifetime. According
to the World Health Organization, only in 2018, cancer was estimated to account for 9.6 million deaths .
We have been fighting cancer from a long time and intensively for decades . Our knowledge and understanding
of the mechanisms that promote cancer development have expanded in the meantime and technology advancements
have brought new hope . With more than 200 forms of cancers and the alarming rise in cancer burden,
scientists specialized in medicine, chemistry, biology, physics, biotechnology, engineering and other fields have to
join their forces to tackle this global health problem . Cancer never rests, so neither should we.
This issue focuses on several aspects of modern anticancer research and provides a comprehensive overview of
the utilization of natural products, nucleobases, saccharides, glycans, peptides and other chemical derivatives as
anticancer agents. Similarly, a review of the modern studies and discoveries of molecular mechanisms linked with
tumors and metastasis, as well as cancer treatment by novel pharmacological approaches in the clinical settings are
reported. Additionally, the utilization of new methods in anticancer drug evaluation as well as the advances in cancer
immunotherapy are described.
Bello’s group has turned the spotlight on the recent advances in peptide-based approaches to treat cancer .
Lopez and co-workers have discussed the utilization of carbohydrates to combat cancer . Furthermore, Marković
et al. have provided a recent overview of marine natural products with high anticancer activities . The delivery
systems for potent anticancer triterpenic agent botulin and its derivatives found in outer birch bark were the topic of
a review article written by Turks and Mierina . Kraljević Pavelić’s group has focused on the role of technological
advances and -omics methods in the preclinical anticancer drug evaluation . Kaštelan and co-workers have
concentrated on the applications and perspectives of immunotherapy to treat melanoma ; and finally, Pavelić et
al. have elaborated on the emerging role of nanotechnology in targeting tumour metastasis .
Contribution of 7 articles to this issue was made by medical doctors, biologists and chemists from five European
countries. As such, this issue provides an overview of valuable insights into scientific and human efforts as well as
research progress in the field of anticancer therapy. We thus expect that this Special Issue dedicated to anticancer
research will encourage further research and promote creativity of many scientists worldwide and help to open new
avenues that remain to be discovered.
The endothelium has an integral role in the maintenance of vascular tone [1, 2]. Endothelial dysfunction is the
first step in atherosclerosis progression and is a well-established cardiovascular risk factor [1, 2]. Moreover, endothelial
dysfunction may precipitate thrombotic events by increasing platelet reactivity through the inadequate production
of nitric oxide and prostacyclin, which counteract platelet aggregation . Endothelial function can be
evaluated through several invasive and non-invasive techniques in the clinical setting . In the context of this evidence,
in this full-length ‘Hot Topic’ thematic issue, we will discuss the role of vascular endothelium in cardiovascular
diseases and will present all the current evidence and data concerning the role of endothelial function in the
prognosis, progression and treatment of cardiovascular diseases.
This special issue contains 5 review articles. The articles focus on the underlying pathophysiologic mechanism
of endothelial dysfunction and coronary artery disease, dyslipidemia, aortic aneurysm disease and atherosclerosis.
The endothelium has the potential in maintaining adequate homeostasis of the vessels, and thereby preventing
the emergence of diseases [1, 2]. This result, of course, depends on its ability to produce protective molecules.
When this normal function is lost or decreased, endothelial dysfunction or endothelial activation occurs [1, 2]. Classical
cardiovascular risk factors such as hypercholesterolemia, hypertension, smoking, diabetes, obesity, sedentary
lifestyle as well as others such as lipoprotein Lp (a), Helicobacter pylori and the shingles virus are directly related to
endothelial dysfunction [1, 5]. The common denominator of all the above factors is oxidative stress, which stimulates
the production of nuclear factor-kB and leads to the growth of pro-atherogenic cytokines (Tumor necrosis factor-
α, interleukins IL-1 and IL-6) and adhesion of molecules and chemokines, thereby preventing NO production
and favoring the synthesis and action of angiotensin II [1, 5].
The mechanism of endothelial dysfunction is associated with reduced NO synthesis and action or an accelerated
degeneration through several processes. The major biochemical pathways for reducing the bioavailability of NO are
triggered by increased oxidative stress, due to increased production or reduced removal of peroxide and oxidized
LDL or reduced antioxidant defense [6-9].
In our reference to endothelial dysfunction, we should not forget the relationship between atherosclerosis and
endothelium. In addition, classical and new risk factors for cardiovascular disease development and how they are
related to endothelial dysfunction have been reported. The same factors are known to play a fundamental role in the
process of atherosclerosis. This coincidence is not at all accidental because endothelial dysfunction represents an
early stage of atherosclerosis, producing the atherosclerotic plaque but also a subsequent and evolutionary stage,
contributing to the continuous development of the plaque [7, 10].
The presence of some of the risk factors could be simplistically claimed to lead to the "injury" of the endothelium.
The "injured" endothelium responds in an undesirable manner. It promotes vasoconstriction, the proliferation
of pro-inflammatory cells, migration of smooth muscle cells, increased cytokine production and other processes that
help in the formation of the atherosclerotic plaque and ultimately lead to plaque rupture and thrombosis .
Any disorder in endothelial functions associated with inflammation, adhesion and cell growth, clotting and vascular
tone preservation influences blood flow and pressure and hence, cardiovascular function. This finding has
been confirmed by a number of scientific studies, which even now recognize endothelial dysfunction as an independent
predictor of cardiovascular diseases [6-9, 12, 13].
Some of the biomedical fields, such as regenerative medicine, are still in their infancy and many hurdles need to
be overcome before effectively complying with their applicability in medicine. Nevertheless, a major progress has
been made within tailored and advanced functional biointerfaces engineering, envisaging both materials and fabrication
methods to comply with the specific requirements of the targeted applications (e.g. drug delivery systems,
tissue regenerative scaffolds, etc.). Within this context, this special issue compiles a series of 4 review articles that
highlight the development and use of active biomolecules and biomaterials, advancing our understanding of the
identification of appropriate approaches and strategies related to biointerfacial design in drug delivery systems, bioscaffolds
and therapeutic applications.
Controlling the interface characteristics of materials with the modulated behaviour of cells and biomolecules on
their surface has been one of the main key factors in the last decades for all the applications related to biology studies
and medicine [1, 2]. Various systems have been designed for mimicking the extracellular and intracellular factors
that influence cell functions, but the main challenges remain related to the ability to develop innovative materials
and their consequent processing techniques to comply with biocompatibility and multifunctionality, as correlated
to the type of application, target tissue, materials and techniques available for biomaterial production .
For example, the innovation of therapies for enhancing osteogenesis still represents a critical challenge in the regeneration
of bone defects. The overall concept focuses on the use of osteoconductive materials in combination
with the use of osteoinductive or osteopromotive factors. An up-to-date view of research on the involvement of Lactoferrin
in bone growth and healing and on its use as a potential therapeutic factor in bone tissue regeneration is
given in the first review titled: Lactoferrin in Bone Tissue Regeneration . Another complex view on the strategies
for improving the characteristics of the interfaces for bone studies is given in the second review titled: Drug delivery
systems based on titania nanotubes and active agents for enhanced osseointegration of bone implants , where
the functionality of TNTs, using five classes of bioactive agents: Growth Factors (GFs), statins, plant-derived molecules,
inorganic therapeutic ions/nanoparticles (NPs) and antimicrobial compounds is presented. Extending the topic
to the fabrication of smart bioactive and tissue-like biomimetic surfaces, the third review: Biomimetic nanostructures
with compositional gradient grown by combinatorial matrix-assisted pulsed laser evaporation for tissue engineering
, provides the research related to obtaining compositional gradient by laser method for attaining a microenvironment
with precise characteristics which directs cells fate towards specific phenotypes. Moreover, the nanocomposite
hydrogels with combined hydrophilic-hydrophobic behaviour are crucial for developing multifunctional
systems for co-delivery of polar/nonpolar substances for the treatment of multiple concomitant affections and steering
cellular behaviour . Within this direction, the fourth review titled: Hydrogel-clay nanocomposites as carriers
for controlled release , summarizes the research efforts undertaken in the last few years in the development
hydrogel-clay nanocomposites as carriers for controlled release of diverse drugs. The different compositions of
polymers/biopolymers with diverse types of clays, as well as their interactions are discussed as hydrogel-clay-drug
pharmaceutical formulations able to respond to a series of demands for the most diverse applications.
The strategies for modifying the surface of biomaterials for modulation of cellular response enhance our understanding
of principles that govern bidirectional cell-material interaction and enable control of the key required
parameters of the envisaged application. The topics explained in the special issue: “Advanced functional biointerfaces
engineering for medical applications: from drug delivery to bioscaffolds” provide a clear overview on the design,
synthesis and use of nanomaterials for fabricating a wide spectrum of exquisitely well-defined functional interfaces
for medicine and other biomedical applications.
Neglected Diseases almost exclusively affect poor and powerless people living in rural regions in low-income
countries [1, 2]. They are sometimes identified as tropical diseases or poverty-related diseases. Leishmaniasis
(Kalazar), onchocerciasis, Chagas disease, leprosy, tuberculosis, schistosomiasis, lymphatic filariasis, African trypanosomiasis
(sleeping sickness), malaria and dengue are all considered neglected diseases . Some neglected diseases
are life-threatening, while others result in high morbidity and severe disabilities. In the developing world, neglected
diseases continue to cause significant morbidity and mortality. However, of the 1,556 new drugs approved
between 1975 and 2004, only 21 (1.3%) were specifically developed for tropical diseases and tuberculosis, though
these alone account for 11.4% of the global disease burden [1, 2-5].
Free ligand databases are widely available today, and in drug discovery, structure-based virtual screening is now
essential. Using peptide homology and crystallographic or modeled protein structures, molecular docking is often
employed to screen such compound libraries, and to predict conformation of protein-ligand complexes to calculate
their affinity energies. In tropical infection research however, it is targeting such interactions with smaller inhibitor
molecules and exploring new therapeutic targets that has increased .
The objective thematic for this issue is to report recent studies and different approaches in medicinal chemistry
as applied to drug discovery for neglected diseases: comprising synthesis, natural products, semi-synthesis, evaluation
of biological activities; and/or theoretical approaches such as ligand and structure-based approaches, SAR,
QSAR, molecular docking and various cheminformatic methods [7, 8].
Bellera et al., in “In Silico Drug Repositioning for Chagas Disease”, discuss applications of computer-aided
technology in systematic approaches to drug repositioning in Chagas disease research. In silico screening is employed
more frequently, while other rational methods such as network-based and signature-based approximations
have yet to be fully explored .
Praziquantel (PZQ) is the drug of choice for treating Schistosoma worm infections. The drug is cheap and effective,
and brings few side-effects. However, despite its use in millions of patients for more than 40 years, its molecular
mechanism of action remains elusive. Early studies demonstrated that PZQ disrupts calcium ion homeostasis in
the worm and the current consensus is that it antagonizes voltage-gated calcium channels. Thomas & Timson, in
“The mechanism of action of praziquantel: can new drugs exploit similar mechanisms?”  discuss the
pressing need for fundamental research into the molecular mechanism(s) of action of PZQ. Such research would
enable new avenues for anti-schistosoma drug discovery.
“Advanced in silico methods for the development of anti-leishmaniasis and anti-trypanosomiasis agents”
 is a review by Halder & Cordeiro, which describes recent applications for certain important in silico approaches,
such as 2D-QSAR, 3D-QSAR, pharmacophore mapping, molecular docking, and so forth; all with the
aim of understanding the utility of these techniques in designing novel therapeutic anti-parasitic agents. The review
focuses on: (a) advanced computational drug design options; (b) diverse methodologies e.g.: use of machine learning
tools, software solutions, and web-platforms; (c) recent applications and advances in the last five years; (d) experimental
validations of in silico predictions; (e) virtual screening tools; and (f) rationales or justifications for selecting
each in silico method.
Hosseini et al., in “Latest Updates in Dengue Fever Therapeutics: Natural, Marine, and Synthetic Drugs”,
 discuss Dengue, its infection mechanisms, molecular characteristics, various components, mechanisms of entry
into the target cell, cyclization of the genome, its replication process, and it includes protein translation for virus
assembly. The major emphasis of this work is on natural products and plant extracts used as palliatives or adjuvant
Dengue treatments. This article further summarizes the latest findings regarding marine products as effective drugs
that target different symptoms of Dengue. An update on synthetic drugs for treating Dengue is given, and as a novel
alternative, monoclonal antibody therapy for Dengue management and treatment is described.
“Structural Basis for Inhibition of Enoyl-[Acyl Carrier Protein] Reductase (InhA) from Mycobacterium
tuberculosis”  is a study by Ávila et al. The authors report analysis of structures complexed with inhibitors that
reveal critical residues responsible for specificity against InhA. Most of the intermolecular interactions involve hydrophobic
residues (with two exceptions), residues Ser 94 and Tyr 158. Examination of the interactions reveals that
many of the key residues involving inhibitor binding are found in InhA gene mutations in isoniazid-resistant Mycobacterium
tuberculosis. Computational prediction of InhA binding affinities reveals a moderate and inclining relationship
to the recorded experimental values.
The development of nanotechnology-based drug delivery systems may well enable targeted delivery of antiretroviral
agents to normally inaccessible viral reservoir sites, and in therapeutic concentrations. In addition, the application
of Computer-Aided Drug Design (CADD) approaches has provided valuable tools for developing anti-HIV
drug candidates with favorable pharmacodynamic and pharmacokinetic properties. These innovations are addressed
by Melo et al., in: “An overview of antiretroviral agents for treating HIV infection in pediatric population”
In our review, entitled “Recent Theoretical Studies Concerning Important Tropical Infections” , several
complementary in silico approaches were presented including: identification of new therapeutic targets, novel
mechanisms of activity, high-throughput screening of small-molecule libraries, in silico quantitative structureactivity
relationships, and current molecular docking studies. Hopefully, today’s active research against parasitic
forms of Neglected Tropical Diseases (NTDs) such as Sleeping Sickness, American trypanosomiasis, Leishmaniasis
and Schistosomiasis infections will lead to safer, more effective, less costly, and more widely available treatments.
We, the Guest-Editors would like to express our gratitude to the many authors who contributed to this special issue;
New Trend in Ophthalmic Drug Delivery
Metal ions play essential roles in the normal functioning of all living cells, while some metal ions and metalcontaining
compounds have toxicological importance. Additionally, a significant number of biomolecules and biochemical
pathways have been described as drug targets for metal-based compounds. Thus, the new molecular design of complex
metal compounds appears as a promising platform for drug development. This thematic issue compiles 6 review articles
including a comprehensive overview of recent studies regarding metal-based compounds from various aspects –
physiological, pharmacological and toxicological.
For metal-based pharmacotherapy, Medić et al.  reviewed pharmacological and toxicological aspects of lithium as
the first-line therapy for bipolar disorders and the adjunctive treatment for psychiatric diseases.
For diagnostic purposes, Biju S. and Parac-Vogt T.N.  summarized recent advances of Ln3+-based nanoarchitectures
as high field magnetic resonance imaging (MRI) contrast agents, with particular attention to multimodal
MRI/CT, MRI/OI and T1/T2 dual-mode MRI contrast agents.
Considering the development of metal-based drugs, Čolović et al.  summarized recent research progresses related
to anti-viral, -bacterial, -tumor, and -diabetic activities of polyoxometalates (POMs), with special attention to putative
mechanisms and molecular targets of the POMs actions. The current challenges and the future directions in the development
of nontoxic POMs based drugs efficient towards biological targets were discussed. Misirlic-Dencic et al.  summarized
the current knowledge related to metal complexes with various types of diamine ligands as promising anticancer agents,
elucidating the relationship between the structure of these compounds and demonstrated anticancer activity. Furthermore,
Pantić et al.  provided recent knowledge on potential silver nanoparticles application as antimicrobial and anticancer
agents and as an important part of various biosensors and bioassays as well.
Considering the role of semimetal selenium in normal and abnormal physiological functioning, Silvestrini et al. 
gave a comprehensive overview of selenium and selenoproteins biochemistry, and their role on oxidative stress and
nonthyroidal illness syndrome.
By compiling these papers, we hope that the thematic issue provides new findings and trends, as well as recent insights
on the medicinal chemistry of metal-based compounds.
In the last two decades, obesity-induced mortality has been significantly increased worldwide. This stimulated
the interest of laboratory and clinical research toward this pathological condition and its associated diseases, such as
cardiac and coronary dysfunction, cancer and diabetes.
Obesity is a multifaceted disease in which many actors play a role. It depends on a complex, and still unrevealed,
interaction between genetic, environmental and psychosocial factors that results in an imbalance between energy
intake and consumption. Under normal conditions, active hypothalamic neural mechanisms maintain energy expenditure
by controlling adaptive stimuli, including appetite, satiation and satiety. Alteration of the energy equilibrium
in favor of food intake has the consequence of an excessive fat accumulation in the adipose tissue. This is associated
to important changes in plasma metabolic parameters that lead to severe dysfunctions including insulin resistance,
diabetes, and cardiovascular alterations.
The physio-pathological mechanisms that sustain the onset and the progression of obesity are only partially recognized.
A functional link between alimentary disorders, obesity, and cardiovascular diseases has been proposed
based on the discovery of a growing number of food-related peptides that coordinate both the gastrointestinal and
the cardiac function. In addition, a bidirectional interaction between the immune system and obesity-induced
changes in metabolism, adipose tissue, and liver has been proposed. Of relevance, obesity is considered a chronic
hypoxic state associated with oxidative stress, inflammation and endothelial dysfunction, as well as with a decreased
nitric oxide (NO) bioavailability.
This issue is not intended to be an exhaustive review on obesity and the complex mechanisms that sustain the
onset and the progression of the pathology and its related morbidities. The six papers of this special issue cover important
areas of research in the field of obesity and nutrition being focused on different aspects of a particular pathological
condition spanning from the use of natural anti-obesogenic drugs therapies to the nutritional treatment of
associated obesity comobidities.
A proper nutrition is a crucial approach for counteracting obesity and obesity-dependent complications. Accordingly,
nutritional strategies, as well as the possibility of taking advantage by the properties of natural remedies, are
receiving increasing attention, with a major purpose to prevent the side effects and the high costs of conventional
anti-obesogenic drugs therapies. Although these interventions are often of some effectiveness, in many cases this
approach fails so that pharmacological therapies remain the elective choice. In this contest, the manuscript by Paccosi
and collaborators  analyses and discusses the actual pharmacological management of obese patients, comparing
the pool of molecules approved by the Food and Drug Administration with those accepted by the European
Medicine Agency. The analisys shows that the protocols for treating obesity in United States and Europe are non
homogeneous since different drugs with central and/or peripheral effects are available. The paper also highlights,
the potential benefits of natural herbal medicines and supplements, as well as their putative side effects, warning at
the same time toward the uncontrolled market in the internet that proposes unapproved remedies, uneffective
against obesity and often dangerous for human health. Natural dietary agents are also the focus of the paper by
Raimondi et al. , that summarizes updated information on the promising role of these substances in controlling
the onset and the progression of cancer. They analyzed the molecular mechanism of dietary natural products such as
Curcumin, Resveratrol, Pterostilbene, Capsaicin, etc, also highlighting their inhibitory potential on oncogenic transduction
pathways, and their epigenetic effects.
In the paper by Avolio and collaborators , they suggest a 4P treatment to improve the health of the intestinal
flora: probiotics, prebiotics, postbiotics and polyphenols. They start from the assumption that adiposopathy, or
“sick fat”, represents a functional and anatomical alteration of adipocyte and adipose tissue, that seems to be the
primary cause of metabolic syndrome and its related cardiovascular risk factors. The manuscript reviewed some
crucial target for human obesity, such as the body composition, the chronic inflammation and the novel role of gut microbiota. Accordingly, obesity and its related cardiometabolic diseases could be prevented by the saving of lean
mass, by reducing the inflammatory state, and, surprisingly, by acting on the gut-microbiota and on the intestinal
The contribution by Femminò et al.  illustrates obesity as an indipendent cardiovascular risk factor which predisposes
to ischemic heart disease, ultimately causing heart failure. Authors highlight, in contrast to the “obesity
paradox” (consisting of the observation that heart failure obese patients have a better clinical condition than lean
heart failure patients), the elevated susceptibility to Ischemia/Reperfusion damages of obese patients and the reduced
effectiveness of cardioprotective maneuvers. They also illustrate the important role played in obese and failing
heart by the NLRP3 inflammasome, which is emerging as a possible therapeutic target.
Moccia and colleagues  explored the consequence of obesity on the endothelial function, particularly in relation
to Ca2+ signalling. It is known that a reduced NO bioavailability and endothelium-dependent hyperpolarization,
which occur in the presence of obesity, negatively affect vasorelaxation of the resistance vessels. Authors suggest
that endothelial Ca2+, whose signals trigger important vascular modulators, could be severely affected in obese vessels.
They hypothesize that targeting endothelial Ca2+ as therapeutic approach could contribute to reduce the vascular
damage subsequent to obesity, also rescuing endothelium-dependent vasodilation.
The study by Agrimi and collaborators  describes new mechanisms that underline the vulnerability of the
heart-brain axis (HBA) during the perioperative period in healthy and morbidly obese patients. Authors suggest a
nutrigenomics approach to both keep the body healthy and minimize the HBA propensity to injury in obese patients
undergoing surgery. In particular, the sustained intake of natural epigenetically active compounds may represent an
emerging non invasive dietary tool that modifies the gene expression and the clinical impact outcome of obese surgical
Since the continuous growth of chemical and pharmaceuticals nowadays, the need to systematize, classify and
pre-industrially predict the toxicological (pharmacological) virtual impact on various or synergistically (combined)
organisms drastically drive the public health politics, along social and even economical development. Accordingly,
the so called pharmaco-dynamics seeks for qualitative (for understanding) and quantitative (for predicting) mechanisms/
models by which given chemical structure or series of congeners actively act on biological sites either by focused
interaction/therapy or by diffuse/hazardous influence. Fortunately, the recent importance accorded to QSAR
[quantitative structure-activity relationships] modeling within the OECD [Organization for Economic and Cooperation
Development] directives and European Commission (by Joint European Research Center programs), for instance,
highly reduces the therapeutically risks and the economically costs through the various pharmaceutical
phases from chemical synthesis, screening till the medical clinical trials and final administration. However, QSAR
itself should be challenged against the limitations regarding the statistical methods, applicability domains of school
congeners, universality of models, and the targeted molecules respecting the envisaged endpoints. To this aim, the
present Special Issue debates and apply on how the current concepts of structure-activity approach may be considered
efficient, viable and robust in predicting pharmacophores’s interaction on various medicinal branches and endpoints
either by quantitative or qualitative models.
The present collection opens with the work on “Sugars and Sweeteners”, lead by Lorentz Jäntschi, focusing on
structure, properties and in silico modeling, especially on how the degree of similarity in structures, and mostly the
optical isomerism, affects biological effects through the metabolic assimilation processes, appearing with an important
role in chronical diseases as obesity, cardiac diseases, diabetes, and even lymphomas, leukemias, cancers of the
bladder and brain, chronic fatigue syndrome, Parkinson's disease, Alzheimer's disease, multiple sclerosis, autism,
and systemic lupus . The next contribution comes from Kathleen F. Edwards and Joel F. Liebman, enriching the
previous contribution, by addressing the orphan drug products (e.g., drugs and biologics) and their thermochemical
understanding, as being crucial in driving rare chronic diseases, often cancer or metabolic disease . The QSAR
approach comes then to molecular modeling, here with the case on the mosquito repellent chemicals, in the study of
Subhash C. Basak and Apurba K. Bhattacharjee, while complementing the pharmacophore based modeling for design
and discovery of novel repellent compounds including virtual screening of compound databases and synthesis
of novel analogues . The historical sterical fit analysis in QSAR and its possible post-modern perspective reload
is approached in the context of the minimal topological difference, in a topo-pharmaceutical review of Duda-
Seiman and co-authors, coordinated by Mihai V. Putz, towards enlarging the perspectives of understanding the
chemical-biological interaction at the level of ligand-receptor sites, cavity, and walls, with a true service to the future
adaptive molecular design . The neurotoxicity of organophosphorous pesticides is subsequently approached
by Bogdan Bumbăcilă and Mihai V. Putz through molecular packing on a topo-cubic structural-construct consisting
of three adjacent cubes, respecting a principle of topological efficiency, that of occupying a minimal space in that
cubic structure, a method that was called the Clef Method; it actually finds an efficient reload of Gilbert Newton
Lewis “cubic atom and molecule” model, here at the level of ligand-receptor interaction . The special issue continues
with chemo- and bio -informatics methods analysis of experimentally available data the natural compounds
therapeutic features in brain disorders, by an original review of Speranta Avram and co-authors, resulting into mapping
of the pharmacological potential of natural compounds in the brain, with identifying the most useful databases
containing molecular and functional features of natural compounds, while focusing on the most important molecular
descriptors of natural compounds in comparison with a few synthetic compounds . The afterwards work details
on the structure of aspirin molecules and crystals, in a collective work coordinated by Marilena Ferbinteanu, which,
glues the reviewing the literature results with modelling and analysis redone by the group itself towards the supramolecular
factors and their mutating role in the conformational preferences; leading to the date appearance that
the intermolecular effects were made responsible for the conformation of the molecule in crystal . In the following contribution, the sources, occurrence and fate of human-use pharmaceutical active compounds (PhACs) in the
aquatic environment have been reviewed, by a group lead by Cristina A. Dehelean, addressing point-by-point the
nowadays concerns of human and environment health by pharma mixtures . The present special issue closes with
a review work of Claudiu Lungu, along with Ionel Mangalagiu and co-authors, treating the novel anticancer DNA
intercalators by hybrid imidazole-pyridine derivatives; from the computed docking energies the QSAR modeling
showed that synthesized compounds have antitumoral and antimicrobial properties, in agreement with experimental
Overall, the included works truly advocate that the present special issues, “Molecular modeling: from chemicalbiological
structure to pharmaco-medical activity and function” is highly regarding to the present and stringent future
of chemical-biological designed interaction and how it is driving and even controlling the medico-pharmacoenvironmental
Development and Application of Computational Methods in
Biology and Medicine
Recent Developments in Anti-Cancer Drug Research
Flavonoids in Health and Disease
Carbon Nanomaterials: Perspective of their Applications in Bio-medicine
Phytosterols and Health: Current Status and Future Perspectives
Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, currently affects millions of people
worldwide although it is only endemic in America. Chagas is considered a neglected tropical disease because it afflicts
the low-income and poorest populations in developing regions of the Americas, particularly in remote, rural
areas where infrastructure such as adequate housing, sanitation and clinical resources are limited. In addition, governments
pay scarce or no attention to this health problem.
Benznidazole and nifurtimox, both discovered more than 50 years ago, are the only two drugs available to treat
Chagas disease and not only present severe side effects but also are ineffective in the chronic phase of the disease
when most of the patients are diagnosed. Recent efforts to develop new treatments for Chagas disease, including
posaconazole repositioning and the prodrug of ravuconazole (E1224) trial, have been unsuccessful and remark the
urgent need to develop new therapeutic alternatives. The scientific effort must be focused in finding simple, safe
and effective drugs that directly target the parasite without harming the patients.
It is known that the identification of reliable molecular targets for drug development is challenging, with high
rates of failure at the stage of validating potential candidates. Thus, we propose in this Special Issue to revise different
potential drug targets of the parasite T. cruzi and to explore the latest advances in drug design and drug repositioning.
The first review introduces the challenges of Chagas disease and evidences the requirement of new therapies to
treat it. Egui et al.  focus on the immunologic profile associated with the clinical status and evolution of Chagas
disease patients as wells as the effectiveness of the current treatment including different biomarkers to monitor the
T. cruzi infection.
In the next revisions, different metabolic pathways and proteins are explored as therapeutic targets against the
parasite T. cruzi, and the final two reviews include the latest strategies to identify new potential targets.
Alonso et al.  explore the bromodomain-containing proteins as potential targets in protozoa since some of
these proteins are essential for viability and diverge from the mammalian ones, which are also approach in their review.
Cordeiro  describes the importance of the NADPH producing enzymes in biosynthetic processes as well as in
the neutralization of reactive oxygen and nitrogen species. He propose them as potential targets, highlighting the
role of glucose-6-phosphate dehydrogenase and the cytosolic malic enzyme.
Schoijet et al.  propose the signal transduction pathway in trypanosomatids as a novel therapeutic target, particularly
the cAMP signaling pathway. The authors shed light in phosphodiesterases (PDEs) as druggable target,
because of the prominent roles they play in the life cycle and the essentiality for parasite survival. Despite they are
highly conserved enzymes, authors highlight the potentiality of differential inhibition from their human orthologs
and suggest the drug repositioning approach as a promising strategy to find inhibitors among the numerous drugs
against human PDEs that are available in the market.
Sangenito et al.  introduce the aspartyl peptidase inhibitors used to treat the infection with the human immunodeficiency
virus (HIV) as a drug repositioning strategy. Co-infection of patients with HIV with other microorganisms,
such as protozoan parasites, is common and the use of HIV peptidase inhibitors evidenced a decrease both in
prevalence and incidence of these co-infections. Indeed, several of these inhibitors have been tested in T. cruzi
showing multiple pathophysiological effects on the parasite.
Talevi et al.  present the thiol-polyamine metabolism, a well-known and validated T. cruzi target because
many of its components are absent or significantly differ from the host homologs offering interesting candidates for
a rational design of selective drugs. In this review, the authors critically revise the state of the art of the thiolpolyamine metabolism deepening in the pharmacological potential of its components and, properly introducing to
the different computer-aided approximations to assist systematic drug repositioning strategies.
Sayé et al.  propose the most represented family of amino acid and derivative transporters in T. cruzi as drug
targets, focalizing in proline and polyamine permeases. This family is absent in the human host and their members
are responsible of the acquisition of relevant nutrients for the survival of the parasite. The review also discusses the
latest advances in drug repositioning strategy applied to these transporters.
Saavedra et al.  explore new fields in drug target development and open new interrogations about target prioritization.
The authors analyse the fundamentals of Metabolic Control Analysis and kinetic modelling of metabolic
pathways and apply them to the trypanothion metabolism of T. cruzi. They conclude that the enzymes with the
highest pathway control are the most convenient targets for therapeutic intervention, leaving under discussion if the
agreed criterion of gene essentiality is enough to guarantee a valid target.
Last, Salas-Sarduy et al.  introduce the initiative made by public-private programs for drug discovery against
Chagas disease. This strategy consists in taking advantage of the resources invested by the pharmaceutical industry
in other commercial areas allowing the evaluation of libraries of millions of low-molecular weight synthetic compounds.
These strategies require high-throughput screenings and setting up of robust enzymatic assays to identify
and validate small molecule inhibitors, a matter as well addressed by the authors.
Recognizing that Chagas disease requires urgent attention is the first step to develop new alternative treatments
with less toxic effects, and this Special Issue is responding directly to this need.
Carbohydrates play an increasingly important role in medicinal chemistry and they have been associated with many important
medicines including antibiotics, antiviral and antitumor agents and also with the development of diagnostic techniques. The
field of carbohydrates continues to open up exciting new opportunities for the discovery of therapeutic agents and new medicinal
The aim of this issue is to highlight some examples that emphasize the importance of carbohydrates as scaffolds in medicinal
chemistry. For example, carbohydrates are now at the forefront in the development of effective vaccines to prevent and control
human gastric-intestinal microbial infections. A large number of children in the autism spectrum disorder suffer from gastrointestinal
conditions, such as constipation and diarrhea. Clostridium bolteae is a part of a set of pathogens being regularly
detected in the stool samples of hosts affected by gastrointestinal and autism symptoms. Studies have pointed out the possibility
that such microbes affect behaviour through the production of neurotoxic metabolites in a so-called, gut-brain connection. In
the first review, Pequegnat and Monteiro discuss the discovery of Clostridium Bolteae surface carbohydrates and the creation of
non-evasive diagnostic tools to evaluate the frequency and role of this microbe in autistic subjects and to a vaccine to reduce
colonization levels in the gastrointestinal tract .
The second review by Cipolla and coworkers addresses the importance and potential of glycans as specific epitopes that can
enhance medicinal chemistry tools’ efficacy . In this article the key examples of glycodendrimers, glyconanoparticles, glycofunctionalized
materials and glyco-biosensors, along with recent experimental evidences of their in vitro and in vivo efficacy or
their potentialities towards cancer treatment, immune system targeting, neuropathologies therapies, antiviral and antibacterial
strategies, tissue engineering, and as diagnostic/theranostic systems are presented.
The third review by Nunes and Coimbra discusses the diverse biological activities of fucose-containing sulfated polysaccharides,
found in seaweed and microalgae, such as anticoagulant, antiviral, antitumoral, immunomodulatory and antiinflammatory
and their potential as scaffolds for biomedical applications .
The search for new metal-efficient drugs has attracted considerable attention from the scientific community. Among them,
ruthenium complexes have emerged as an excellent alternative to platinum complexes. Ruthenium compounds containing carbohydrate
ligands represent a small but challenging field in the medicinal chemistry. The last review by Fernandes, the guest
editor, reviews the synthesis and biological activity of the most important ruthenium complexes containing carbohydrates,
demonstrating their great potential as diagnostic and therapeutic agents .
We hope that this thematic issue will benefit academics, researchers and students and stimulates the development of new
applications of carbohydrates in medicinal chemistry as well as be a source of new ideas and perspectives.
Finally, as a guest editor of this special issue, I sincerely thank the authors for their valuable and excellent contributions, and
I am also very grateful to the referees for their expert comments.
Biomarkers in Migraine Headache: Prognostic and
Chemotherapy still remains the major therapeutic option for patients suffering from unresectable or disseminated
tumors. The use of chemotherapeutic “cocktails” based on drug combinations of non-selective conventional antitumor
agents and selective small molecules/biologic compounds is the standard care currently administered by oncologists.
However, the narrow therapeutic index of each drugs, their poor solubility and rapid clearance, as well as
the intrinsic and acquired drug resistance developed by tumors are major causes of adverse side effects and failure
to control disease, often requiring suspension of the therapy and leading to patients death. In order to counteract
these drawbacks, and drug resistance, several strategies have been considered over the years. This thematic issue
addresses some aspects of drug resistance in cancer chemotherapy by exploring some targets (fibrillarin and ribosome
biogenesis, tyrosine kinases and androgen receptor) and related cellular mechanisms subtending drug resistance
in tumor cells. Finally, the rational development of dual inhibitors as well as the encapsulation of therapeutics
into nanodevices as potential novel strategies for fighting drug resistance are also discussed.
The contribution by El Hassouni and co-authors  takes into consideration the chance to circumvent chemotherapy
resistance and reduce genotoxic effects of cancer treatment by targeting ribosome biogenesis, a biological
process upregulated in tumors, including pancreatic and breast tumors. The paper overviews compounds that, by
hitting different targets, impact on ribosome biogenesis at various levels (rRNA transcription, early and late rRNA
processing) and emphasizes how the inhibition of RNA polymerase I represents an interesting promising strategy to
potentiate antitumor chemotherapy and bypass drug resistance.
A methodological guideline for approaching and overcoming the drug resistance developed by tumors against tyrosine
kinase inhibitors is reviewed by Zanforlin and co-workers . The contribution tackles the state-of-the-art of
how this drawback has been addressed for imatinib, the first kinase inhibitor that reached the market for chronic
myeloid leukemia malignancy. The development of derivatives able to overcome imatinib resistance, including
dasatinib, bosutinib, nilotinib and ponatinib, is clearly described from the point of view of a pharmaceutical chemist,
addressing the structural and functional properties of drugs and targets. Moreover, the authors suggest possible
new therapeutic options, including the development of allosteric inhibitors, which interact with Bcr-Abl and induce
inactive conformational changes, as well as drugs capable of interfering with SET/PP2A that in turn improve PP2A
activation and lead to the down-regulation of the complex.
A survey on non-steroidal chemical structures antagonists of the androgen receptor is addressed in the manuscript
by Ferroni and Varchi . Medical interventions in patients suffering from prostate cancer often result in the
growth of castrate-resistant tumors (insensitive to bicalutamide, flutamide and enzalutamide) owing to the selection
of androgen receptor point mutations or constitutive splice variants. This feature implies continuous efforts for the
development of new challenging drugs. The manuscript overviews the non-steroidal compounds targeting androgen
receptor bearing point mutations in the ligand binding domain, as well as agents that hit different domains of the
receptor, including N-terminal domain, co-regulator binding sites and DNA binding domain. The authors address
also CYP17A inhibitors functioning as androgen receptor antagonists, molecular conjugates engineered to selectively
target the androgen receptor, and new compounds in the discovery pipeline.
Stankovic and co-workers  address the potential of fighting drug resistance in cancer using a single agent that
hits several cellular pathways and recapitulates the administration of chemotherapeutic “cocktails” in clinical practice.
The manuscript focuses on compounds that inhibit the membrane transporter P-glycoprotein (e.g., drug efflux)
beside their recognized cellular targets, including tyrosine kinase inhibitors (e.g., Bcr-Abl, EGFR, VEGFR and
ALK inhibitors), compounds of natural origin (e.g., polyphenols, coumarins, terpenoids, saponins and alkaloids), as
well as microtubule and topoisomerase I/II inhibitors. Finally, hybrid compounds (e.g., camptothecin conjugated
with cisplatin or histone deacetylase inhibitors) endowed with dual/multiple target functions that show interesting
potential in overcoming drug resistance are considered. The review by Guo and co-workers  summarizes the recent research progress of nano/microporous inorganic
and hybrid (inorganic/organic) systems in the applications of drug delivery. Four classes of porous particles (silica,
calcium carbonate, metal-phenolic network, and metal-organic framework particles) are discussed for their capacity
to encapsulate a large amount of therapeutic or other functional molecules for drug delivery and theranostics. The
authors further provide additional emphasis on overcoming the different issues in medicinal delivery, including
unique and interesting perspectives on the potential to circumvent drug resistance, and the also expect their promising
roles in agro-industrial applications. The manuscript provides a wide range of attractive and promising research
directions for the communities of medicine, biology, biochemistry, and materials science.
Along this line, the paper by Arrighetti and co-authors  reviews the different attempts considered so far to exploit
exosomes as medical devises in cancer therapy. Besides to overview the several biological properties that
make exosomes a recognized useful medical tool (e.g., good biodistribution, biocompatibility, permeability as well
as the capability to bypass the blood-brain barrier), the contribution summarizes the various approaches available
for their synthesis preparation, surface modification for tumor targeting and cargo loading. Additionally, the authors
dissect the differences between synthetic and tumor-derived exosomes, and provide further insight into their unique
features as carrier delivery for both small molecules and nucleic acids.
Flavonoids are one of the most abundant class of secondary metabolite found in various fruits and
vegetables, as well as in many plant derived beverages. Epidemiological evidences suggest that their
regular uptake can increase wellnes of organisms and can actively modulate the intracellar signal cascade.
In fact, although great attention has been mainly focus on their antioxidant activity, these compounds and
their metabolites show promising and hidden aspects, which can be utilize to promote cell survival or
death. Many of them are also characterized by well-defined target of action. They have inhibitory or
stimulatory effects on metabolic key enzymes influencing signalling pathways, cellular functions and
gene expressions. These elements make them a very promising element to develop strategies for the
prevention and treatment of pathological conditions. The final aim of this issue is to discuss the
challenges of flavonoids utilization in different pathological conditions, as well as to review the
mechanism of action useful to proposed valuable strategies for future therapies, characterized by high
selectivity towards biological targets and low side effects.
Medicinal chemistry is an important discipline dealing with life science and human health, and is also an attractive
discipline platform for collaboration of scientists from different fields in researching and developing new drugs
[1-5]. The principal aim of this special issue is to report some recent progresses in the field of medicinal chemistry
using theoretical and experimental approaches of biophysics.
One of the fundamental goals in molecular cell biology and proteomics is to determine the subcellular locations
of proteins in an entire cell [6-8]. It is also indispensable for prioritizing and selecting the right targets for drug development.
In the review paper “Advance in predicting subcellular localization of multi-label proteins and its
implication for developing multi-target drugs” , Professor Dr. K.C. Chou summarized the progresses in this
area, especially on those bioinformatics tools that have the capacity to deal with multi-label proteins. Protein molecules
with this kind of characteristic are vitally important for finding multi-target drugs, a current hot trend in drug
development. Focused on this review are also those computational methods that have use-friendly web-servers established
so that the majority of experimental scientists can use them to get the desired results without the need to
go through the detailed mathematics involved.
Hyperoxaluria, excessive urinary oxalate excretion, is a significant health problem worldwide. Disrupted oxalate
metabolism has been implicated in hyperoxaluria and accordingly, an enzymatic disturbance in oxalate biosynthesis
can result in the primary hyperoxaluria. The review article entitled “Metabolism of Oxalate in Humans: A Potential
Role Kynurenine Aminotransferase/Glutamine Transaminase/Cysteine Conjugate Beta-lyase Plays in
Hyperoxaluria” by Professors Dr. J.Y. Li and Q. Han , reviewed all aminotransferases in the liver for their
functions in glyoxylate metabolism. Particularly, kynurenine aminotransferase-I and III were carefully reviewed
regarding their biochemical and structural characteristics, cellular localization, and enzyme inhibition. Kynurenine
aminotransferase-III is, so far, the most efficient putative mitochondrial enzyme to transaminase glyoxylate to glycine
in mammalian livers, and should be carefully investigated for its involvement in oxalate metabolism.
In a target-based drug discovery project, NMR can serve an important function in the steps of hit identification
and lead optimization. The review article titled “19F-NMR in Target-based Drug Discovery” by Dr. C.B. Kang
, summarized the application of 19F-NMR in understanding protein-ligand interactions. 19F-NMR will play an
important role in drug discovery by providing a fast and robust way for novel hit identification. This technique can
be used for ranking compounds with different binding affinities and particularly useful for screening competitive
compounds when a reference ligand is available.
Diffusion of chemical analytes in the cellular boundary layer reflects physiology and metabolism of healthy and
diseased cells. The review article titled “Advances in Electrochemistry for Monitoring Cellular Chemical Flux”
by Dr. M. A. Messerli and colleague , reviewed the recent advances in electrochemical detection, and application
of new detection strategies, for non-invasive, label-free monitoring of these chemical gradients. They described
advances in characterization of transport proteins, and function of rare cells, using temporal and spatial selfreferencing,
and scanning electrochemical microscopy. The methods for measurement of drug flux, and the future
potential of biological macromolecules for enhancing detection by ultramicroelectrodes were introduced. In addition,
they also reviewed the improvements to enhance measurement throughput, and to screen embryos and stem
cells prior to implantation.
As we can see from the aforementioned papers collected in this special issue, the developments of novel theories
and approaches in biophysics have very high impacts on the research of medicinal chemistry.
FDA defined “botanicals” as products of plant materials, algae, macroscopic fungi, and their combinations and
considered them as finished, labeled products containing vegetables as ingredients, that can be used as conventional
foods, dietary supplements, drugs, cosmetics, or medical devices depending on its route of administration, formulation,
safety and intended use [1, 2].
Today, the use of medicinal plant remains widespread, and a significant portion of the world's population utilizes
herbal natural products and supplements as the primary mode of healthcare [3,4]. In the United States, for instance,
nearly 20% of adults and 5% of children utilize botanical supplements to treat different diseases.
The increase in adoption of herbal remedies may be ascribed to: a general preference of natural therapies and
aversion for other interventions like surgery, allopathic medicines etc; inclination towards self-medication based
upon experience; affordable cost of herbal medicines and ease of availability; side effects associated with conventional
medicines (especially in cases of chronic problems) and growing promotion of herbal medicines .
Botanicals in medicine are usually recommended for disease prevention and to maintain good health, while
rarely their use is suggested for acute and/or life-threatening problems. More recently, it is observed a growing use
of herbal medicine when conventional medicine is ineffective or for pain palliation in case of long-standing problems
like cancer, arthritis etc. .
Also cosmetic market has been influenced by botanicals. In particular, it has been observed a growing trend in
incorporating antioxidants in sunscreens and skincare products to replenish the natural reservoirs in the skin .
This “new renaissance” of herbal product obliges us to employ them with a real scientific method. Researchers
having access to innovative technologies can optimize the use of herbal ingredients in natural formulations, to give
safety and efficacy to the formulation across a scientific view, validating the traditional use, with no previous scientific
On these basis, this special issue is aimed to give an overview on the current state of botanicals research, in order
to collect recent scientific data on the development of pharmaceutical products, cosmetics and nutraceuticals. The
attention is focused on the chemical composition, biological activities [7-11] and nutritional aspects of new herbal
product [8, 11,12] and on the application of innovative technologies or formulative approaches to improve their stability
and bioavailability [8-10, 12-15]. Readers will find information about new natural products endowed with
healthy activities. Flaxseed oil, for instance, is a very important product characterized by anti-oxidant, antiinflammatory
and anti-dysmetabolic effects and has been evaluated for a potential application in different diseases
. Brassica vegetables also possess anti-oxidative properties and are associated with the risk reduction of chronic
diseases including cardiovascular diseases and cancer . The focus of the present special issue is also on some indigenous
underutilized wild edible plants, such as Pereskia aculeate, a natural diet supplement studied as “novel
food” in virtue of its high nutritional value  and Momordica cochinchinensis, a super fruit, of the functional
food industry .
Finally, our readers will find interesting examples of innovative delivery strategies to increase the bioavailability
of natural active compounds from vegetable sources . Extensive discussion on this special issue about different
nanocarriers for the delivery of natural products, functional foods, dietary supplements and herbal medicinal products
is also addressed [13-15].
The Editors thank the authors who contributed to this special issue with high-quality manuscripts that increased
The aim of this issue is to present some important contributions of researchers mainly from the
Academia about the drug design and discovery of bioactive compounds on Neglected Diseases.
The researches have been developed by important and specialized Brazilian and foreign groups
dedicated to the search for new bioactive compounds in some of the most important Neglected
Diseases worldwide. The diseases involved are: Chagas disease, leishmaniasis, malaria,
tuberculosis, dengue, schistosomiasis and leprosy. Well-known molecular targets and also new
ones are comprehended in the subtopics in general. Then, rational design, especially SBDD –
Structure Based Drug Design – is the subject of some topics, and, in addition, LBDD – Ligand
Based Drug Design is involved in some topics. Molecular modification as bioisosterism,
molecular hybridization and prodrug design are used as approach to design some leads and hits,
described for their potential activity on Neglected diseases. Polypharmacology and also drug
repositioning are discussed concerning its importance on Neglected Diseases.
Diabetes mellitus is defined as a pathological condition characterized by unbalanced blood glucose levels due to
the disruption in the cell signaling linked to its main regulator factor, insulin. An initial classification of patients was
done according to an impaired insulin body function, thus patients were considered as type 1 and type 2 diabetic .
Nevertheless, besides the progression in the knowledge regarding this syndrome, new subtypes have been identified
and designed. On the other hand, the development of molecular biology, biotechnology and genetic tools has provided
to the scientific community the discovery of new molecules and proteins, as well as genes, that have been associated
with the development or affect the progression of this syndrome and, in turn, will force the description of
new subtypes of diabetes mellitus. In fact, a diversity of the available diagnostic tools, together with a reduction in
the cost of these molecular and genetic diagnostic procedures, have made the physicians to change the way of approaching
different diseases; the concept of a personalized medicine is becoming more relevant and it is gaining
more support. The basis of this new approach is the comprehensive information available in the literature regarding
the molecular pathways and/or proteins altered, or involved in the development of a particular disease. For instance,
the discovery of the regulatory function of certain miRNAs opens a new field in the diagnosis of certain diseases
such as cancer, so it would also assist in case of patients suffering from diabetes mellitus [2, 3].
In this special issue, we provide an updated overview of new molecular and genetic markers (such as the identification
of new miRNAs) that can be used for the diagnosis and monitoring of the progression of the several complications
linked to diabetes mellitus, like thrombosis, kidney failure, neurological complication, etc. Furthermore,
readers could find information about the latest diagnostic tools, and/or possible future therapies based on the use of
stem cells and antagomirs [4-7]. We have also included information regarding the close relationship between adipose-
tissue and pancreas, by enumerating several adipokines that link both these tissues in order to regulate or integrate
the metabolism and bioavailability of either glucose or lipids .
In addition to the molecular marker described above, we have included reviews including some clinical aspects,
as well as some references to more patophysiological aspects such as alteration in platelet function that compromises
the cardiovascular system, and other diabetes mellitus linked complications such as heart failure and vascular
myopathy [9, 10]. It is also worth mentioning that some experts in the field of melatonin provide us with information
regarding the contribution of this hormone to modulate the impact of hyperglycaemia in diabetic patients .
Finally, related to the vascular dysfunction presented in diabetic patients, in-depth knowledge of the contribution of
diabetes mellitus to the appearance of male reproduction dysfunction is further explained. In this review, authors
also describe the benefits and/or side effects on male reproduction of some drugs that are currently in use for the
treatment of diabetes mellitus .
The editors would like to thank all the contributors of this issue, as well as the reviewers whose contributions
enhanced the quality of the manuscripts published in this special issue.
Computational approaches have been greatly appreciated as an important pillar of drug discovery and development.
This special issue compiles a series of review articles that, in the era of personalized medicine, advance our
understanding and foster the identification of appropriate in silico resources in this area.
Computer-Aided Drug Design (CADD) has been at the forefront of the search for new drug targets and design of
therapeutic compounds for a long time. Bruno et al. (2017) analysed the early phases of the drug-discovery pipeline
and discussed the pathway from disease choice to lead optimization . The challenges of individual steps in the
discovery pipeline are assessed, as well as computational tools and in silico resources widely in use. Successful results
of pharmaceutical companies in the recent period show the benefits of technological advances that translate
into more efficient and accurate computational tools. On the other hand, analyses of major failures show that we are
still facing the challenge of treating the targets in a more physiological context. This compendium of the drugdiscovery
process is valuable both as an overview to the professionals and as an educational resource. Vucicevic et
al. (2017) discussed in silico techniques used in rational drug design of antineoplastic agents and presented optimal
combinations of computational methods for design of safer and more efficient antineoplastic drugs . An overview
of QSAR studies applied in development of modulators of epigenetic targets and inhibitors of Bcl-2, Bcl-xl, mTOR
inhibitors, and CDK1 is provided. There are generally two distinct approaches to computational drug design, structure
based and ligand based. The authors discuss the successful project as well as technical requirements of both
virtual screening and docking techniques. Protein-Protein Interactions (PPI) underlie key cellular processes and offer
immense possibilities to the search for druggable interactions as well as for off-target candidates. In their review,
Gemovic et al. (2019) described public computational tools for PPIs that rely on statistical and machine learning
methods . The authors tested the capacity of several popular tools to predict newly discovered interactions and
provide guidelines with background information necessary to understand the results. In addition to that, this review
presents a detailed overview of databases and other public resources that store information of both experimental and
predicted PPIs. For some time, PPIs were considered difficult drug targets, but due to the numerous compounds in
clinical studies this perspective is changing, thus emphasizing the importance of PPI bioinformatic tools for the
drug discovery community. Protein aggregation into β-sheet-enriched insoluble assemblies has been found to be
associated with both systematic or organ diseases, such as Alzheimer's, Huntington's, Parkinson's, type II diabetes
and prion diseases. Protein aggregation also represents a barrier in the design and development of protein-based
therapeutics. Parales and Ventura (2017) reviewed bioinformatic tools for prediction of the targetable proteome
prone to aggregation which are based either on sequence or on structural information . Although some of the sequence
based algorithms rely on rather simple principles, they are capable of efficiently detecting aggregation of
nucleating peptides. Structure based algorithms leverage on ever-increasing tertiary structure data. AGGRESCAN
3D is a popular web tool that identifies residues susceptible to aggregation and provides an option for testing amino
acid substitutions that increase solubility. The application of aggregation prediction methods enhances our understanding
of principles that govern aggregation and enables control of the solubility of biotherapeutics.
In the era of Big Data , the topics tackled in the special issue: “Recent in silico resources for drug design and
discovery” will become even more significant, particularly with a focus on making the process of choosing the drug
candidate more efficient, and on the use of various available data to better assess attrition risks.
The steadily increasing epidemiological prevalence of age-related neurodegenerative diseases and the deepening
of knowledge on basic mechanisms underlying physiologic and pathologic aging processes of the brain account for
the need of constant up to date of data emerging from fundamental, translational and clinical research.
Accordingly, original data from Bonfiglio et al.  offer a measure of the impact of environmental stimulation
on the release of neurotransmitters (noradrenaline, glutamate and gamma amino butyric acid (GABA)) suggesting
that these undergo different adaptations during aging and that they are differently tuned by “cognitive training”. The
impact of “cognitive training” on neurotransmitter exocytosis might account for the cellular events involved in the
reinforcement of “cognitive reserve” in both young and old animals. Although translation from rodent studies to
clinical situation could be difficult, the results from pre-clinical models are of high clinical relevance, since they
may allow a better understanding of the effects of environmental interventions in aging-associated chronic derangements
in mammals. Also, they improve our understanding as to whether “cognitive training” promotes compensatory
effects or, alternatively, if it elicits genuine recovery of neuronal defects.
There is no doubt that everyone experiences adverse events during life that impact both the health and quality of
life. However, trajectories of health in aging can vary significantly depending on the individual. According to this
hypothesis, Brivio et al.  envisage that a reduction of resilience may underlie an increased risk to develop pathological
conditions during aging. In line with this idea, fragility in elderly would be the consequence of reduced function
and responsiveness of biological systems, crucial for coping with stressful events. For the authors, it is therefore
fundamental to identify and characterize the mechanisms that may contribute to the resilience or the vulnerability
to stressful events, since such mechanisms may be significantly altered in the aged brain. However, a major gap
in this field of research is that the studies are limited to assess molecular alterations under basal or resting conditions,
without information on, if and how these functional impairments result in lack of stress responsiveness. The
investigation of these mechanisms will be critical to identify genes and pathways the changes in which may contribute
to achieve a better understanding of the risk architecture for age-related vulnerability and may represent potential
targets for the development of novel pharmacological interventions.
In the above streamline of thoughts, Cerri and Blandini  report on dysregulation of the autophagic pathway as
a contributing factor to PD pathogenesis via α-synuclein accumulation. Heterozygous mutations in the GBA1 (glucosylceramidase
beta 1) gene are currently recognized as the most relevant risk factor for the disease pointing to
lysosomal defects as major players in the PD-related impairment of the autophagic process. Preclinical findings
support the use of therapeutic agents boosting autophagic activity, as potential disease-modifying agents. However,
a deeper understanding of the mechanisms that may lead to autophagy defects in PD will be required to facilitate the
design of new therapeutic interventions. The multifactorial nature of the disease allows this consideration to be extended
to other mechanisms involved in PD pathogenesis, such as neuroinflammation oxidative stress, and mitochondrial
Kustrimovic et al.  discuss the evidence accumulated supporting a fundamental role for neuroinflammation in
PD; also, they originally contribute to the understanding of the active participation of peripheral immune mechanisms.
The definition of the peculiar profile of CD4+ T naive and memory cells with likely consequent proinflammatory
changes of immune system in PD patients suggests that these peripheral immune challenges can exacerbate
the process of neuroinflammation and hence the symptoms of the disease also providing the rational basis
for the proposal of immunotherapy for the treatment of PD.
Mancino et al.  demonstrate as the development of advanced neuroimaging techniques allows some degenerative
diseases, considered of exclusive ocular relevance, to be associated with neurodegenerative phenomena of the
Central Nervous System (CNS). Thus, a strong connection between the stage of glaucoma and alterations of the optic
nerve and of the optic radiations has been assessed using diffusion tensor MRI (DT-MRI). In particular, with this technique damage is measured by extrapolating from the images two numerical parameters: the Mean Diffusivity
(MD) and the Fractional Anisotropy (FA). The finding showing increased values of MD and decreased values of
FA, measured in the retrobulbar portions of the optic nerve of patients with glaucoma, suggests that also the extra
bulbar portions of the optic nerve are affected by glaucoma. Interestingly, the analysis of DT-MRI parameter in
glaucomatous patients at different stages of the disease showed that alterations in the early glaucoma are predominantly
located at the level of retro-laminar region while, in the advanced stages, they also affect the distal portion of
the nerve. Glaucomatous alterations may therefore be an expression of a neurodegenerative disease, which from the
central areas extends to the retina. In this regard, recent studies using MRI reported that glaucoma affects not only
the RGCs, but also the CNS with a similar mechanism found in other neurodegenerative diseases such as Alzheimer’s
The latter disease accounts for approximately 50% of all cases of dementia and, in spite of the great effort, disease-
modifying drugs are not available yet. Adherence to the current therapy of cognitive decline is needed for a
better control of the disease and this is proven to reduce, though it does not abolish, the associated Behavioural and
Psychological Symptoms of Dementia (BPSDs). On this aspect, Scuteri et al.  discuss how this cluster of symptoms,
remarkably affecting patients’ health-related quality of life (HRQL), is tightly associated to pain states. Actually,
antipsychotics are the only treatment for BPSDs though they are able to manage aggression but not agitation
and they cannot control pain. Clinical trials with Melissa officinalis and Lavandula officinalis have demonstrated
efficacy in handling BPSDs but strong evidence to offer relief from pain is lacking. At variance with the latter, Bergamot
Essential Oil (BEO) is endowed with strong analgesic activity implicating pharmacological mechanisms, i.e.
enhanced autophagy, a process undergoing derangement in chronic pain lending support to the pharmacological
basis for clinical translation of aromatherapy with BEO in the treatment of BPSDs.
Altogether, the issue offers the perfect setting to discuss very interesting topics and to share studies and knowledge,
thus widening our understanding of normal and diseased aging and giving rise to novel research lines for the
development of better neurotherapeutics.
Nutrients are digested and absorbed in the body at different locations in the gastrointestinal tract, and diet plays a
key role in bringing fats, proteins, carbohydrates, fiber, micronutrients including vitamins, and antioxidants in close
contact with the intestinal mucosa where absorption occurs.
The human intestinal microbiota, through its diversity and functions in health and disease, is greatly involved by
providing substrate metabolism of branched-chain and aromatic amino acids, components of diet, drugs, bile acids,
xenobiotics, biosynthesis of short-chain fatty acids, steroid hormones, neurotransmitters, and vitamins [1-4]. A great
deal of evidence has shown that nutrients act as mediators contributing to the pathophysiology of biological processes,
including oxidation, inflammation, and organ dysfunction. Moreover, their synergistic mechanisms result in
greater effects, thus highlighting the importance of focusing on food groups, in addition to nutrients . In this respect,
diet can be regarded as a type of beneficial agent, and currently much attention is given to the contribution of
diets to health maintenance as well as to the complex pathogenesis of diseases .
Thus, nutrition should be placed at the forefront of public health programs as a cost-effective means to prevent a
number of chronic diseases, which include metabolic disorders (obesity, type 2 diabetes), cardiovascular diseases
(coronary heart disease, hypertension and stroke) [7-9], cancer [10, 11], liver disorders, dental diseases and osteoporosis
With this scenario in mind, the Editors of the present issue of Current Medicinal Chemistry have gathered valuable
evidence from a large number of experts worldwide in order to focus on “Medicinal” diets and their role in
health and disease. From a basic science perspective, this area provides opportunities to advance our understanding
of related pathophysiological mechanisms. From a clinical perspective, this opens new avenues to provide patients
with an active and empowering role in health maintenance, with numerous positive repercussions.
In Section 1, the Basic Implications are Examined.
Teixeira et al. discuss the role of four dietary polyphenols – resveratrol, curcumin, epigallocatechin-3-gallate
(EGCG) and quercetin – in molecular pathways regulated by mitochondria and their potential impact in human
health. The mechanisms underlying the polyphenols’ beneficial effects include, among others, the attenuation of
oxidative stress, the regulation of mitochondrial metabolism and biogenesis and the modulation of cell-death signaling
cascades, among other mitochondrial-independent effects.
Wang et al. focus on the complex molecular mechanisms linking the neurohormonal response of the gallbladder
to the gastrointestinal hormone cholecystokinin (CCK), which, under food stimulation, initiates gallbladder contraction
and bile secretion, thus preventing the precipitation of excess biliary cholesterol and gallstone formation. Gallbladder-
specific CCK-1R-selective agonists may provide an efficacious novel strategy for preventing gallstone formation
by promoting gallbladder emptying, particularly in subjects with gallbladder contractile dysfunction, e.g.
patients with celiac patients as well as patients on total parenteral nutrition.
Silva & Jones review the effect of “functional foods” on metabolic control, and potential implications in health
and disease. Given the high and increasing incidence of glucose intolerance and type 2 diabetes related to overnutrition
in Westernized societies and the potentially significant role of diet and food awareness in preventing or
reversing this condition, the review will focus on those food components or supplements that specifically improve
Vergani focuses on free fatty acids (FA) which are the major mediators of hepatic steatosis; patients with
NAFLD have elevated levels of circulating FA which correlate with disease severity. Steatosis is a reversible condition
that can be resolved with changed behaviors, or that can progress towards more severe liver damage such as
steatohepatitis (NASH), fibrosis and cirrhosis. Thus, excess of fatty acids, an essential component of digested foods, essential
step in the onset and perpetuation of liver steatosis.
Cataldo et al. describe the subtle mechanisms linking the function of Aquaporins (AQPs), a family of membrane
channel proteins widely expressed in the human body, to the beneficial action played by some food nutrients and
phytochemical compounds. The authors provide an overview of what is known regarding the AQP modulation exerted
by healthful dietary patterns and plant polyphenols.
In Section 2, the “Clinical Implications” are Reviewed.
Di Ciaula et al. discuss the close connection between overweight, obesity, dyslipidemia, insulin resistance and
altered cholesterol homeostasis to increased gallstone occurrence. A number of specific nutrients acting as risk factors
with respect to gallstone formation include increased energy intake with highly refined sugars and sweet foods,
high fructose intake, low fiber contents, high fat, consumption of fast food and low vitamin C intake. On the other
hand, high intake of monounsaturated fats and fiber, olive oil and fish (rich in ω-3 fatty acids) consumption, vegetable
protein intake, fruit, coffee, moderate alcohol consumption and vitamin C supplementation exert a protective
Stokes et al. place the burden of non-alcoholic fatty liver disease (NAFLD) into clinical perspective with a focus
on the impact of nutrition and cite examples of short-term interventions that assess direct effects of dietary-related
components on hepatic steatosis. The main focus is on the three macronutrients, i.e. dietary carbohydrates, fats, and
Surdea-Blaga et al. summarize current knowledge regarding food and gastroesophageal reflux. For example, fat
intake increases the perception of reflux symptoms. Regular coffee and chocolate induce gastroesophageal reflux
and increase the lower esophageal exposure to acid. Spicy foods might induce heartburn, but the exact mechanism
is not known. Beer and wine induce gastroesophageal reflux, mainly in the first hour after intake. For other foods,
such as fried food or carbonated beverages data on gastroesophageal reflux is scarce. Similarly, there is limited data
on the type of diet and gastroesophageal reflux. Mediterranean diet and a very low carbohydrate diet, by contrast,
appear to protect against reflux.
Portincasa et al. discuss a frequent functional gastrointestinal disease, namely irritable bowel syndrome (IBS),
which can be influenced by foods. Dietary education is essential to deal with foods that are potential triggers for the
onset or worsening of symptoms. However, further studies are required to link the ultimate role of diets in different
Ferri et al. provide evidence that healthy diet and improved dietary practices contribute to reduced chronic disease
risk among shift workers. A possible role of education programs on eating behavior as preventive strategies in
this group of workers should incorporate several important lifestyle changes.
Carbone et al. discuss the role of ethanol as a potential direct cardioprotective agent and update current knowledge
on the intracellular mechanism underlying the cardioprotective effects of polyphenols and ethanol. The need
for randomized clinical trials able to clarify the potential role of red wine consumption in reducing cardiovascular
risk is also discussed.
De Angelis et al. address the issue of diet, benefits to human health and activity of gut microbiota. Habitual diet
(Western, Agrarian and Mediterranean omnivore diets, vegetarian, vegan and gluten-free diets) drives the composition
of the gut microbiota and metabolome. Specific relationships between diet and microbes, microbes and metabolites,
microbes and immune functions and microbes and/or their metabolites and some human diseases are being
Garruti et al. report on nutritional factors, other lifestyle components including excess body fat in interfering
with female reproduction and fertility. In an attempt to define “the optimal fertility diet“, the authors will consider
the role played by a Mediterranean lifestyle and specific macronutrients (animal and vegetable proteins) on ovulatory
disorders and female fertility.
Ezquerro et al. discuss the effects of diets on adipose tissue. In obesity, dietary changes should be individualized,
tailored to food preferences and allow for flexible approaches to reducing caloric intake in order to increase
the motivation and compliance of overweight and obese patients. The review summarizes compelling evidence showing body composition changes, impact on cardiometabolism and potential adverse effects of very-low calorie,
low- and high-carbohydrate, high-protein or low-fat diets.
Almeda-Valdes et al. discuss the role of diet in patients with the metabolic syndrome, a very common metabolic
disorder. The goal of treating metabolic syndrome is to reduce the risk of coronary heart disease and the development
of type 2 diabetes. Lifestyle modification therapy combines specific recommendations on diet alone or combined
with other strategies.
Di Ciaula and Portincasa focus on the dangerous link between diet and contaminants in driving the rise of obesity
epidemics. Indeed, maternal diet, intestinal microbiota and chemicals introduced as contaminants with food, are
all factors able to increase the risk of obesity. Widely diffused toxics are able to promote obesity in children and
adults, mainly by acting on the differentiation pathway linking multipotent stromal stem cell to mature adipocyte,
modulating epigenetic factors and influencing a series of mechanisms finally leading to altered dietary habits, increased
adipocyte formation and fat storage. The efficacy of primary prevention strategies acting on all these factors
might contribute to reversing the continuous rising of the obesity epidemic.
Badimon et al. underscore the importance of the link between diet and cardiovascular disease (CVD). Current
research places the Mediterranean dietary pattern, rich in fruits and vegetables, as the most cardioprotective, because
of its high concentration of bioactive compounds such as unsaturated fatty acids, polyphenols, fiber, phytosterols,
vitamins and minerals, which exert antioxidant, anti-inflammatory and anti-thrombotic effects contributing to
the delay of CVD initiation and progression.
Mastronuzzi and Grattagliano examine the problem of adequate caloric intake as a major determinant of health
status especially when degenerative conditions become a predominant risk for difficult-to-treat diseases, as in aging.
The maintenance of nutritional status is the best measure to counteract the risk of protein-caloric malnutrition and
its complications which often affect elderly populations and frail patients. Attention is placed on certain aspects associated
with malnutrition as an indicator of disease severity and health costs in the elderly population. The impact
of nutritional interventions and nutrient supplementation on general indices of malnutrition is also discussed as a
Altomare et al. review the topic of cholecystectomy, as a condition which can have nutritional and metabolic
consequences in the short-term (diarrhea, abdominal pain and bloating) and in the long-term (increased body mass
index with metabolic syndrome, gastritis, liposoluble vitamin deficiency). Pathogenic mechanisms behind these disturbances
are reviewed and the need for an early post-operative nutritional intervention based on a low-lipid, highfiber
diet, is highlighted.
In conclusion, the continuously evolving field of nutrition with respect to prevention and treatment, as well as
induction and perpetuation of chronic diseases, is central in modern clinical medicine with a myriad of translational
implications. We as Editors believe that undergraduate and postgraduate students, residents, researchers, clinicians
and nurses alike will enjoy and take advantage from reading the following chapters in Current Medicinal Chemistry.
All contributions have been reviewed, include updated bibliographies and current guidelines, and are enriched
with concise tables and figures, dealing with the key pathophysiological mechanisms and chemical formulas.
Drug discovery and development, is vital for contribution to human health and for saving the lives. In this regard, enzymes, the active biological
catalysts in organisms, are involved in many pathways and speed up or regulate many reactions in the body. Enzyme inhibitors are the
compounds interacting with an active gorge of any enzyme to prevent or alter its regular catalytic function in a permanent (irreversible) or
temporary (reversible) manner and in competitive or non-competitive mode. Enzyme inhibitors are also of value to treat many diseases at the
moment, most of which are in clinical use and, therefore, they have become a very attractive target for drug development and discovery. For
instance, glucocerebrosidase inhibitors for Gaucher disease, cholinesterase inhibitors for Alzheimer’s disease (AD) and myasthenia gravis
(MS), angiotensin-converting enzyme (ACE) inhibitors for the treatment of hypertension, 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA)
reductase inhibitors for hypercholesteramia, protease inhibitors for AIDS treatment, monoamine oxidase-A (MAO-A) for depression, tyrosinase
inhibitors for hyperpigmentation, and α-glucosidase inhibitors for diabetes mellitus, etc. can be exemplified to underline their role in
the treatment of a wide range of diseases. Consequently, designing and discovering novel enzyme inhibitors are a prevalent research approach
and an immense number of studies are being published each year. Consistently, the prominence of various enzyme inhibitors has been discussed
extensively by many researchers in comprehensive systematic reviews [1-8].
The paper by Anna Boguszewska-Czubara et al., initially introduces structural and functional characteristics of matrix metalloproteinase
inhibitors (MMPs) as a large enzyme family in detail. Then, they discuss their vigorous role in the central nervous system (CNS)-related diseases
like stroke, Alzheimer’s disease (AD) and vascular dementia, Parkinson’s disease (PD), and multiple sclerosis (MS). They elaborate the
role of matrix metalloproteinase inhibitors (MMPs) which play a key role in re-modeling of the extracellular matrix (ECM) and also influence
cell differentiation, migration, proliferation, and survival. It covers the information on tissue inhibitors of metalloproteinases (TIMPs) expressed
in various structures of adult brain as well as well-known natural endogenous tissue inhibitors of TIMPS through exogenous synthetic
ones like (4-phenoxyphenylsulfonyl)methylthiirane (SB-3CT), tetracyclines (e.g. minocycline and doxycycline), batimastat (BB-94), and FN-
439. The authors conclude that more clinical studies are required due to lack of human studies evidencing the effects of MMP inhibitors
found in animal models as attractive therapeutic targets .
The paper by Miguel D. Ferrer et al. deliberates the latest outcomes on selective cyclooxygenase-2 (COX-2) inhibitors (e.g. non-steroidal
anti-inflammatory drugs, NSAIDs) in relevance to inflammatory pathologies characterized by a prolonged pro-inflammatory status, including
autoimmune diseases, metabolic syndrome, obesity, atherosclerosis, neurodegenerative diseases, chronic obstructive pulmonary disease, arthritis,
chronic inflammatory bowel disease, and cardiovascular pathologies. In fact, COX-2 selective inhibitors have been reported to be a
promising approach to counteract the higher inflammatory mediator production induced by over-expressed COX-2 in inflammatory diseases.
The authors in their paper briefly covered the structural and physiological properties of COX family, conventional inhibitors of COX-2, their
vital role in inflammatory diseases, and their side effects, while they also discussed the imperative role of pure natural or chemically-modified
compounds along with examples of medicinal plants in preventing inflammation through COX-2 inhibition as well as several other relevant
mechanisms such as NF-κB signalling, phosphorylation of ERK1/2, p38 and/or Akt, activation of PPARγ pathway, suppressing iNOS transcription.
The authors finally pointed out to the need to develop new anti-inflammatory molecules from natural sources .
The paper by Giuseppina Lagana et al., discusses the most recent developments in the design and development of inhibitors of lactate dehydrogenase
(LDH), an enzyme found in all living organisms, which functions for glucose restoration during gluconeogenesis. The text by
the authors firstly gives a brief introduction to structural characteristics of LDH along with its isozymes and their physiological role in human
metabolism related to cellular homeostasis of redox balance, pH regulation, and signal cascade modulation. Then, they deliberate Nhydroxyindole-
based, azole-based, quinoline-derivative, oxamate-derivative, and bifunctional inhibitors as well as galloflavin as a promising
inhibitor of LDH in particular, where molecular interactions between the enzyme and inhibitors were mentioned. In conclusion, they brought
out attention to finding new LDH inhibitors of synthetic or natural origin considering their therapeutic importance .
The paper by Seyed Mohammad Nabavi et al. gives an outline on the role of aporphines in Alzheimer’s disease (AD). The paper firstly
introduces AD with its pathophysiological mechanisms; e.g. the formation of β-amyloid plaques and neurofibrillary tangles (NFT), in particular.
Then, the authors described some treatment options towards AD such as acetylcholinesterase (AChE) inhibitors obtained from alkaloids
of aporphine group. The paper explains how aporphine-derivative drugs in alkaloid form used against AD can act through ChE inhibition and
some other mechanisms. For instance, nuciferine as an alkaloid with aporphine skeleton has been proven to be a quite promising ChE inhibitor.
On the other hand, oxoisoaporphines, the synthesized alkaloids, were shown to inhibit ChE as well as Aβ self-induced aggregation. In
fact, protoberberine alkaloids were revealed to exert a strong inhibition against ChEs. Many of the isolated aporphines from various herbal
sources seem to be a remarkable anti-Alzheimer effect. Finally, the authors came to a conclusion that aporphine-type of alkaloids isolated
from plants as well as their synthetic counterparts could bear a future potential to become novel anti-AD drug candidates due to their low
cytotoxicity and high bioavailability in the organism via its high solubility in an aqueous medium .
The paper by H. Ozan Gulcan et al. gives a short introduction to Alzheimer’s disease (AD) and treatment strategies along with an overview
of benzimidazole derivatives as drugs. After that, the authors describe benzimidazole derivatives designed for the treatment of AD via
different mechanisms for various targets such as the inhibition of amyloid-β1-42, amyloid precursor protein (APP) through the catalytic functions
of ß- (also referred to as BACE), and γ-secretase enzymes as well as the prevention of β-amyloid plaques and neurofibrillary tangles
(NFT). In addition, many benzimidazole derivatives have been shown to act as H3 (histamine 3) receptor antagonists, gamma aminobutyric
acid (GABA)-A receptor modulators, glutaminyl cyclase inhibitors, and peroxisome proliferator-activated receptor (PPAR) modulators. They
also discussed some structure-activity relationships between cholinesterase and β/γ-secretase (BACE) enzymes and these compounds, while their efficacy through Tau-protein aggregation and NFT. In the paper, H3 antagonism and (GABA)-A receptor modulation have also been
mentioned as one of the mechanisms of action for benzimidazole derivatives towards AD. Glutaminyl cyclase inhibition and PPAR (peroxisome
proliferator-activated receptors) modulation were other mechanisms proposed by the authors for the efficacy of benzimidazoles in AD.
In conclusion, the authors underlined that the molecules with a benzimidazole ring could be a new target for drug design against AD .
The paper by Marco Bonesi et al. gives an extensive overview of inhibitors of tyrosinase (TYR), which are responsible for enzymatic
browning in fruits and fungi as well as hyperpigmentation and melanoma, from herbal sources including such plant families as Anacardiaceae,
Araceae, Arecaceae, Asteraceae, Cannabaceae, Celastraceae, Convolvulaceae, Ephedraceae, Euphorbiaceae, Fabaceae, Lamiaceae,
Orchidaceae, Solanaceae, etc. Besides, active tyrosinase-inhibiting natural molecules, i.e. liquiritin, pinocembrin, eriodictyol, norartocarpetin,
and some ginsenosides, (-)-7,8-dihydroxycalamenal, etc. have been also discussed in this text. They also mentioned why inhibition of TYR
for in vitro and in vivo anti-melanogenesis particularly by plant extracts and plant-originated molecules is necessary. In this review, polyphenols,
particularly flavonoids (e.g. liquiritin, pinocembrin, norartocarpetin, resveratrol), some ginsenosides from Panax ginseng, several phenolic
acids such as benzoic acid and orcinol, iridoid glycosides (e.g. iridoid glycosides melittoside, 5-allosyloxy-aucubin), and sesamol, along
with several terpenoids including (-)-7,8-dihydroxycalamenal come into prominence. The authors concluded that the discovery of novel TYR
inhibitors from plants is a highly attractive option, whereas toxicity studies for short- and long-term effects, as well as pharmacokinetic and
pharmacodynamic studies on these inhibitory compounds, are still needed .
In conclusion, in the existing special issue of Current Medicinal Chemistry, 6 review articles from eminent scientists highlighting important
enzyme inhibitors related to critical diseases of CNS will be published. The special issue covers the most recent concept of conventional
and/or natural inhibitors of matrix metalloproteinases (MMPs), cyclooxygenase-2 (COX-2) inhibitors, lactate dehydrogenase (LDH) inhibitors,
and aporphines as attractive target molecules for Alzheimer’s disease (AD), and benzimidazole-derived compounds as cholinesterase
(ChE) inhibitors and preventers of β-amyloid plaques and neurofibrillary tangles (NFT) towards AD, along with natural tyrosinase (TYR)
inhibitors as active anti-melanogenic agents as introduced above, which will shift researchers’ attention to the importance of enzyme inhibition
as a popular target for treatment of many diseases once more.
I am grateful to Prof. Atta-ur-Rahman, the Editor of Current Medicinal Chemistry, who devoted this special issue to me. I would also like
to take this opportunity to acknowledge all the authors for their valuable contributions.
Tumor immunotherapy has entered a phase of rapid development, based on the understanding that the immune
system is the best tool humans have for fighting cancer by recognizing and eliminating malignant cells.Treatment
with engineered CAR T cells, checkpoint antagonists including anti-cytotoxic T lymphocyte antigen-4 (anti–CTLA-
4), anti-programmed death-receptor 1 (anti–PD-1), and anti-PD ligand-1 (anti–PD-L1), has induced striking responses
in subsets of patients with a range of solid tumors. With the FDA approval of sipuleucel-T, ipilimumab
(anti–CTLA-4; Bristol-Myers Squibb), and the two anti–PD-1 antibodies, pembrolizumab (formerly MK-3475 or
lambrolizumab; Merck) and nivolumab (Bristol-Myers Squibb), immunotherapy has become a mainstream treatment
option for some cancers. Such clinical advances also promote massive interest in the search for
novel immunotherapy targets, and to understand the mechanism of action of current drugs.Despite the new treatment
having shown unprecedented rates of durable clinical responses, with an activity range from 10% to 45% in
the context of unselected populations affected by advanced solid tumors,many other patients with solid cancer resistant
to immunotherapy such as colon, ovary, and pancreatic cancer have yet to benefit from the innovative therapeutic
approaches. Further advances in the effectiveness of cancer immunotherapies will require targeting antitumor
immune response at multiple levels, which may be accomplished through combination approaches involving the use
of various therapeutic agents to modulate sensitivity to immunotherapy.
The review by Zhao and Zhang  provides an extensive literature survey of recent advances in the understanding
of how HDAC inhibitors alter immune process and discussed their effects on various cytokines. The authors
also review the challenges in optimizing the use of these inhibitors as immune modulators in cancer treatment, which
may be helpful for designing tumor immunotherapy trials involving HDAC inhibitors.In their overview of basic principles
of immune checkpoint inhibitors in both antibody and small-molecule forms. Bin Li et al.  discuss potential
mechanisms of resistance, which may shed light on further investigation to achieve higher clinical efficacy for immune
check point inhibitors.
In the next article, Zhou et al.  summarize recent progress on targeting CXCL12/CXCR4 axis because of its
critical roles in tumor initiation and progression by activating multiple signaling pathways, as well as regulating
cancer stem cells. They review the potential utility of targeting CXCL12/CXCR4 axis in combination of immunotherapy
and/or chemotherapy based on up-to-date literature and ongoing research progress. From a unique perspective
of natural herbal products, Patanaponpibul and Chen  review possible immune modulations of various herbal
medicines and extracts. The review also provides a useful table listing the origin of species, key chemical components,
and clinical studies of these herbal medicines and edible mushrooms.
In a systematic review of efficacy and safety of adoptive immunotherapy for B-cell malignancies using CD19-
targeted chimeric antigen receptor T-cells, Hao et al.  perform a meta-analysis to evaluate the efficacy and side
effects of CAR-T on relapsedB-cell malignancies, including leukemia and lymphoma. The review concludes that
CD19-targeted CAR-T is an effective modality in treating refractory B-cell malignancies including acute and
chronic lymphatic leukemia, Hodjkin’s and non-Hodjkin’s lymphoma.
In the present special issue for cancer immunotherapy and immunomodulation, we highlight the current representative
progress and encouraging developments in cancer immunotherapy and immunomodulation, with an aim
to discuss the challenges and to provide future perspectives on how to exploit a variety of new immunotherapeutic
approaches for the treatment of all kind of tumor patients. Future strategies will continue focusing on investigating
the complex interplay between targeted agents and immunotherapy and optimizing parameters, exploring different
clinical settings and combinations of immunotherapy and chemo or radiotherapy to boost immune response and improve
patients outcomes, as well as developing the next generation of predictive biomarkers for immunotherapy.
With the prolongation in life expectancy, a continuously-ageing population is more prone to developing
chronic diseases, mainly cancer, cardiovascular, neurologic and inflammatory diseases. The prevalence of
such conditions is always increasing, and there is an unmet need for life-saving treatments. Basic and
clinical research are upfront in the quest for novel therapeutic strategies to fight such diseases. A growing
number of therapeutic targets are being studied for the treatment of chronic diseases. In this mini-thematic
issue, we aim at updating the readers of CMC with major advancements in therapeutic strategies for the
treatment of chronic diseases.
Metalloenzymes are key enzymes involved in a number of crucial physiological processes. Thus, the dysregulation
of metalloenzymes activity is a widespread and pivotal event associated with the onset of the most common
diseases of our age, including cancer, rheumatoid arthritis, atherosclerosis, nephritis, neurodegenerative diseases
and dry eyes syndrome.
In recent years, research on the life sciences has considerably attracted scientists to investigate metalloenzymes
and their modulators to meet the challenges of improving human health by discovering new therapeutic targets. In
this regard, the fine-tuning of new technologies has allowed the scientific community to better define the structure
of the catalytic sites of some metalloenzymes and the role played by the metal. Relying on this information, high
affinity inhibitors/ligands, able to modulate the activity of these enzymes, have been successfully identified.
Due to the key role of these enzymes in the pathophysiology and pathogenesis of a variety of human disorders, a
special issue entitled: Metalloenzymes as therapeutic targets is proposed. Here an interdisciplinary group of scientists
(including chemists, biochemists, biologists, pharmacologist, crystallographers, pharmacists and clinicians),
which are widely recognized as experts in their research field, have presented, in ten comprehensive review papers,
a detailed overview about the most relevant and recent advancements in this field.
F. Carta & C. Supuran et al., reported a detailed overview on the most effective modulators of Carbonic Anhydrases
(CAs) Metalloenzymes. This review paper provides valuable insights on the key interactions involved in
CAs inhibition/activation and the mechanistic details have been highlighted. A clear and updated picture of the
structure-activity relationships among the most prominent modulators is provided.
M. Ciubotaru et al. , deal with the issue related to high level of mutagenesis associated to HIV enzymes and
the implication in the discovery of efficient HIV inhibitors. An overview about HIV-integrase structure and functional
activity and on the most representative inhibitors is reported. This brings the reader to an easier understanding
of the relevance of the ‘Multiple microdomain targeted docking’ as emerging and efficient strategy in HIV integrase
The contribution of P. Colinas et al. , is focused on a peculiar and less explored cohort of CAs inhibitors. In
particular, they described the influence of the conjugated C-glycosides as hydrophilic ‘tail’ on selected CAs inhibitors,
on the inhibition selectivity and binding affinity.
C. Luchinat & M. Fragai et al. , reported a comprehensive overview on the most relevant and recent structural
and mechanistic insights on Matrix metalloproteinases (MMPs). Special focus is dedicated on collagenolysis and
elastolysis where structural information at the atomic details is described. Moreover, the lastest progress on the development
of MMPs inhibitors has been reported.
The contribution of R. Honkanen et al. , is focused on PPP-family phosphatases (PPPase) providing in-depth
insights on the catalytic mechanisms based on relevant biochemical and structural studies. This review starts with a
detailed description of diverse PPPase types, moving to the architecture of the phosphatase domain, to the catalytic
mechanism. Many PPP-family phosphatases retain a high degree of similarity and make difficult the identification
of selective inhibitors. A picture on the structural diversity of phosphatases inhibitors is reported.
The aim of the review paper of E. Nuti et al. , is to give a systematic overview on the most recent advancements
on ADAMs and in particular, on the biological outcomes of the related sheddase activity. Special focus is
dedicated to ADAM8, ADAM10 and ADAM17 and on the tuning of their enzymatic activity by using synthetic inhibitors.
R. Žalubovskis & J.-Y. Winum  contributed a detailed review on inhibitors of four clinically relevant bacterial
metalloenzymes, namely peptide deformylase (PDF), metallo-β-lactamase (MBL), methionine aminopeptidase
(MetAP) and UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC). The review gives an overview on inhibitors-enzyme interaction mechanisms as well as development of novel inhibitors as potent anti-bacterial agents. The review
includes also details on clinical development of most successful examples as novel antibiotics.
Georgiadis D. and Stratikos E. et al.  review the latest developments in the discovery of inhibitors of two enzymes,
ERAP1 and ERAP2 which are emerging tractable targets for the regulation of immune responses, with possible
applications in the treatment for a broad spectrum of diseases ranging from cancer to inflammatory autoimmune
disease. The potential and limitations of these inhibitors for clinical applications is also discussed.
The latest findings on the structure-activity relationship of the heme domain of the soluble guanylate cyclase and
its bacterial homologues is reviewed by S. Topouzis et al.  An overview of the structural properties of these domains
is provided in a thorough and comprehensive way. Furthermore, it is given a detailed review of the chemical
and structural properties of the "activators" and "stimulators of the sGC as well as their pharmacological profile.
Bertrand, P.’ et al.  review paper deals with the topic related to post-translational modifications (PTMs) and,
in particular, it is focused on metalloenzymes that regulate these crucial processes. A detailed and comprehensive
presentation of zinc-dependent histone deacetylases (HDACs), the iron-dependent lysine demethylases of the Jumonji
family (JMJor KDM), and, for DNA, the iron-dependent ten-eleven-translocation enzymes (TET) responsible
for the oxidation of methylcytosine prior to the demethylation of DNA is reported. Structural and catalytic details,
together with a report on the pathologies involving each of these enzymes, and an update on the most relevant
modulators of the enzymatic activity give a clear picture of the state of the art in this relevant research field.
Lignocellulosic biomass, such as wood, grasses, and agricultural residues, is a natural composite of cellulose,
hemicelluloses, lignin and extractives/natural compounds, and has been recognized as the most abundant renewable
resource. Lignocellulosic biomass is one of the most ancient materials that have been industrially utilized and such
practices are continued in the modern society. Lignocellulosics are also rich sources for natural ingredients that are
essential for the traditional medicine, and have been playing an increasingly important role in medicine/drug development.
These subject matters, along with their chemical and pharmacological challenges are still receiving much
attention in the research community. The present special issue describes a series of the latest exciting research in the
field of medicinal application from lignocellulosic biomass, which covers 1) the development of extraction, separation,
purification, activity evaluation processes; 2) structure identification and modification of extractives, cellulose,
hemicellulose and lignin to be used for medicine/drug applications; 3) designing and construction of novel drug deliveries
based on biobased materials, among others. All these contributions, which take into account the medical
applications of the above topics, are summarized as follows.
In the paper by Dai and Si , an account of the major new findings on the cellulose-based nano-drug delivery
systems (nano-DDS) is given. Although cellulose has its own advantages, the structure of pure cellulose has some
inherent drawbacks. Herein, various types of cellulose-based nano-DDS employed for the functionalization, pharmacodynamic
actions and applications have been covered, including prodrugs, prodrug nanoparticles (NPs), solid
NPs, amphiphilic NPs, and polyelectrolyte complex NPs. These interesting research works put forward many
strategies for overcoming the free drug molecule shortcomings like poor solubility, suboptimal pharmacokinetics or
excess toxicity. Among all the methods described in this review, cellulose-based amphiphilic NPs (including cellulose-
lipophilic drug NPs) are most frequently used for constructing cellulose-based nano-DDS. However, the studies
on cellulose-based nano-DDS are not without problems, such as the lack of thorough physicochemical characterization
and profound understanding of interactions of the nano-DDS with cells in vitro and in vivo, optimization
of process parameters and scale up from the laboratory to production level.
Along this line, in the paper by Liu and co-workers , the role of hemicellulose in medical and pharmaceutical
application is addressed. In this contribution, the focus is on the introduction of isolated hemicellulose from
plant biomass, degraded hemicellulose, hemicellulose derivatives and hemicellulose-based materials. The effects
are depicted on the immune regulation and anti-microbial of nature hemicellulose including xylan, mannan, xyloglucan
and β-glucan. The hemicellulose degraded products such as xylo-oligosaccharides, xylitol, xylose, arabinose,
mannose and manno-oligosaccharides have some excellent properties for improving the body functions. The modifications
of hemicellulose containing esterification and etherification can broaden the medical application in anticoagulant,
scaffold materials and anti-tumor. They also present the advantages of hemicellulose-based hydrogels and
hemicellulose-macromolecule composites materials on drug delivery and wound dressings.
In the contribution by Zhang et al. , lignocellulosic biomass materials and their chemical constituents are
highlighted as the potential alternatives for the applications in biomedical. In this context, the pretreatment methods
for extracting cellulose, hemicellulose and lignin from lignocellulosic biomass by means of milling, irradiation, microwave,
steam explosion, ammonia fiber explosion, supercritical CO2, alkaline hydrolysis, liquid hot-water pretreatment,
oxidation, dilute- and concentrated- acid hydrolyses and biological pretreatments, as well as their biological
applications in the form of hydrogel and membranes, such as drug delivery, biosensor, tissue engineering
etc. are summarized. As natural, abundant and renewable resources, the materials derived from lignocellulosic biomass
have great potential to be explored for biological applications. In particular, cellulose, as the most abundant
natural polymer on earth, is given special focus on the recent development of cellulose-derivatives in drug delivery systems. The authors review the different forms of polymeric systems based on cellulose for drug delivery, such as
hydrogels, membranes, microcapsules and nanoparticles.
The review by Zhang and Too  discusses the potential of using modern biotechnology, especially tools in
genomics, metabolic engineering and synthetic biology, to valorize lignocellulose to produce high value pharmaceuticals.
In the past decades, biofuels have been the research hotspot in using lignocellulosic waste which contributes
a substantial proportion of the agro-industrial biomass. In the review, they discuss the cutting-edge advances in
genomic analysis of natural lignocellulose-degrading organisms (for example, fungi and cellulolytic bacteria) and
how these studies inspire the development of next generation of carbohydrate active enzymes (CAZymes) and lignin-
degrading enzymes (FOLymes). The authors subsequently review the most frontier studies in metabolic engineering
of industrial workhorse’ organisms (Escherichia coli and Saccharomyces cerevisiae) for the biosynthesis of
natural products. Coupling the forefront genomic study with achievements in metabolic engineering and synthetic
biology, the authors project the future directions of developing consolidated bioprocess to manipulate either single
microorganism or microbial consortium for the production of drug compounds directly from lignocellulose.
The contribution by Sun et al.  takes consideration the applications of cellulose-based materials in sustained
drug delivery systems. As a natural polymer, cellulose has unique optical, mechanical, and rheological properties
and is easy to be chemically reconfigured. The typical modifications of cellulose are esterification and etherification
at its hydroxyl groups, and the oxidation of cellulose chain/surface groups, which will impart hydrophilic and hydrophobic
properties to suit for unique applications. Micro- and nano-cellulose, produced via mechanical, chemical,
enzymatic treatments, and/or their combinations, possess unique properties. When used in drug delivery system,
cellulose and its derivatives can modify the solubility/gelling behavior of drugs, resulting in different mechanisms
for controlling the release profiles of drugs. The specific applications of cellulose and its derivatives, both the conventional
and innovative ones, in the drug delivery area were critically reviewed, aiming at exploring their potential
applicability in the novel formulation of pharmaceutical dosage forms.
In the review by Khan and co-authors , the suitability and future of chitosan in drug delivery are highlighted
with special attention to drug loading and release from chitosan based hydrogels. This work demonstrates
that extensive studies on the favorable non-toxicity, biocompatibility, biodegradability, solubility and molecular
weight variation have made this polymer an attractive candidate for developing novel drug delivery systems including
various advanced therapeutic applications such as gene delivery, DNA based drugs, organ specific drug carrier,
cancer drug carrier, etc.
drugs, antimicrobial drugs, antivirus drugs and others, have been saving thousands of people’s lives all over
the world every year. However, several limitations, such as bio-stability, drug resistance, limited blood-brain barrier
transport and other factors, have substantially hindered the in vivo efficacy of drugs. In order to bring together more
researchers from various fields to solve these problems through multidisciplinary approaches, we launch a special
issue in this renowned journal, in which we summarize recent advances in strategies and tools for efficient drug discovery
Aurora A (AurA) kinase is one of important mitotic proteins playing important roles in many cellular functions.
Although there are several inhibitor candidates at different stages of clinical trials, these kinds of inhibitors targeting
ATP binding sites often suffer from selectivity problems, thus causing undesirable off-target effects. To solve the
selectivity problems linked to ATP binding site inhibitors and increase the drug efficacy, Panicker et al.  summarize
developments of small molecule inhibitors of AurA targeting non-ATP binding sites as well as their prospect
on future therapeutics and tools for more efficient drug discovery.
Influenza virus infection causes the death of numerous people every year all over the world. Due to limited efficacy
of current influenza vaccines and drug resistance of current small molecule antiviral drugs, it is imperative to
develop more efficient antiviral drugs with a new mechanism of action. Therefore, Zhang et al.  in this review
highlight recent advances on drug discovery and assay developments targeting a new biomarker named influenza
virus polymerase complex, and also envision their therapeutic potential.
Although Polyethylenimine (PEI) has been widely used as a non-viral gene delivery vector for oligonucleotides
delivery, its clinical applications and delivery efficiency were hindered by many factors including high cationic
charge, low cell recognition and nonspecific interactions with proteins and non-target cells in the biological fluids,
thus leading to lower efficiency for oligonucleotides delivery. To conquer these limitations, Hao et al.  summarize
different modifications of PEI with optimized parameters of PEI or PEI-based formutations for efficient oligonucleotides
As we know, protein and peptide drugs can be easily degraded in vivo, thus leading to lower drug efficacy or
shorter half-life. To achieve better drug efficacy and longer drug sustained-release, new sustained-release systems
should be applied. Yang et al.  summarize recent materials and methods as well as existing opportunities and
challenges to fabricate microspheres for better protein delivery.
Due to more and more threats of antibiotic resistance, it is urgent and imperative to develop new strategies to
combat bacterial infections. Cai et al.  review the relatively new pathways that are related to staphylococcal virulence
and introduce high-throughput screening strategies to identify novel anti-virulence inhibitors together with
their advantages and disadvantages. These are different from traditional strategies and methods in killing bacteria or
inhibiting their growth.
Compared to normal peptides with limitation in stability and short half-life in vivo, "γ-AApeptides" showed
many advantages in drug discovery. In this review by Nimmagadda et al. , they review different examples of γ-
AApeptides with great potential in biomedical applications, such as application as potential drug carriers due to
good cell permeability, as anti-HIV agents, anti-bacterial agents, anti-cancer agents and also anti-Alzheimer’s Disease
With scientific and technological advancements, peptide therapeutics have become more and more important. To
help scientists to develop even better peptide drugs, this review by Parthasarathy et al.  summarize key methodologies
and strategies applied in the development of therapeutic peptide drugs focusing on selected examples of the
most recent advances in the relevant fields.
Although various types of self-assembled micelles have been used to improve diagnostic and therapeutic efficacy
of drugs depending on their types, they sometimes suffer from the limitation of low in vivo bio-stability. To
conquer this kind of limitation, Fan et al.  summarize different types of chemical reactions as crosslinking strategies
for enhanced drug delivery abilities of micelles, and also review recent advances on crosslinking polymeric
nanoparticles for cancer therapy.
It is of great importance to reduce drug toxicity to normal cells while showing good drug efficacy on cancer
cells. Among various types of strategies, stimuli-responsive carriers have become more attractive. To better understand
how to design a good stimuli-responsive carrier for controlled intracellular drug release, Sheng et al. 
summarize recent advances on the development of various types of stimuli-responsive carriers for spatially and
temporally controlled release of different drugs responsive to different intracellular stimuli, and emphasize optimization
of stimuli-responsive materials in terms of molecular design and formulation to improve the clinical drug
efficacy via multi-functionality and multiple stimuli-responsiveness.
By compiling these different research summaries above, this special issue focuses on introducing new strategies
or methods for efficient identification of better therapeutic molecules (e.g. high-throughput screening), or using
novel materials, such as nanomaterials, polymers, peptides or other biomolecules, to improve drug efficacy or drug
resistance as well as reduce side effects.
It is hoped that this special issue will provide readers from the field of medicinal chemistry with valuable information
and useful guidelines for innovative drug discovery and improved drug delivery for better drug efficacy.
A biomarker is a measurable characteristic that indicates normal or pathogenic biological processes, or pharmacological
responses to therapeutic intervention. There is a strong clinical need to identify novel biomarkers for diagnosis,
prognosis, and treatment of human diseases. This Hot topic thematic issue includes articles addressing a
multi-disciplinary approach to the unveiling of several aspects of biomarker development against human pathogeneses.
An effort is being made to bring together researchers from different countries and to merge complementary
approaches, which range from biophysics and biochemistry to microbiology and animal models. A number of key
molecules involved in various human pathogens are discussed in this issue as an opportunity to develop molecular
entities of diagnostic and therapeutic interest. In particular, this issue describes potential diagnostic tools for cancer
disease as well as for bacterial diseases due to Streptococci, Mycobacteria, Salmonella, Pseudomonas. Described
tools include not only proteins, but also lipids and nanomaterials.
Tumor markers are used to help detect, diagnose, and monitor the evolution of some types of cancer. Elucidating
the mechanisms of recurrence of embryonic signaling pathways in tumorigenesis has led to the discovery of oncofetal
players, which have physiological roles during normal development but result aberrantly re-activated in tumors.
In this context, we describe the roles of the two recognized as onco-developmental factors, Nodal and Cripto-
1, which are absent in normal tissues but are overexpressed in several solid tumors. Data demonstrate the clear connection
between Nodal and Cripto-1 presence and their multiple oncogenic activities across different tumors. Therefore,
Nodal and Cripto-1 represent two innovative and effective biomarkers for developing potential theranostic
anti-tumor agents to overcome both pharmacological resistance and tumor relapse .
Biomarkers are becoming increasingly important tools also in infectious diseases, to distinguish bacterial from
nonbacterial infection, to monitor the response to therapy, and to predict therapy outcomes. The cell walls of bacteria
bear an arsenal of molecules that elicit host immune responses and may act as biomarkers. Group A Streptococcus
(GAS) infections are responsible for significant morbidity and mortality worldwide. At the portal of entry, GAS
binds to the newly deposited extracellular matrix, which is rich in cellular fibronectin isoforms with extra domain A
via a surface adhesin, the streptococcal collagen-like protein 1 (Scl1) [2-4]. Similarly, Mycobacterium tuberculosis,
the etiological agent of Tuberculosis (TB), binds to epithelial cells using the HBHA adhesion [5, 6]. In both cases,
these adhesins have been shown to be interesting diagnostic tools. Notably, HBHA was shown to distinguish between
an active and a latent state, a reversible low metabolism state of the Mycobacterium, rendering itself extremely
resistant to host defense and drug treatment due to modifications of the mycobacterial cell wall [7, 8]. Similarly,
other tools to diagnose TB at the latent and active stages and to recognize prospective TB diagnostic methods
have been based on lipids and nanomaterials [9,10].
In Gram-negative bacteria, including Salmonella and Pseudomonas aeruginosa, bacterial life activities and interactions
with external environments relief on outer membrane proteins (OMPs) and OM-associated proteins .
The role of key OMPs involved in Salmonella serum and antibiotics resistance, is described here as an opportunity
to develop biomarkers against multi-drug resistant bacteria. P. aeruginosa is of great interest as a model of biofilmforming
organism and research in this area has contributed to understand how biofilms are formed and how they can
act as biomarkers of disease .
Overall, this issue provides complementary views, by experts in the field, of various scenarios of biomarker
identification and validation. It is yearned that knowledge of molecular events involved in biomarker recognition
will significantly impact the development of diagnostic and therapeutical agents.
Atherosclerosis is driven by lipid accumulation in the arterial wall that leads to narrowing the vessel lumen and
increasing risk of thrombus formation. Deposition of lipids, mostly cholesteryl esters, in the arterial wall layer
called intima, is one of the earliest manifestations of the disease. Intracellular accumulation of lipids takes place in
so called foam cells that have their cytoplasm filled with lipid droplets that are visible microscopically. Circulating
low-density lipoprotein (LDL) particles serve as the primary source of lipids. Numerous attempts were made to establish
a clear link between circulating LDL levels and atherosclerosis formation. In the experiments conducted on
cultured cells, if was demonstrated that native LDL failed to induce intracellular lipid accumulation. At the same
time, LDL chemically modified in vitro (acetylated, malondialdehyde-treated, oxidized with ions of transient metals,
etc.) induced lipid deposition in cultured cells, i.e., was atherogenic. It was therefore suggested that not native,
but modified LDL contributes to lipid deposition leading to atherosclerosis. However, the attempts to find modified
LDL in circulation were unsuccessful. That resulted in a paradox that for a long time remained unsolved: (i) LDL is
the source of lipids accumulated in the vascular wall; (ii) native LDL does not induce intracellular lipid accumulation
(foam cell formation); and (iii) in vitro modified forms of LDL are atherogenic but cannot be found in circulation.
To solve this paradox, several research groups began the search for atherogenic modified LDL present in circulation
of atherosclerosis patients.
LDL can exist in several forms with different physical-chemical properties. Small dense (sd) LDL and electronegative
LDL (LDL(-)) are characterized by increased density, decreased size and acquired electric charge. Oxidized
LDL (oxLDL) is the product of chemical modification of particles. All these forms of LDL are regarded as
pro-atheroginic, the level of high-density lipoprotein (HDL) may have an important protective role serving as cholesterol
transporter from the arterial wall to the liver, where it is further metabolized. Numerous studies have demonstrated
that low plasma levels of HDL are associated with increased risk of cardiovascular disease. Moreover,
experiments on animal models have shown that HDL inhibits lipid oxidation and have beneficial effects improving
endothelial function, alleviating inflammation and protecting cells from apoptosis. It was suggested that during local
or systemic inflammation, HDL can be converted to a dysfunctional form with decreased anti- atherogenic effect.
Dysfunctional HDL can be formed as a result of loss of anti-inflammatory and anti-oxidant proteins possibly combined
with up-regulation of pro-inflammatory proteins.
In this Thematic issue, we provide an overview of the current knowledge on the roles of dysfunctional or modified
HDL and LDL in atherosclerosis pathogenesis. This knowledge may provide an important contribution to the
development of novel therapeutical methods to combat atherosclerosis. The first review by Sobenin and Orekhov
 addresses the mechanistic role of LDL and HDL in atherogenesis. The authors question the widely accepted hypothesis
of the central role of oxLDL in atherogenesis while proposing an alternative concept of multiple modification
of LDL particles. The authors also address the important question of whether LDL and HDL are biomarkers,
effectors, or both in cardiovascular disease. The answer to this question would allow setting priorities for using
lipoprotein particles as therapeutic targets or diagnostic tools.
The contribution by Arnao and Tuttolomondo  takes into consideration the measures of functional features of
lipoproteins, instead of conventional routine serum evaluation of lipoproteins, that could offer a valid contribution
in experimental studies as in clinical practice to stratify atherosclerotic risk. Along this line, in the review by Chroni
and Kardassis , it is also claimed that HDL functionality is more important than HDL-cholesterol (HDL-C) levels
for cardiovascular risk prediction. Thus, detailed characterization of changes in HDL composition and functions in
various pathogenic conditions is critically important in order to identify new biomarkers for diagnosis, prognosis
and therapy monitoring of cardiovascular diseases. The authors provide an overview of how HDL composition, size
and functionality are affected in patients with monogenic disorders of HDL metabolism due to mutations in the
genes that participate in HDL biogenesis and remodeling. The authors also review the findings from various mouse models with genetic disturbances in the HDL biogenesis pathway that have been generated for validation of the data
obtained from humans and discuss how these models could be utilized for the evaluation of novel therapeutic
strategies such as the use of adenovirus-mediated gene transfer technology that aims to correct HDL abnormalities.
Itabe and co-workers  discuss the significance of circulating oxLDL in various systemic diseases, including acute
myocardial infarction and diabetes mellitus. Several different enzyme- linked immunosorbent assay procedures
measuring oxLDL were utilized. Accumulating evidence reveals changes in oxLDL levels under certain pathological
conditions. Since oxLDL concentration tends to correlate with LDL-cholesterol, the ratio of oxLDL and LDL
rather than oxLDL concentration alone should be considered. In addition to circulating plasma, LDL and oxLDL are
found in gingival crevicular fluid (GCF), where the ratio of oxLDL to LDL in GCF is much higher than in plasma.
LDL and oxLDL levels in GCF are increased in diabetic and periodontal patients, suggesting that GCF might be
useful for examining systemic conditions. GCF oxLDL increased when the teeth were affected by periodontitis. It is
likely that oxLDL levels in plasma and GCF could reflect oxidative stress. The paper by Schnitzler and co-authors
 describes LDL modifications that convey inflammatory and pro-atherogenic effects that affect the endothelial
function and promote foam cell formation. Apart from the central role in lipid transport and metabolism, LDL can
have direct effects on the composition of circulating monocytes promoting immune cells migration and accumulation
in the subendothelial space. Current evidence shows that other lipoprotein particles, including triglyceride(TG)-
rich remnants and lipoprotein (a) [Lp(a)] can also influence atherogenesis. For instance, Lp(a) can promote peripheral
monocyte activation followed by increased migration of the immune cells through the endothelium. Cholesterol
contained in TG-rich remnants can affect endothelial dysfunction and monocyte activity.
The paper by Ossoli et al.  presents an updated review of pathologic mechanisms, especially those associated
with inflammatory signaling, involved in alterations of HDL protein and lipid contents that lead to the formation of
dysfunctional HDL; The authors discuss the currently available and investigational drugs that are aimed at normalizing
the lipid metabolism and alleviate HDL deficiency and dysfunction.
The aim of the paper by Miyazaki and Miyazaki  is to contribute to the current debate on the insufficient protein
catabolism that affects cholesterol handling by macrophages. Impaired autophagy and clearance of dying cells
promotes cholesterol accumulation in the cells which leads to the formation of the most dangerous vulnerable
plaques associated with thrombotic events. Proteasome plays a central role in the degradation of ATP-binding cassette
transporters affecting cholesterol efflux from macrophages. Next, the authors discuss calpains, overactivation
of which can contribute to the excessive degradation of functional proteins that promotes receptor-mediated oxLDL
uptake and reduces cholesterol efflux. Calpain-6 is non-proteolytic calpain of macrophages that potentiates pinocytosis,
in particular, the uptake of native LDL, and attenuates efferocytic clearance of dying cells. The authors discuss
how the defective protein catabolism affects macrophage cholesterol handling and atherogenesis.
As in the first reviews of this Special Issue [2, 3], the review by Pirillo and co-workers  states that focus
should be shifted from HDL-C levels toward HDL functional properties. The authors note that dysfunctional HDL
extracted from the plasma of atherosclerotic patients has both impaired atheroprotective functions and marked proatherogenic
properties. Dysfunctional HDL can be defected even in the presence of normal or elevated HDC-C levels.
Therefore, drugs that allow restoring of HDL functions may have a more potent role in treatment of cardiovascular
diseases than therapies that simply increase HDL-C level. The authors discuss the mechanisms of dysfunctional
HDL formation and their role in atherogenesis and beyond.
The paper by Rivas-Urbina with co-authors  is focused on LDL(-), which is known to have certain proatherogenic
properties. Electronegative LDL is a heterogeneous LDL fraction that can be isolated on the basis of the
negative electric change by physical methods. It probably has different biochemical origins, but in general is known
to be atherogenic. However, in some cases, LDL(-) can have anti-atherogenic properties. Several molecular modifications
leading to LDL(-) formation have been described, but their relationship with the pathology development
remains to be studied in detail. The authors discuss the recent advances on the studies focusing on LDL(-) biology
and relationship with cardiovascular risk. They highlight the importance of minor lipoproteins associated with
LDL(-) that may play a crucial role in modified LDL properties.
The paper by Lopes-Virella and Virella  is dedicated to the antigen-antibody complexes (immune complexes,
IC). IC that are recognized primarily by copper oxLDL antibodies were isolated from patients with progressive
atherosclerosis measured by intima-media thickness (IMT) and increased coronary calcification scores. At the same time, patients who had ICs reacting with antibodies to the heavily oxidized malondialdehyde LDL prepared in
vitro (MDA-LDL) had increased risk of acute vascular events, in particular, myocardial infarction. As demonstrated
in in vitro studies, oxLDL IC induce both cell proliferation and mild to moderate macrophage apoptosis, while
MDA-LDL IC induce a more marked macrophage apoptosis but not cell proliferation. Moreover, MDA-LDL IC
induce the release of higher levels of matrix metalloproteinases and TNF than oxLDL IC. These factors play a
prominent role in apoptosis promoting thinning of the fibrous cap leading to the formation of vulnerable plaques
and therefore increasing the risk of acute cardiovascular events.
Kattoora and co-workers  consider the LOX-1, a transmembrane glycoprotein, as a receptor for oxLDL,
modified lipoproteins, activated platelets and advanced glycation end-products. LOX-1 is expressed on macrophages,
where it inhibits the immune cell migration. In atherosclerosis, this molecule plays a role in promoting foam
cell formation and vulnerable plaque formation by stimulating the generation of metalloproteinases. LOX-1 mediates
the effect of oxLDL on the endothelial cells, causing up-regulation of leukocyte adhesion molecules, activating
apoptosis, increasing the production of reactive oxygen species and causing endothelial dysfunction. This signaling
pathway stimulates vascular smooth muscular cells to proliferation, migration and collagen synthesis. LOX-1-
targeting drugs may therefore have a great potential for atherosclerosis treatment. Many naturally occurring compounds
have been shown to modulate LOX-1 expression and have an effect on atherosclerosis. Current efforts are
focused on identifying molecules that can bind to LOX-1 and inhibit its activation by oxLDL. Other approaches
include RNA interference techniques and monoclonal antibodies binding LOX-1.
Öörnia et al.  discuss the findings of recent observational and genetic studies that have discovered that
the TG-rich lipoproteins and their remnants are linked with cardiovascular disease risk. The authors describe the
potential mechanisms by which the TG-rich remnant lipoproteins can contribute to the development of atherosclerotic
lesions and highlight the differences in the atherogenicity between LDL and the remnant lipoproteins.
We hope that this Special Issue will be of interest to the readers and will contribute to the growing knowledge on
lipoprotein biology and its involvement in atherosclerosis pathogenesis.
Activatable theranostics are novel clinical solutions, combining diagnostics and therapeutics moieties, for early
diagnosis, monitoring, and prognosis of diseases. This thematic issue compiles 7 review articles including a series
of latest advances in the field of activatable theranostic platforms for different diseases such as cancer, diabetes,
neural diseases, and so on.
For cancer theranostics, G. Liu and coworkers  summarized recent research progresses related to green synthesized
nanoparticles for cancer theranostic applications, elucidating the current challenges and insight into the
future directions in these areas. W.-G. Zhu and coworkers  summarized the important roles of epigenetics, especially
histone modifications in cancer diagnostics and therapeutics, and also discussed the developmental implications
of activatable epigenetic targets in cancer theranostics. Y. Gao and coworkers  provided insights into the
strategy using enzyme instructed self-assembly in biological milieu for theranostics purpose. Meanwhile, D. Ling
and coworkers  summarized recent advances of stimuli-responsive organic-inorganic hybrid nanogels for activatable
For drug delivery and diagnosis, Z. Gu and coworkers  summarized recent advances of cysteine-rich proteinbased
biomedical materials and their applications in tumor-targeted drug delivery and diagnostics. K. Pu and coworkers
 reviewed recent progress of organic nanomaterials including near-infrared dyes and semiconducting
polymer nanoparticles in photoacoustic imaging-guided cancer phototherapy, and also addressed their challenges
and potential in clinical applications. T. Wang, P. Huang and coworkers  introduced the development of phototriggered
drug delivery systems in neuroscience research and their neuron-related applications including regulating
neural activities, treating neural diseases and inducing nerve regenerations.
By compiling these papers, we hope to enrich our readers and researchers with respect to activatable theranostics.
The ATP-binding cassette (ABC) transporters belong to a superfamily of export pumps. They are expressed in
many tissues at variable membrane domains, and recognize as substrates a wide spectrum of therapeutic agents.
Placed in strategic epithelia such as liver, intestine and kidneys, together with biotransformation systems and other
membrane transporters, they constitute an important regulator of drug absorption, pharmacokinetics and therapeutic
efficacy. ABC transporters also play a role in elimination of potentially toxic derivatives of endogenous compounds.
In this special issue, we provide updated information starting from basic concepts related to their mechanism
of function to strategies for manipulation of their activities with therapeutic purpose.
To begin this series, Arana and Altenberg introduce ABC transporters and describe their classification in subfamilies
according to common structures . They provide, in a comprehensive way, explanation for the mechanism
of transport. Reference about correlation between recently acquired structural information and function is also
made, including the molecular mechanisms involved, with particular emphasis in participation of nucleotidebinding
domains. Comparison of the structures of two important members of the ABC family, P-glycoprotein (P-gp,
MDR1) and Multidrug resistant-associated protein 1 (MRP1) provides important clues for our understanding of
The activity of ABC transporters is not static but rather subjected to a dynamic modulation through transcriptional,
post-transcriptional and post-translational regulations. Rigalli et al. compiled information about transporter
regulation by nuclear receptors, mainly involving transcriptional mechanisms . Updated information links receptors
activation (or inhibition) with modulation of ABC transporters and, this way, with a desired pharmacological
effect. Main receptors considered in this review are xenobiotic receptors, bile acid and lipid receptors and retinoid
Transport activity can be regulated also at post-translational level in an acute manner, as a consequence of
changes in transporter localization. An extensive description of this mechanism is presented by Roma et al. with
hepatic canalicular transporters being selected examples . These transporters are localized either in the plasma
membrane domain or in an endosomal, recycling compartment, and the balance between these localizations determines
the capability to express transport activity, ultimately conditioning bile formation and elimination of endoand
xenobiotics. The possible mechanisms explaining such regulation are also well described in the review.
Regulation of expression and activity of ABC transporters were also well characterized in extrahepatic tissues.
Villanueva et al. present an extensive description of function and regulation of ABC transporters in heart and small
intestine, as examples of extrahepatic tissues, in which ABC proteins play clearly different roles . In heart, they
are involved in tissue pathogenesis as well as in protecting this organ against toxic compounds and drug-induced
oxidative stress. In small intestine, they strongly influence absorption and pharmacokinetics of drugs incorporated
While a significant function of ABC transporters in polarized epithelia is related to the apical secretion of substrates
contributing to their elimination from the body, several family members are located in the basolateral membrane
and play a different role. In the review by Ghanem and Manautou, detailed information is provided on studies
examining the changes in expression and regulation of the basolateral hepatic transporter MPR3 by xenobiotics and
by different pathophysiological conditions . The authors emphasize the consequences of such changes in the
pharmacokinetic, pharmacodynamic and toxicity of different drugs of clinical use.
Development of multidrug resistance (MDR) leads to chemotherapy failure generally associated with overexpression
of ABC transporters such as P-gp, several members of the MRP subfamily, and breast cancer resistance
protein (BCRP). Ceballos et al. compiled information about transcriptional and post-transcriptional regulation of
ABC transporters and discussed their role in the development of MDR in cancer cells . They particularly focus on drug resistance exerted by ABC efflux transporters in hepatocellular carcinoma and colorectal carcinoma. The
authors also discuss aspects of the chemotherapy failure and future directions to overcome MDR.
Unlike physicians, veterinary practitioners deal with different animal species with crucial differences in anatomy,
physiology and metabolism, so that pharmacokinetics, clinical efficacy and adverse effects of drugs may also
be different. Moreover, the use of drugs in food-producing species constitutes a risk for humans due to the generation
of chemical residues in edible products. Virkel et al. review the information available on major ABC transporters
which affect the disposition of drugs used to treat livestock and domestic animals . Investigations reveal the
major relevance for P-gp, BCRP and different MRP members in both companion and livestock animals.
While studies on basic aspects of ABC transporters structure, expression and function are largely available, not
much can be found in the literature on targeting ABC transporters with therapeutic intention. MRPs have been
linked to several diseases and have been proposed as promising therapeutic targets, e.g. by using selective inhibitors.
To reduce the adverse effects of candidate inhibitors, it is necessary to revise the structure of the target proteins
and at the same time to particularly consider their physiological functions. In the review by Yaneff et al., both aspects
are thoroughly studied using MRP4 as example . The authors evaluate homology models together with
mutagenesis assays, and carefully scanned MRP4 structural characteristics and compared them with other MRP
family members. They postulate several candidate residues consistent with highly probable cAMP binding sites that
may serve as a basis for the future development of inhibitors of MRP4-mediated cAMP transport.
The constant improvement in technology and in the comprehension of molecular biology has allowed to conceive a series of
biological treatments of cancer and of many inflammatory and chronic degenerative diseases. These treatments are usually less
invasive than pharmacological ones and in many cases can be used in a concomitant way with the canonical treatments so that
it is now possible to draw up new guidelines for integrated treatments related to human chronic diseases. This special issue,
devoted to " New Insights into the Complexity of Cancer and of Inflammatory Diseases” certainly moves within this direction
and collects a series of reviews-articles which strictly reflects the recent advances. Many articles are focused on treatment or
prevention of cancer. One article by Nicolini A. et al.  describes breast cancer treatments with the use of an innovative and
more general biological or immunological approach while another by Antonelli et al.  regards the use of sunitinib in thyroid
cancer patients. This is quite interesting issue being a so called "target therapy" so far usually investigated in other types of cancers.
However its efficacy in thyroid cancer patients no more responsive to radio-iodine is currently under evaluation. The third
article by Cullen et al.  describes the role of some important biological substances used as integrative treatments of many
cancer diseases, whereas the fourth by Biava et al.  describes how it is possible to reprogram cancer cells to a healthy
phenotype. The model presented in that article is a quantum field theory model in which the factors taken during the stages of
cell differentiation are able to trigger symmetry breakdown processes during cancer development. The model is consistent with
the real situation and especially it applies to the reverting process of cancer cells to a healthy phenotype. It provides a possible
understanding of how we can achieve such a result and reprogram cancer cells. The fifth article by Klener et al.  is a review
about the biological treatments in hematologic malignancies, while the review-article by Pavelka et al.  about the inflammatory
and degenerative diseases regards the chronic low back pain and the most important pharmacological therapies in this disabling
In the seventh article by Pistello et al.  the role of virome in modulating inflammation in cancer and various degenerative
diseases is illustrated and strong evidences that anelloviruses are useful and practical molecular markers to monitor inflammatory
processes and immune system competence also is provided. The last review article by Anceschi et al.  represents an
updating about the biomarkers related to prostate cancer and describes the old and new biomarkers of this kinds of tumor.
Atrial fibrillation (AF) is a frequent cardiovascular entity (almost 33 million subjects worldwide suffering from
different forms of this entity) especially in developed countries  accompanied by poor quality of life and posing
significant morbidity and mortality which may explain the increasing amount of research on ion and cells mechanisms,
the identification of electric circuits and the introduction of novel pharmaceutical and invasive strategies.
Despite the advancements in diagnostic strategies, the recognition of the multiple wavelet hypothesis and rotors
as sources of AF, the introduction of invasive strategies targeting specifically the generation of AF and the introduction
of improve anticoagulant strategies we are far away from a treatment highly efficient since the best results for
example of AF ablation reach only 60-70% success rate .
Therefore, there are gaps in evidence such as the basic pathophysiologic mechanisms underlining ion channels
alterations, re-entry circuits and electrical remodeling, the identification of the patients best responsible to atrial fibrillation
ablation, the selection of the optimum anti-arrhythmic management in each case and risk categorization of
the patients concerning stroke risk, bleeding risk and recurrence of atrial fibrillation.
As the role of biomarker in the research relative to AF initiation and progression and in the management of clinical
AF episodes is limited we believe that further insights into the role of specific biomarkers can be proved usefully
in the understanding and management of this entity. In this thematic issue, we will discuss the role of biomarkers
in the pathophysiology of AF, in prognosis, in the risk stratification for stroke and bleeding and in treatment
strategies and in specific comorbidities associated with AF.
This special issue contains 13 review articles. The first 4 articles focus on the underlying pathophysiologic
mechanism of AF [3-6]. The following 4 reviews present the possible role of biomarkers under specific circumstances
[7-10]. Finally the prognostic role of biomarkers is presented in the last 5 articles [11-15]. All these issues
are supported by appropriate illustrations and tables.
The role of inflammation in several cardiovascular diseases has been revealed over 3 decades ago which continues
to focus interest since the modification of inflammatory cataract appeals as an attractive alternative therapeutic
approach. The association of inflammation with AF seems to be bidirectional (AF may initiate the inflammatory
cataract and a pro-inflammatory status precipitates episodes of AF). The purpose of the first article  is to examine
this association and present data how biomarkers such as C reactive protein, Interleukin-1 and tumor necrosis factor
are implicated in the genesis and perpetuation of AF.
Redox stress has been revealed as a significant factor affecting not only atherosclerosis progression and heart
failure but several comorbidities. Formation of superoxide, hydroxyl radicals and peroxynitrate may cause oxidative
modification of proteins and mitochondrial DNA damage, leading to cellular death and altered ion channels function.
Under these circumstances, electrical properties of myocardial cells are modified and oxidative stress is implicated
in the genesis of AF as it is presented in the second review of this issue .
The role of atrial fibrosis and remodeling has for long been recognized as a pathophysiologic mechanism of AF.
Dilaveris et al.  focus on the underlying mechanisms of extracellular remodeling and present useful data how
biomarkers can be used to monitor and evaluate the extent of remodeling and the prognostic yield of these biomarkers
in the treatment strategies.
The role of small non-coding RNAs (microRNAs) has been recently revealed. They can orchestrate many biologic
processes and organ functions. Their role in cardiovascular system focus is on the research interest in the setting
of AF specific MicroRNAs as presented by Briasoulis et al.  which can not only be used to further understand
pathophysiologic mechanisms but also to identify subjects prone to develop AF.
Atrial fibrillation is associated with several comorbidities. The specific issues raised when AF coexist with aortic
stenosis, heart failure, hypertension and metabolic syndrome which are examined in the following 4 review articles.
Toutouzas et al.  give insights in the interaction between AF and aortic valve stenosis and focus on the biomarkers
that can be used to determine the prognosis of arrhythmias in patients after transcatheter aortic valve implantation.
The close interrelationship between AF and heart failure is well established. In the following review , the
significant role of a set of biomarkers in the prognosis of HF and atrial fibrillation is presented and the article focuses
on the mechanistic links between raised natriuretic peptides and altered myocardial cell electrical properties
which may precipitate in the episodes of AF. The prevalence of AF is increased in patients with hypertension and
may further deteriorate patients’ functional status or may lead to clinical evident heart failure. Tsioufis et al.  present
the biomarkers involved in the atria electrical remodeling in patients with hypertension and they propose a
combination of multiple indices to effectively detect both AF and adverse characteristics of high risk patients with
hypertension. Metabolic syndrome is an entity that encompasses a cluster of derangements such as obesity, hypertension,
diabetes mellitus and dyslipidemia which may further deteriorate cardiac function and may adversely impact
atrial remodeling and electrophysiologic properties. Vlachopoulos et al.  provide the most recent data concerning
the link of these entities with the biomarkers associated with maladaptive changes in atrial remodeling.
Unfortunately, AF may cause significant complications in morbidity and mortality especially when it causes
stroke or hemorrhage. Several prognostic models are used the last years in cardiovascular patients. A series of biomarkers
are examined by Mazaris et al.  for their effort to support the clinician’s prognostication ability while
the additive prognostic value of biomarkers in determining the stroke risk is examined in a review article by Ioannou
et al. . In an interesting review, Sideris et al.  focus on the prognostic ability of biomarkers in the bleeding
risk and how they can be used to altertherapeutic decisions.
The last two review articles covered two interesting issues. Development of atrial fibrillation after cardiac surgery
may complicate post cardiac surgery period and may need specific treatment. Manfrini et al.  focus on the
biomarkers which can be used to determine prognosis and identify patients needing preventing strategies. Finally
Tsiachris et al.  examine how biomarkers can be used in atrial fibrillation ablation. Since results of atrial fibrillation
are modest achieving a success rate of 60-70%, the identification of best candidates for this invasive strategy
is of importance since it may change treatment decisions. The additive prognostic information obtained by the use
of specific biomarkers is examined in this review as well as the role of biomarkers in the monitoring of AF recurrence.
After Rosenberg’s discovery (in the early 1960s) of therapeutic potential of cis-diamminedichloroplatinum(II) (cisplatin),
we witnessed a great development of coordination chemistry. Many researchers worked on synthesis, structure
and cytotoxic effect of platinum(II) complexes with different ligands, but soon other metal ions and their complexes entered
the stage. Nowadays, they are also tested in several other ways as potential drugs in, e.g. neurodegenerative diseases,
as well as chemotherapeutic, antimicrobial, and antifungal agents. More specific areas of interest involve metaldrug
interaction and metalloproteins as drug targets. These aspects, together with an important role played by transition
metals, like iron(II)/(III), copper(II), or zinc(II), constitute a field of intense multidisciplinary studies. Seven reviews collected
in this special issue were intended to show results of the research mostly from the biological/medical point of view,
with less attention paid to the chemistry.
Chapter described by Kiss and co-authors  deals with the problems of speciation of metal complexes of medicinal
interest: The authors discuss several biologically active metal-ligand families and try to find relationship between solution
equilibria of the metal-ligand systems and the pharmaceutical properties of the complexes formed in the systems.
Due to various biotransformation reactions the original form of a bioactive molecule is very often differs from the physiologically
active form of the drug. For this reason the biospeciation of metal complexes with biological or medicinal activity
are discussed in the chapter in order to emphasize the importance of the distribution of metal ions in biological milieu.
The exact knowledge of the chemical species present in the different organs/compartments/fluids/cells may provide essential
information about the pharmacokinetic properties and the biological effect of the metal ion or the drug candidate
metal complex. The transport of essential and toxic metal ions in the blood serum is discussed first, which is followed by
the description of biodistribution of several important metal complexes with medicinal interest such as (i) anticancer, (ii)
insulin-enhancing and (iii) MRI contrast agents in biological fluids.
A chapter by Petanidis et al.  entitled ”Tumor cell chemoresistance is a major challenge in cancer therapeutics”
presents the molecular immune-related mechanism in the tumor microenvironment, leading to drug resistance. Whereas
metal-based drugs are potent anticancer agents, they are often effective against only few types of cancers and cause severe
side-effects Therefore new drugs with an improved spectrum of efficacy and lower general toxicity are needed.
Their development is stimulated by considerable efforts aimed at elucidation of the mechanisms of action, thus their bioactivity
can be optimized through structural modification. In that respect, knowledge on the molecular factors involved in
drug resistance and immune response may help to develop new anticancer strategies and new promising chemotherapies,
and to reduce the rate of relapse. The important part of this review was the investigation of strategies for reversing drug
resistance while concurrently optimization of the design of metal complexes bearing anti-tumor activity, is discussed in
an effort to identify and overcome underlying mechanisms of resistance to both standard chemotherapeutic agents and
targeted molecular therapies.
Hecel et al.  discussed the use of silver(I) complexes in medicine and pharmacy. Silver is a non-essential element,
although traces of silver salts can be found in various tissues. From a historical perspective, it has been that Ag(I) and its
complexes have been used by humans for thousands of years. At present, they are widely used in chemistry and industry,
and improper utilization of the silver containing products and wastes poses hazard to health and environment. In medicine,
pharmacy and cosmetology, the silver containing compounds are being used for important antibacterial and antifungal
properties. The chapter summarizes the latest findings on the bioinorganic chemistry of silver complexes and
nanoparticles. The coordination chemistry of silver is given a reasonable amount of attention, summarizing the most
common silver binding sites and giving examples of such binding motifs in biologically important proteins. The already
developed and future applications of this metal and its complexes in medicine, in particular as antibacterial and antifungal
agents and in cancer therapy, are discussed.
Malinowska and co-authors  described the medical applications of complexes of metal ions with small heterocyclic
compounds containing nitrogen atoms within three-or five-membered rings. Such derivatives of pyrazoles, aziridines and
diaziridines with metal ions like Cu(II), Zn(II) and Ru(III) exhibit interesting biological activity and their antioxidant,
anticancer, anti-inflammatory, immunomodulatory and antimicrobial properties are presented. The authors have collected
the results of the studies from the last years that concern antimicrobial and anticancer properties of pyrazoles complexes
and the potential application of aziridine-containing natural compounds as chemotherapeutics with anti-cancer, and antimicrobial
agents. The article also pointed out the need of conducting of more detailed pharmacological studies on these
kind of compounds as in vitro research seems to be interesting but also insufficient.
A chapter entitled "Antimicrobial and structural properties of complexes of selected metal ions with thiosemicarbazide
and its thiosemicarbazone derivatives" by Namiecinska and myself  consists of a chemical and a biological part.
The first one shows the synthetic methods and the structures of complexes of metal ions [Cu(II), Cd(II), Pd(II), Ni(II),
Ru(II), Zn(II) and Mn(II)] with ligands containing a thiosemicarbazide motif. The second one provides data on antibacterial,
antifungal and antiviral activities of those complexes. Thiosemicarbazide and thiosemicarbazones constitute many of
the synthesized complexes that possess two important classes of sulphur, nitrogen donor ligands, particularly well interacting
with many transition metal ions. The presented properties kindle some hopes for application of these complexes in
the combat of infectious diseases, especially those caused by pathogens resistant to antibiotics, including biofilm-type
An interesting review “Mitochondria-targeting anticancer metal complexes” has been wrote by Andrea Erxleben .
About five years ago, the acronym ‘mitocan’ was coined for ‘mitochondria and cancer’. Mitochondria play a fundamental
role in cell death and survival signaling and have become an important target for cancer therapy. In this review, anticancer
metal complexes are discussed that exert their cytotoxic activity by damaging the mitochondria or by interacting with
mitochondrial proteins. The review starts with a short introduction into mitochondria-mediated pathways of apoptosis and
experimental methods to study metal complex uptake of the mitochondria. The three main sections then cover metal
complexes that - due to specific carrier ligands or due to their lipophilic cationic nature – accumulate in the mitochondria,
metal complexes that damage the mitochondria and metal complexes that interact with mitochondrial thioredoxin reductase
and the translocator protein in the outer mitochondrial membrane. The current state of the art in the design, antiproliferative
activity and mechanistic understanding of antimitochondrial metallodrugs is described with a focus on metal
ions such as Au, Ru, Ir and Pt.
The last chapter entitled “Recent Research Trends on Bismuth Compounds in Cancer Chemo and Radiotherapy” has
been written by Kowalik and co-authors . For many years bismuth(III) complexes have been widely used in medicine
with satisfactory therapeutic effects, mostly in Helicobacter pylori eradication, but also as potential antimicrobial and
anti-leishmanial agents. Recently, special attention in the field of coordination chemistry has been continuously focused
on medicine based on bismuth(III), containing therapeutic compounds. Therefore, in the first part of this review, the
authors would like to characterize not only ligands from such classes as: thiosemicarbazones, hydrazones, and dithiocarbamates,
but also anticancer properties of selected bismuth(III) complexes. In the second part of this review, Kowalik
will discuss the current knowledge connected with: (1) radiation therapy based on Bi-nanoparticles and nanodots, and (2)
targeted radioimmunotherapy based on bismuth(III) radionuclides. In radiotherapy, nanoparticles based on bismuth compounds
are primarily utilized as radiosensitizers, to obtain dose enhancement effect of radiationoncology. In turn, 213Bi
alpha-radioimmunotherapy represents an emerging therapeutic modality for tumour treatment that is currently under active
investigation based on (i) the choice of targeting vector, (ii) the use of proper bifunctional chelator, and (iii) the retention
studies of 213Bi as recoiling daughter nuclide of 225Ac. To summarize, this review presents recent research studies
on bismuth compounds in cancer chemo- and radiotherapy, suggesting directions for future research.
I think that the presented paper will be interesting for the readership of Current Medicinal Chemistry.
Proteins function as the major executors of genetic programs in all living organisms, including humans. However,
only a minority of pharmaceuticals available in drugstores contain proteins or peptides as active compounds.
This contradiction stems from multiple limitations accompanying the development of pharmacologically active proteins,
their production, and pharmacological use. Nonetheless, it is now clear that these limitations can be effectively
solved, resulting in an increase of implemented protein-based pharmaceuticals. Furthermore, the initial successes
in the field of regenerative medicine point to novel applications for matrix proteins. Therefore, this special
issue of Current Medicinal Chemistry entitled “Proteins in Pharmacology: restrictions, challenges and opportunities”
has collected recent review papers dedicated to pharmacologically active proteins, their therapeutic applications,
recombinant proteins as sources of pharmacologically active compounds (including their expression, purification,
refolding and proper posttranslational modifications), antibodies, enzymatic therapy assays, matrix proteins for
regenerative medicine, novel molecular targets and more.
Pharmaceutical proteins are used for the diagnosis, prevention and treatment of diseases creating a strong demand
to produce recombinant proteins on an industrial scale. Many expression platforms including bacteria, yeast,
plants, mammalian and insect cell cultures as well as transgenic animals have been established for commercial protein
production. Each of these systems has specific benefits and short comings with respect to costs, scalability and
safety. Plant-based transient expression platforms have become leading manufacturing technology due to the advantages
in protein production yield and speed. Kopertekh and Schiemann  describe the recent advances in current
design, status and future perspectives of plant transient expression systems for the production of biopharmaceutical
proteins and provide the most illustrative examples of pharmaceutical proteins produced by transient expression in
plants. The review article by Komarova et al.  focuses on the feasibility of plant-based systems for recombinant
antibody production demonstrating illustrative examples of products and highlighting the beneficial properties of
To date, monoclonal antibodies are already broadly used in anti-cancer therapy but many have several disadvantages
resulting in insufficient efficacy and side-effects. Kholodenko et al.  describe the potential applications of
various types of antigen-binding fragments from antibodies as separate molecules or as a part of complex conjugates
in anti-cancer therapy focusing on their structural features. Heat shock proteins (HSPs) represent multifunctional
agents and are broadly involved in the activation of the immune response against tumors. These features are
exploited in HSP-based vaccines aimed at inducing cytotoxic responses against tumor cells. Baldin et al.  reviewed
the recent advantages in this field, but also focused on the problems of identifying and selecting the tumorspecific
antigens suitable for HSP-based vaccine development. Potentially novel antigenic epitopes used in HSPbased
vaccines may increase efficacy and allow for an extension of the range of target tumors.
Large parts of known proteins possess enzymatic activity. So far, some of them are already being exploited in
different enzymic therapy assays. The review article by Pokrovsky and coworkers  is focused on the family of
amino acid degrading enzymes. Available therapeutic applications involving these enzymes are based on the deprivation
of certain amino acids for the treatment of amino acid-dependent cancers, which exploit the compromised
metabolism of malignant cells. The focus of the article is on L-asparagine, L-methionine, L-arginine and L-lysine
degrading enzymes and their formulations as promising agents for the treatment of several types of cancers.
Plants may serve not only as biofactories for pharmaceutical proteins but also as a source of novel enzymes possessing
unique functions, and, in particular, as in the case of proteolytic enzyme production. Balakireva et al. 
summarizes the recent advances and possible biomedical applications for plant proteases, proposing further development
of plant-derived proteolytic enzymes from the biotechnology and pharmaceutical industries for the treatment
of different diseases. Shekhter, Balakireva et al.  cover an area dedicated to collagenolytic enzymes. This
review contains not only the data on existing collagenase-based medications and their applications in different collagen-related diseases and conditions, but collagenases from different sources for their potential application in enzymatic
therapy are also proposed.
Collagen has been successfully used in medicine for over 50 years. More recently collagen-based materials have
been successfully applied as treatments for chronic wounds, burns, venous and diabetic ulcers, in plastic, reconstructive
and general surgery, urology, proctology, gynecology, ophthalmology, otolaryngology, neurosurgery, dentistry,
cardiovascular and bone and cartilage surgery, as well as in cosmetology. The review article by Shekhter,
Fayzullin and coworkers  contains details on classic and modern applications of collagen in medicine such as in
soluble collagen injections, solid constructs reconstructed from solution, and decellularized collagen matrices used
in regenerative medicine applications.
Zernii et al.  covers the area of the treatment of corneal epithelial defects using therapeutic proteins. Such
treatments could be applied to protect the corneal surface, mimicking tear components, stimulation of corneal
wound healing, regeneration of corneal innervation, and suppressing oxidative stress, inflammation and neovascularization.
The article summarizes the existing data on protein-based drugs for the treatment of corneal epithelial
defects that are currently under preclinical development or testing in clinical trials, or that have been approved for
Peptide signaling is one of the main animal chemical communication systems involved in a multitude of physiological
processes. Several examples of drugs influencing peptidergic signaling show the important role of peptides
in the mechanisms of specific pathological conditions and in pharmacology. Fetissov et al.  describes the recent
advances in the development of bacterial protein mimetics of peptide hormones as a new class of protein-based
drugs. The authors pay special attention to the development of potential drug based on bacterial α-MSH homolog
ClpB and conclude that the original approach leading to the identification of E. coli ClpB as α-MSH mimetic protein
can be also applied for identifying mimetic proteins of other peptide hormones and developing a new type of
peptide-like protein-based drugs.
Human mucin MUC1 was discovered approximately 40 years ago as a component of milk fat globules, and to
date it is assumed to play an important role in cell signaling as well as in all the stages of oncogenesis, from malignant
cell transformation to tumor dissemination. Rubtsov et al.  describe the evolution in the understanding of
MUC1 function, which has identified this molecule as a potential a potential target for anticancer therapy. One more
potential protein target is described in detail in the review article by Orlov et al . This article is dedicated to
Na+,K+-ATPase as a molecular target for the treatment of tissue fibrosis, and takes into account recent data showing
that cardiotonic steroids (CTS) that are known as potent inhibitors of Na+,K+-ATPase affect myofibroblast differentiation
in a cell type-specific manner.
In summary, the contributors to this special issue highlighted various topics within area of selection, development,
production and application of biopharmaceutical proteins. We hope that this special issue will serve as a useful
resource of the recent progress in these areas while offering inspiration to the broad spectrum of scientists involved.
The first monoclonal blicking TNF has been recently approved in 2013, and biosimilars represent a key
opportunity for doctors caring for infla mmatory bowel disease. Multiple issues are still contreoversial
and deserve full attention. Aim of the issue is to review the state of the art of biosimilars in
inflammatory bowel disease.
1. Introduction: Biosimilars, challenges and opportunities
2. Biosimilars and originators: similarities and differences
3. Biosimilars in IMID: efficacy and safety
4. Biosimilars in IBD: efficacy, safety and immunogenicity
5. The regulatory process of biosimilars
6. Patient's profile for biosimilars in IBD
7. Can we extrapolate data from one IMID to another one?
8. The problem of naming: which name for which biologic
9. Cost issues with biosimilars: what can be expected?
Development of robust, sensitive and reproducible methods for diagnosing a diseases is crucial for the effective therapy.
A major challenge facing modern medicine is not only rapid and accurate diagnosing a disease in an early stage but
also minimizing the invasiveness of the diagnostic technique. Currently, metabolomics is used for the discovery of diagnostic
biomarkers of various diseases, to better understand their complexity and monitor the metabolic biomarkers during
therapeutic intervention. Metabolic profiling is usually defined as a qualitative analysis and quantification of the metabolites
which are associated with particular path. This approach may also give clues to personalized treatments for various
diseases by providing useful information about the response to treatment. A prerequisite for the clinical use of biomarker
is standardization of analytical methods used to metabolic profiling. In the last few years dozens of papers have been
published on application of separation techniques coupled to mass spectrometry or nuclear magnetic resonance to identification
biomarkers of several diseases. Although impressive improvements have been observed methodological challenges
are still running. The scope of this Issue focuses on the strategies and current challenges in metabolomics in cancer;
cardiology, steroid metabolomics and personalized medicine; direct biomarkers of alcohol consumption; applications
of electronic noses in medical diagnostics; current progress of lipid analysis in metabolic diseases, as well as application
of chromatography coupled to mass spectrometry to microorganisms detection.
In the first review, by Burton and Ma  new achievements in urinary metabolomics, including application of hyphenated
techniques in untargeted and targeted metabolomics applied to cancer biomarker discovery were described. The
Authors pointed that urinary metabolomics has benefitted from recent technological developments in nuclear magnetic
resonance, mass spectrometry, gas and liquid chromatography, and capillary electrophoresis; and discussed technical and
clinical limitations in addition to the emerging challenges in the field of urinary metabolomics. Extensive metabolic profiling
in urine has revealed a significant number of altered metabolic pathways and putative biomarkers, including
pteridines, modified nucleosides, and acylcarnitines, that have been associated with cancer development and progression.
The contribution by Kotłowska and Szefer  takes into consideration challenges and recent developments in steroidbased
metabolomics and its potential in the area of clinical biomarkers discovery. The Authors have described the application
of hyphenated techniques including GC-MS and LC-MS later combined with data processing using chemometric
techniques. Moreover, application of steroid-based metabolomics in the studies on cancer, mental, and central nervous
system disorders, adrenal diseases, endocrine disorders, of metabolism, impact of drug therapy, influence of dietary components,
doping control, or prolonged physical activity was described. Apart from that, the main research targets in metabolomics
are cardiovascular diseases due to their social and medical relevance, as well as the important role that metabolic
changes play in their pathogenesis and evolution. Metabolomics can be used for a full spectrum of cardiovascular
diseases: from risk assessment to myocardial infarction and heart failure. However, despite numerous studies describing
the recent achievements in application of metabolomics in cardiovascular diseases, it has not yet been used in routine
clinical practice. In the review by Barba et al. , application of metabolomics in the area of cardiovascular diseases was
described. The usefulness of mass spectrometry in the qualitative and quantitative analysis of lipids was shown in Mika et
al.  review. The Authors pointed that MS techniques combined with: GC, HPLC, and MALDI are the most commonly
used in lipid analysis. Their application in lipidomics of obesity and other metabolic alterations, such as metabolic syndrome,
diabetes, atherosclerosis, and nonalcoholic fatty liver disease are discussed in detail. The review by Spodzieja et
al.  covers recent developments in discovery of biomarkers in different types of amyloidosis. The Authors described
application of hyphenated techniques coupled with mass spectrometry in analysis of proteins occurring in tissues, blood
and cerebrospinal fluid as a tools for diagnosis of amyloidosis, the current trends in improved pathogens separation and
detection methods and their subsequent use in medical diagnosis. Whereas, the development of analytical and biological
methods in the analysis of microorganisms, in biological and environmental samples such as blood, urine, lymph, and
wastewater was presented in the publication by Chylewska et al.  In addition to describing the structure, surface, properties,
size of microbes, and then pivotal points in the bacteria, viruses, and fungi, the Authors showed the progress, limitations,
and challenges of separation techniques in selective fractionation of microorganisms. Application of hyphenated
techniques for LMWH anticoagulants separation was described by Sadowski et al. . These compounds mainly prevent
blood clotting and growing of the existing clots in blood vessels. The Authors indicated that sensitive and high resolution
analytical methods such as UHPLC play an increasingly important role in the analysis of LMWHs. Different types of liquid chromatography including SAX chromatography and RPIP chromatography and their use for di- and oligosaccharide
components analysis of LMWHs were described. The HILIC chromatographic method and 2D LC method for separation
and structural characterization of heparin anticoagulants were also described. The review by Woźniak et al. 
covers recently published studies focusing on the sample preparation methods and chromatographic or biochemical techniques
for the determination of alcohol biomarkers in whole blood, plasma, serum, and urine. Possibilities and limitations
of separation techniques in routine analytical toxicology for monitoring alcohol consumption or sobriety during alcohol
therapy were discussed. In the review by Wojnowski et al. , the use of electronic nose technology to identify aromas in
a way parallel to the biological olfaction was described. Electronic noses are a non-invasive tool useful for early detection
of human diseases based on exhaled air analysis, volatile fractions, blood, saliva, sweat, other body fluids and skin odor.
Every pathological change affects the chemical composition of body fluids, and when registering these changes, it is possible
to diagnose early disease. The development of this technology enables the identification of potential patients suffering
from diabetes mellitus, asthma, uremia, tuberculosis or monitoring of dialysis progress and diagnosis of infections
and cancer such as lung cancer and breast cancer. The comprehensive summary of research in medical diagnostics using
electronic noses was presented in this review. Along this line, in the paper by Mpanga et al. , determination of urine
metabolic fingerprints in urogenital tract cancer patients and healthy controls was done. GC-MS and LC-MS were applied
to urine metabolic profiles identification. The Authors showed a panel of various statistically significant metabolites
between urogenital cancer and healthy groups. Those compounds belong to different physicochemical groups such as
carbohydrates, nucleosides, purines, and amino acids. It was also found that two metabolites, namely glucocaffeic acid
and lactic acid, can be considered as markers in bladder, prostate, and kidney cancer. The Authors pointed to future directions
which can lead to its use in clinical settings. In turn, the main goal of the study by Wawrzyniak et al.  was to
determine plasma metabolomic profiles in resistant and non-resistant hypertensive patients. Application of LC-ESITOF/
MS allows to verify patients compliance to antihypertensive pharmacotherapy what was a crucial step before biochemical
interpretation 19 up-regulated and 13 down-regulated metabolites in RH were identified. The Authors pointed
that abnormal metabolomic profiles are linked mainly to lipid, amino acids, and purine metabolism. Lipids play many
important roles in disease processes and lipidomics is a specialized subset of metabolomics.
The aim and the scope of this special issue is to represent an exhaustive and comprehensive review on the current
treatment of OCD, a quite common psychiatric disorder that has been recently considered a distinct nosological
category. The pharmacological treatment of OCD is still mainly based on the serotonin hypothesis of the disorder
that, although important, it is now evident that cannot fully explain the complexity of this condition. Therefore, there
is an urgent need of novel pathophyiosological data, reliable animal models, still very limited, as well as innovative
pharmacological targets. Emphasis will be given also to the problem of treatment resistance and chronicity of a large
portion of OCD patient, as well as on current and new strategies to overcome this issue.
This thematic issue is dedicated to combine our current knowledge of mechanisms and molecular targets for
photo-induced skin diseases and signs of premature cutaneous ageing as well as the discovery and development of
effective targeted substances and compositions for the prevention and treatment of these diseases and age-related
skin defects. Newly developed photosensitisers-drugs for photodynamic therapy is another key topic of the thematic
issue where 7 full-length reviews from the leading groups in the field were collected.
The first review by L. Marot  from L’Oreal Advanced Research, France speaks about a deleterious synergy
between pollution and sun exposure and overviews the opportunities for cosmetological skin protection. The author
underlines that an association of ultra-fine dust particles with toxic chemicals, heavy metals, polyaromatic hydrocarbons
(PAH) or, especially, with photo-reactive PAH strongly aggravates oxidative stress associated with UVA
exposure. The principle of cutaneous damage by pollutants from “outside” and “inside” is strongly supported by
large epidemiological data showing a significant correlation between the exposure to pollutants/cigarette smoke and
premature ageing signs/biological markers. Similar correlation was observed for atopic skin diseases and external
hazards. The mechanisms of damaging synergy (f.e. oxidative stress, metabolic impairment, and inflammation) between
pollution and sunlight, first of all, UVA radiation are discussed in detail. On these grounds, the author proposes
combined protection strategies from outside (topical UVA absorbers and antioxidants-blockers of lipid peroxidation)
and inside (mitochondria-targeting oral antioxidants and inducers of endogenous antioxidant and detox
skin barriers via Nrf2 pathway).
The next review by S.E. Dickinson & G.T. Wondrak  from Arizona University is focused on TLR4-directed
molecular pathways underlying skin photodamage and photocarcinogenesis. In this comprehensive paper, improved
molecular strategies for targeted photo-protection and photo-chemoprevention are suggested. The Toll-like receptor
4 (TLR4), which, since a long time, had been known as a key regulator of anti-bacterial defence, wound healing,
and chronic inflammation in the skin, has been recently recognised as a molecular target for skin photoprotection
and photo-chemoprevention. Both pharmacological and genetic suppression of TLR4 led to the impairment of UVinduced
inflammatory signalling through NF-kappaB and AP-1 pathways. Several small molecules-antagonists of
TLR4, such as eritoran, (+)-naloxone, ST 2825, and resatorvid were identified to modulate altered TLR4-dependent
The group of C.A. O’Neil  contributed the excellent overview on the impact of UV radiation on the barrier
function of human skin: from molecular mechanisms to the development of topical therapeutics. A complex epidermal
barrier includes the control of water content and temperature, mechanical protection, photochemical, toxicological,
redox, immune, and metabolic defence systems to prevent the skin and underlying organisms against biotic
and abiotic stresses and invaders. The effects of UV radiation (UVR) on barrier functions are still to be elucidated.
Of importance, higher erythemal doses of UVR induce increased trans-epidermal water loss and reduction in tight
junction functions in the granular layer, while sub-erythemal doses exert positive protective effects. According to
the authors’ opinion, topical sunscreens should have double action: to block UV interaction with skin components
and to prevent the water loss in order to provide a proper defence of barrier functions. Browsing the dedicated literature,
the authors identified specific botanical extracts providing both UV protection and occlusive (moisturising)
The group of researchers from King’s College London, UK  presented a review dedicated to mycosporine-like
amino acids for effective and safe photo-protection. The search for ecologically friendly and sustainable sunscreen has been going on for decades in an attempt to substitute synthetic sunscreens - pollutants for marine and terrestrial
environment/ecosystems. In this review, the limited literature sources showing sun protective properties of mycoplasma-
like amino acids are collected and thoroughly evaluated. These natural amino acids occurring in marine organisms
as different as protozoa, algae, seaweed, corals, invertebrates, and fish are considered as a valuable and
biocompatible alternative to synthetic sunscreens. There is an evidence that these amino acids have essential role of
photoprotection of marine organisms against UVR, particularly in shallow clear waters. Due to specific chemical
structure, they seem to act as broadband UV screens and antioxidants to interrupt free radical-driven chain reactions.
Moreover, these amino acids are capable of inducing endogenous antioxidant defence systems through Nrf2
pathway like extracts of a number of terrestrial plants and plant cell cultures. The authors honestly admit that the
current lack of pre-clinical and human studies does not allow these natural amino acids to be considered as substitutes
of synthetic sunscreens.
The second pool of review articles describes research and development of novel photo-sensitizers to be feasible
for photo-dynamic therapy widely used in cancer, psoriasis, and vitiligo treatments.
Thus, I. Bilkis and co-authors  and co-authors from Weizmann Institute (Rehovot, Israel) critically evaluate
literature dedicated to the mechanisms, by which photo-sensitisers elicit chemical modifications in amino acid residues
of proteins. They focus on singlet oxygen as a key player in the above modifications. The authors logically
suggested three possibilities for singlet oxygen to specifically attack malignant cells while leaving normal cells intact.
The first one involved photo-sensitiser methylene blue with high affinity to the protein acetylcholinesterase.
The second one used hydrophobic photo-sensitiser hypericin with the capacity to interact selectively with partly
unfolded proteins which are characteristic for rapidly growing cancer cells. In the third case, the photo-sensitiser
emodin was coupled to a specific protein hormone GnRH, which recognises malignant cells via specific receptors to
the hormone. This approach seems to be applicable in the search and optimisation of different photo-sensitisers for
photodynamic therapy of cancer.
The review by a group from Romania  is concentrated mainly on laboratory and clinical studies of photodynamic
therapy in melanoma. Photo-dynamic therapy has been successfully used as the first line of therapy for the
treatment of lung, esophageal, bladder, nonmelanoma skin, head, and neck cancers. At the same time, melanoma
was resistant to classical photo-dynamic protocols. Melanoma resistance is thought to be dependent on melanosome
trapping, presence of melanin, altered antioxidant defence, defects in the apoptotic pathways, immune evasion, and
stimulation of angiogenesis. The review describes in detail: (a) the major signalling molecular pathways deregulated
in melanoma cells, for example, RAS/RAF/MEK/ERK pathway, as targets for novel photo-dynamic therapy; (b) the
clinical data on the efficacy of photodynamic therapy in metastasising melanoma; (c) the new designs of antimelanoma
photo-sensitisers; (d) photo-sensitisers as new inhibitors of angiogenesis. There is a critical overview of
the clinical results obtained in combinatory protocols consisting of photo-dynamic therapy plus conventional immune
therapy. The authors conclude that up-to-now, photo-dynamic therapy of malignant melanoma at the advanced
stages may be used as an adjuvant tool to improve the survival rate or as a palliative treatment.
The researchers from the Netherlands-German group  contributed a review on the molecular mechanisms and
therapeutic opportunities of visible blue light (UV-free part of the spectrum) therapy. In the review, the current
knowledge of the molecular photo-acceptors (blue light sensors), signalling transmission, and future therapeutic
applications of visible blue light in the treatment of chronic skin inflammatory conditions was collected and discussed.
As the very first molecular event, blue light is absorbed by many bio-active molecules located in the skin,
such as flavins, porphyrins, nitrosated proteins, etc. These activated photo-sensors transmit signals to induce ROS
and RNS generation and the activation of G protein-coupled signalling pathway. Cellular mechanisms connected
with these molecular pathways remain unknown so far. However, there is clear evidence that visible blue light has
the potential to suppress chronic inflammatory conditions in the skin.
Parasitic infections represent a major challenge for global health and economy. Despite their high prevalence and
clinical impact, treatment options are still incomplete. There are a limited number of effective medicines, many
have serious side effects, and increasing drug resistance is also a real threat. Even if these diseases have been largely
neglected for drug development because they affect poor people in poor regions of the world, in recent years, the
search for antiparasitic drugs received a new impulse. Thus, this issue will focus on recent efforts to reinvigorate the
drug development targeting major parasitic diseases.
One interesting strategy recently used to fight these diseases is based on the inhibition of enzymes involved in
metabolic pathways essential for parasite survival and/or infectivity and absent or sufficiently different at a structural
level from those present in the host. In this context, the first paper of the issue  explores the possibility to
target in trypanosomal diseases, the enzymes of the pentose phosphate pathway, which includes an oxidative
branch, important in the maintenance of cell redox homeostasis, and a non-oxidative branch in which ribose 5-
phosphate and erythrose 4-phosphate, precursors of nucleic acids and aromatic amino acids, are produced. In particular,
the authors provide a comprehensive overview of the available chemotherapeutic options against trypanosomal
diseases and discuss the potential of genetically validated enzymes from the pentose phosphate pathway of
trypanosomatids to be explored as potential drug targets.
The second paper  analyzes Carbonic Anhydrase (CA) metallo-enzymes as a new possible drug targets for
parasitic diseases. CAs catalyze the reversible hydration of carbon dioxide to bicarbonate and protons. Compelling
data in the literature strongly indicate that interference with CA activity in various parasites leads to an impairment
of parasite growth and virulence, which in turn leads to a significant anti-infective effect. All the existing studies on
CAs from protozoa responsible for the major human parasitic diseases, namely Malaria, Leishmaniasis and Chagas
disease, are analyzed, and the emerging role of these enzymes as targets for the development of new anti-parasitic
drugs is critically discussed.
In the past, the lack of high-resolution structural information on parasitic proteins has been a big obstacle in
structure based drug discovery programmes. However, the recent renaissance of electron microscopy (EM), which
has seen a remarkable rise in the number of available structures, represents an important impulse in drug discovery
for parasitic diseases. Thus, the third paper of the issue  addresses the challenges associated with the structural
determination of parasitic proteins by EM and provides some examples of parasitic protein structures determined
with this technique. Finally, limitations which need to be overcome before using EM as a mainstream technique in
parasitic drug development are also discussed.
The resistance of common pathogens to first-choice drugs increased by up to 100% during the last decades.
Moreover, the resistance of some strains to second- or third-choice drugs can be found. The development of crossresistant
or multidrug-resistant strains is a serious global problem. The selection of resistant pathogens is especially
caused by the irrational and unavailing application of anti-invasive agents in human, veterinary medicine, and in
agriculture. Resistance may complicate the treatment regardless of how mild the disease was at the early stage. Increasing
resistance refers to the urgency to design new effective anti-invasive drugs and develop strategies focused
on overcoming drug resistance.
The rational design of new entities from new chemical classes influencing new targets is considered as the most
valuable approach. In addition, various combinations of existing drugs with other molecules, e.g., efflux pump inhibitors,
are investigated. New effective anti-invasive agents or compounds mitigating resistance can be also designed
based on the structures of natural products. Natural products are structurally diversified, and many of them
have been reported to exhibit anti-invasive activity or have synergy effect with conventionally used drugs. The application
of nanotechnology represents also an excellent alternative for improvement of existing anti-invasive drugs
due to the fact that nanomaterials exert cytotoxicity through various mechanisms.
The paper entitled “Design and discovery of new antibacterial agents: Advances, perspectives, challenges” is focused
on recently reported new antibacterial chemotherapeutics approved for clinical practice, antibacterial chemotherapeutics
in clinical trials and antibacterial agents under development. In addition, particular attention is given
to agents decreasing bacterial resistance .
Tsang et al.  describe furano-naphthoquinones as potential candidates for new-generation lead compounds
acting directly on cancer stem cells to overcome the chemotherapy resistance. Apart from natural plant sources,
there are a number of synthetic furano-naphthoquinone derivatives that are effective in reducing the stemness of
cancer cells and thus are anti-invasive. In the review, the anti-invasion mechanisms of the furano-naphthoquinones
together with their natural origins, synthetic derivatives as well as their synthetic routes are discussed.
The anti-invasive and anti-metastatic activities of some potential plant compounds with their sources of isolation
and mechanistic pathways in different types of cancer cells and xenograft models are reviewed by Sarwar et al. .
Qing et al.  summarize isoquinoline-based alkaloids in relation to their cytotoxic and multidrug-resistant reversing
activities against various cancer cells. Additionally, the structure-activity relationships of different types of
isoquinoline alkaloids are discussed.
Besides a severe upper respiratory illness, influenza viruses are able to cause pandemics with a significant loss of
life in all age groups. Small molecule therapeutics are a critical part of antiviral strategies to control influenza virus.
In the review written by Han et al. , the status of existing anti-influenza drugs, mechanisms of antiviral resistance,
and novel antiviral drugs currently under development to target influenza viruses are discussed.
Comprehensive data from in vitro and in vivo studies to elucidate the functional roles of natural compounds used
in traditional Chinese medicine in reversing multidrug resistance during cancer therapy are summarized by Lou
et al. .
Zitko and Doležal  devote their review to synthetic antitubercular drugs, discussing the recent research on the
mechanism of action and molecular targets of first-line and second-line drugs and suggesting how this knowledge
can be used to design simple derivatives with improved properties. In addition, they annotate old and known drugs
from various pharmacodynamical groups as candidates for repurposing to become effective in combatting tuberculosis.
Review of Luo et al.  examines the chemistry and antioxidant, anti-inflammatory, and cytotoxic activities of
selected Gaultheria species that are used worldwide, especially as food and medicine in China, and their benefit for
In spite of the fact that Ebola virus is one of the most dangerous viruses, currently there are no FDA-approved
therapeutics or vaccines to treat Ebola virus infections. Schafer et al.  summarize major findings on the Ebola
virus replication cycle and explore therapeutic approaches to the treatment of this devastating disease. The major
focus of this review is on small molecule inhibitors.
Inflammatory bowel disease is an uncontrolled chronic inflammatory intestinal disorder, which requires medications
for long-term therapy. The great potential of plant-sourced phenols for the treatment or prevention of inflammatory
bowel disease and their mechanisms of actions are discussed by Xiao et al. .
Compounds with a benzothiazole scaffold show promising activities against Gram-positive and Gram-negative
bacteria as well as Mycobacterium tuberculosis. Gjorgjieva et al.  assess the importance of the benzothiazole
scaffold in the discovery of new antibacterial compounds, the potential of benzothiazole-based compounds against
resistant bacterial strains, optimization of their antibacterial activity, and the future perspectives of benzothiazolebased
Phytochemicals for Human Diseases: From Kitchen to Clinic
Cancer, an abnormal division of cells, is one of leading causes of death worldwide. A large number of
anti-cancer drugs, which have been approved commercially, are derived from plants. To meet the ever
increasing demand for anti-cancer compounds, plants have been harvested ruthlessly from their natural
habitat. Due to this, many plants have become extinct or are at the risk of becoming endangered.
Production of anti-cancer drugs through chemical synthesis is not economically viable due to highly
complex structures of compounds involved in biosynthesis pathways and high cost.
Biotechnology by employing plant tissue and cell culture offers a valuable tool to produce compounds of
interest for treating the cancer diseases. It is also possible to advantageously alter the biosynthesis
pathway of plants to obtain the desired products in required amount as well as within shortest possible
time. This method has successfully been employed for the large scale production of anti-cancer
compounds e.g. vincristine, vinblastine, taxol and podophyllotoxin.
We invite investigators to contribute original research as well as review articles that encourage the
ongoing efforts on enhanced production of anti-cancer compounds from different plant species using
various biotechnological means. A particular interest will be given to papers exploring or discussing the
different strategies to produce anti-cancer compounds from plants in an environment friendly way.
Circulating progenitors cells (CPCs), including Endothelial progenitor cells (EPCs), are a heterogeneous population
of cells in different states of maturation, originated from bone marrow (BM). Since their first identification in
1997 , great efforts are being made to explore the regenerative/reparative potential of EPCs, including their abilities
of self-renewal, of starting reparative mechanisms, and of neoangiogenesis. The role of CPCs in vivo is still
debated; however, the evidence of the involvement of CPCs in the pathophysiology of disease and their complications,
as well as in aging and other physiological conditions, are growing [2-6]. There are many reports on associations
between cell number, their activity and oxidoreductive status, and disease; growing evidence are being provided
on the effects of different pharmacological treatments on CPCs, and also preliminary observations of the potential
role of CPCs as therapy [7-11]. The mechanisms underlying cell mobilization into peripheral blood, circulation,
and activities, and their relationships with medical therapy are far to be completely clarified .
The challenge of this special issue will be to bring together the leading experts in the field to add new insight
into pathophysiological, drug-related and pharmacological aspects of CPCs, also to address the issue of why different
subjects with similar risk profile could have a different outcome. This Thematic issue aims to provide a comprehensive
literature review of the current knowledge, by different points of view. It is accepted that excessive inflammatory
burden or imbalanced immune responses may underlie number or function alterations of EPC . Rodriguez-
Carrìo and coll. summarize the current knowledge regarding the cutting-edge area of the modulation of EPC
levels and function by inflammatory cytokines in systemic diseases, suggesting these mediators as potential biomarkers
for risk stratification in non-CV disease [14, 15]. Rigato and Fadini describe the prognostic role of
CPCs/EPCs measurement on the development of cardiovascular disease and microangiopathy confirming that low
CPCs/EPCs levels predict the onset or worsening of microalbuminuria and retinopathy in diabetic patients .
Autologous cell therapy represents a novel treatment option for vascular regeneration in different disease conditions.
Bianconi, Pirro et al. report on therapeutic potential of different proangiogenic cells (PCs), including endothelial
progenitor cells (EPCs), in the treatment of peripheral artery disease; however, despite a number of potential
clinical applications of PCs are emerging, there is evidence that CV risk factors and chronic inflammation may induce
PC dysfunction, rising possible limitations for the efficacy of autologous PC therapy . In their article,
Ruggeri and coworkers address another aspect: elevated CECs and EPCs levels have been reported in the peripheral
blood of patients with different types of cancers and some other diseases, suggesting that these cells may be involved
in disease progression and the neoplastic angiogenesis process. Moreover, abnormal CECs and EPCs are
probably involved in endothelial damage that is a marker of several complications following allogeneic hematopoietic
stem cell transplantation . Last, another current challenge about EPCs as therapy regards the chronic
kidney disease (CKD). Coppolino and coll. describe the potential role of EPC therapy in repairing injured renal tissue;
strategies using EPCs to induce a reparative process with functional restoring of a diseased kidney or to delay
CKD by direct stem cells infusion or stimulating endogenous release of EPCs are also described .
Nanomedicine is a growing field of medical research focused on the development of therapeutics and diagnostics
tools in the nanoscale range (from 1 nm to 100 nm). Early diagnosis and effective cancer therapy are required to
treat cancer, which causes approximately 14.1 million new cases and 8.2 million deaths in a year worldwide.
“Nanomedicine uses nano-sized tools for the diagnosis, prevention and treatment of disease and to gain increased
understanding of the complex underlying pathophysiology of disease. The ultimate goal is improved quality of life”
as defined by the European Science Foundation.
Nowadays, this new branch of science is a point of interest for many investigators, due to the important scientific
and technological advances over the last few decades, in particular for cancer treatment. Cancer nanomedicine has
been applied in different fields, such as drug delivery, nanoformulation and nanoanalytical contrast reagents. In the
last two decades, nanotechnology has been rapidly developed allowing the incorporation of multiple therapeutics,
sensing and targeting agents into nanoparticles in order to set up new nanodevices capable of detecting, preventing
and treating complex diseases, such as cancer.
The aim of this special issue is to highlight the state-of-art of diagnostic and therapeutic tools that nanomedicine
is offering to fight cancer.
In the first review, Mascheroni and Schrefler  take into consideration computational models that help in understanding
biological mechanisms to provide quantitative analyses. To date, the use of mathematical modeling in
cancer is a long-standing practice, covering several aspects such as tumor biology, cancer progression and tumor
treatments. The authors report computational models based on in silico approaches, which address several aspects
of tumor treatment through the use of nanoparticles. The authors also highlight four main topics related to nanoparticle
formulations, namely the delivery to the tumor tissue, their uptake by tumor cells, drug release from the nanocarriers
and their therapeutic use. In silico approaches constitute a valuable tool to aid clinical studies, guiding the
rational design of new nanoparticle formulations and identifying the optimal strategies for existing treatments.
Molinaro et al.  examine the role of inflammation in different steps of tumor development and the strategies
based on the use of both conventional and biomimetic nanoparticles, which exploit the inflammatory pathways to
selectively target the tumor-associated microenvironment for therapeutic and diagnostic purposes.
In the review of Palazzolo et al.  the authors describe the main drug nanoformulations based on different
types of organic nanoparticles (e.g. polymeric nanoparticles, liposomes, micelles and exosomes), including the advantages
presented by the encapsulated drugs compared to their free form and how nanodrugs have improved the
Bayda et al.  illustrate the development of nanotechnology for diagnostic and therapeutic purposes of different
types of inorganic nanoparticles, which are currently undergoing clinical development, and of those already approved
by the FDA, which are being used in the market. In addition, the authors investigate the preclinical work and
clinical trials to highlight the path of these NPs from the lab to the clinic.
The review by Bedin et al.  aims at surveying the nanotechnological devices and approaches applied to the
detection of circulating cancer biomarkers and to show how the integration of biotechnology, nanotechnology and
microfluidic can produce quantitative, sensitive and high-throughput assays useful for new point-of-care testing
(POCT) development. Specifically, the authors give an overview of nanomaterial-based approaches for the detection
of nucleic acids and proteins for the diagnosis, prognosis or monitoring of cancer. Furthermore, the authors envision
that the current molecular diagnostics frontiers will be pushed forward by nanobiosensors evolution in the
next decade, thus allowing the introduction of new POCT in the personalized medicine.
Several nanoscale carriers have been developed for diagnostic purposes or were studied by imaging techniques
to design a prospective drug delivery process. Molecular imaging modalities include magnetic resonance imaging (MRI) and spectroscopy methods (fMRI), optical imaging techniques, ultrasonography and the nuclear medicinal
modalities such as single photon emission computed tomography (SPECT) and positron emission tomography
(PET). The review by Polyak and Ross  takes a short historical overview to radiocolloids, the great ancestors of
(radiolabeled) nanoparticles, and then describes the general features of current types of PET and SPECT imaging
associated with nanoparticle-based products and key radiolabeling methods. Finally, insights on potential prospective
challenges related to radiotheranostic approaches and imaging guided therapies are described.
Finally, Meneghello et al.  define how biosensors of different technological nature are gaining an increasing
share of attention for therapeutic drug monitoring as a valid, effective alternative to conventional laboratory tests,
since they can provide a revolutionary technology and tools with superior performances. Although there are still
challenges that have to be addressed before such devices will enter the clinical practice, several analytical platforms
have emerged in recent years, which show promising results. Primarily, the techniques employing nanobiosensors
are mainly based on electrochemical, optical, and mass detection systems. In the very next future, the portability,
rapid analyses, user friendly and low fabrication costs will make biosensors advantageous in view of a point of care
After the development of technology, pharmaceutical analysis in medicinal chemistry has become important for
the drug development, fabrication stage, formulation, stability and quality.. The development of sensitive, selective
and fully validated, new analyzing methods for pharmaceutical dosage forms is important and continuous. From this
point of view, I invite you to meet “Current Medicinal Chemistry” current issue under the thematic issue called as
“Advances in Medicinal Chemistry from Analytical Perspectives”.
The aim of the proposed special issue is to focus on the novel developments in medicinal chemistry from analytical
point of view including novel developments on drug analysis, medicinal chemistry, drug targets and disease
mechanism, dissolution test profiles, all analytical techniques for medicinal chemistry such as solid phase extraction,
LC analysis, spectroscopic, chemometric, electrochemical techniques etc. This special issue is contributed to
the field since the recent developments in medicinal chemistry researches are important and continuous. In this
thematic issue you may find new innovations in medicinal chemistry, recent researches on drug targets and disease
mechanism, dissolution test profiles, new analytical methods for medicinal products, novel developments on drug
assay, assay methods and validation processes in drug analysis.
In this thematic issue, there exist 13 review papers by several important scientists who contributed their ideas. In
the latest years, a large number of adsorbent carriers of natural and synthetic origin have increasingly attracted attention
due to their biocompatibility, acceptable ecological and toxicological characteristics, high capability for
simple modification of physical chemical characteristics, high stability and a relatively low price.
Subsequently, in this issue, the first review, by Razic, addresses the “Analytical approaches to the characterization
of solid drugs delivery systems with porous adsorbent carriers”. Korecká et al., shared their ideas about “Immunosensors
in Early Cancer Diagnostics: From Individual to Multiple Biomarker Assays”. In this review, recent
developments in the area of electrochemical immunosensors applicable for the detection of cancer biomarkers that
occur in a wide concentration range including extremely low levels, which are typical for the early stage of the disease,
are discussed. Furthermore, “Tyrosinase electrochemical biosensors monitoring medicinally significant substances”
topic is well discussed by the authors Milan Sýs and Karel Vytřas. In this review overview of applications
of electrochemical tyrosinase biosensors in the analysis of medicinally significant substances, otherwise also known as
biomarkers are shared. In the review entitled “In-vitro Drug Dissolution Studies in Medicinal Compounds”, the topic
is well discussed by Bozal-Palabiyik, et al. This review paper aims to analyze in-vitro drug dissolution testing in
solid dosage forms since 2010 in order to present a comprehensive outlook of recent trends. Another interesting
study entitled as “Advanced methods for analysis of testosterone suggested by Livia Alexandra Gugoasa and Raluca-
Ioana Stefan-van Staden. This review is dedicated to surveying recent determination methods of testosterone from
different biological samples such as: serum, saliva, plasma, urine or fingernail samples. Besides, Jean-Michel
Kauffmann et al., contributed to this thematic issue with a fascinating review paper entitled “Electrochemical Detectors
in Liquid Chromatography: Recent Trends in Pharmaceutical and Biomedical Analysis”. The authors review the
selected data in the literature devoted to pharmacologically active compounds in their dosage forms, herbal drugs in
natural products, drug residues in feed and/or in biological samples. Ana-Maria Chiorcea-Paquim, Teodor Adrian Enache,
and Ana Maria Oliveira-Brett, contributed a review paper entitled “Electrochemistry of Alzheimer disease amyloid
beta peptides”. The recent advances on the Aβ peptides electrochemical characterization are reported in this review.
In another contribution, “The role of oxidative stress modulators in breast cancer” is discussed by Gurer-Orhan
et al. The authors focuses more on melatonin which we have been working on during the last decade. Since a large
spectrum of electrochemical MIP-sensors has been described in the literature for the whole arsenal of drugs, e.g. the
most frequently used analgesics, antibiotics and anticancer drugs, “Yarman et al., stated the recent studies on “Electrochemical
MIP-Sensors for Drugs”. Meanwhile the studies of the interactions of DNA with small molecular drugs,
especially anti-tumor agents, antibiotics and drugs of abuse are currently being performed to explore their mechanism
of action and develop new drugs with lower side effects and high curative properties, Campuzano et al., contributed their interesting review paper “Electrochemical Nucleic Acid-Based Biosensing of Drugs of Abuse and Pharmaceuticals”.
In the review by Hosu et al. “Electrochemical Immunosensors for Disease Detection and Diagnosis” topic
was discussed. The authors report the research progresses of electrochemical immunosensors applied in clinical
analysis that have been published in the last years. Smarzewska et al., also contributed the review paper entitled “Recent
Applications of Silver Amalgam Electrodes for Analysis of Pharmaceuticals and Vitamins”. The features and applications
of silver amalgam electrodes in electroanalysis of pharmaceuticals and vitamins are summarized in this review.
The state-of-art in the preparation and construction of solid silver amalgam electrodes for prolonged and userfriendly
use is presented. And finally, Gumustas et al., shared a short summary of the basic principles of chiral separations
on an analytical and preparative scale, with the review paper entitled “Analytical and preparative scale separation
of enantiomers of chiral drugs by chromatography and related methods”. In addition, some selected applications
for analytical techniques, such as gas chromatography, supercritical fluid chromatography, high performance
liquid chromatography, capillary electrophoresis and capillary electrochromatography for the separation of enantiomers
of chiral pharmaceuticals published in last two years are also discussed.
We tried to combine all different kinds of analyzing methods to maintenance the richness of analytical chemistry.
Therefore, this thematic issue entitled “Advances in Medicinal Chemistry from Analytical Perspectives” will be
very useful for the readers who want to have broad knowledge.
I believe that you, as the valuable readers of Current Medicinal Chemistry journal, will find out new information,
topic of interest and new ideas in this thematic issue and I hope that this thematic issue will encourage researchers to
achieve the analysis of pharmaceutical active compounds using different kinds of methods.
I would like to thank to all of the authors for their excellent contributions, and Prof. Dr. Atta-ur-Rahman , the
Editor-in-Chief of “Current Medicinal Chemistry”, his kind invitation to act as a guest editor for this thematic issue.
Inflammatory response is originated by tissue injury and triggers a cascade of biochemical reactions that prime
the nervous system for pain perception. Protracted inflammation supports adaptive changes that can cause altered
pain signal processes. Indeed, different chronic (i.e. neuropathic) or inflammatory injuries to nervous system trigger
structural and functional changes in the peripheral or central sensory circuits, resulting in behavioral dysfunctions,
such as hyperalgesia and allodynia, and comorbidities. Current treatments for chronic pain are quite unsatisfying.
Hence, there is a great, unmet need for research aimed at discovering novel biological targets together with the development
of new pharmacological approaches for optimizing the side-effects of the classical drugs.
In this mini special issue, different signaling pathways in the peripheral and central nervous systems implicated
in inflammation and chronic pain and possible therapeutic approaches have been described.
- The review by Magni et al.  focuses on the pathophysiology and therapeutic potential of purinergic signaling
in pain, by reporting the available literature pre-clinical data together with the results of clinical trials. The
authors accurately illustrate the complex organization of purinergic system by providing the vast variety of
different (neuronal and non-neuronal) targets for resolution of chronic pain and inflammation. They also highlight
the role of purines in non-conventional therapeutic approaches.
- Posa and collaborators  show the analgesic properties of the neurohormone melatonin in several preclinical
studies and patients. They systematically describe the melatonin receptor functions in the neurobiology of
pain. Given the weakness of pharmacokinetic profile of melatonin per sè, they suggest the importance of developing
new pharmaceutical formulations or synthetic drugs acting on melatonin receptors, giving particular
emphasis to the effects mediated by MT2 receptors. Indeed, they discuss the analgesic properties of MT2 receptor
partial agonists in different chronic and acute/inflammatory pain conditions.
Negri et al.  summarize the evidence for the involvement of a new class of chemokine, the prokineticins
and their receptors, in chronic pain. They appropriately describe distribution of ligands and their receptors in
the periphery and at central nervous system level, by giving detailed information on their role in nociceptive,
as well as, chronic pain modulation. Indeed, they indicate that a number of preclinical studies proved the effects
of endogenous ligands or novel non-peptide drugs in controlling inflammation and inflammatory/
neuropathic pain. They discuss the possible molecular mechanisms responsible for prokineticins effects,
by highlighting the neuron-glia and neuron-immune cells interaction in prokineticins signaling.
Bedini et al.  remark advantages and drawbacks in the pharmacological manipulation of opioid system, by
highlighting the poor effectiveness of opiates in neuropathic pain condition. In this context, they describe innovative
opioid peptides (analogues of endomorphin 1 and dermorphin), showing similar analgesic properties,
but reduced side effects, as compared to classic opiates (i.e. morphine), as possible lead compounds for the
development of new drugs.
Roohbakhsh et al.  describe the orexinergic system as a potential candidate for finding alternative analgesics
with good efficacy and low side effects. Indeed, they clearly describe the cellular and molecular mechanisms
responsible for orexins effects in pain control at both spinal and supraspinal levels. Moreover, they give
information about recent preclinical findings on the manipulation of orexin signaling in pain modulation.
Russo and collaborators  discuss the possible involvement of gut-brain axis in the regulation of inflammation
and pain, that nowadays represents a hot topic research area. They report recent studies showing that the
deregulation of intestinal microbioma, commonly associated with gut inflammatory disorders, is responsible
for the development of several CNS pathologies. In this contest, they highlight the role of endogenous lipids,
as NAEs (AEA, PEA and OEA) and the most well studied short fatty acid (butyrate) in the inflammation
process, pain perception and in the CNS dysfunctions, by mainly focusing on endocannabinoids system involvement.
Since its introduction in the current clinical practice, Positron Emission Tomography (PET) provided a sensitive
tool for the evaluation of several biochemical processes and for the imaging of pathological substances in-vivo.
Several radiolabelled compounds for PET use were developed for the evaluation of central nervous system in the
last decade. These compounds allow the evaluation of tumour metabolism, the pathological accumulation of several
substances responsible for various neurodegenerative diseases and inflammation. In nuclear medicine, the creation
of a radiotracer that is able to satisfy these purposes is challenging. In particular, a radiotracer for clinical use is
characterized by a rapid pharmacodynamics with a significant affinity for the target thus resulting in a good signal
to noise ratio. As for radiolabelled compounds designed for the evaluation of metabolic processes, a good target to
background is desirable especially in brain tumours. The radiolabelled compound must ensure the detection of relapse
by detecting a pathological metabolic process that is different from those of the surrounding normal brain tissue.
Lastly, all these compounds should cross the blood brain barrier rapidly and, finally, levels of radiation exposure
for patients should be limited.
In this issue, the authors will address the pharmacological aspects and the in vivo applications of the radiotracers
used for PET imaging of brain in various diseases, thus providing an in depth review of the properties and applications
of these novel radiolabelled compounds.
We are pleased to introduce the present Special Thematic Issue “Brain Imaging with Positron Emission Tomography:
novel radiopharmaceuticals” that reviews different aspects concerning the usefulness of Positron Emission
Tomography in the field of neurological sciences and cutting-edge frontiers of neuroscience. The aim of the present
volume is to give an up-to-dated state of the art of those clinical and research boundaries within which this kind of
methodology achieved interesting advances.
In the field of clinical neuro-oncology, On hand interesting works by Treglia et al. highlighted the implementation
of 18F-FET PET in differentiating brain tumours from non-neoplastic lesions as well as low-grade from highgrade
gliomas, on the other hand the revised work of Quartuccio and Asselin evaluated the availability of PET radiotracers
availability in measuring the high-grade gliomas related adverse hypoxia. These themes appear of relevance,
considering the fundamental consequences related to treatment planning in terms of clinical efficacy, patients’
quality of life and targeting treatments.
However, the present volume - overcoming these aspects also by an in depth study of PET imaging diagnostic
procedures showing the involvement of Central Nervous System in systemic autoimmune diseases (Ursini et al.),
focused on recent important advantages related to PET procedures in neurodegenerative disorders. In particular,
Bauckneht et al. and Cistaro et al. respectively deepened the feasibility of PET procedures in evaluating Lewy bodies
and Amyloid-related neurodegenerative disorders, thus representing new frontiers in diagnosis, treatment and
prognosis of such health and social burden.
In conclusion, this Special Issue is really trustworthy to be read considering that PET imaging may be actually
considered as the present and the future in clinical research.
Cancer has become one of the fatal human diseases around the world. Every year there are millions of deaths because
of cancer in the world. The golden rule for cancer is early detection/diagnosis and early treatment. If cancer
can be detected or diagnosed early, particularly before its metastasis, it can prolong the lifetime and improve the
quality of life. Early detection and diagnosis of cancer is still a huge challenge. The various types of functional materials,
especially, a lot of functional nanomaterials can provide some opportunities for early detection and diagnosis
of cancer. Based on the functional materials, it can enhance the contrast properties between the tumor area and the
normal tissue, for example, contrast agents in magnetic resonance imaging (MRI) and fluorescent imaging, etc.
Moreover, the diverse contrast agents are with some additional therapeutic functions, which extend the function of
the contrast agents and offer the visualization capability during the therapy/treatment of cancer. In this thematic issue,
we will provide new progress in some following interesting fields for cancer imaging, therapy and theranostics
based on different types of functional materials:
The first work was reported by Dr. Gang Wei and Prof. Zhiqiang Su and their collaborators. They reviewed “Recent
advance in the cancer bioimaging with graphene quantum dots”. They present the synthesis and chemical
modification of GQDs firstly, and then introduce their unique physical, chemical, and biological properties like the
absorption, PL, and cytotoxicity of GQDs. Finally and most importantly, the recent applications of GQDs in cancer
bioimaging are demonstrated in detail, in which they focused on the biofunctionalization of GQDs for specific cancer
cell imaging and real-time molecular imaging in live cells. This work would provide valuable information on the
synthesis and modification of GQDs with adjustable properties for various biomedical applications in the future.
The second work was presented by Prof. Mingqian Tan and his co-workers. The title of his paper is “Multicolorful
carbon dots for tumor theranostics”. This review introduces a brief history and basic photoluminescence properties
of carbon dots, and then discusses synthesis strategies and applications of carbon dots in biological imaging,
targeted drug delivery, photodynamic therapy, photothermal therapy as well as gene delivery for cancer theranostics.
Future directions of carbon dots in cancer theranostics are also highlighted.
The third work came from Prof. Renjun Pei and his group. In their review work entitled “Biocompatible Gdbased
Polymeric Magnetic Resonance Imaging Agents for Tumor-Targeted Imaging”, Prof. Pei and co-workers focused
on the recent progress of biocompatible Gd-based polymeric MRI agents for tumor-targeted imaging, including
structures, properties and applications. Meanwhile, his review also highlights the emerging MRI mCAs with
smart response and multi-function: tumor microenvironment-stimulated MRI, multi-mode imaging and MRI-based
The fourth work reported by Prof. Bingbo Zhang and his group is entitled
The pharmacological therapy of children diseases is changing very quickly in the last decades. In this
respect, chronic autoimmune and inflammatory diseases are becoming a major issue for the pediatricians.
In spite of the availability of new biological drugs, which has allowed to assist to a great improvement in
the prognosis and quality of life of many patients, new therapeutic tools are urgently needed. This special
issue will discuss innovative approaches for rational drug design and therapy personalization in the
pediatric population, potentially leading to precision medicine improving efficacy and reducing adverse
effects of therapy, that are particularly significant in chronic diseases. The repositioning of old drugs to
treat rare pediatric immune diseases will be discussed, such as lapaquistat for Mevalonate Kinase Disease
and antimalarials in interferonopathies. Also severe oncological pediatric diseases could benefit from
precision drugs such as kinase inhibitors targeting specific genetic alterations; this approach will be
considered. Innovative disease models are needed to lead to improved drug design and innovative
therapies, and the promising application of pluripotent induced stem cells will be presented. Finally,
pharmacokinetics and pharmacogenomics based on innovative molecular markers such as
transcriptomics, and their application to therapy personalization and drug discovery for pediatric
inflammatory bowel disease, will be also discussed.
The potassium channels family represents the most widely distributed among ion channels families.
Thanks to this feature and to their ability of inducing hyperpolarization, potassium channels are involved
in many physiologic processes such as tune of musculature, release of neurotransmitters, regulation of
diuresis or glycemia and so on, and these properties make potassium channels suitable targets for many
pharmacological approaches to different pathologies in several districts. The purpose of this issue is to
offer a broad overview on the most important pharmacological tools, novel and well-known molecules,
having potassium channels as therapeutic target in order to highlight promising drugs with exciting
perspectives for the treatment of cardiovascular, neurological and metabolic diseases.
Keywords: KATP potassium channels, BKCa potassium channels, ROMK potassium channels, Kv
potassium channels, Mito-K+ potassium channels.
Pharmacological and chemical aspects of drugs or new molecules targeting: ATP-sensitive
(KATP) potassium channels.
Large conductance Ca2+-activated (BKCa) potassium channels.
Renal Outer Medullary (ROMK) potassium channels.
Voltage-gated (Kv) potassium channels and mitochondrial potassium (Mito-K+) channels.
Pancreatic cancer (PC) is a highly aggressive cancer usually diagnosed at an advanced stage, and has the worst
prognosis of any cancer malignancy, with a 5-year survival rate of <8%. Lack of early detection and effective interventions
are major factors contributing to the poor prognosis and dismal survival rates of pancreatic cancer patients.
Moreover, recent incidence and mortality rates suggest an increasing trend of pancreatic cancer patients.
Recent developments demonstrate that pre-invasive precursors, such as PanINs, IPMNs, and cystadenomas, progress
slowly over many years to develop into invasive pancreatic cancers. Thus, there is a time frame of several
years for effective chemoprevention and intervention strategies. Despite many advances in the molecular genetics of
human pancreatic cancers, targeted therapies have not yet translated to improved overall survival. Hence, developing
chemoprevention strategies that delay/inhibit/prevent the progression of each subtype of pre-invasive lesions to
pancreatic cancer is of utmost importance. Several genetically engineered mouse models (GEMs) of pancreatic cancer
that recapitulate human disease progression have recently been developed. The KrasG12D and KrasG12V dependent
GEM models which mimic the therapeutic response of human pancreatic cancer offer novel treatment development
opportunities. The biggest challenges are to elucidate the regulatory mechanisms controlling the progression of pancreatic
precursor lesions to pancreatic cancer, and to develop strategies that provide effective chemoprevention.
Equally challenging is identifying high-risk cohorts with specific pancreatic precursor lesions using early detection
In this special issue, different aspects of this problem are presented focusing on current challenges and opportunities
aimed to address chemoprevention aspects for pancreatic cancer. Possible pancreatic cancer chemoprevention
targets, mouse models and early detection, immuno-prevention of pancreatic cancer, drug candidates for pancreatic
cancer chemoprevention, regulatory mechanisms controlling pancreatic cancer progression, combination chemoprevention
strategies and different approaches are also considered and discussed.
The first review by Mohammed et al addresses the current challenges and potential opportunities for chemoprevention
of pancreatic cancer. In this review, they focused on the current situation of PC, the potential challenges, the
progress in existing strategies and available opportunities, as well as suggested key areas for research within the
increasingly important area of pancreatic cancer chemoprevention. They suggested that novel technologies such as
next generation sequencing should be employed to identify high-risk individuals with early genetic changes in the
initial lesions or even explored in blood samples to detect the presence of circulating tumor derived or related
mRNA, miRNA, DNA, tumor educated platelet-mRNA as biomarkers of early detection. GEM serve as excellent
models to study the early stages of PC and for early detection by molecular imaging technologies. GEM models
should be extensively utilized for developing existing chemoprevention agents or screening and optimizing new
agents and identifying ideal chemoprevention targets. High-risk individuals presenting IPMN/PanINs and those
with hereditary PC history should be considered for chemopreventive clinical trials. Combination chemoprevention,
multi-targeted agents and multi-agent low dose chemoprevention strategies might be considered to reduce toxicity
and enhance efficacy.
The contribution by Dhar et al. takes into consideration the mechanisms and drug targets for pancreatic cancer
chemoprevention. They discussed the available drugs and their limitations, and move on to discuss the wide realm
of chemopreventive efficacy that natural agents offer. While the intake of fruits and vegetables in routine diets has
been linked to reduced risk of developing pancreatic cancer, a wide variety of natural agents is being evaluated as
adjuvant therapies in combination with frontline chemotherapeutics in pancreatic cancer clinical trials. Completed
and ongoing human studies with these natural agents have shown surprisingly successful rates for regulating pancreatic
carcinogenesis. Furthermore, the underlying mechanisms of action and available information from extensive
literature analysis to highlighting the novelty of these agents for their antitumor effects against pancreatic cancer,
In the review by Hildegard, the regulatory role of G protein-coupled receptors in pancreatic cancer development
and progression are described. Smoking, psychological stress, diabetes, pancreatitis and alcohol abuse are known
risk factors for pancreatic cancer that cause hyperactive cyclic adenosine monophosphate (cAMP) signaling via
cancer stimulating Gαs-coupled β-adrenergic and prostaglandin (PG) E2 receptors and/or by suppressing signaling
via inhibitory Gαi-coupled GABAB-receptors. The activation of Gαi-coupled GABAB-receptor signaling by treatment
with GABA, inhibition of β-adrenergic signaling by a beta-blocker and/or suppression of Gαs-coupled PGE2
receptor signaling by a cyclooxygenase (COX) inhibitor prevented the development and progression of PC in hamsters
induced by carcinogenic nitrosamines and in transgenic mice. The re-purposing of cardiovascular therapeutics
(beta-blockers, COX-2 inhibitors, Ca2+-channel blockers) that inhibit β-adrenergic and PGE2 signaling for PC intervention
is problematic due to undesirable side effects under chronic treatment protocols. To avoid such side effects
while effectively reducing excessive cAMP signaling, nutritional GABA supplementation or positive allosteric
modulators (PAMs) of Gαi-coupled receptors (GABAB-Rs) currently in clinical trials for the treatment of addiction
should be explored for pancreatic cancer intervention.
Rao et al. review discusses the novel approaches of immunoprevention for PC. Vaccine-based treatments for
several cancers are currently under intense investigation. Current vaccine testing for PC is usually performed in advanced
stages of cancer, during which the patient's impaired immune responses improved to suppress the growing
tumor. However, so far such strategies have had limited success and have not become mainstream therapies. Thus,
early diagnosis is imperative for immunoprevention using vaccines. Developing vaccines towards non-self-antigens
has been successful, whereas vaccines against self-antigens, without any adverse effects on normal cells, have been
challenging. The development of new technologies to identify mutated antigens, post-translational alterations in
proteins, and tumor-specific antigens is currently underway, with a view toward vaccine development. Combining
vaccines with immune stimulators or non-toxic anticancer agents are promising for cancer prevention. Successful
vaccination strategies for PC at different stages of tumor development and future challenges for immunoprevention
are discussed in this review.
Along this line, the paper by Subramaniam and co-authors reviewed approaches to target cancer stem cells for
chemoprevention of pancreatic cancer. Emerging evidence supports the presence of a unique population of cells
called cancer stem cells (CSCs) as potential cancer inducing cells and efforts are underway to develop therapeutic
strategies targeting these cells. Studies have been shown that CSCs are highly resistant to standard therapy and responsible
for drug resistance, cancer recurrence and metastasis. To overcome this problem, novel preventive agents
that target these CSCs are needed. Natural compounds or phytochemicals have the ability to target these CSCs and
their signaling pathways. Therefore, they summarized current understanding of pancreatic CSCs and their signaling
pathways, and the phytochemicals that target these cells including curcumin, resveratrol, tea polyphenol EGCG
(epigallocatechin-3-gallate), crocetinic acid, sulforaphane, genistein, indole-3-carbinol, vitamin E δ-tocotrienol,
Plumbagin, quercetin, triptolide, Licofelene and Quinomycin. These natural/synthetic compounds or phytochemicals,
which inhibit cancer stem cells, may prove to be promising agents for the prevention and treatment of pancreatic
Together with the data summarized by Yu et al., the paper provides a systematic literature review and metaanalysis
on the effect of metformin and statin use on survival in PC patients. Current epidemiological studies report
conflicting results for the effect of statin or metformin on overall PC survival. They systematically searched for
studies about the association between statin or metformin use and overall pancreatic cancer survival in electronic
databases. A meta-analysis based on hazard ratios (HRs) and 95% confidence intervals (CIs) was performed using
random effect models. Heterogeneity between the studies was examined using I2 statistics, and sensitivity analyses
were conducted to assess the robustness of the findings. Of 116 statin-related articles identified, 6 retrospective cohort
studies representing 12,057 patients were included. There was significant heterogeneity between the studies.
Statin use was associated with improved survival among pancreatic cancer patients. Of 311 metformin-related articles,
8 retrospective cohort studies and 2 randomized clinical trials, representing 3,042 patients were identified.
Metformin use was associated with better overall survival among pancreatic cancer patients (meta-HR = 0.79; 95%
CI: 0.70, 0.92, P < 0.001), and significant heterogeneity was observed between the studies. These findings suggest
that the improved survival time of pancreatic cancer patients is associated with statin or metformin use. Due to the
multiple sources of heterogeneity of the original studies, these findings should be considered cautiously, and confirmed
with larger prospective individual-level studies.
The last review by Torres and co-authors focused on the complexity of omega-3 fatty acids modulation of signaling
pathways related to PC. Recently, the role of nutrition in health and disease has attracted much attention.
Several dietary ingredients are involved in metabolic, physiological, and cellular signaling affecting tumor growth
and progression. Although lipids, and more specifically polyunsaturated fatty acids, have been traditionally studied
due to their health effects in cardiovascular disease, it is now clear that they can affect an extensive array of cellular
processes that influence a wide range of diseases such as type II diabetes, inflammatory disorders and cancer. These
biological activities may be grouped as regulation of membrane structure and function, intracellular signaling pathways,
transcription factor activity, gene expression, and production of bioactive lipid mediators. In this review, specifically,
the current state of knowledge about the potential mechanism(s) of action and signaling pathways modulated
by polyunsaturated fatty acids in pancreatic cancer are discussed.
Cardio-metabolic complications are multifactorial diseases with different facets, many of which are poorly understood,
although genetics, epigenetics, humoral, habitual and environmental factors may be involved. Moreover,
with the dramatic escalation of obesity, diabetes and hypertension in all segments of the population including adults,
adolescence and children, the incidence of cardio-metabolic disease and related complications will further increase.
Therefore, this special issue puts together a collection of review articles by leading experts in the area to give a
critical appraisal of the current state of knowledge and recent accomplishments as well as challenges and future directions.
The role of pigment epithelium-derived factor (PEDF) in cardiometabolic disease is a among the emerging
themes of scientific interest, with the role of pigment epithelium-derived factor (PEDF) in cardiometabolic disease.
PEDF is a glycoprotein that has been shown to possess anti-thrombotic and anti-fibrotic properties besides its effects
against oxidative stress and inflammatory. Accordingly, in an article featuring in this special issue, Yamagishi
& Matsui underscored the role of PEDF in cardiometabolic diseases and related complications, with particular focus
on diseases such as diabetic retinopathy, renal dysfunction, hepatic insufficiency and disorders affecting the male
and female reproductive systems. The authors discussed the potential clinical relevance of modulating PEDF for the
prevention and management of these cardiometabolic disorders. In another related article, Shinlapawittayatorn et al.
gave profound insights on the effects of obese insulin-resistance, a common risk factor for ischemic heart disease on
ischemia-reperfusion injury of the heart. Amongst the pertinent points raised by the authors is whether improving
insulin sensitivity by pharmacological interventions could ameliorate reperfusion induced myocardial injury. Dysfunctional
myocardium is a common complication of diabetes. To expatiate on this problem further, Tarquini et al.
wrote an article about diabetic cardiomyopathy, a pathophysiological condition in which the myocardial interstitium
undergoes alterations resulting in abnormal contractile function. The authors reported that in the early stages of the
disease, diastolic dysfunction is the only abnormality, but systolic dysfunction supervenes at later stages with impaired
left ventricular ejection fraction. Furthermore, the authors underscored a putative correlation between diabetes
and cardiomyopathy, especially in diabetic patients with co-morbid with microvascular complications, and suggested
that this correlation parallels the duration and severity of hyperglycemia.
Besides the heart, the kidney is an important organ for the regulation of extracellular volume and thus blood
pressure. Renal dysfunction is associated with hypertension, proteinuria and kidney failure. Accordingly, novel insights
on structures of the kidney, such as the glomerular filtration barrier, are important. In a related article that
appears in this special issue, Ndisang wrote about the putative cross-talk amongst the major components of the
glomerular filtration barrier including podocytes, endothelial cells and the basement membrane, and how the dynamic
interplay and interaction between these constituents may be fundamental for effective filtration. Furthermore,
the author highlighted some of the challenging issues about the interaction between: (i) glomerular endothelial cells
and podocytes; (ii) glomerular endothelial cells and glomerular basement membrane; (iii) podocytes and glomerular
basement membrane; (iv) the simultaneous interaction among the three components, and suggested that the elucidation
of these multifaceted interactions will pave the way for greater understanding of the pathophysiology of kidney
dysfunction and the formulation of novel therapies for kidney disease. In another related article, Krämer and Weidemann
gave their insights on Fabry disease, pathophysiological condition associated with X-linked lysosomal storage
caused by deficient activity of α-galactosidase A and intracellular accumulation of globotriaosylceramide in
different physiological entities such as the vascular endothelium, nervous system, eyes, skin, heart and kidneys.
A wide variety of drugs are used for the treatment and management of cardiometabolic diseases. For example,
proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors are used to lower low-density lipoprotein cholesterol in
patients with dyslipidemia, hypercholesterolemia or atherosclerosis. In an article, in this special issue, Schremla and Gouni-Berthold gave an in-depth insight on the use of monoclonal antibodies against PCSK9 to attenuate hypercholesterolemia,
and reported that antibody-derived PCSK9 drugs such as alirocumab (Praluent®) and evolocumab
(Repatha®) can reduce low-density lipoprotein cholesterol by 70%. Generally, drugs are routinely reviewed for their
efficacy and safetyly. In this light, Eleftheriadou and co-workers insights on the cardiovascular safety of older and
newer anti-diabetic medications. The authors reported that metformin, a first line drug for the treatment of type 2
diabetes, is also endowed with cardio- protective effects and should be considered the primary choice, while second
line agents such as empagliflozin, liraglutide and semaglutide are reasonable options for patients with cardiovascular
disease, whereas the class of sulfonylureas with the exception of gliclazide should be administered to diabetic
patients co-morbid with other cardiometabolic diseases. In addition, the authors reported that Saxagliptin, alogliptin,
sitagliptin and lixisenatide have been evaluated in cardiovascular safety trials and were shown to have neutral effects
on cardiovascular outcomes, whereas pioglitazone has some cardiovascular benefits. However, Saxagliptin
and alogliptin should be avoided in patients with heart failure. Consistently, in another article featuring in this special
issue, Schmitz and Gouni- Berthold gave clinical evidence on the efficacy and safety of volanesorsen for the
treatment of hypertriglyceridemia.
Besides, drugs and other pharmaceutical formulations, dietary fibres and polyphenols are cyto-protective. Accordingly,
the protective effects of dietary fibres and the antioxidant and anti- inflammatory properties of polyphenols
such as curcumin, quercetin, genistein, caffeic acid phenethyl ester were examined by Pittala and co-workers.
They discussed the effects of various naturally occurring polyphenols in the management of metabolic dysfunctions
Collectively, the contributions of the authors of this special issue have underscored to the complexity of cardiometabolic
diseases, highlighting the different facets, the accomplishments to date, the challenges that obscure the
horizon and the prospects for the future, to which we can all look toward with some degree of optimism.
Nanotechnology is growing in prevalence in consumer products and medicine. Most nanomedicine are carriers that are capable of homing in, taken up easily by the target cells and eventually delivering their drug payload to the target sites and some have smart designs that release the payload according to designed stimuli. However, while there are many advantages offered through bionanotechnology, there are potential unintended consequences especially on the non-targeted cells remain a problem of toxicity of these very small particles. This special issue describes a series of the latest most exciting research in the fields of nano medicine covering cancer and anti-microbial applications and balanced with some nanotoxiological studies covering nano biology and more realistic nano materials testing platforms.
Growing evidence supports a primary role of inflammatory reactions, both acute and chronic, in the development and progression of the main human diseases. The redoxmediated pathophysiological mechanisms are crucial in the evolution of various diseases, in which inflammation is involved. In this theme issue we would like to consider the role of inflammation and redox balance in the genesis and worsening of diseases, such as atherosclerosis, metabolic syndrome, and ischemia/reperfusion injury. Reviews by scientists, with basic and clinical background, will contribute to give a comprehensive picture of the inflammation- and redox-mediated pathogenesis of the diseases and an up-to-date scenario of therapeutic approaches.
This mini theme issue will consider some classes of bioactive natural products and their role in the medicinal chemistry. Many studies have pointed out new bioactivities for well-known natural products, showing that not only” new chemical entities” obtained by natural sources but also known and “old” natural products can be a valuable source of new therapeutic agents. In the issue triterpene, sesquiterpene, coumarins, stilbenoids, and also phenolics from Cannabis will be considered focusing on both natural and
synthetic (or semisynthetic) compounds, their bioactivity and their potential importance in the field of medicinal chemistry.