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Volume 26, 42 Issues, 2019
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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.
Currently, biosimilars are definitely a reality in the medical management of inflammatory bowel diseases (IBD),
namely Crohn's disease (CD) and ulcerative colitis (UC). The growing published evidence has demonstrated that the
infliximab (IFX) biosimilar (CT-P13) seems to be efficacious, and safe with a similar immunogenicity profile as the
originator product (Remicade™) in the management of IBD. This pharmacological profile, in addition to a reduction
in the direct costs of the medications, leads to an increased use of biosimilars for IBD worldwide [1, 2].
In this edition of Current Medicinal Chemistry, interesting articles exploring several issues regarding the use of
biosimilars in IBD are presented in detail. In an interesting review, Martelli and Peyrin-Biroulet demonstrate several
aspects of CT-P13, the most studied IFX biosimilar to date, in the real-world setting . Nine studies with 1245
IBD patients (744 CD, 499 UC and 2 IBD-unclassified patients) demonstrated the efficacy of CT-P13 in different
cohorts around the globe. Moreover, a total of 8 studies reviewed suggest that the biosimilar IFX is well-tolerated in
real-life setting, with no significant safety differences from the originator. These studies mostly included patients
with no previous exposure to biologics, and positioned IFX biosimilar at the same level as the originator product,
covering the gap between them.
However, controversy still exists regarding the approval process of the IFX biosimilar by regulatory agencies.
Magro et al. describe in detail the extrapolation data regarding other diseases, such as rheumatoid arthritis and ankylosing
spondilitis, that shortened the timeline process for the approval of CT-P13 for IBD in Europe and the
United States . Could data from rheumatology be extrapolated to IBD? CD and UC have different inflammatory
pathways as compared to other immune-mediated diseases. There is also the involvement of luminal agents and microbiota,
which can play a significant role in inflammatory response in IBD. Moreover, would rheumatoid arthritis
be the right model to test an anti-TNF biosimilar? Are rheumatology populations included in the studies representative
of IBD patients? One should also remember the story of etanercept, an anti-TNF agent which proved no efficacy
in IBD patients. Several arguments can still keep a wider gap between a biosimilar and an originator product,
despite growing evidence on efficacy and safety.
One of the most important advantages of biosimilars is the reduction of costs. Gulacsi et al., from Hungary (one
of the countries with wide experience with biosimilars), reviewed a complete set of economic considerations involved
with the use of biosimilars in IBD . Cost reduction with the use of IFX biosimilar can save an important
portion of budget for public and private payors, as it can be priced with a 15-75% discount as compared to the
originator. This means several advantages for patients and health care practitioners. First, obviously with the price
reduction, more patients can have access to and be treated with biological agents, with the same limited dispended
budget of a specific country or health insurance population. This shortens the gap towards improved clinical outcomes,
as adequately timed biological therapy can change the natural history of CD, for example, reducing the need
for hospital admissions and surgery. Secondly, we currently know that several patients need the dose optimization
of biologics during treatment, what can be nicely covered with cost reduction. In addition to that, specific phenotypes
of IBD (e.g. perianal fistulizing CD) may need higher doses of biologics to achieve deep remission and better
outcomes, differently from luminal disease. These patients, who could benefit from higher doses, would have the
access to the drugs facilitated with cost reduction. By shortening the gap between biosimilars and originators, all
involved parts are winners in the complex chess match of costs in IBD (patients, physicians and payors).
Still, the definition of which patient profile would benefit more with the use of biosimilars needs to be better
studied. Danese and Fiorino, after a literature review, stated that IFX biosimilar can be safely used in adults and pediatric
patients with no previous use of any IFX . The controversy of switching from the originator to the
biosimilar, and vice-versa, leads to important discussion on pharmacovigilance. One must also remember that more
biosimilars of IFX will emerge, and other anti-TNF biosimilars, such as adalimumab, have already been approved in some countries. This emphasizes the need for a careful vigilance program to understand which specific drug to
monitor, if aleatory switching is used with no medical reasons.
The amount of data comparing the originator IFX with biosimilars demonstrates similar efficacy and safety, in
addition to reduction of costs and possibilities to include more patients and to use higher doses in specific scenarios,
what could shorten the gap between the two products. On the other side, issues regarding extrapolation of indications
and non-medical switching still tend to widen the gap. In medicine, physicians must have a high sense of attention
when new strategies are more used, in this specific situation, due to the large number of biosimilars that will
be used in the IBD scenario in the near future. Despite we tend to keep ourselves minding the gap, it becomes clear
with growing evidence that the gap between originator product and the IFX biosimilar in IBD is becoming shorter.
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.
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