ISSN (Print): 0929-8673
ISSN (Online): 1875-533X
Volume 25, 42 Issues, 2018
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ISSN (Print): 0929-8673
ISSN (Online): 1875-533X
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42 Abstract Ahead of Print are available electronically
408 Ahead of Print article(s) are available electronically
The pharmacological therapy of children diseases is changing very quickly in the last decades. In this
respect, chronic autoimmune and inflammatory diseases are becoming a major issue for the pediatricians.
In spite of the availability of new biological drugs, which has allowed to assist to a great improvement in
the prognosis and quality of life of many patients, new therapeutic tools are urgently needed. This special
issue will discuss innovative approaches for rational drug design and therapy personalization in the
pediatric population, potentially leading to precision medicine improving efficacy and reducing adverse
effects of therapy, that are particularly significant in chronic diseases. The repositioning of old drugs to
treat rare pediatric immune diseases will be discussed, such as lapaquistat for Mevalonate Kinase Disease
and antimalarials in interferonopathies. Also severe oncological pediatric diseases could benefit from
precision drugs such as kinase inhibitors targeting specific genetic alterations; this approach will be
considered. Innovative disease models are needed to lead to improved drug design and innovative
therapies, and the promising application of pluripotent induced stem cells will be presented. Finally,
pharmacokinetics and pharmacogenomics based on innovative molecular markers such as
transcriptomics, and their application to therapy personalization and drug discovery for pediatric
inflammatory bowel disease, will be also discussed.
The potassium channels family represents the most widely distributed among ion channels families.
Thanks to this feature and to their ability of inducing hyperpolarization, potassium channels are involved
in many physiologic processes such as tune of musculature, release of neurotransmitters, regulation of
diuresis or glycemia and so on, and these properties make potassium channels suitable targets for many
pharmacological approaches to different pathologies in several districts. The purpose of this issue is to
offer a broad overview on the most important pharmacological tools, novel and well-known molecules,
having potassium channels as therapeutic target in order to highlight promising drugs with exciting
perspectives for the treatment of cardiovascular, neurological and metabolic diseases.
Keywords: KATP potassium channels, BKCa potassium channels, ROMK potassium channels, Kv
potassium channels, Mito-K+ potassium channels.
Pharmacological and chemical aspects of drugs or new molecules targeting: ATP-sensitive
(KATP) potassium channels.
Large conductance Ca2+-activated (BKCa) potassium channels.
Renal Outer Medullary (ROMK) potassium channels.
Voltage-gated (Kv) potassium channels and mitochondrial potassium (Mito-K+) channels.
Pancreatic cancer (PC) is a highly aggressive cancer usually diagnosed at an advanced stage, and has the worst
prognosis of any cancer malignancy, with a 5-year survival rate of <8%. Lack of early detection and effective interventions
are major factors contributing to the poor prognosis and dismal survival rates of pancreatic cancer patients.
Moreover, recent incidence and mortality rates suggest an increasing trend of pancreatic cancer patients.
Recent developments demonstrate that pre-invasive precursors, such as PanINs, IPMNs, and cystadenomas, progress
slowly over many years to develop into invasive pancreatic cancers. Thus, there is a time frame of several
years for effective chemoprevention and intervention strategies. Despite many advances in the molecular genetics of
human pancreatic cancers, targeted therapies have not yet translated to improved overall survival. Hence, developing
chemoprevention strategies that delay/inhibit/prevent the progression of each subtype of pre-invasive lesions to
pancreatic cancer is of utmost importance. Several genetically engineered mouse models (GEMs) of pancreatic cancer
that recapitulate human disease progression have recently been developed. The KrasG12D and KrasG12V dependent
GEM models which mimic the therapeutic response of human pancreatic cancer offer novel treatment development
opportunities. The biggest challenges are to elucidate the regulatory mechanisms controlling the progression of pancreatic
precursor lesions to pancreatic cancer, and to develop strategies that provide effective chemoprevention.
Equally challenging is identifying high-risk cohorts with specific pancreatic precursor lesions using early detection
In this special issue, different aspects of this problem are presented focusing on current challenges and opportunities
aimed to address chemoprevention aspects for pancreatic cancer. Possible pancreatic cancer chemoprevention
targets, mouse models and early detection, immuno-prevention of pancreatic cancer, drug candidates for pancreatic
cancer chemoprevention, regulatory mechanisms controlling pancreatic cancer progression, combination chemoprevention
strategies and different approaches are also considered and discussed.
The first review by Mohammed et al addresses the current challenges and potential opportunities for chemoprevention
of pancreatic cancer. In this review, they focused on the current situation of PC, the potential challenges, the
progress in existing strategies and available opportunities, as well as suggested key areas for research within the
increasingly important area of pancreatic cancer chemoprevention. They suggested that novel technologies such as
next generation sequencing should be employed to identify high-risk individuals with early genetic changes in the
initial lesions or even explored in blood samples to detect the presence of circulating tumor derived or related
mRNA, miRNA, DNA, tumor educated platelet-mRNA as biomarkers of early detection. GEM serve as excellent
models to study the early stages of PC and for early detection by molecular imaging technologies. GEM models
should be extensively utilized for developing existing chemoprevention agents or screening and optimizing new
agents and identifying ideal chemoprevention targets. High-risk individuals presenting IPMN/PanINs and those
with hereditary PC history should be considered for chemopreventive clinical trials. Combination chemoprevention,
multi-targeted agents and multi-agent low dose chemoprevention strategies might be considered to reduce toxicity
and enhance efficacy.
The contribution by Dhar et al. takes into consideration the mechanisms and drug targets for pancreatic cancer
chemoprevention. They discussed the available drugs and their limitations, and move on to discuss the wide realm
of chemopreventive efficacy that natural agents offer. While the intake of fruits and vegetables in routine diets has
been linked to reduced risk of developing pancreatic cancer, a wide variety of natural agents is being evaluated as
adjuvant therapies in combination with frontline chemotherapeutics in pancreatic cancer clinical trials. Completed
and ongoing human studies with these natural agents have shown surprisingly successful rates for regulating pancreatic
carcinogenesis. Furthermore, the underlying mechanisms of action and available information from extensive
literature analysis to highlighting the novelty of these agents for their antitumor effects against pancreatic cancer,
In the review by Hildegard, the regulatory role of G protein-coupled receptors in pancreatic cancer development
and progression are described. Smoking, psychological stress, diabetes, pancreatitis and alcohol abuse are known
risk factors for pancreatic cancer that cause hyperactive cyclic adenosine monophosphate (cAMP) signaling via
cancer stimulating Gαs-coupled β-adrenergic and prostaglandin (PG) E2 receptors and/or by suppressing signaling
via inhibitory Gαi-coupled GABAB-receptors. The activation of Gαi-coupled GABAB-receptor signaling by treatment
with GABA, inhibition of β-adrenergic signaling by a beta-blocker and/or suppression of Gαs-coupled PGE2
receptor signaling by a cyclooxygenase (COX) inhibitor prevented the development and progression of PC in hamsters
induced by carcinogenic nitrosamines and in transgenic mice. The re-purposing of cardiovascular therapeutics
(beta-blockers, COX-2 inhibitors, Ca2+-channel blockers) that inhibit β-adrenergic and PGE2 signaling for PC intervention
is problematic due to undesirable side effects under chronic treatment protocols. To avoid such side effects
while effectively reducing excessive cAMP signaling, nutritional GABA supplementation or positive allosteric
modulators (PAMs) of Gαi-coupled receptors (GABAB-Rs) currently in clinical trials for the treatment of addiction
should be explored for pancreatic cancer intervention.
Rao et al. review discusses the novel approaches of immunoprevention for PC. Vaccine-based treatments for
several cancers are currently under intense investigation. Current vaccine testing for PC is usually performed in advanced
stages of cancer, during which the patient's impaired immune responses improved to suppress the growing
tumor. However, so far such strategies have had limited success and have not become mainstream therapies. Thus,
early diagnosis is imperative for immunoprevention using vaccines. Developing vaccines towards non-self-antigens
has been successful, whereas vaccines against self-antigens, without any adverse effects on normal cells, have been
challenging. The development of new technologies to identify mutated antigens, post-translational alterations in
proteins, and tumor-specific antigens is currently underway, with a view toward vaccine development. Combining
vaccines with immune stimulators or non-toxic anticancer agents are promising for cancer prevention. Successful
vaccination strategies for PC at different stages of tumor development and future challenges for immunoprevention
are discussed in this review.
Along this line, the paper by Subramaniam and co-authors reviewed approaches to target cancer stem cells for
chemoprevention of pancreatic cancer. Emerging evidence supports the presence of a unique population of cells
called cancer stem cells (CSCs) as potential cancer inducing cells and efforts are underway to develop therapeutic
strategies targeting these cells. Studies have been shown that CSCs are highly resistant to standard therapy and responsible
for drug resistance, cancer recurrence and metastasis. To overcome this problem, novel preventive agents
that target these CSCs are needed. Natural compounds or phytochemicals have the ability to target these CSCs and
their signaling pathways. Therefore, they summarized current understanding of pancreatic CSCs and their signaling
pathways, and the phytochemicals that target these cells including curcumin, resveratrol, tea polyphenol EGCG
(epigallocatechin-3-gallate), crocetinic acid, sulforaphane, genistein, indole-3-carbinol, vitamin E δ-tocotrienol,
Plumbagin, quercetin, triptolide, Licofelene and Quinomycin. These natural/synthetic compounds or phytochemicals,
which inhibit cancer stem cells, may prove to be promising agents for the prevention and treatment of pancreatic
Together with the data summarized by Yu et al., the paper provides a systematic literature review and metaanalysis
on the effect of metformin and statin use on survival in PC patients. Current epidemiological studies report
conflicting results for the effect of statin or metformin on overall PC survival. They systematically searched for
studies about the association between statin or metformin use and overall pancreatic cancer survival in electronic
databases. A meta-analysis based on hazard ratios (HRs) and 95% confidence intervals (CIs) was performed using
random effect models. Heterogeneity between the studies was examined using I2 statistics, and sensitivity analyses
were conducted to assess the robustness of the findings. Of 116 statin-related articles identified, 6 retrospective cohort
studies representing 12,057 patients were included. There was significant heterogeneity between the studies.
Statin use was associated with improved survival among pancreatic cancer patients. Of 311 metformin-related articles,
8 retrospective cohort studies and 2 randomized clinical trials, representing 3,042 patients were identified.
Metformin use was associated with better overall survival among pancreatic cancer patients (meta-HR = 0.79; 95%
CI: 0.70, 0.92, P < 0.001), and significant heterogeneity was observed between the studies. These findings suggest
that the improved survival time of pancreatic cancer patients is associated with statin or metformin use. Due to the
multiple sources of heterogeneity of the original studies, these findings should be considered cautiously, and confirmed
with larger prospective individual-level studies.
The last review by Torres and co-authors focused on the complexity of omega-3 fatty acids modulation of signaling
pathways related to PC. Recently, the role of nutrition in health and disease has attracted much attention.
Several dietary ingredients are involved in metabolic, physiological, and cellular signaling affecting tumor growth
and progression. Although lipids, and more specifically polyunsaturated fatty acids, have been traditionally studied
due to their health effects in cardiovascular disease, it is now clear that they can affect an extensive array of cellular
processes that influence a wide range of diseases such as type II diabetes, inflammatory disorders and cancer. These
biological activities may be grouped as regulation of membrane structure and function, intracellular signaling pathways,
transcription factor activity, gene expression, and production of bioactive lipid mediators. In this review, specifically,
the current state of knowledge about the potential mechanism(s) of action and signaling pathways modulated
by polyunsaturated fatty acids in pancreatic cancer are discussed.
Cardio-metabolic complications are multifactorial diseases with different facets, many of which are poorly understood,
although genetics, epigenetics, humoral, habitual and environmental factors may be involved. Moreover,
with the dramatic escalation of obesity, diabetes and hypertension in all segments of the population including adults,
adolescence and children, the incidence of cardio-metabolic disease and related complications will further increase.
Therefore, this special issue puts together a collection of review articles by leading experts in the area to give a
critical appraisal of the current state of knowledge and recent accomplishments as well as challenges and future directions.
The role of pigment epithelium-derived factor (PEDF) in cardiometabolic disease is a among the emerging
themes of scientific interest, with the role of pigment epithelium-derived factor (PEDF) in cardiometabolic disease.
PEDF is a glycoprotein that has been shown to possess anti-thrombotic and anti-fibrotic properties besides its effects
against oxidative stress and inflammatory. Accordingly, in an article featuring in this special issue, Yamagishi
& Matsui underscored the role of PEDF in cardiometabolic diseases and related complications, with particular focus
on diseases such as diabetic retinopathy, renal dysfunction, hepatic insufficiency and disorders affecting the male
and female reproductive systems. The authors discussed the potential clinical relevance of modulating PEDF for the
prevention and management of these cardiometabolic disorders. In another related article, Shinlapawittayatorn et al.
gave profound insights on the effects of obese insulin-resistance, a common risk factor for ischemic heart disease on
ischemia-reperfusion injury of the heart. Amongst the pertinent points raised by the authors is whether improving
insulin sensitivity by pharmacological interventions could ameliorate reperfusion induced myocardial injury. Dysfunctional
myocardium is a common complication of diabetes. To expatiate on this problem further, Tarquini et al.
wrote an article about diabetic cardiomyopathy, a pathophysiological condition in which the myocardial interstitium
undergoes alterations resulting in abnormal contractile function. The authors reported that in the early stages of the
disease, diastolic dysfunction is the only abnormality, but systolic dysfunction supervenes at later stages with impaired
left ventricular ejection fraction. Furthermore, the authors underscored a putative correlation between diabetes
and cardiomyopathy, especially in diabetic patients with co-morbid with microvascular complications, and suggested
that this correlation parallels the duration and severity of hyperglycemia.
Besides the heart, the kidney is an important organ for the regulation of extracellular volume and thus blood
pressure. Renal dysfunction is associated with hypertension, proteinuria and kidney failure. Accordingly, novel insights
on structures of the kidney, such as the glomerular filtration barrier, are important. In a related article that
appears in this special issue, Ndisang wrote about the putative cross-talk amongst the major components of the
glomerular filtration barrier including podocytes, endothelial cells and the basement membrane, and how the dynamic
interplay and interaction between these constituents may be fundamental for effective filtration. Furthermore,
the author highlighted some of the challenging issues about the interaction between: (i) glomerular endothelial cells
and podocytes; (ii) glomerular endothelial cells and glomerular basement membrane; (iii) podocytes and glomerular
basement membrane; (iv) the simultaneous interaction among the three components, and suggested that the elucidation
of these multifaceted interactions will pave the way for greater understanding of the pathophysiology of kidney
dysfunction and the formulation of novel therapies for kidney disease. In another related article, Krämer and Weidemann
gave their insights on Fabry disease, pathophysiological condition associated with X-linked lysosomal storage
caused by deficient activity of α-galactosidase A and intracellular accumulation of globotriaosylceramide in
different physiological entities such as the vascular endothelium, nervous system, eyes, skin, heart and kidneys.
A wide variety of drugs are used for the treatment and management of cardiometabolic diseases. For example,
proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors are used to lower low-density lipoprotein cholesterol in
patients with dyslipidemia, hypercholesterolemia or atherosclerosis. In an article, in this special issue, Schremla and Gouni-Berthold gave an in-depth insight on the use of monoclonal antibodies against PCSK9 to attenuate hypercholesterolemia,
and reported that antibody-derived PCSK9 drugs such as alirocumab (Praluent®) and evolocumab
(Repatha®) can reduce low-density lipoprotein cholesterol by 70%. Generally, drugs are routinely reviewed for their
efficacy and safetyly. In this light, Eleftheriadou and co-workers insights on the cardiovascular safety of older and
newer anti-diabetic medications. The authors reported that metformin, a first line drug for the treatment of type 2
diabetes, is also endowed with cardio- protective effects and should be considered the primary choice, while second
line agents such as empagliflozin, liraglutide and semaglutide are reasonable options for patients with cardiovascular
disease, whereas the class of sulfonylureas with the exception of gliclazide should be administered to diabetic
patients co-morbid with other cardiometabolic diseases. In addition, the authors reported that Saxagliptin, alogliptin,
sitagliptin and lixisenatide have been evaluated in cardiovascular safety trials and were shown to have neutral effects
on cardiovascular outcomes, whereas pioglitazone has some cardiovascular benefits. However, Saxagliptin
and alogliptin should be avoided in patients with heart failure. Consistently, in another article featuring in this special
issue, Schmitz and Gouni- Berthold gave clinical evidence on the efficacy and safety of volanesorsen for the
treatment of hypertriglyceridemia.
Besides, drugs and other pharmaceutical formulations, dietary fibres and polyphenols are cyto-protective. Accordingly,
the protective effects of dietary fibres and the antioxidant and anti- inflammatory properties of polyphenols
such as curcumin, quercetin, genistein, caffeic acid phenethyl ester were examined by Pittala and co-workers.
They discussed the effects of various naturally occurring polyphenols in the management of metabolic dysfunctions
Collectively, the contributions of the authors of this special issue have underscored to the complexity of cardiometabolic
diseases, highlighting the different facets, the accomplishments to date, the challenges that obscure the
horizon and the prospects for the future, to which we can all look toward with some degree of optimism.
Nanotechnology is growing in prevalence in consumer products and medicine. Most nanomedicine are carriers that are capable of homing in, taken up easily by the target cells and eventually delivering their drug payload to the target sites and some have smart designs that release the payload according to designed stimuli. However, while there are many advantages offered through bionanotechnology, there are potential unintended consequences especially on the non-targeted cells remain a problem of toxicity of these very small particles. This special issue describes a series of the latest most exciting research in the fields of nano medicine covering cancer and anti-microbial applications and balanced with some nanotoxiological studies covering nano biology and more realistic nano materials testing platforms.
Growing evidence supports a primary role of inflammatory reactions, both acute and chronic, in the development and progression of the main human diseases. The redoxmediated pathophysiological mechanisms are crucial in the evolution of various diseases, in which inflammation is involved. In this theme issue we would like to consider the role of inflammation and redox balance in the genesis and worsening of diseases, such as atherosclerosis, metabolic syndrome, and ischemia/reperfusion injury. Reviews by scientists, with basic and clinical background, will contribute to give a comprehensive picture of the inflammation- and redox-mediated pathogenesis of the diseases and an up-to-date scenario of therapeutic approaches.
This mini theme issue will consider some classes of bioactive natural products and their role in the medicinal chemistry. Many studies have pointed out new bioactivities for well-known natural products, showing that not only” new chemical entities” obtained by natural sources but also known and “old” natural products can be a valuable source of new therapeutic agents. In the issue triterpene, sesquiterpene, coumarins, stilbenoids, and also phenolics from Cannabis will be considered focusing on both natural and
synthetic (or semisynthetic) compounds, their bioactivity and their potential importance in the field of medicinal chemistry.
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