Dietary flavonoids: Nano delivery and nanoparticles for cancer therapy.

Application of nanotechnologies to cancer therapy might increase solubility and/or bioavailability of bioactive compounds of natural or synthetic origin and offers other potential benefits in cancer therapy, including selective targeting. In the present review we aim to evaluate in vivo studies on the anticancer activity of nanoparticles (NPs) obtained from food-derived flavonoids. From a systematic search a total of 60 studies were identified. Most of the studies involved the flavanol epigallocatechin-3-O-gallate and the flavonol quercetin, in both delivery and co-delivery (with anti-cancer drugs) systems. Moreover, some studies investigated the effects of other flavonoids, such as anthocyanins aglycones anthocyanidins, flavanones, flavones and isoflavonoids. NPs inhibited tumor growth in both xenograft and chemical-induced animal models of cancerogenesis. Encapsulation improved bioavailability and/or reduced toxicity of both flavonoids and/or co-delivered drugs, such as doxorubicin, docetaxel, paclitaxel, honokiol and vincristine. Moreover, flavonoids have been successfully applied in molecular targeted nanosystems. Selectivity for cancer cells involves pH- and/or reactive oxygen species-mediated mechanisms. Furthermore, flavonoids are good candidates as drug delivery for anticancer drugs in green synthesis systems. In conclusion, although human studies are needed, NPs obtained from food-derived flavonoids have promising anticancer effects in vivo.

Proteomic Signature and mRNA Expression in Hippocampus of SAMP8 and SAMR1 Mice during Aging.

Aging is a complex process often accompanied by cognitive decline that represents a risk factor for many neurodegenerative disorders including Alzheimer's and Parkinson's disease. The molecular mechanisms involved in age-related cognitive decline are not yet fully understood, although increased neuroinflammation is considered to play a significant role. In this study, we characterized a proteomic view of the hippocampus of the senescence-accelerated mouse prone-8 (SAMP8), a model of enhanced senescence, in comparison with the senescence-accelerated-resistant mouse (SAMR1), a model of normal aging. We additionally investigated inflammatory cytokines and cholinergic components gene expression during aging in the mouse brain tissues. Proteomic data defined the expression of key proteins involved in metabolic and cellular processes in neuronal and glial cells of the hippocampus. Gene Ontology revealed that most of the differentially expressed proteins are involved in the cytoskeleton and cell motility regulation. Molecular analysis results showed that both inflammatory cytokines and cholinergic components are differentially expressed during aging, with a downward trend of cholinergic receptors and esterase enzymes expression, in contrast to an upward trend of inflammatory cytokines in the hippocampus of SAMP8. Together, our results support the important role of the cholinergic and cytokine systems in the aging of the murine brain.

Assessment of IL-18 Serum Level and Its Promoter Polymorphisms in the Saudi Coronary Artery Disease (CAD) Patients.

The purpose of the current study was to find out the possible changes polymorphic site at the promoter region of IL-18 gene in Saudi CAD patients. We have also measured serum IL-18 level to find out, the likely association between its level and polymorphic site. The present study included total 197 subjects (98 confirmed CAD patients both men and women and 99 healthy control individuals). Serum concentration of IL-18 was measured by enzyme linked immuno-sorbent assay. For SNPs analysis, sanger method of DNA sequencing was followed. We observed variable numbers of SNPs at -137 C/G, -607 A/C, and -656 T/G promoter sites in our studied samples. However, the observed changes in the number of SNP hotspots were found to be non-significant compared with control. IL-18 level was found to be significantly (P < 0.001) elevated in CAD patients compared with control individuals. The highest rise of around 36% (P < 0.001) in IL-18 level was recorded in unstable angina (UA) patients. Moreover, the group belonging to UA and non-ST segment elevation myocardial infarction (NSTEMI) showed only 6% rise. On the basis of our result, inflammation seems to have a role in the pathogenesis of CAD but not leading to the significant changes at the genetic level. J. Cell. Biochem. 118: 1849-1854, 2017. © 2017 Wiley Periodicals, Inc.

Reduction in CD16/CD56 and CD16/CD3/CD56 Natural Killer Cells in Coronary Artery Disease.

BACKGROUND: Natural killer (NK) cells are the potential modulators of inflammatory reactions that exert several unique biological effects and could lead to future adverse events of coronary artery disease (CAD). HYPOTHESIS: The purpose of this study was to find out the possible association of modulation in NK cell, TNK cells, T cells, B cells, and tumor necrosis factor alpha (TNF-α) in CAD patients and various forms of myocardial infarction. METHODS: The present study included total 190 subjects (98 confirmed CAD patients both men and women and 92 healthy control individuals). Serum concentration of TNF-α was measured by ELISA method. For the measurement of various immune cells, viz., NK cell, TNK cells, T cells, and B cells, flow-cytometric analysis was performed. RESULTS: A significant reduction by 15% (P < 0.001) in CD16/CD56 NK cells was observed in CAD patients. Moreover, non-ST segment elevation myocardial infarction (NSTEMI), ST segment elevation myocardial infarction (STEMI), unstable angina (UA), and combined UA + NSTEMI group also showed a significant decline in NK cells compared with control individuals. CD16/CD56/CD3 TNK cells showed a significant reduction in CAD, NSTEMI, STEMI, and UA categories. However, UA + NSTEMI group did not show any significant change in TNK cells. On the other hand, the level of TNF-α was found to be significantly elevated in CAD, STEMI, and UA groups. NSTEMI and combined UA + NSTEMI group did not show any significant change in TNF-α level. CONCLUSION: Current study provides an insight toward the association of immune cells and inflammation with CAD.

Assessment of genetic diversity in IL-6 and RANTES promoters and their level in Saudi coronary artery disease patients.

BACKGROUND: The present study consisted of a total of 200 subjects (100 confirmed coronary artery disease (CAD) patients), both men and women, and 100 healthy control individuals. METHODS: Serum concentration of IL-6 and RANTES were measured by enzyme-linked immunosorbent assay kit. For SNPs analysis, sanger method of DNA sequencing was followed. RESULTS: We observed variable numbers of SNP sites at -174 G/C, -572 G/C, and -597 G/A in IL-6 and -28 C/G and -109 C/T in RANTES promoters in CAD patients compared with control individuals. However, the observed changes in the number of SNPs were found to be non-significant compared with control individuals. The IL-6 level was found to be significantly (P<.001) elevated in CAD patients compared with control. Moreover, RANTES serum level did not show any significant change in CAD patients. CONCLUSION: Based on our result, it is quite clear that inflammation has a role in the pathogenesis of CAD but does not lead to significant changes at the genetic level in our population. As far as our knowledge goes, this is the first report that shows the genetic diversity in IL-6 and RANTES promoters and their respective levels in Saudi CAD patients.

Neopterin: An immune biomarker of coronary artery disease and its association with other CAD markers.

Neopterin has been considered as an important marker of cellular inflammation. The primary objective of the current study was to determine the role of neopterin in cardiovascular disease and its association with other well known cardiac markers. The study was composed of total 200 subjects (100 confirmed coronary artery disease (CAD) patients, 50 recently diagnosed, and 50 managed CAD patients) both men and women and 100 healthy control individuals of matching age and weight. Serum neopterin analysis was done using commercial available ELISA kits. Other cardiac markers viz. troponin, creatine kinase (CK), CK MB isoenzyme (CKMB), lactate dehydrogenase (LDH), fibrinogen, C-reactive protein (CRP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) estimation was done by standard routine biochemical methods. Neopterin level was found to be remarkably enhanced by 150% and 513% in the recently diagnosed and managed CAD patients, respectively. CK level also showed a significant rise by 62% in the managed patients. However, recently diagnosed patients did not show any significant change. Moreover, cross correlation study showed statistically significant (P < 0.01) change in neopterin and CK levels between recently and managed patients. In the other studied CAD markers such as CKMB, fibrinogen and LDH also showed a significant increase in both categories of patients. CRP level was also found to be significantly enhanced by 357% (P < 0.01) and 341% (P < 0.05) in recently diagnosed and managed patients respectively. Because of cost effectiveness, easy and quick analysis of neopterin in the serum sample, we propose neopterin as the prognostic as well as diagnostic biomarker of CAD before other markers could be tested especially in Saudi population.

In silico analysis of the amido phosphoribosyltransferase inhibition by PY873, PY899 and a derivative of isophthalic acid.

Selectively decreasing the availability of precursors for the de novo biosynthesis of purine nucleotides is a valid approach towards seeking a cure for leukaemia. Nucleotides and deoxynucleotides are required by living cells for syntheses of RNA, DNA, and cofactors such as NADP(+), FAD(+), coenzyme A and ATP. Nucleotides contain purine and pyrimidine bases, which can be synthesized through salvage pathway as well. Amido phosphoribosyltransferase (APRT), also known as glutamine phosphoribosylpyrophosphate amidotransferase (GPAT), is an enzyme that in humans is encoded by the PPAT (phosphoribosyl pyrophosphate amidotransferase) gene. APRT catalyzes the first committed step of the de novo pathway using its substrate, phosphoribosyl pyrophosphate (PRPP). As APRT is inhibited by many folate analogues, therefore, in this study we focused on the inhibitory effects of three folate analogues on APRT activity. This is extension of our previous wet lab work to analyze and dissect molecular interaction and inhibition mechanism using molecular modeling and docking tools in the current study. Comparative molecular docking studies were carried out for three diamino folate derivatives employing a model of the human enzyme that was built using the 3D structure of Bacillus subtilis APRT (PDB ID; 1GPH) as the template. Binding orientation of interactome indicates that all compounds having nominal cluster RMSD in same active site's deep narrow polar fissure. On the basis of comparative conformational analysis, electrostatic interaction, binding free energy and binding orientation of interactome, we support the possibility that these molecules could behave as APRT inhibitors and therefore may block purine de novo biosynthesis. Consequently, we suggest that PY899 is the most active biological compound that would be a more potent inhibitor for APRT inhibition than PY873 and DIA, which also confirms previous wet lab report.

Nanoneurotoxicity to nanoneuroprotection using biological and computational approaches.

Nanoparticles (NPs) that are ∼100 nm in diameter can potentially cause toxicity in the central nervous system (CNS). Although NPs exhibit positive aspects, these molecules primarily exert negative or harmful effects. Thus, the beneficial and harmful effects should be compared. The prevalence of neurodegenerative diseases, such as Alzheimer disease, Parkinson disease, and some brain tumors, has increased. However, the major cause of these diseases remains unknown. NPs have been considered as one of the major potential causes of these diseases, penetrating the human body via different pathways. This review summarizes various pathways for NP-induced neurotoxicity, suggesting the development of strategies for nanoneuroprotection using in silico and biological methods. Studies of oxidative stress associated with gene expression analyses provide efficient information for understanding neuroinflammation and neurodegeneration associated with NPs. The brain is a sensitive and fragile organ, and evolution has developed mechanisms to protect it from injury; however, this protection also hinders the methods used for therapeutic purposes. Thus, brain and CNS-related diseases that are the cause of disability and disorder are the most difficult to treat. There are many obstacles to drug delivery in the CNS, such as the blood brain barrier and blood tumor barrier. Considering these barriers, we have reviewed the strategies available to map NPs using biological techniques. The surface adsorption energy of NPs is the basic force driving NP gathering, protein corona formation, and many other interactions of NPs within biological systems. These interactions can be described using an approach named the biological surface adsorption index. A quantitative structural activity relationship study helps to understand different protein-protein or protein-ligand interactions. Moreover, equilibrium between cerebrovascular permeability is required when a drug is transferred via the circulatory system for the therapy of neurodegenerative diseases. Various drug delivery approaches, such as chemical drug delivery and carrier-mediated drug delivery, have been established to avoid different barriers inhibiting CNS penetration by therapeutic substances. Developing an improved understanding of drug receptors and the sites of drug action, together with advances in medicinal chemistry, will make it possible to design drugs with greatly enhanced activity and selectivity; this may result in a significant increase in the therapeutic index.

Nanotechnology: A Promising Targeted Drug Delivery System for Brain Tumours and Alzheimer's Disease.

Nanotechnology is the process of modulating shape and size at the nanoscale to design and manufacture structures, devices, and systems. Nanotechnology's prospective breakthroughs are incredible, and some cannot even be comprehended right now. The blood-brain barrier, which is a prominent physiological barrier in the brain, limits the adequate elimination of malignant cells by changing the concentration of therapeutic agents at the target tissue. Nanotechnology has sparked interest in recent years as a way to solve these issues and improve drug delivery. Inorganic and organic nanomaterials have been found to be beneficial for bioimaging approaches and controlled drug delivery systems. Brain cancer (BC) and Alzheimer's disease (AD) are two of the prominent disorders of the brain. Even though the pathophysiology and pathways for both disorders are different, nanotechnology with common features can deliver drugs over the BBB, advancing the treatment of both disorders. This innovative technology could provide a foundation for combining diagnostics, treatments, and delivery of targeted drugs to the tumour site, further supervising the response and designing and delivering materials by employing atomic and molecular elements. There is currently limited treatment for Alzheimer's disease, and reversing further progression is difficult. Recently, various nanocarriers have been investigated to improve the bioavailability and efficacy of many AD treatment drugs. Nanotechnology-assisted drugs can penetrate the BBB and reach the target tissue. However, further research is required in this field to ensure the safety and efficacy of drug-loaded nanoparticles. The application of nanotechnology in the diagnosis and treatment of brain tumours and Alzheimer's disease is briefly discussed in this review.

Antifungal Activity of Plant Secondary Metabolites on Candida albicans: An Updated Review.

Fungal infections have been increasing continuously worldwide, especially in immunocompromised individuals. Fungi, regarded as eukaryotic pathogens, have many similarities to the host cells, which inhibit anti-fungal drug development progress. Various fungal model systems have been studied, and it was concluded that Candida spp. is the most common disease-causing fungus. Candida species are well known to cause infections not only in our mouth, skin, and vagina, but they are also a frequent cause of life-threatening hospital bloodstream infections. The morphological and developmental pathways of Candida have been studied extensively, providing insight into the fungus development. Candida albicans is known to be the most pathogenic species responsible for a variety of infections in humans. Conventional anti-fungal drugs, mainly azoles drugs available in the market, have been used for years developing resistance in C. albicans. Hence, the production of new anti-fungal drugs, which require detailed molecular knowledge of fungal pathogenesis, needs to be encouraged. Therefore, this review targets the new approach of "Green Medicines" or the phytochemicals and their secondary metabolites as a source of novel anti-fungal agents to overcome the drug resistance of C. albicans, their mechanism of action, and their combined effects with the available anti-fungal drugs.

The Role of Non-coding RNAs in Alzheimer's Disease: Pathogenesis, Novel Biomarkers, and Potential Therapeutic Targets

OBJECTIVE: Long non-coding RNAs (IncRNAs) are regulatory RNA transcripts that have recently been associated with the onset of many neurodegenerative illnesses, including Alzheimer's disease (AD). Several IncRNAs have been found to be associated with AD pathophysiology, each with a distinct mechanism. In this review, we focused on the role of IncRNAs in the pathogenesis of AD and their potential as novel biomarkers and therapeutic targets. METHODS: Searching for relevant articles was done using the PubMed and Cochrane library databases. Studies had to be published in full text in English in order to be considered. RESULTS: Some IncRNAs were found to be upregulated, while others were downregulated. Dysregulation of IncRNAs expression may contribute to AD pathogenesis. Their effects manifest as the synthesis of beta-amyloid (Aß) plaques increases, thereby altering neuronal plasticity, inducing inflammation, and promoting apoptosis. CONCLUSION: Despite the need for more investigations, IncRNAs could potentially increase the sensitivity of early detection of AD. Until now, there has been no effective treatment for AD. Hence, InRNAs are promising molecules and may serve as potential therapeutic targets. Although several dysregulated AD-associated lncRNAs have been discovered, the functional characterization of most lncRNAs is still lacking.

Suppression of retinol-binding protein 4 with RNA oligonucleotide prevents high-fat diet-induced metabolic syndrome and non-alcoholic fatty liver disease in mice.

Conflicting data have been reported regarding the role of retinol-binding protein (RBP4) in insulin resistance, obesity, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). In this study, we used pharmacological methods to investigate the role of RBP4. RNA oligonucleotide against RBP4 (anti-RBP4 oligo) was transfected into 3T3-L1 adipocytes. RT-PCR analysis showed that RBP4 mRNA expression decreased by 55% (p<0.01) compared with control cells. Validated RNA oligo was used in an in vivo study with high fat diet (HFD) fed - mice. 14 weeks of HFD feeding increased RBP4 expression (associated with elevated serum levels measured with immunoblotting and ELISA) by 56% in adipose tissue (p<0.05) and 68% in the liver (p<0.01). Adipose RBP4 levels were significantly reduced after 4 weeks treatment with anti-RBP4 oligo (25mg/kg, p<0.01) and rosiglitazone (RSG, 10mg/kg, p<0.05) compared with scrambled RNA oligo (25mg/kg) treated mice. Only anti-RBP4 oligo significantly inhibited RBP4 protein (p<0.01) and mRNA expression (p<0.01) in the liver and reduced serum RBP4 levels. Anti-RBP4 oligo and RSG showed comparable effects on impaired glucose tolerance, hyperinsulinaemia and hyperglycaemia. Anti-RBP4 oligo significantly enhanced adipose-GLUT4 expression (p<0.01) but did not increase muscle-GLUT4. Both RSG and anti-RBP4 oligo significantly reduced hepatic phosphoenolpyruvate carboxykinase expression (both p<0.05). Histological analysis revealed that anti-RBP4 oligo ameliorated hepatic steatosis and reduced lipid droplets associated with normalized liver function. Histological and pharmacological results of this study indicate that RBP4 is not only an adipocytokine, but also a hepatic cytokine leading to metabolic syndrome, NAFLD and type 2 diabetes.

Application of Artificial Intelligence in Drug Discovery.

Due to the heap of data sets available for drug discovery, modern drug discovery has taken the shape of big data. Usage of Artificial intelligence (AI) can help to modify drug discovery based on big data to precised, knowledgeable data. The pharmaceutical companies have already geared their departments for this and started a race to search for new novel drugs. The AI helps to predict the molecular structure of the compound and its in-vivo vs. in-vitro characteristics without hampering life, thus saving time and economic loss. Clinical studies, electronic records, and images act as a helping hand for the development. The data mining and curation techniques help explore the data with a single click. AI in big data analysis has paved the red carpet for future rational drug development and optimization. This review's objective is to familiarise readers with various advances in the AI field concerning software, firms, and other tools working in easing out the labor of the drug discovery journey.

In Silico and Ex Vivo Analyses of the Inhibitory Action of the Alzheimer Drug Posiphen and Primary Metabolites with Human Acetyl- and Butyrylcholinesterase Enzymes.

Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide. Ongoing research to develop AD treatments has characterized multiple drug targets including the cholinergic system, amyloid-ß peptide, phosphorylated tau, and neuroinflammation. These systems have the potential to interact to either drive or slow AD progression. Promising agents that simultaneously impact many of these drug targets are the AD experimental drug Posiphen and its enantiomer phenserine that, currently, are separately being evaluated in clinical trials. To define the cholinergic component of these agents, the anticholinesterase activities of a ligand dataset comprising Posiphen and primary metabolites ((+)-N1-norPosiphen, (+)-N8-norPosiphen, and (+)-N1,N8-bisnorPosiphen) were characterized and compared to those of the enantiomer phenserine. The "target" dataset involved the human cholinesterase enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Binding interactions between the ligands and targets were analyzed using Autodock 4.2. The computationally determined inhibitory action of these ligands was then compared to ex vivo laboratory-measured values versus human AChE and BChE. While Posiphen lacked AChE inhibitory action, its major and minor metabolites (+)-N1-norPosiphen and (+)-N1,N8-bisnorPosiphen, respectively, possessed modest AChE inhibitory activity, and Posiphen and all metabolites lacked BChE action. Phenserine, as a positive control, demonstrated AChE-selective inhibitory action. In light of AChE inhibitory action deriving from a major and minor Posiphen metabolite, current Posiphen clinical trials in AD and related disorders should additionally evaluate AChE inhibition; particularly if Posiphen should be combined with a known anticholinesterase, since this drug class is clinically approved and the standard of care for AD subjects, and excessive AChE inhibition may impact drug tolerability.

Current Insights and Molecular Docking Studies of the Drugs under Clinical Trial as RdRp Inhibitors in COVID-19 Treatment.

Study Background & Objective: After the influenza pandemic (1918), COVID-19 was declared a Vth pandemic by the WHO in 2020. SARS-CoV-2 is an RNA-enveloped single-stranded virus. Based on the structure and life cycle, Protease (3CLpro), RdRp, ACE2, IL-6, and TMPRSS2 are the major targets for drug development against COVID-19. Pre-existing several drugs (FDA-approved) are used to inhibit the above targets in different diseases. In coronavirus treatment, these drugs are also in different clinical trial stages. Remdesivir (RdRp inhibitor) is the only FDA-approved medicine for coronavirus treatment. In the present study, by using the drug repurposing strategy, 70 preexisting clinical or under clinical trial molecules were used in scrutiny for RdRp inhibitor potent molecules in coronavirus treatment being surveyed via docking studies. Molecular simulation studies further confirmed the binding mechanism and stability of the most potent compounds. MATERIAL AND METHODS: Docking studies were performed using the Maestro 12.9 module of Schrodinger software over 70 molecules with RdRp as the target and remdesivir as the standard drug and further confirmed by simulation studies. RESULTS: The docking studies showed that many HIV protease inhibitors demonstrated remarkable binding interactions with the target RdRp. Protease inhibitors such as lopinavir and ritonavir are effective. Along with these, AT-527, ledipasvir, bicalutamide, and cobicistat showed improved docking scores. RMSD and RMSF were further analyzed for potent ledipasvir and ritonavir by simulation studies and were identified as potential candidates for corona disease. CONCLUSION: The drug repurposing approach provides a new avenue in COVID-19 treatment.

Current Overviews on COVID-19 Management Strategies.

The coronavirus pandemic hit the world lately and caused acute respiratory syndrome in humans. The causative agent of the disease was soon identified by scientists as SARS-CoV-2 and later called a novel coronavirus by the general public. Due to the severity and rapid spread of the disease, WHO classifies the COVID-19 pandemic as the 6th public health emergency even after taking efforts like worldwide quarantine and restrictions. Since only symptomatic treatment is available, the best way to control the spread of the virus is by taking preventive measures. Various types of antigen/antibody detection kits and diagnostic methods are available for the diagnosis of COVID-19 patients. In recent years, various phytochemicals and repurposing drugs showing a broad range of anti-viral activities with different modes of actions have been identified. Repurposing drugs such as arbidol, hydroxychloroquine, chloroquine, lopinavir, favipiravir, remdesivir, hexamethylene amiloride, dexamethasone, tocilizumab, interferon-ß, and neutralizing antibodies exhibit in vitro anti-coronaviral properties by inhibiting multiple processes in the virus life cycle. Various research groups are involved in drug trials and vaccine development. Plant-based antiviral compounds such as baicalin, calanolides, curcumin, oxymatrine, matrine, and resveratrol exhibit different modes of action against a wide range of positive/negative sense-RNA/DNA virus, and future researches need to be conducted to ascertain their role and use in managing SARS-CoV-2. Thus this article is an attempt to review the current understanding of COVID- 19 acute respiratory disease and summarize its clinical features with their prospective control and various aspects of the therapeutic approach.

Current Trends of Computational Tools in Geriatric Medicine and Frailty Management.

While frailty corresponds to a multisystem failure, geriatric assessment can recognize multiple pathophysiological lesions and age changes. Up to now, a few frailty indexes have been introduced, presenting definitions of psychological problems, dysregulations in nutritional intake, behavioral abnormalities, and daily functions, genetic, environmental, and cardiovascular comorbidities. The geriatric evaluation includes a vast range of health professionals; therefore, we describe a broad range of applications and frailty scales-biomarkers to investigate and formulate the relationship between frailty lesions, diagnosis, monitoring, and treatment. Additionally, artificial intelligence applications and computational tools are presented, targeting a more efficacy individualized geriatric management of healthy aging.

Chinese herbal extracts (SK0506) as a potential candidate for the therapy of the metabolic syndrome.

The metabolic syndrome has reached epidemic proportions worldwide, but currently there is a lack of effective therapies for this multifactorial endocrine disease. TCM (traditional Chinese medicine) has been utilized to treat a wide variety of diseases for centuries in the People's Republic of China, subsequently becoming a promising source for the development of new therapeutic agents. Chinese medicinal herbs Gynostemma pentaphyllum, Coptis chinensis and Salvia miltiorrhiza have been shown to have anti-atherosclerotic and antidiabetic properties. In this study, we have investigated the metabolic effects of a mixture of these three herbal extracts (SK0506) in a rodent model of the metabolic syndrome induced by an HFD (high-fat diet). SD (Sprague-Dawley) rats that were fed on an HFD for 4 weeks gained 33% more weight compared with chow-fed rats (P<0.05). Four weeks treatment with SK0506 prevented weight gain with decreased visceral fat (P<0.01 compared with vehicle treatment). SK0506 also significantly reduced plasma triacylglycerols (triglycerides), NEFAs (non-esterified fatty acids) and cholesterol. SK0506 exerted similar effects to RSG (rosiglitazone) on impaired glucose intolerance. SK0506 also significantly enhanced glucose uptake and glycogen synthesis in adipose tissue during hyperinsulinaemic-euglycaemic clamp. Western blotting analysis revealed that SK0506 enhanced GLUT4 (glucose transporter 4) expression in adipose tissue, and RSG markedly up-regulated GLUT4 translocation in skeletal muscle. Overall, the present study has discovered that SK0506 can reverse several components of the metabolic syndrome primarily through acting on hyperlipidaemia and visceral obesity. The results from the present study suggest that it is worthwhile to conduct a randomized clinical trial to confirm the potential that SK0506 may be a new oral agent for treating the metabolic syndrome and preventing Type 2 diabetes.

Emergence and Re-emergence of Human Coronaviruses: Spike Protein as the Potential Molecular Switch and Pharmaceutical Target.

BACKGROUND: Recent emergence of COVID-19 caused by a new human coronavirus (CoV) strain (SARS-CoV-2), which originated from China, poses the future emergence of additional CoVs. In most of the cases of emergence of human CoVs, bats, palm civets, raccoon dogs and camels have been identified as the sources of human infections and as reservoir hosts. A review of comparative genomic and phenotypic characteristics of human CoV strains vis-à-vis their comparison with the corresponding animal isolates shall provide clues regarding the potential genomic, phenotypic and molecular factors responsible for host-switching, which may lead to prospective emergence and re-emergence of human CoV outbreaks in the future. METHODS: The seven known human strains of CoV were analyzed for the host and viral factors responsible for human outbreaks. The molecular factors responsible for host-susceptibility, virulence and pathogenesis were reviewed to predict the emergence and re-emergence of additional human CoV strains. CoV spike protein was evaluated as a potential viral receptor for host switching and the target for pharmaceutical design. RESULTS: A review of the factors associated with host-susceptibility, virulence and pathogenesis of seven known human CoV strains presents significant possibilities for the emergence of new CoV strain(s), leading to more human outbreaks. Continuous exposure of animals' handlers to the infected animals, environmental changes, improper sanitations, non-disposal of the solid waste and resumption of exotic animals markets provides favorable conditions for "host switching" and the emergence of new and potentially more virulent human CoV strains. Mutations in target genes (like spike protein), which facilitate the viral entry into the host-cells, provide a potential "molecular switch" for preferences of new host-receptors, genetic diversity, genetic-recombination and high virulence. Additionally, the clinical and environmental factors, asymptomatic carriers, the paucity of efficacious vaccines & therapeutics, inefficient disease management and infection control measures, lack of public awareness, and effective communication of information about more virulent human-adapted virus isolates are critical for the emergence of new and virulent SARS-CoV strains with high mortality and varied incubation period in the near future. Small molecules binding with conserved druggable regions of the CoV spike proteins may be effective against multiple strains of CoVs. CONCLUSION: High propensity of mutations and "molecular adaptations" in coronaviruses creates the hot spots and high potential for "host switching", leading to the emergence of more virulent strains of human CoVs. The public/global health agencies, medical communities and research scientists should be prepared for the emergence and re-emergence of new human CoV strain(s) leading to potential disease outbreaks. The inhibitors binding with conserved druggable regions of spike proteins from multiple strains CoV may have utility as broad-spectrum antiviral drugs to combat future emergence of CoVs.

Tumor Angiogenesis and VEGFR-2: Mechanism, Pathways and Current Biological Therapeutic Interventions.

BACKGROUND: Angiogenesis, involving the formation of new blood vessels from preexisting vessels, caters an important biological phenomenon for the growth and development of bodily structures in the human body. Regulation of angiogenesis in non-pathological conditions takes place through a well-defined balanced angiogenic-switch, which upon exposure to various pathological conditions may get altered. This makes the cells change their normal behavior resulting in uncontrolled division and angiogenesis. METHODS: The current review tries to present a brief framework of angiogenesis and tumor progression phenomenon along with the latest therapeutic interventions against VEGFR-2 and its future directions. RESULTS: The tumor angiogenic pathways functioning in diverse mechanisms via sprouting angiogenesis, intussusceptive angiogenesis, vascular co-option, vascular mimicry, and glomeruloid angiogenesis are normally activated by varied angiogenic stimulators and their receptors are interrelated to give rise to specialized signaling pathways. Amongst these receptors, VEGFR-2 is found as one of the key, critical mediators in tumor angiogenesis and is seen as a major therapeutic target for combating angiogenesis. Though a number of anti-angiogenic drugs like Ramucirumab, Sunitinib, Axitinib, Sorafenib, etc. showing good survival rates have been developed and approved by FDA against VEGFR-2, but these have also been found to be associated with serious health effects and adverse reactions. CONCLUSION: An improved or alternative treatment is needed shortly that has a higher survival rate with the least side effects. Innovative strategies, including personalized medicine, nano-medicine, and cancer immunotherapy have also been outlined as an alternative treatment with a discussion on advancements and improvements required for their implementation methods.