ISSN (Print): 1381-6128
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Volume 24, 46 Issues, 2018
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(School of Basic Medical Science, Beijing University of Chinese Medicine, Beijing 100029, China)
23 Abstract Ahead of Print are available electronically
82 Articles Ahead of Print are available electronically
Abstract: This article summarizes several contributions on the coronary microcirculation. Many of the participant authors belong to the
Working Group on Coronary Pathophysiology and Microcirculation of European Society of Cardiology. These contributions explored a variety
of topics pertaining to coronary microvascular physiology and pathophysiology. The latest methodologies that are being used to investigate
the coronary microvasculature, including myocardial contrast echocardiography, fractional flow reserve and and instantaneous wave free
ratio, are discussed. Advances in the mechanisms of dysfunction of the coronary microcirculation - for example, enhanced arginase activity
and production of free radicals by dyslipidemia or hyperhomocysteinemia and its myogenic and flow-dependent responses--are reported. The
articles touched on the relation of the microcirculation to clinically important conditions, such as the coronary no reflow phenomenon and
offered recommendations for future research in important areas, such as angiogenesis and restoration of the microvascular network. This research
is providing new ways to explore abnormalities of myocardial perfusion and its relationship with post infarction myocardial damage,
an area of inquiry that until recently has been limited to examination of coronary pressure-flow relationships using doppler wire-based measures.
Keywords: Microcirculation, no reflow, vasospastic angina, myocardium, angiogenesis, dyslipidemia.
THE MICROCIRCULATION AND THE HEART
The coronary microcirculation has the significant function of maintaining the proper balance between oxygen supply and oxygen demands.
To accomplish this task the resistance vessels of the heart integrate the input from many intrinsic vasodilator and vasoconstrictor signals.
The goal is to discuss the innumerable outside inputs in the context of their actions on coronary blood flow and coronary resistance vessel.
Many pathophysiological disturbances may alter the regulatory processes within the coronary microcirculation. Many are the clinical
conditions that can be associated with microcirculatory disorders including ischemic heart disease.
RECENT PHYSIOLOGICAL FINDINGS AND CLINICAL ASPECTS OF THE CORONARY MICROCIRCULATION
We refer the reader first to the papers by Axel R. Pries et al.  and Lucian Calmac et al.  for a detailed discourse on regulation of
microcirculation in patients with stable coronary artery disease. It has become increasingly apparent that microvascular dysfunction can aggravate
tissue hypoxia and maintain a compromised state even after recanalization of the epicardial vessels. Single-photon emission computed
tomography performed six months after Percutaneous Coronary Intervention (PCI) in normocholesterolemic patients shows reversible perfusion
defects in 3% of patients treated with pravastatin and in 29% of those with placebo . These data supports the hypothesis of a protective
vascular action of statins on an otherwise compromised coronary microcirculation.
Generally, small arterioles respond differently than larger arterioles and small arteries. However, there are neural interactions between
small and large arteries, and arterioles which may account for some similarities in the development of coronary tone abnormalities in both the
epicardial and endocardial segments. The epicardial and intramyocardial coronary arteries are densely innervated by postganglionic sympathetic
and parasympathetic nerve fibers. Therefore, norepinephnne and acetylcholine released from these fibers interact with coronary adrenergic
and muscarinic receptors to control coronary vascular resistance. The paper by Edina Cenko et al. clearly shows that the microcirculation
is still the major culprit in patients having vasotonic angina or diffuse coronary epicardial artery spasm . The primary cause of coronary
vasospasm is coronary hyperreactivity that is commonly due to a deficiency in endothelial nitric oxide. Oxygen-derived free radicals
scavenge and rapidly inactivate nitric oxide, thereby promoting coronary endothelial dysfunction and constriction of both the large and small
coronary arteries even in myocardial sites remote from the ischemic region . Further mechanisms that contribute to the regulation of coronary
blood flow include the metabolic activity of the myocardium. The papers by Akos Koller et al.  and Teresa Padro et al.  show that
hyperhomocysteinemia and dyslipidemia may affect myocardial cellular function of the resistive vessels. The pathogenic mechanisms underlying
the relationship between microvascular dysfunction and dyslipidemia involve an enhanced arginase activity and production of free radicals
with recruitment and accumulation of leukocytes through their diffusion in the post-capillary venules. Hyperhomocysteinemia dependent
mechanisms seem to preferentially modulate tone in small arteries by increasing the uptake of glucose and lactate and decreasing the uptake
of free fatty acid by the heart. Metabolic control mechanisms seem the most important, because they link flow to metabolism and are involved
in ischemic vasodilation.
Many of the well-accepted risk factors for no-reflow are the traditional cardiovascular risk factors, such as hypertension, smoking,
dyslipidemia, diabetes, and other inflammatory processes. The most important seems to be hypercholesterolemia . As such, in individuals
with hyperlipidemia, intensive statin therapy before PCI is beneficial in reducing no-reflow. In a meta-analysis of 7 studies that examined
3,086 patients treated with statins before PCI, there was a complete prevention of no-reflow in 4.2% of patients treated with high dose statins,
compared with control patients receiving placebo, usual care, or lower dose statin therapy . Coronary no-reflow phenomenon occurs when
cardiac tissue fails to perfuse normally despite opening of the occluded vessel. The paper by Marialuisa Scarpone et al.  demonstrates that
often after prolonged occlusion the cardiac tissue did not recuperate normal perfusion despite opening of the large epicardial coronary arteries,
indicating that prolonged ischemia leads to damage of the microvasculature and precludes normal perfusion. The mechanism by which
prolonged occlusion triggers the damage to the microcirculation is still unclear. Some recent work has suggested a role for the endothelial
glycocalyx. The Endothelial Glycocalyx (EG) is an uneven soft polysaccharide coating over the vascular wall toward the vessel lumen.
Changes in the glycocalyx lead to the alteration of the transendothelial permeability, thereby causing the swelling of the endothelial cells,
which is one of the regulatory factors for functional capillary density. Rapid development of myocardial tissue edema may facilitate the impact
of vasoactive peptides such as endothelin and angiotensin on the microcirculation, which, in turn, may deteriorate vessel diameter and
flow, leading to the no reflow as illustrated by Evangelos Oikonomou et al. .MEASUREMENTS OF THE CORONARY MICROCIRCULATION
Although the focus of this special issue of Current Pharmaceutical Design is on the regulatory mechanisms of the microcirculation and
their translation to targets in clinical practice, it is important as well to highlight some methods that may be able to assess the distribution and
regulation of resistance vessels across the wall of the left ventricle in clinical practice . A number of noninvasive modalities are able to
accurately assess microvascular dysfunction as shown by the paper by Danijela Trifunovic et al. ; however, these are not readily available
in the catheterization laboratory and can be challenging to use in acutely ill patients, as those presenting with no reflow after PCI. For these
reasons, there has been long-standing interest in developing invasive methods for assessing microvascular function in the catheterization laboratory.
A number of Doppler wire-based measures are described by the paper of Sasko Kedev et al. . The findings from this study confirm
those of previous studies showing that Fractional Flow Reserve (FFR) and instantaneous wave Free Ratio (iFR) measured at the time of
catheterization correlate with evidence of microvascular dysfunction on noninvasive imaging.
With this background in mind, it is interesting to read the reports by Davor Milicic et al.  and Zorana Vasiljevic et al. . These
papers focused on the role of microcirculation in congestive heart failure. Still, there is no solid proof to directly correlate coronary microvascular
dysfunction to heart failure in human patients to date, which is probably due to the lack of proper models and the need for more advanced
finer techniques. Much more importantly, there is no single drug regimen that could effectively reverse cardiac dysfunction after
myocardial infarction. The paper by Lina Badimon et al.  offers an overview of the relationship between angiogenesis and the coronary
microcirculation. The restoration of the microvascular network, which has been damaged during ischemia as well as upon reperfusion, appears
a promising approach to refrain the deleterious effects of coronary obstruction. Monocytes can trans-differentiate into endothelial celllike
promoting angiogenesis. In rodents, both growth factors and cell therapy can induce angiogenesis. However, uncertainties and controversies
still remain. In this regard, the most common questions are: what type of cells can be primarily regenerated by angiogenesis: myocytes or
endothelial cells? Are these cells able to strengthen cardiac performance? The answers to these questions may largely addresses our difficulty
in understanding the mechanisms underlying the restoration of the microvascular network as well as myocardium after myocardial infarction.
Human trials performed to stimulate angiogenesis in patients undergoing primary PCI have mostly failed. Investigating thoroughly the potential
of different subsets of monocytes/macrophages in angiogenesis promotion, as well as the study of their receptors are needed to develop
and optimize future therapies aimed to restore myocardial function after ischemia.
In summary in this issue of Current Pharmaceutical Design, we summarized several aspects of control mechanisms that govern the level
and the size of the coronary microcirculation: endothelial and myogenic control mechanisms in the coronary microcirculation and the translation
in their clinical counterparts.
Current Approaches to Diagnostics and Therapies of Chronic Diseases: Focus on Molecular and Cell Biology
Chronic diseases, also known as non-communicable diseases, are long-lasting complex disorders. Worldwide, millions of people die each
year from chronic diseases including cardiovascular, neurological, lung diseases, type II diabetes mellitus and cancer. This cause of death
increases in rate both in developed and developing countries [1-3].
Chronic diseases are often characterized by similar features, such as pathophysiological mechanisms and molecular alterations. Reactive
oxygen species production causing oxidative stress, mitochondrial dysfunction, inflammation, accumulated DNA damage, dysregulation of
autophagy are the common features of many chronic diseases [4-6]. During the recent years, the search for new therapeutic targets for the
treatment and diagnosis of chronic diseases led to the discovery of novel biomarkers and therapeutic targets. Thus, current approaches to diagnosis
and therapy of chronic diseases are based on the researches in the fields of cell and molecular biology.
This special issue is focused on diagnosis and therapy of chronic diseases such as cancer, renal fibrosis, inflammatory bowel diseases,
diabetes, atherosclerosis and others. The presented review papers authored by international experts in the field describe the current knowledge
on therapy of chronic diseases and propose some unusual approaches such as traditional Chinese medicine.
Fu et al. in their review “The anticancer effect of Sanguinarine, a review” discussed the anti-cancer properties of alkaloid sanguinarine.
Sanguinarine possesses anti-inflammatory, proapoptotic, antioxidant and growth inhibitory activities on tumor cells. “This paper describes
various anti-cancer mechanisms, such as inhibition of erroneously activated signal transduction pathways, apoptosis and inhibition of tumour
cell proliferation, exhibited by sanguinarine” .
Sun et al. in their review “Individualized Tacrolimus Therapy for Children with Nephrotic Syndrome: Mind both the Ontogeny and
Pharmacogenetics of CYP3A” have focused on individualized tacrolimus therapy for children with nephrotic syndrome. Authors discussed
the role of ontogeny and genetics in the individual dosing regimen of tacrolimus, whereas current guideline has recommended that the tacrolimus
dosage should be adjusted according to the Cytochrome P450 3A5 genotype (i.e. genetics) .
International team from UK and China have presented a rather unusual review “Chinese herbal formulas and renal fibrosis: An overview”
by Shen et al. have focused on the therapy of renal fibrosis by Chinese herbal formulas of traditional Chinese medicine. It has been shown
that Chinese herbal formulas can act as anti-fibrosis agents due to their anti-oxidant, anti-inflammatory and anti-proliferative properties.
“Chinese herbal formulas are determined according to traditional Chinese Medicine theory and this review highlights these formulas and suggests
a possible mechanism for their use in the treatment of renal fibrosis” .
International team from Saudi Arabia and China in the review paper “IRW and IQW attenuate induced-1 DSS inflammatory responses in
colitis mice” by Ma et al. focused mainly on the antibiotics therapy of inflammatory bowel diseases and discussed alternative therapy with
bioactive peptides (IRW and IQW). The effects of bioactive peptides on intestinal inflammation were described. “Intracolic administration of
IRW and IQW might be a novel option for preventing inflammatory bowel disease via regulating the level of serum amino acid and enhancing
the intestinal immune defense” .
International team of authors from UK and Iran have presented a review paper “Immunosuppression-lipid metabolism interplay and medicinal
plants in atherosclerosis: a review” by Moradi et al. focused on medicinal herbs treatment of atherosclerosis. The authors described
the most important medicinal herbs effective on atherosclerotic lesions through impact on the immune system. Effects of such medicinal
herbs as garlic, Ginkgo biloba, Quercus infectoria, Astragalus mongholicus Bunge and others were discussed .
Diemberger et al. (Italian group) in their review “Meta-analysis of sinus rhythm restoration and maintenance by electrical cardioversion
or catheter ablation in patients with chronic kidney disease: atrial fibrillation recurrences, thromboembolic events and modification of glomerular
filtration rate.” discussed non-pharmacological treatments for sinus rhythm restoration/maintenance by electrical cardioversion and
catheter ablation in Chronic kidney disease patients. Efficacy of such therapy for Chronic kidney disease patients and non-сhronic kidney
disease patients was compared .
Yamagishi and Matsui from Japan in their review “Therapeutic potential of DNA-aptamers raised against AGE-RAGE axis in diabetesrelated
complications” focused on discussion of the current literature on the therapeutic potential of DNA-aptamers raised against the advanced
glycation end products - a receptor for advanced glycation end products (AGE-RAGE) in various diabetes- and aging-related disorders.
Particular attention was paid to diabetes-associated complications, especially focusing on vascular complications of diabetes and cancer
International team from the USA and Russia in the review paper “Approaches to the NK cell modification for anti-tumor immunotherapy”
by M.A. Streltsova et al. focused on the therapy by the genetically modified natural killer cells. Authors compared the efficiency of recognizing
and destroying tumor targets by the genetically modified natural killer cells in comparison with the therapeutic T cells. The perspectives
and advantages of various approaches to modification of natural killer cells were discussed .
International team of authors from UK and China (Xiao-Qin Li et al.) in their review “Chemical constituents and pharmacological activities
of Stellera Chamaeja” discussed anti-tumor effects of Stellera Chamaejasme. Authors mainly focused on the pharmacological properties and the chemical composition of S. Chamaejasme. The authors hypothesize that S. Chamaejasme has anti-tumor activity. They discussed antiliver
cancer activity anti-lung cancer activity anti-leukemia activity and others .
International team from Pakistan, Saudi Arabia, Qatar and USA (Kaneez et al.) in their review “The dual specificity role of transcription
factor FOXO in type 2-diabetes and cancer” summarized information about the biology of Forkhead box O transcription factors. “The Forkhead
box O transcription factors are implicated in several signaling pathways and play a vital role in various cellular and physiological processes
include, for instance, ROS (reactive oxygen species) response, cell proliferation, regulation of programmed cell death, longevity, metabolism
and cancer and regulation of cell cycle.” These proteins can be used for elaborating on novel therapeutic approaches to treat cancer
The review “Sulfur mustard-related ocular complications: a review of proteomic alterations and pathways involved” by Panahi et al. from
Iran is focused on eye injuries caused by sulfur mustard. Sulfur mustard causes deficient of iron-dependent regulations and pathological
changes in vascular endothelial growth factor expression. Furthermore, sulfur mustard related proteomic alterations and the association of the
found proteins with other eye disorders and diseases were reviewed .
The remaining articles of this issue are devoted to current approaches to diagnostics of chronic diseases, new diagnostics targets were also
Yuan et al. (Chinese group) in their review “The Mechanism of Exosomes Function in Neurological Diseases: a progressive review” discussed
potential mechanisms of exosomes function in neurogenesis, angiogenesis and BBB delivery and differentiated various sources of
exosomes in traumatic brain injury, Alzheimer’s disease, stroke and tumor. Moreover, authors focused on the potential application of
exosomes in diagnostics and treatment of various diseases .
Hassan et al. (Iranian group) in their review article “The role of epigenetic alterations involved in sepsis: An overview” focused on the
diagnosis of sepsis based on detection of epigenetic alterations (DNA methylation pattern, histone modification). Authors also discussed drug
targets validation for the treatment of sepsis. “Epigenetic mechanisms can provide a highly sensitive and accurate method for sepsis diagnosis
using blood and other body fluids” .
Karagodin et al. (Russian group) in their review “Diagnostics and Therapy of human diseases - Focus on sialidases” discussed diagnostics
of sialidase-related disorders such as sialidosis, cancer, atherosclerosis and others. Therapeutic approaches by sialidase inhibition were also
discussed. “Sialidases are involved in the pathogenesis of a whole range of diseases, so the knowledge and expertise gained from genetic
defects leading to human sialidase inhibition can be used in the design of the drugs. In vitro studies suggest that some sialidase inhibitors
might be useful therapeutics for treating sialidosis, cancer, infections, immune diseases, atherosclerosis and other pathologies” .
Prasad from Canada in his review “Does HbA1c Play a Role in the Development of Cardiovascular Diseases?” compared diagnosis of
diabetes by hemoglobin A1c and advanced glycation end products. Hemoglobin A1c is considerate as a useful marker for the diagnosis and
management of diabetes. Author concluded that advanced glycation end products cannot replace HbA1c in the diagnosis of diabetes because
there is no correlation between advanced glycation end products with serum glucose .
A research article “Tumor necrosis factor-α and C-C motif chemokine ligand 18 associate with atherosclerotic lipid accumulation in situ
and in vitro” by Orekhov et al. (Russian team) describes the expression of tumor necrosis factor-α and C-C motif chemokine ligand 18 under
the accumulation of intracellular cholesterol in atherosclerosis. Authors assumed that the accumulation of intracellular lipid induces pro- and
anti-inflammatory responses in the arterial cells. Authors did not discuss the direct clinical implementation of their results; however, perspective
to use these results in the development of diagnostics of atherosclerosis and anti-atherosclerotic therapy is obvious .
We hope that the presented thematic issue will be of interest to our readers, as well as helpful for generalizing the current knowledge in
various areas of clinical science.
Gene therapy is a promising approach to treat chronic and acquired diseases because it allows the regulation of a gene sequence that is
identified as benefitial or detrimental to the proper functioning of the organism. By gene therapy it is possible to repair, replace, add or silence
the target gene. In this special issue, gene therapy involving gene silencing by the RNA interference (siRNAi) mechanism will be presented
and discussed as a promising therapeutic strategy for a wide variety of diseases; however it has not become clinically available yet because
some shortcomings still need to be addressed for effective delivery, for instance, the instability and poor cellular uptake of RNAi molecules.
Taking this into account, in our special issue, Kumavat et al. reviewed the nanotechnology aspects applied for the delivery of RNAi at the
targeted site with fewer off-target effect and high stability. The manuscript also expounds on various types of nanoparticles, associated challenges
and modalities to overcome the same with potential biomedical applications. A special emphasis ongoing clinical trials, regulatory and
safety status has also been presented . In addition, main challenges of topical delivery approaches mainly are related to the delivering of
siRNA into skin due to the highly effective defensive skin barrier function, the high molecular weight of siRNA and also to the net siRNA
negative charge under physiological conditions and the need to cross the negatively charged cell membrane. The development of siRNA delivery
systems that overcome one or more of these limitations improves the efficiency of gene silencing. Thus, an update on the advances in
topical siRNA-based non-viral delivery systems to prepared carrier molecules able to mask siRNA-negative charges, compress siRNA molecule
to make it smaller and protect siRNA from degradation as a powerful therapeutic strategy for several skin diseases are deeply discuss by
Rosa et al. . The targeting liposomes containing siRNA to overexpressed receptors of cancer cells that represents a strategy for better
therapeutic outcome, with improved efficacy and reduced toxicity were herein discuss by Eloy et al. . Considering that efficient delivery of
siRNA to the target tissue is a major challenge, the liposomes could be functionalized with several chemical moieties that can be recognized
by cancer cells more than by normal cells. These ligands include folate, transferrin, peptides, oligosaccharides, monoclonal antibodies and
aptamers. In this article, the authors describe chemical functionalization strategies and address the major in vitro and in vivo findings in the
field of cancer treatment. Thereafter, Yoko Endo-Takahashi et al. summarize the Ultrasound-mediated nucleic acid delivery systems and discuss
the possibility of combining liposome and ultrasound for RNAi-based therapies . Emerging platform for siRNA delivery from
hyaluronic acid (HA) is also discussed in this issue by Shah et al. . This biopolymer offers a variety of properties such as biodegradability,
biocompatibility, aqueous solubility, viscoelasticity, and non-immunogenicity. Numerous HA-based nano-vector delivery systems such as
polymeric nanoparticles, liposomes, and others when hybridized with siRNA, have been delivering this genetic material safely and efficiently
overcoming the stability problem. This review aimed to uncovers the HA and HA hybridized nanoplatforms for siRNA delivery systems with
particular focus on the discussion of available reports with addressing the future potential of this combination. In the last article of this issue,
Marinho et al. shows the use of gene therapy of RNAi targeting transcription factors involved in Ischaemia-reperfusion injury, the crucial
choice of siRNA targets and the advantages and problems of the siRNA use for preventing liver Ischaemia-reperfusion injury during transplantation
are also highlight . Moreover, the authors discuss how the use of liposomes contributes to the improvement of siRNA therapy by
increasing siRNA stability in vivo and avoiding siRNA off-target effects. Finally, we, the guest editors, would like to thank to Current Pharmaceutical
Design publishing team, specially Dr. Kazim Baig for their help and patience, and to the authors for their excellent contributions,
and to the guest-reviewers given your expertise in this area, they contributed to this special issue quality.
Abstract: Depressive disorders affect more than 300 million people all over the world and 16% of US population. Depression is also the
leading cause of disability worldwide and a major contributor to the overall global burden of disease. The first antidepressant was approved in
the 1950s. In 2013, antidepressants became the most commonly prescribed drugs in the United States. However, the diagnosis and treatment
of depression is changeling since depression is a rather heterogeneous disorder with various co-occurring symptoms and divergent responses
to treatment. In this theme issue, we brought together 12 papers written by the leading scientists from all over the world. The special issue
was divided into 4 sections. The first set of papers explored topics in the precision medicine of depression. The next section was about the
application of pharmacometabolomics on the discovery and development of new antidepressants. In the third section, we had a series of papers
focusing on the status of current and future antidepressants. The final section described the alternative therapy for depression. This theme
issue added our understanding of the diagnosis and treatment of depressive disorders.
Keywords: Depression, neuroimaging, antidepressants, metabolomics, fast-onset, medicinal plants, nutrition, Ayurveda
PRECISION MEDICINE IN DEPRESSION
Precision medicine, the capacity to really tailor treatments to specific populations and individuals, is a novel approach for the treatment of
depression. The effective treatment would only be achieved through the diagnosis and precise classification of depression subtypes. Magnetic
Resonance Imaging (MRI) is an especially useful modality for depressive disorders due to its high resolution for soft tissues such as the brain.
In the first 2 papers of this theme issue, Song, et al.  and Qiu, et al.  reviewed the recent advances for the diagnosis of depression and
the evaluation of treatment response using MRI. The selection of antidepressant choices relies on the development of new techniques for
measuring antidepressants. Mansour et al.  developed a simple, fast and sensitive method to determine venlafaxine in biological fluids
and pharmaceutical formulations using just a pH meter and ion-selective electrodes.
PHARMACOMETABOLOMICS IN THE DEVELOPMENT OF NEW ANTIDEPRESSANTS
Pharmacometabolomics aims to assess the metabolic effects of the pharmaceutical treatment. With the technical advances in analytical
instruments, metabolomics is entering into a “new generation”. Jian, et al.  summarized the broad applications of Next-Generation Metabolomics
(NGM) in facilitating the discovery and development of antidepressants. Albiflorin was used as an example to illustrate how
NGM improves our understanding of drug candidate actions and facilitates drug safety evaluation.
CURRENT AND FUTURE ANTIDEPRESSANTS
Pharmacotherapy is the main treatment approach for depression. Antidepressants have become the most prescribed drugs in the U.S.
Amidfar and Kim reported the selective agonists and antagonists of 5-HT receptors in the treatment of major depression . Sleep disorders
are the core symptoms of depression. Satyanarayanan, et al. reviewed the pharmacologic interventions targeting on circadian rhythm and
melatonin receptors . The majority of current antidepressants are limited by their slow action. The conventional antidepressants can take as
long as six weeks to have an effect. Potentially safe and fast-acting interventions would be invaluable. Jeff, et al.  and Kuo, et al.  discussed
the molecular mechanisms of the promising fast-onset antidepressants. Depression is the most common neuropsychiatric illness associated
with Parkinson disease (PD). Kabra and the co-authors reviewed the emerging and alternative therapies for the treatment of depressive
patients with PD .
ALTERNATIVE THERAPY FOR DEPRESSION
The current synthetic antidepressant drugs have limited efficacy and might undesirable side effects. Dietary improvement may provide an
efficacious and accessible treatment strategy for depression. Xu, et al.  summarized the recent advances in nutrition for the treatment of
depressive disorder. The use of complementary therapies is gaining popularity. Le, et al.  highlighted the psychotherapy of cancer patients
with the secondary depressive disorder. Indian Ayurveda is one of the most ancient medicine in the world. Sharma and the co-authors 
reviewed the herbal and holistic solutions of Ayurveda for depression. Ismail, et al.  described some important medicinal plants and their
reported active constituents with antidepressant activity.
This special issue covers all the major aspects related to the diagnosis and treatment of depression. Both the guest editors and all the
authors hope that the special issue will help the readers quickly grab the recent advances in this field. Moreover, the critical visions from the
contributors in this special issue would motivate other scientists to develop more effective treatments for major depressive disorders in the
Crystallization is defined as the process in which solid crystal is precipitated from a fluid media (i.e. vapor, solution or melt). It has been
widely applied in many areas including pharmaceuticals, fine chemicals, functional materials, agrochemicals and foods. Generally, it can be
used to prepare high quality crystal substance by crystallizing it from a fluid media or to concentrate substance in fluid media by precipitating
In recent years, crystallization science and technology have received a lot of attention, especially in the field of development of new drugs
and foods. The crystallization technology of drug products is common with that of food products (food additives, functional foods, etc) in
many aspects. The works mainly focus on the molecular mechanisms of crystallization, new crystallization methods of active pharmaceutical
ingredients and food ingredients, development of novel characterization technology of crystals and crystallization process, application of
crystallization in the field of pharmaceutical and food science and industry.
Thematic Issue “Crystallization for Pharmaceutical and Food Science” of Current Pharmaceutical Design is a platform to discuss the
development and application of crystallization for pharmaceutical and food science. Marco Stoller et al. discuss process intensification techniques
for the production of nano- and submicronic particles for food and medical applications . Na Wang et al. introduce cocrystal and its
application in the field of active pharmaceutical ingredients and food ingredients . Nandi Chen et al. summarize the properties and the
applications of existing soft biomaterial-based nanocrystal in pharmaceutical . Hyerim Yang et al. review the pharmaceutical strategies for
stabilizing drug nanocrystals . Yanan Zhou et al. analyze the effects of polymorphism on physicochemical properties and pharmacodynamics
of solid drugs . Lek Wantha summarizes the kinetics of the solution-mediated polymorphic transformation of organic compounds .
Leming Sun et al. summarize the recent trends in nanocrystals for pharmaceutical applications . Daisy Arora et al. introduce recent advances
in nanosuspension technology for drug delivery . Mingxue Fan et al. review nanocrystal technology as a strategy to improve drug
bioavailability and antitumor efficacy for the cancer treatment . Cao Wu et al. summarize the preparation, precise control, and application
of nanocrystals toward the pharmaceutics and foods industry . Qi Zhang et al. summarize recent advances in magnetic nanoparticle-based
molecular probes for hepatocellular carcinoma diagnosis and therapy . Preshita P. Desai et al. summarize crystal engineering approaches
for the design of pulmonary delivery systems . Chandrakant R. Malwade et al. introduce process analytical technology for crystallization
of active pharmaceutical ingredients . Jaleh Varshosaz et al. review crystal engineering techniques for enhanced solubility and bioavailability
of poorly soluble drugs . Zhongyao Cheng et al. provide a comprehensive review on nanocrystals technology in the field of pharmaceutical
science and biochemical engineering . J. R. Campos et al. analyze the phase behavior of polymorphic fats in drug delivery
Editing this Thematic Issue for Current Pharmaceutical Design has been a great honor for us. We appreciate very much the invitation of
Prof. William A. Banks, and kind support from the staff members of Current Pharmaceutical Design. Our special thanks goes to Director
Kazim Baig for his continuous support during the whole process. In addition, we would also like to thank the authors for such grand writing
and the reviewers for their careful and diligent peer-review.
Oxidative stress, antioxidants and disease. One of the most fundamental challenges to prevention and management of disease-associated
tissue damage occurring as a result of oxidative stress, in particular, excessive activation of inflammatory processes, is the requirement to
counteract the effects of highly reactive biomolecules, typically containing single unpaired electrons on oxygen atoms. These compounds,
called reactive oxygen species (ROS), rapidly alter structure and chemistry of proteins, lipids, nucleic acids and other components of cells in
ways that may severely disrupt cellular metabolism, causing oxidative damage to affected tissues, which manifest as symptoms of a disease
. Numerous antioxidant compounds, most often produced by plants, (phytochemicals), are capable of quenching ROS activity to levels that
significantly augment health. Thus, aqueous-soluble antioxidants like vitamin C, and the lipid-soluble tocopherols (vitamin E), are necessary
components of human diet  and may positively affect prognoses of some diseases , but lack the stand-alone potency to definitively safeguard
against disease-associated oxidative tissue damage. This is due to the way such phytochemicals are utilized systemically. Such dietary
supplements, distribute into the interstitium, but mostly fail to achieve sufficient levels inside cells, to thoroughly counteract whole-organism
oxidative damage. As a consequence, endogenous defenses such as glutathione, and other antioxidant compounds active within cells, are often
overwhelmed by elevated ROS levels, which are a prominent feature of many diseases . For this reason, use of dietary supplements is
ineffective as a primary preventive or therapeutic countermeasure against any disease at the time of this writing, with the exception of disorders
such as scurvy, which develop as a result of deficiency of a dietary component (vitamin C) .
Current drug treatment doctrine: Major drawbacks. Current doctrine in pharmacotherapy for most disease states, has become reliant on
small molecule compounds such as corticosteriods and Non-Steroidal Antiinflammatory Drugs (NSAIDs), which may act intracellularly to
counteract a specific process – such as activity of a particular enzyme, critical for progress of a disease. Unfortunately, such interventions
impose artificial alterations on normal physiology, which may interfere with cell signalling vital for healthy homeostasis, with significantly
deleterious consequences. A well-known example of such an occurrence, was the case of Vioxx (Rofecoxib), that proved to be an excellent
analgesic due to its ability to block activity of cyclooxygenase 2 (COX-2) and resulting pain-inducing prostaglandin synthesis, but resulted in
cardiotoxic downstream effects that were occasionally fatal .
Heme oxygenases and novel approaches to pharmacotherapy. An emerging alternative strategy in current drug treatment approaches, is
use of benign, Generally Regarded As Safe (GRAS) compounds (most often phytochemicals) that amplify the strength of endogenous cytoprotective
mechanisms and mostly or completely avoid use of molecules that may interfere with normal cellular metabolism as an adverse
side reaction. Modulation of Heme Oxygenases (HOs), a heat shock protein (hsp) enzyme which is a primary defense against oxidative stress,
offers enormous promise for such an approach. HOs are produced by all animal cells studied at the time of this writing and are active in both
extracellular (eHO) and intracellular spaces (iHO) . The present special edition of Current Pharmaceutical Design (CPD) reviews the major
structural and functional properties of these fascinating stress response proteins, in the context of their capacity to protect against a diverse
range of pathological conditions in which particular diseases states may damage a host by imposing excessive oxidative stress on its component
tissues. The topic material considered in the present review, examines the putative role played by heme oxgygenases in maintenance of
normal homeostatic function and extends this insight to describe mechanisms by which their bioactivities constitute a core adaptive response
to various forms of trauma. HO function is here illustrated for several disease states, with focus on cardiovascular, neurologic, neoplastic and
immunoregulatory processes. This very exciting subject material is presented in the form of 11 essays by researchers and clinicians from
around the globe, who have emerged as leaders in their respective branches of biomedical science and are providing unprecedented insight
into the diverse means by which these enzymes may be exploited clinically.
Essays within this special edition: topic summaries. Dr. Daniel Bereczki Sr. at Department of Neurology, Semmelweis University in Budapest,
and Dr. Daniel Bereczki Jr, at the Department of Neurology, Hungarian Defence Forces Medical Center, along with Dr. Jozsef Balla
at the Institute of Internal Medicine, University of Debrecen, in Hungary, describe the clinical relevance of heme oxygenase-1 (HO-1) in
ischemic stroke ; a team of authors led by Prof. Vladislav Chernov at the Institute of Fundamental Medicine and Biology of Kazan Federal
University in Russia analyze mechanisms by which membrane components of mycoplasmas, an important class of human pathogen, affect
inflammation by modulating Nrf2 signaling – a pathway that includes hemе oxygenases ; Drs R. Clive Landis, Kim Quimby and André
Greenidge at UWI’s Edmund Cohen Laboratory for Vascular Research in Barbados, describe how Nrf2/HO-1 signaling in macrophages influences
differentiation of these cells to affect the pathogenesis of diabetic nephropathy ; Mark F. McCarty, founder and CEO of Catalytic
Longevity, in San Diego, California, describes how the spirulina chromophore, phycocyanobilin (PhyCB) a structural analog of the HO degradation
product biliverdin,and antioxidant potency in the same range as bilirubin may be combined with phase 2-inducer nutraceuticals for
prevention of opiate tolerance  – and in a second essay, reporting on a research initiative led by Dr. Iloki Assanga Simon Bernard at University
of Sonora in Hermosillo México, outlines a possible role for these enzymes in mitigating the severity of preeclampsia ; A U.S.-
German team led by Harvard Medical School Professor Leo Otterbein provides a cautionary note to expectations over the past two decades,
that strategies for inducing and regulating heme oxygenases will rapidly evolve into clinical tools with widespread use. Their essay outlines
the enormous promise such methods hold for healthcare improvements, but emphasizes the limitations of this technology and the slow pace at
which its implementation has proceeded ; Authors in the laboratory of Dr. Ana Lúcia S. Rodrigues at Brazil’s Federal University of Santa
Catarina provide state-of-the-art insight into roles played by HO-1 in the underlying pathomechanisms of neuropsychiatric and neurodegenerative
diseases ; Another team of Hungarian researchers, led by Professor Attila Szöllősi at University of Debrecen, Medical School,
outline the participation of heme oxygenases on a wide range processes necessary for health of the skin, along with autoimmune, allergic and
neoplastic dermatological disorders ; A second Brazilian team in the laboratory of Professor Leonardo Travassos, at the Federal University
of Rio de Janeiro, describe the interplay of cellular signaling processes in which both HO-1 activity and autophagy are involved ; A
team of collaborating researchers, with members in the USA, Russia, Mexico, Hungary and Kuwait, outline the role of heme oxygenases in
the pathophysiology of Parkinson's disease (PD)– and a bold approach to treatment of the disorder by use of nanoparticles that potentially
decrease alpha synuclein aggregation – a primary driver of PD pathogenesis ; Finally, Dr. David Haines and Dr. Arpad Tosaki at University
of Debrecen, provide a description of the current understanding as to the role of heme oxygenases in maintenance of normal, healthy
function of cardiovascular cells, tissues and organs, further describing how activity of these enzymes influence cardiovascular syndromes and
Plants are natural reservoirs of a diversity of compounds, many of which have pharmacological/nutraceutical activities towards a variety
of diseases. One important class of plant bioactive compounds is polyphenols. The term phenol is used to describe a structure with at least one
aromatic ring containing one or more hydroxyl groups attached and the flavonoids, with several aromatic rings, represent a well-known subgroup
of bioactive polyphenols. Other compounds, including hydroxycinnamates and phenolic acids, with only one phenolic ring, are also
referred to as polyphenols. These phytochemicals occur naturally in plants and epidemiological, pre-clinical and clinical studies have shown
their importance for human health as they reduce the incidence and prevalence of cardiovascular diseases, cancer, diabetes, inflammation and
age-related disorders. Modern pharmacopeia has received significant input from natural small molecules (such as polyphenols); however, the
process of identifying novel bioactive compounds from biological sources has been a central challenge in the discovery of natural products.
Moreover, the exploitation of polyphenols as sources of molecules with pharmacological/nutraceutical interest depends on effective methods
for compounds extraction to be further tested as regards their chemical and biological activities. Additionally, the use of fractionation procedures
coordinated with bioactivity/antimicrobial screenings – bio-guided fractionation – is required for the identification of single compounds
with therapeutic potential. Once identified, the pharmacokinetics and modus operandi of compounds need to be gathered to support the rational
design and synthesis of medicinal chemistry derivatives. Alternatively, large-scale production of potential bioactive polyphenols can be
achieved by means of synthetic biology. At last, technologies of controlled delivery must ensure that the compounds are carried to the site of
action. The ultimate goal of this pipeline is to discover and make available to society therapeutic alternatives for chronic diseases including
cancer, neurodegenerative, cardiovascular, and metabolic diseases.
The thematic issue is a journey in the field of polyphenols as bioactive compounds for health, exploring the current strategies for identification,
characterization, improvement and production of these protective molecules.
Foito et al. described the state of the art methodologies used for structural elucidation and annotation of novel bioactive compounds .
An overview of the metabolomics toolbox available, from hyphenated Mass Spectrometry (MS) and Nuclear Magnetic Resonance (NMR)-
based analytical technologies, is described alongside with technical developments in instrumentation and data processing. In addition, the
authors explore the importance of the integration of these tools in the bioprospection and drug discovery workflows. Overall, the review assesses
the huge potential of metabolomics for application in the process of drug/bioactive discovery from plants.
The degeneration of neurons in specific brain regions is one of the main causes of chronic Neurodegenerative Diseases (NDs) and the
formation of aggregates of misfolded proteins has been considered a hallmark underlying the pathophysiology of these diseases. Kostelidou et
al. discussed the available microbial (bacteria and yeast) genetic screens and selection systems targeting NDs-associated protein misfolding,
which facilitate the identification of cellular factors and disease processes as well as the discovery of synthetic and natural compounds with
protective activities .
The simplest eukaryotic organism yeast shares fundamental biological processes with mammalian cells, including some processes associated
with human diseases. This feature allows the use of Saccharomyces cerevisiae as test-tubes to decipher the molecular mechanisms underlying
disease pathology as well as to accelerate the discovery of protective molecules. In addition, mammalian cell models have been widely
used in polyphenol research to identify/validate polyphenol bioactivity for chronic diseases. Rosado-Ramos et al. reviewed the use of eukaryotic
cell models of NDs and their contribution for the identification of novel bioactivities as well as the benefits and limitations of their use as
tools in the search for bioactive polyphenols .
The use of the nematode Caenorhabditis elegans has been largely explored in aging research and, more recently, to investigate the multifaceted
properties of polyphenols as protective candidates for aging-related conditions. In this issue, Papaevgeniou & Chondrogianni compiled
the studies addressing the anti-aging and neuroprotective potential of polyphenols using C. elegans as multicellular model organism .
Epidemiological evidence suggests that polyphenol-rich diets lower the risk of certain cancers whereas epidemiological, in vitro, in vivo
and clinical studies point to the fact that natural polyphenols can be potentially used for the prevention and treatment of cancer. Momtazi et
al. reviewed the effects of curcumin on nasopharyngeal cancer, a rare type of head and neck cancer that is mainly treated by radiotherapy .
Curcumin is a well-established polyphenol with chemosensitizing, chemotherapic and radiosensitizing effects and its chemopreventive potential
has been studied in a variety of cancers. The authors highlight recent studies showing that curcumin has therapeutic and radio-sensitizing
effects on cells as well their mechanism of action. Overall, the potential of using curcumin as co-adjuvant of chemotherapy
without secondary systemic toxic effects in humans is discussed. Besides cancer, the therapeutic benefits of curcumin have also
been described for inflammatory processes, immunological disorders, diabetes, and oxidative stress. The molecule has a unique molecular
structure that easily interacts with biomolecules like protein and enzymes, thereby impacting their function/activity. Hatamipour et al. discussed
the underlying mechanisms responsible for those chemical interactions of curcumin .
The cardiovascular system is another field where the protective activity of polyphenols is well documented, particularly for atherosclerosis,
hypertension, myocardial infarction, anthracyclin-induced cardiomyopathy, angiogenesis and heart failure. Santos et al. reviewed the
knowledge of the main pharmacological effects and mechanisms of cardioprotection mediated by polyphenols in the heart and vessels obtained,
from in vitro, animal and human studies .
Hydroxytyrosol and its derivatives from virgin olive oil are important phytochemicals with proved activity for lifestyle-associated pathologies
such as cancer, cardiovascular and neurodegenerative diseases, as indicated by the epidemiological evidence. Hazas et al. reviewed
their natural occurrence, metabolic fate and bioavailability as well as their health beneficial effects together with newest perspectives on the
mechanisms of action based on in vitro and animal studies . The authors concluded that hydroxytyrosol, and its derivatives, could have
potential clinical use in cardiovascular diseases. However, more epidemiological data is needed to evaluate their preventive effects for NDs
Diabetes is a chronic metabolic disorder associated with several comorbidities, including diabetic retinopathy (DR), and increased oxidative
stress in the retina seems to trigger the damage of both neuronal and vascular cells. Ola et al. reviewed the evidence pointing out the potential
metabolic sources and pathways related to the increase of oxidative stress in DR and the role of dietary flavonoids, particularly flavonones,
flavanols, flavonols, isoflavones, flavones and anthocyanins, in the modulation of redox homeostasis in the diabetic retina .
Given the myriad of bioactivities described for polyphenols, these molecules have emerged as lead compounds for the design and synthesis
of improved molecules with a therapeutic application for several diseases. Almeida et al. described how organic synthesis has been essential
for the development of these new analogs, providing a wide range of structural modifications for structure-activity relationship studies
and improving/modulating the biological activity of promising compounds .
The studies reviewed in this issue unequivocally show the potential of polyphenols to modify pathological processes associated with
chronic diseases and the efforts of organic chemistry to develop novel molecules with improved activity. Nonetheless, the majority of these
compounds are still obtained from plant material by means of costly and inefficient extraction procedures. Dudnik et al. reviewed the use of
metabolic engineering and microbial cell factories (Escherichia coli, S. cerevisiae, Corynebacterium glutamicum and Lactococcus lactis) as
emerging alternatives allowing efficient and sustainable production of protective polyphenols .
Overall, eleven outstanding international experts were invited to contribute to this thematic issue and to share their opinions, with perspectives
of polyphenol research for the advance in therapy for chronic diseases. We hope that the multidisciplinary topics discussed with the
theme issue will promote further discussion among pharmaceutical/nutraceutical industry and researchers.
As it is pointed out in this special issue of Current Pharmaceutical Design, despite the extensive and multidisciplinary research during the
last years, a lot of basic and clinical research is still needed to better understand the manifestations, central and peripheral molecular regulators
of new mechanisms of GI ulceration and healing, physiology, pharmacology and pathology, especially in relation to the classic modes
of prevention/management of gastrointestinal ulceration and healing or their transformation into new concepts and the treatment of gastrointestinal
ulceration and healing. This is particularly important for acquiring new vistas in the therapy of gastrointestinal tract disturbances.
Therefore, “New mechanisms of GI ulceration & healing: Physiology, pharmacology & pathology” attempts to cover a huge area of
the pertinent scientific research. Between various concepts, the Robert’s cytoprotection concept is still one of the most fascinating concepts in
science development, particular with respect to conceptual disagreements, or on the other hand, novel agents, and attempts to improve concept,
as well as to finally realize some or all of the concept postulates in gastrointestinal tract therapy. Therefore, it seems interesting to review
again this issue, covering a huge area, by eminent experts, providing their most recent findings, including the development of new medicines
and new approaches.
Bilski et al.  in their review Exploiting significance of physical exercise in prevention of gastrointestinal disorders revealed the particular
relationship between physical exercise with different intensity and alterations the morphology and function of the gut including its protective
influence on the lipid metabolism and chronic systematic inflammation as well as the diversity, distribution and metabolite of the gut
microbiota. Based on the evidence provided in this overview, the regular, moderate exercise can reduce the risk of colorectal cancer and exert
a beneficial effect on upper and lower GI-tract disorders such as reflux esophagitis, peptic ulcers, cholelithiasis, constipation and IBD leading
to the attenuation of the symptoms. On the other hand, the high-intensity training or prolonged endurance training can exert a negative influence
on these same entities .
Olsen et al.  in the review New approaches for weight loss: experiments in animal models emphasized the interesting points such as
animal models (i.e., VBLOC (implanted hunger-blocking device) and knockout of muscarinic acetylcholine M3 receptor) known to reduce
food intake and body weight versus the expression of energy-balance regulating peptides in the hypothalamus as a drive for increased food
intake. Finally, emphasizing that the brain-gut axis plays an important role in the regulation of body weight, they proposed that the brainstem
may be more important in the regulation of food intake than hypothalamus in the context of the brain-vagus nerve-gut axis .
Review Similar and distinct mechanisms in the protective processes of upper and lower GI tract by Gyires et al.  is an excellent overview
of the protective mechanisms of upper and lower gastrointestinal tract providing their own findings purposefully elaborated. This review
analyzed many factors involved in various forms and levels of protection of mucosal tissues, mucosal protection in the periphery (barriers and
mediators), intestinal defense mechanisms (mucosal barriers, bile acids), stimulation of gastrointestinal mucosal protection (pre-epithelial,
epithelial, sub-epithelial possibilities) and central nervous system involvement .
The authors, Kang E.A. and collaborators  in review BPC 157 as potential agent rescuing from cancer cachexia summarized signaling
pathways and promising drug candidates to treat cancer-associated cachexia and focused their review on the possible application of BPC 157
for cancer cachexia with the mode of action. They showed the significant relieving effects of BPC 157 on C-26 colon adenocarcinomainduced
muscle degeneration and inflammation. The presented review is very informative and may provide support for the potential use of
stable gastric pentadecapeptide BPC 157 as a cachexia-rescuing therapeutic agent .
The author, Gaetano Iaquinto  in his review, The several activities of 4-methypyrazole in animals and humans, reviews 4-
methypyrazole (4-MP), a pyrazole derivative in animal and humans. 4-MP is a potent competitive inhibitor of ADH activity with an affinity
about a 1000 times more than toxic alcohols. 4-MP was shown to reduce the formation of toxic metabolites in lethal methanol and ethylene
glycol poisoning in animal models and in methanol poisoning in humans, and in particular, 4-MP provides significant protection of the human
stomach against alcohol-induced acute mucosal injury .
Kodama et al.  in their review MALT lymphoma, stress ulcer and cholinergic nerves from the viewpoint of bilateral and unilateral
truncal vagotomy and substance P follow the evidence that the vagal nerves play an important role in gastric function providing rich innervation
to this area and that the vagal nerve activity was shown to be related to both gastric cancer development and progression, but its relation
to the mesenchymal tumors such as MALT lymphoma is not known. Thereby, the authors were focused on the effect of vagotomy on gastric
MALT lymphoma development by in the Helicobacter heilmannii-mouse infection model .
The review Role of formyl peptide receptors in gastrointestinal healing by Prevete and collaborators  assessed the role of a particular
class of PRRs, the Formyl Peptide Receptors (FRP), in gut mucosa homeostasis. They report studies that strongly suggest the possibility that FRP activation is crucial for the maintenance of gut homeostasis. Furthermore, they provide indications for the potential clinical relevance of
novel directions related to FPR modulation in various gastrointestinal disorders .
The authors, Seiwerth and collaborators , in review BPC 157 and standard angiogenic growth factors. Gastrointestinal tract healing,
lessons from tendon, ligament, muscle and bone healing focused on gastric pentadecapeptide BPC 157, a peptide always given alone vs. standard
peptidergic angiogenic growth factors such as EGF, FGF and VEGF, and numerous carriers. They also reviewed how the healing could
happen involving angiogenic growth factors in the gastrointestinal tract and in extra-gastrointestinal tissues, such tendon, ligament, muscle
and bone, providing a carrier, use (i.e., EGF, FGF and VEGF) or no use (BPC 157). The effects of EGF, FGF, VEGF, and BPC 157 were
compared in various injuries, such as gastrointestinal ulcer, tendon, ligament, muscle and bone healing. They found that BPC 157 was the
only factor being consistently effective in all of the models, given per-orally or locally, unlike FGF, EGF, and VEGF. The authors found that
on the healing mechanism of BPC 157 is related to its own angiogenic effect in the healing .
The authors, Sikiric and collaborators , in review Novel cytoprotective mediator, stable gastric pentadecapeptide BPC 157. Vascular
recruitment and gastrointestinal tract healing cover an intriguing story about the stable gastric pentadecapeptide BPC 157 and the whole
story about the concept of the cytoprotection and possibly new insights. The basic concept providing the stomach cytoprotection as the most
fundamental concept, stomach cell protection and endothelium protection was largely elaborated. Having managed these two points, stomach
cell protection and endothelium protection, either one or together, even much more than standard cytoprotective agents do, BPC 157 employed
large scale of its beneficial effects seen in various organs. This provides an additional realization of blood vessels controlling, described
as “vessel recruitment depending on injury”, “bypassing vessel occlusion” or “running toward the defect”, leading to reestablishing
blood flow. This was taken as a final implementation of the concept of cytoprotection. Obviously, the reestablished blood flow, and largely
reversed injurious course may practically implement the cytoprotection concept .
The authors K. Takeuchi and K. Amagase  in their review Roles of cyclooxygenase, prostaglandin E2 and EP receptors in mucosal
protection and ulcer healing in the gastrointestinal tract reviewed how the PGE2 prevents acid-reflux esophagitis and affords protection of
the stomach against NSAIDs through the activation of EP1 receptors. Although CRS-induced gastric lesions were aggravated in IP but not
EP1 KO mice, endogenous PGE2 may also be partly responsible for mucosal protection during CRS via the activation of EP4 receptors, in
addition to that afforded by PGI1
/IP receptors. Similar observations were done in the other parts of GI tract (duodenum, small intestine, stomach,
large bowel) .
Racz et al.  in their review Defense mechanisms against acid exposure by dental enamel formation, saliva and pancreatic juice production
review defense mechanisms of different tissues. The similarities of enamel, salivary glands and pancreas are well emphasized and
described. The authors highlight the importance of bicarbonate buffer system and highlight the possible failures as well. The intracellular
transport and secretion mechanism are also reviewed .
Yanaka in his review Contribution of NRF2 in gastrointestinal protection from oxidative injury  reviews the evidence that dietary
intake of sulforaphane, derived from broccoli sprouts, ameliorates H. pylori-induced gastritis, NSAIDs-induced small intestinal injury, and
functional constipation. The additional focus was on many other compounds, which enhance the nuclear factor erythroid 2-related factor 2-
mediated antioxidant system, and in particular on some reports, which have shown that excessive stimulation of nuclear factor erythroid 2-
related factor 2 enhances chemoresistance and facilitates the growth of cancer cells .
The review Lifestyle and peptic ulcer disease from Yegen  extends a general point such as the risk of developing peptic ulcer disease
shown to be associated with genetic inheritance, lifestyle and social status of the patients, to an extensive and very informative review providing
particular chapters (Stress, NSAIDs, Diet and body weight, Alcohol, Smoking, Physical activity, Sleep) with a list of the references that
seems to be quite extensive and well chosen .
We hope multidisciplinary topics discussed with the theme issue will promote further discussion among pharmaceutical industry and researchers.
As the guest editor, I would like to thank all the authors and co-authors for their excellent contributions. Also, I would sincerely
thank and acknowledge the diverse group of experts and colleagues who offered their substantial reviewing efforts and suggestions. Last but
not least, I would like to express my gratitude to the Bentham Science Publishers for the wonderful experience while working with the journal
on this thematic issue. It was a great pleasure working with the Director Kazim Baig and for the opportunity to publish in Current Pharmaceutical
Design. It was a wonderful experience working with Editorial Assistant Aamer M. Khan at the time of submission and processing of the
manuscripts. I would like to acknowledge the contributions of others who took care of editing and processing the manuscripts to obtain the
best final quality at the time of publication.
CNS Therapeutics: Drugs and Peripheral Influences
Unique Approaches to Drug Delivery
It has been absolute honor to serve as a guest editor for this special issue of Current Pharmaceutical Design. Inflammation is the common
pathological basis for age-related diseases such as cancer, neurodegenerative diseases, cardiovascular diseases, and diabetes. Life expectancy
is estimated to dramatically increase in the upcoming decades, and despite it should be a great accomplishment for our societies, the increase
of longevity is a significant challenge for the global economy because this increase leads to an enhance in the incidence of age-related diseases.
There is great interest by pharmaceutical/biotechnology industries to focus on drug development strategies for inflammatory-related
pathologies. Nowadays, anti-inflammatory therapeutics market is the major part of global pharmaceutical industries and is expected to grow.
The pharmaceutical industries are benefiting of academic inflammation research, and are adopting novel approaches in drug designing as key
strategies to gain additional market share. In fact, according with Allied Market Research report, the global anti-inflammatory market is expected
to garner $106.1 billion by 2020. However, still the challenge is to design new anti- inflammatory drug with lesser side effects.
This special issue will cover several inflammatory research areas. For example, a growing number of researchers have discovered various
signaling pathways that are associated with the initiation and progression of inflammation. An excellent manuscript by Yeung and Colleagues
 focus on classical inflammatory pathways: p38 MAPK, IL-6/JAK/STAT3 and PI3K; and a non-classical inflammatory pathway, the
Hippo. The molecular mechanisms, associated pathologies, selected drugs of these signaling pathways and limitations and potential risks of
anti-inflammatory drugs will be summarized. The central nervous system may be the target of several chronic inflammatory-related pathologies
where the inflammatory component acts either as a primary cause of the disease or as a secondary outcome of the tissue damage. An
outstanding manuscript by Degan and colleagues  summarize current data on Alzheimer’s disease, Parkinson’s disease, Huntington’s disease,
Amyotrophic Lateral Sclerosis, stroke and traumatic brain diseases and discuss the potential anti-inflammatory therapeutic approaches
acting at different levels and stages of the diseases.
Alcohol consumption causes comprehensive liver disorders, designated as Alcoholic Liver Disease (ALD). In an interesting manuscript
Lu and Cederbaum  summarize the consequences of liver damage, the relationship of CYP2E1/CYP2A5 and ALD development, the
mechanisms involved and recent advances, some unpublished data of cytochrome P450 enzymes dysregulation in inflammatory disease
states. Mucositis or inflammation of the mucosa that occurs throughout the alimentary tract from the mouth to anus, is a side effect associated
with the use of chemotherapy. Mahendran and colleagues  in an excellent reviews focus the pathobiology of chemotherapy-induced oral
and gastrointestinal mucositis and recent research examining the role of agents with anti-inflammatory activity in treatment and prevention of
the condition. The skin is the largest organ in the human body which function is to protect the body from external hazards. Skin inflammation
leads to skin aging that can eventually promote cellular damage and the development of cancer. An interesting manuscript by Kim and Lee
 summarize some proteins and signaling pathways involving in skin inflammation, which can be modulated by phytochemicals with the
purpose to attenuate skin inflammation.
Considerable progress has been made in the understanding of inflammatory mechanisms which may open new avenues for preparation of
novel anti-inflammatory drugs. Medicinal plants are promising sources for preparation of such novel drugs. Taking into consideration the
anti-inflammatory activities of a large group of medicinal plants, Kazemi and colleagues  remarkably describe recent advances in progresses
in understanding the molecular basis of inflammation, and presents the most important medicinal plants with anti-inflammatory activity.
Melatonin is an indolamine synthesized and secreted by the pineal gland and other extrapineal sources including immune system cells,
brain, skin and the gastrointestinal tract. Carrascal and colleagues  present very timely manuscript evaluating the use of melatonin in the
control of inflammation underlying the Alzheimer, Amiotrophic lateral, Multiple Sclerosis, Huntigton´s disease and ulcerative colitis. The
authors propose that these actions of melatonin are mediated through their receptors but also with their direct antioxidant action and melatonin's
ability to break the vicious cycle of ROS-inflammation.
The use of nanomedicine, nanoscale structures for drug delivery, exhibits a really high therapeutic potential in the field of neuroinflammation
therapy. In an excellent manuscript Cayero-Otero and colleagues  analyzes a wide variety of compounds as possible candidates to
cross the Blood-Brain Barrier (BBB) and reach the brain in sufficient concentration to be able to exert its effect. The authors also describe
PLGA nanoparticles as one of the most versatile drug delivery nanosystems, and other strategies, as direct intranasal administration (nose-tobrain),
novel viral vectors and novel implanted catheters. Computational biology approaches could be useful to design novel drugs for inflammation
treatment. Virtual screening involves applying computational methods to discover new ligands for biological structures from the
formation of large libraries composed of a large number of compounds. In an interesting manuscript Scotti and colleagues  illustrate different
studies employing a variety of virtual screening approaches to find molecules that have actions on important, diverse targets implicated in
Drug Delivery Systems and Drug Targeting
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Antibodies and Immunotherapeutics
In this special issue of Current Pharmaceutical Design, entitled: “Antimicrobial peptides as mediators of innate immunity”, the major
features of Antimicrobial Peptides (AMPs) are outlined. In particular, their classification, cellular sources, and biological properties in health
and disease are described. Finally, clinical applications of AMPs, as novel therapeutics in the course of infections caused by antibioticresistant
bacteria, fungi, protozoa and viruses as well as in cancer, are discussed.
Magrone et al.  at first review the phylogenic sources of AMPs as well as their anti-inflammatory and immunomodulating activities.
Moreover, lantibiotics, as new potential anti-infective drugs, are described. Authors also point out the ability of dietary bioactive principles
and food supplements to induce AMP production.
Pizzo et al.  place emphasis on the exploitation of structure, function and mechanisms of action exerted by AMPs in drug targeting. In
this review, cryptic AMPs are introduced as proteins hidden in their primary structure and, then, released by the host and/or bacterium proteases.
Their discovery has enlarged the spectrum of known AMPs, also allowing investigation of new functions and applications.
Drago-Serrano et al.  describe the role of Lactoferrin (LF) and lactoferricins (Lfcins) in the control of pathogens also in virtue of their
immune regulatory properties. LF and Lfcins are molecules of pharmacological interest and native LF and its N-terminus peptides seem to
have potential applications as adjunctive anti-infectious agents. Finally, these compounds have the property to retard tumor growth and attenuate
Chieosilapatham et al.  review the role played by human cathelicidin LL-37 in the modulation of innate immune response. Particularly,
LL-37 exerts pro- and anti-inflammatory activities, also inducing maturation, proliferation and regulation of apoptosis. Finally, according to
its anatomical distribution, LL-37 seems to play different roles in the regulation of innate immunity.
Kiatsurayanon et al.  illustrate the role of human beta-defensins (hBDs) in the maintenance of skin barriers. They exert a broad spectrum
of microbicidal activities also displaying several immunoregulatory activities in the course of skin infections and inflammation. A better
knowledge of hBD physiology may contribute to develop new therapeutic remedies in the course of skin barrier impairment, such as atopic
dermatitis and psoriasis.
Skovbakke et al.  outline the property of Formyl Peptide Receptors (FPRs) in mediating the immunomodulatory activities of AMPs
and peptidomimetics. In this framework, for their function neutrophils express FPRs which behave as targets of AMPs. On these bases, peptidomimetics
represent new molecules able to modulate neutrophil activities.
Adolph et al.  describe the function of intestinal Paneth cells as producers of AMPs finalized to the homeostatic control of microbiota.
Emphasis is placed on the alteration of Paneth cell function in inflammatory disease and, especially, in the course of ulcerative colitis and
Khurshid et al.  point out the unique structure of human defensins based on amino acid sequences bearing disulphide bridges which
allow their synthesis or natural production with the help of bacteria. In particular, in this review, the role exerted by oral defensins in health
and disease is stressed out.
Rivas-Santiago and Torres-Juarez  highlight the ability of AMPs to kill mycobacteria both in vitro and in vivo. Then, AMPs can be
used as an adjunctive therapy in the course of human tuberculosis. However, to avoid collateral effects depending on the multiple activities
exerted by AMPs, Authors suggest that certain features, such as comorbidity, family history and risk factors in patients with tuberculosis
should be taken into consideration prior to AMP therapy start.
Magrone et al.  emphasize the concept that AMPs in comparison to antibiotics possess a larger spectrum of antimicrobial activities
without inducing bacterial resistance. Therefore, their use in different clinical settings, even including septic shock is discussed. Finally, a
series of novel compounds derived from AMPs for their potential capacity to reinforce the immune response are illustrated.
Approximately 15 million babies are born preterm each year and one million die of complications of prematurity. As of the close of 2016,
the latest year for which data are available, the preterm birth rate rose for the second year in a row in the United States, and now stands at
9.8%. This setback in the US is likely tied to major lifestyle and environmental factors that have negatively impacted other health outcomes
Recent data indicate that increased obesity and oxidative stress lead to dysregulation of the immune response, which, in turn, leads to
disease. Inflammation, resulting from immune dysregulation, has been linked to cardiovascular, neurodegenerative and oncologic disorders.
Inflammation, in the absence or presence of microorganisms, is also the single most common driving force behind spontaneous preterm birth.
In this second volume of our “hot topics” issue focused on emerging pharmacotherapy for preterm birth (PTB), we move into the realm of
investigative approaches at the cutting edge of the field that target immune dysregulation. Recognizing that toll-like receptor 4 (TLR4) lies at
the crossroads of both infectious and sterile inflammatory pathways, Sarah Robertson et al. review the evidence supporting the targeting of
toll-like receptor 4 (TLR4) to prevent preterm labour . The authors review the role of TLR4 in both normal parturition and preterm birth as
well as how this receptor interacts with both pathogen-derived and endogenous ligands. Finally, the authors summarize recent exciting data
supporting the use of specific TLR4 antagonists to prevent PTB, including (+)-naloxone.
In a comprehensive review on the topic, Carlos Salomon et al. propose that preterm birth may be triggered by extracellular membrane
vesicles involved in the regulation of signaling cascades during pregnancy and parturition, known as exosomes . These highly stable
nanovesicles, serving as transporters of mRNA, miRNA, DNA, lipid, cell-surface receptor and protein mediators, communicate between the
maternal and fetal compartments in pregnancy. The authors present the provocative proposal that exosomes carry the signals for the initiation
Kiersten Giusto and Charles Ashby point to the role of the sphingosine kinase/endothelin-1 pathway as a novel putative target of prevent
PTB . The data summarized in their review provide solid evidence for the dual role of this pathway in PTB, which mediates both a proinflammatory
response as well as uterine contraction. The fact that this pathway is regulated by positive feedback underlines its explosive
role in inflammation-driven PTB.
Samir Gorasiya et al. describe an exciting new class of cytokine suppressive anti-inflammatory drugs, based on the accidental discovery
that N,N-dimethylacetamide, a common pharmaceutical excipient, rescues timed pregnant mice from lipopolysaccharide induced preterm
birth . These molecules represent a novel group of nuclear factor kappa B (NF-κB) inhibitors. As NF-κB is implicated in so many disorders,
these new drugs may have broad clinical impact.
Finally, Nicole Olgun of the Centers for Disease Control and Prevention reviews the special considerations related to viral infection in
pregnancy and Ebola virus in particular . Dr. Olgun reminds us of the devastating toll viral infections exert on neonatal health. Her review
emphasizes the value of preparedness as unexpected epidemics emerge.
The development of pharmacotherapy to prevent preterm birth presents a special challenge because of the vulnerability of the developing
fetus. Even agents proven to be safe in other clinical settings that show potential tocolytic activity can not simply be repurposed for the prevention
of preterm labor without being carefully vetted for teratogenic effects. The successful approach to this far-reaching clinical problem
will come from collaborative efforts among investigators with different perspectives and expertise. This issue, the second of a two volume
series on this topic, brings together insightful reviews written by experts from around the globe.
Infections caused by microorganisms are one of the most common issues and a serious threat to patients in the clinic. These microbial
infections often result in disease progression and surgical failure. To address this problem, many efforts have been made to exploit various
biomaterials and medical devices with antibacterial properties.
Currently, various materials, namely antibiotics, inorganic nanomaterials, polymers, and Antimicrobial Peptides (AMPs), have been
widely investigated and used as antimicrobial agents. The morphologies, molecular structures, or release behaviors of these materials may
significantly affect their functionality. Meanwhile, the antibacterial mechanisms of these materials have also gained much attention and may
direct the design of advanced antibacterial materials or medical devices. In this theme issue, ten reviews from researchers in differing fields
were collected together with a primary focus on the design of antibacterial materials and their applications.
Hydrogels, an important biomaterial, have been widely used in biomedical fields. Weiguo Xu et al. gave a review on the recent development
of antimicrobial hydrogels and discussed their potential prospects . Polymers with antibacterial functions have also been investigated.
Cansu Ergene and Edmund F. Palermo introduced a wide range of antimicrobial polymers and gave a review on state-of-the-art methods employed
to optimize macromolecular structures for high antibacterial activity . Diego and his colleagues gave a comprehensive introduction
on antibacterial coatings with different molecules, and the striking developments of chitosan-based functional coatings for pharmaceutical and
biomedical applications were well reviewed .
Besides polymers, inorganic materials also made a significant impact in antibacterial fields. Zhou Chen et al. evaluated recent developments
regarding bioactive glass, graphene-based antibacterial materials, as well as metal ion coatings . The antibacterial mechanisms of
nanoparticles have been well investigated by Scott and his colleagues as they summarized the challenges metal oxide antibacterial materials
face and presented novel methods to evaluate the antibacterial potency and efficiency of these nanoparticles .
AMPs are another promising therapeutic agents to combat infectious diseases. However, the applications of AMP are limited due to insufficient
sources, instability, toxicity, and bioavailability. In this theme issue, Huping Jiao’s group provided a review on the design and modification
of AMPs, and summarized both chemical and biological methods to adjust the properties of AMPs .
The controlled release of antibiotics is an efficient method to prevent or treat implant-associated infections. Liqun Xu et al. provided a
summary on the carrier platforms used for loading antibiotics and their drug release behaviors were also highlighted . Layer-by-layer
(LBL) is also a versatile method to construct functional surfaces and films. Lan Liao and coauthors gave a brief introduction and summarized
the applications of LBL to construct antibacterial surfaces or films .
Antibacterial agents play an important role in the wound healing process. Zhengwen Li and Menno Knetsch gave a review on current
antibacterial strategies of wound dressings, the wound infection process, antibacterial agents, and a controlled drug delivery system .
The real-time monitoring of bacterial infections and drug evaluation are also important topics. Xiwen Wang and his colleagues provide a
review about bacterial luciferase gene cassette as a real-time bioreporter for infection model and drug evaluation .
This special issue covers various fields of antibacterial materials. The guest editors and all the authors hope this theme issue may help
readers discover advanced ideas and guidance, while simultaneously motivating readers to contribute to researches on antibacterial materials.
Abstract: In the field of inflammation/infection imaging, nuclear medicine techniques offer non-invasive tools to detect early pathophysiological
changes before the development of anatomical changes detected by radiological procedures and, often, before clinical onset
of symptoms. This field has been recently developed with several new radiopharmaceuticals for SPECT and PET used to define new
strategies for imaging immune cells as well as pathogens.
In particular, we count now several dozens of new radiopharmaceuticals designed for bacterial imaging and new peptides and antibodies
for imaging neutrophils, T-cells, B-cells and macrophages.
These may have important applications not only for diagnostic purposes but also for prognostic purposes, therapy decision making and
for early follow-up of therapy efficacy, thus allowing us to define specific therapies for each individual patient.
Inflammatory disorders, infections and cancer, have a tangible impact for health and social costs. For this reason, it is advisable to establish,
in each hospital, a multi-disciplinary team of experts for the management of patients with chronic inflammatory/infectious diseases, as
well as for cancer patients, to optimize diagnostic protocols, therapy decision and follow-up. Nowadays, among the several imaging modalities
available, nuclear medicine techniques play a secondary role after radiation-free methods such as ultrasound (US) and Magnetic Resonance
Imaging (MRI). Nevertheless, a multidisciplinary approach combining radiology and nuclear medicine often represents a suitable diagnostic,
prognostic, and monitoring tool in patient management. Nuclear medicine techniques, in particular, offer non-invasive tools to detect
early pathophysiological changes before the development of anatomical changes detected by radiological procedures and often before clinical
onset of symptoms.
Hence, this monographic issue is well-timed for providing clinicians current knowledge on molecular imaging in inflammatory disorders
and infections, since an early and accurate diagnosis represents an important step to prevent serious or long-lasting complications as well as to
monitor therapeutic responses.
Functional imaging with radiopharmaceuticals has been shown to detect inflammatory processes with high sensitivity and specificity and
constitute the basis of molecular imaging with Positron Emission Tomography (PET) or Single-Photon Emission Computed Tomography
These techniques are also of great importance for therapy decision making and in monitoring response to therapy. Thanks to the possibility
of deeply understanding the nature of an inflammatory process and what cells or cytokines are present in the inflamed site we are now able
to decide the most appropriate therapy and to verify its efficacy.
As an example, I could mention the role of 99mTc-anti-TNFα antibodies [1-5] or 99mTc-anti-CD20 antibodies [6, 7] or 99mTc-octreotide [8,
9] in patients with rheumatic diseases, or the role of 99mTc-Interleukin-2 in patients with Type 1 diabetes [10, 11], or the role of 99mTc-labelled
antibiotics in defining the nature of pathogen causative of an infection , or other radiopharmaceuticals in neuro-inflammation  and
heart inflammation .
Along this line, many other radiopharmaceuticals have been developed and studied including those for targeting chemotaxis, cell recruitment,
matrix metalloproteinase production, macrophage metabolism, angiogenesis, and several other specific against cells and soluble antigens
involved in inflammatory and infective diseases as reviewed in this issue by Signore et al.  and Sollini et al. . The approach of
specific imaging of bacteria has been reviewed by Ebenhan et al.  whereas the new radiopharmaceuticals labelled with 68Ga for PET imaging
have been reviewed by Vorster et al. .
It must be clarified, however, that in some pathological condition it is not so relevant to use a highly specific radiopharmaceutical, being
more relevant its high sensitivity or even the strategy used for image acquisition that could improve the disease specificity of a non-highly
specific radiopharmaceutical as clearly explained by S. Skehan and M. Peters in early 2000 [19, 20] and others .
The understanding of the properties of radiopharmaceuticals and of the most appropriate image acquisition modality, relies on the success
of the use of radiolabelled neutrophils [22-24] and on the use of 18F-FDG is certain specific pathological conditions [25-27] as also reviewed
by Ankrah et al. in case of fungal infections in children  or as described by Keidar in case of diabetic infections  or by Palestro et al.
in case of fever of unknown origin .
Colchicine has been used for over two thousand years. Recently research studies have shed light on potential new indications. While colchicine
is in fact an ancient drug, there is a lack of “big” data on its utilization in modern medicine.
Tsoucalas et al.  searches back in ancient Greek and Byzantine sources for documentation of colchicine utilization. While initially
considered as an effective poison to “kill a rebellious slave, or a rival nobleman”, later on Late Greek antiquity its potential therapeutic aspects
were recognised . Karamanou M et al.  unveils the modern historical course of colchicine from distribution through empiric physicians
(charlatans) in the 15th century to the contemporary pharmacopeia of the 19th century.
Colchicine exploits a plethora of pathophysophysiological pathways and is in general characterized by a relatively safe profile. Side effects
are mainly of gastrointestinal origin, while toxicity is associated to doses multiple of the common therapeutic regimens. Angelidis C.
et al. , review pharmacokinetics, mechanisms of action and side effects of colchicine.
Drosos E. et al.  reviews potential indications of colchicine in the fields of low-back pain, gliomas and stroke from the viewpoint of
neurosurgery. Tsivgoulis G. et al.  review available data and ongoing studies in utilization of colchicine’s anti-inflammatory properties for
prevention cerebral atherosclerotic events.
Marinaki S et al.  provide an overview of colchicine employment in a series of entities affecting the kidneys (fibrotic disorders, diabetic
neuropathy, familial Mediterranean fever and amyloidosis, renal transplantation, hypertensive kidney disease, autosomal dominant
polycystic kidney disease, focal segmental glomerulosclerosis).
Colchicine as a treatment for gout, a classic indication, is comprehensively reviewed by Parcart T and Richette P . Further, Lantinioti
G. et al.  present current perspectives on indications of colchicine in autoinflammatory disorders (Familial Mediterranean Fever, Periodic
fever with aphthous stomatitis, pharyngitis and adenitis, Behcet’s disease, Idiopathic recurrent acute pericarditis).
Finally, colchicine has been suggested as a means of primary prevention for post-operative atrial fibrillation. A series of randomized studies
and meta-analyses have lately been available and are presented in detail by Vrachatis D. et al. . Last, but not least, a “traditional” indication
of colchicine, pericardial syndromes, is thoroughly reviewed by Lazaros G. et al. .
Heart diseases are the world’s leading cause of morbidity and mortality. For a broad spectrum of heart diseases, though each has its own unique features in pathogenesis and disease evolution, the inflammatory processes are commonly shared among them. The initial inflammatory reaction is a cardioprotective response to triggers such as ischemia, tissue injury and infection. However, prolonged inflammation, can damage normal tissue, cause cardiac dysfunction, result in adverse cardiac remodeling including myocyte hypertrophy and necrosis, fibrosis, and at last contribute to a poor prognosis. Recent findings suggest that regulation of inflammation is a potential target for development of therapies for heart diseases. In the purpose of facilitating further management of heart diseases, this issue will systemically review recent studies focusing inflammation in heart diseases. The issue contains 12 papers that summarize inflammatory pathways and potential therapeutic targets for heart diseases.
Lifestyle modifications and diet therapy are two of the most important tools in prevention and treatment of cardiovascular risk factors, cancer and other chronic diseases. In keeping to this, increasing epidemiological data support the concept that diet rich in fruit and vegetables promotes health and attenuate, or delay, the onset of various diseases, including heart disease, hypertension, cancer and certain age-related degenerative disorders. Over the past decades increasing research interest has been addressed to the potential health benefits of polyphenols. According to this, it has been suggested that the health benefits from fruit and vegetables can be partially linked to their content of a certain group of polyphenols, the flavonoids. A large body of evidence supports that dietary intake of polyphenols (particularly flavonoids and the specific class of flavonoids named flavanols largely contained in red wine, cocoa, tea, fruits and vegetables) might exert some beneficial vascular effects, reduce the risk of cardiovascular morbidity and mortality and contribute to the prevention of other chronic diseases. Among phytochemicals, polyphenols constitute one of the most numerous and widely distributed groups of substances in the plant kingdom, with more than 8000 phenolic structures. They occurred in a variety of fruits, vegetables, seeds, flowers, beverages and even some manufactured food as a component of the natural ingredients used.
These bioactive compounds typically occur in small quantities in foods. They are being intensively studied to evaluate their effects on health. The impetus sparking this scientific inquiry was the result of many epidemiologic studies that have shown protective effects of plant-based diets on cardiovascular disease and cancer. According to this, growing interest has been addresed to many bioactive compounds. These compounds vary widely in chemical structure and function and are grouped accordingly.
Plant polyphenols have drawn increasing attention due to their potent antioxidant properties and their marked effects in the prevention of various oxidative stress associated diseases. In the last few years, the identification and development of phenolic compounds or extracts from different plants has become a major area of health- and medical-related research.
Adequate nutrition is one of the pillars of public health. Before developing and implementing effective intervention programmes to improve nutrition at the population level, it is important to know the nutritional situation of the target group.
Therefore, the time lapse for hidden progression of pathological process may take years and even decades. During this time, both the person at risk and physician remain unaware of the existing premorbid pathological condition. As a result, no preventive measures are undertaken to reduce the individual risk of the development of the overt disease.
Polyphenols are abundant nutraceutical micronutrients in our diet, and evidence for their role in the prevention of degenerative diseases is emerging.
The WHO estimated that the costs of not engaging in prevention and therapy will be fastly growing in the next years, with a more severe impact in developing countries. Several natural nutraceutical from our diet and ingredients marketed for use in dietary supplements address such risk factors. The ability of nutraceuticals to favorably influence cardiovascular risk factors and atherosclerotic vascular disease as well as a number of different chronic disease should be recognized as an enormous opportunity for the prevention or treatment of this common condition.