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Volume 26, 42 Issues, 2019
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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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