Current Drug Targets - Volume 20, Issue 4, 2019

Objective: The primary focus of this review is to highlight the current and emerging proinflammatory role of MK2 kinase signaling in p38MAPK pathway and to provide a detailed evaluation on the prospects of MK2 inhibition with special emphasis on the etiology of chronic inflammatory airway diseases, such as asthma, idiopathic pulmonary fibrosis, lung cancer, acute lung injury and acute respiratory distress syndrome. Background: MK2 belongs to serine-threonine kinase family and is activated directly by stress and inflammatory signal through p38MAPK phosphorylation in diverse inflammatory conditions through the Toll-like receptor signaling pathway. MK2 has been thought to be a critical factor involved in the regulation of synthesis and release of pro-inflammatory (TNF-α, IL-6 and IL-1β, etc.) proteins. Targeted inhibition of MK2 kinase has been shown to significantly reduce the production and release of these cytokine molecules. Therefore, MK2 has been identified as an effective strategy (alternative to p38MAPK) to block this pro-inflammatory signaling pathway. Results: The inhibition of MK2 may lead to similar or better efficacy as that of p38 inhibitors, and interestingly avoids the systemic toxicity shown by the p38 inhibitors. Thus, MK2 has been the focus of intense interdisciplinary research and its specific inhibition can be a novel and potential therapeutic strategy for the treatment of chronic airway inflammatory diseases. Conclusion: Promising advancement in understanding and rigorous exploration of the role of MK2 kinase in inflammatory processes may contribute to the development of newer and safer therapy for the treatment of chronic airway inflammatory diseases in the future.

Aim: The role of rifaximin in the prevention of Spontaneous Bacterial Peritonitis (SBP) is not well studied. The aim of this meta-analysis was to evaluate the role of rifaximin in the prevention of SBP. Methods: A computerized literature search for relevant clinical trials was conducted during August 2017. Data on Frequency of SBP, the success rate of prevention of SBP, mortality rate, hepatorenal syndrome, septic shock, hepatic encephalopathy, and GIT bleeding were extracted and pooled as Risk Ratio (RR) with their 95% Confidence Interval (CI) in a meta-analysis model. Heterogeneity was assessed by Chi-square test. Results: Six studies involving 973 patients were included in the final analysis. The pooled effect estimate showed that the rifaximin plus norfloxacin group had less incidence of SBP (RR 0.58, 95% CI[0.37, 0.92], P=0.02) and hepatic encephalopathy (RR 0.38, 95% CI[0.17, 0.84], P=0.02) than the norfloxacin-based regimen group. No significant difference between rifaximin and norfloxacin in terms of frequency of SBP and success rate of primary prevention of SBP (RR 0.49, 95% CI [0.24, 1.01], P=0.05; RR1.21, 95% CI [0.95, 1.55], P=0.13, respectively). Conclusion: Based on our analysis, Rifaximin is a promising drug and appears to be a good alternative to norfloxacin in the prevention of SBP.

Stem Cell Research and Tissue Engineering, in present time, have emerged as a legalized and regulated stem cell treatment option globally, but scientifically, their success is unestablished. Novel stem cell-based therapies have evolved as innovative and routine clinical solutions by commercial companies and hospitals across the world. Such rampant spread of stem cell clinics throughout UK, US, Europe and Asia reflect the public encouragement of benefits to incurable diseases. However, ever growing stem cell therapy developments need constant dogwatch and careful policy making by government regulatory bodies for prompt action in case of any untoward public concern. Therefore, researchers and physicians must keep themselves abreast of current knowledge on stem cells, tissue engineering devices in treatment and its safe legal limits. With this aim, stem cell scienctific developments, treatment options and legal scenario are introduced here to beginner or actively inolved scientists and physicians. Introduction to stem cell therapy will provide basic information to beginner researchers and practice physicians on engineered stem cell research concepts and present stem cell therapy federal regulations in different North American, European and Asian countries. FDA, CDC, EU, ICMR government policies in different countries include information on the current legal position, ethical policies, regulatory oversight and relevant laws.

Background: Obesity has become a worldwide health concern. Pharmacotherapies are now being introduced because lifestyle modifications alone are insufficient for weight management. The treatment outcomes of current approved anti-obesity agents are not satisfying due to drug-related intolerances. And so natural therapies including herbal medicines are popular alternatives for weight reduction; however, there are limited studies about their mechanism of actions. Methods: Five databases (PubMed, Scopus, Google Scholar, Science Direct, Proquest) were searched to investigate the targets and safety profiles of the current and past anti-obesity drugs that have been approved by the Food and Drug Administration (FDA) or the European Medicines Agency (EMA) as well as the commonly used off-label agents. The targets for weight-loss natural products and their principle bioactive components have also been searched. Only articles in English were included. Results: The targets for current anti-obesity single agents include pancreatic lipase, Glucagon Like Peptide-1(GLP-1) receptor, and serotonin 2C (5-HT2C) receptor. Potential targets such as amylin, pancreatic alpha amylase, leptin receptor, melanocortin receptor 4 receptor (MC4R), Peroxisome Proliferator- Activated Receptors gamma (PPAR γ), endocannabinoid 1 (CB1) receptor and Adenosine Monophosphate (AMP)-Activated Protein Kinase (AMPK) were discussed in various studies. Natural compounds have been found to interact with targets like pancreatic lipase, pancreatic alpha amylase, AMPK and PPAR γ to achieve weight reduction. Conclusion: Current pharmacotherapies and natural chemical compounds do act on same targets. Further investigations on the interactions between herbal compounds and the above targets are essential for the development of novel weight-loss therapies.

Background: Air pollution is a major cause of asthma exacerbation. Most studies have shown that exposure to coarse and fine particulate matter is associated with asthma exacerbation. Ultrafine particles (UFPs, aerodynamic diameter ≤ 0.1 μm) are the smallest airborne particles, which are capable of penetrating deep into the lungs. Toxicological studies have suggested that exposure to UFPs may have serious effects on respiratory health. However, epidemiological evidence on the effects of UFPs exposure on asthma exacerbation in children remains unclear. Objective: We conducted a meta-analysis to quantitatively assess the effects of exposure to UFPs on childhood asthma exacerbation. Methods: We searched four databases for epidemiological studies published until March 20, 2018. Pooled Odds Ratios (OR) and 95% confidence intervals (95% CIs) per 10000 particles/cm3 were estimated using fixed-effect models. Subgroup analyses, sensitivity analyses, and Begg’s and Egger’s regression were also performed. Results: Eight moderate–high quality studies with 51542 events in total satisfied the inclusion criteria. Exposure to UFPs showed a positive association with childhood asthma exacerbation [OR (95% CI): 1.070 (1.037, 1.104)], increased asthma-associated emergency department visits [OR (95% CI): 1.111 (1.055, 1.170)], and asthma-associated hospital admissions [OR (95% CI): 1.045 (1.004, 1.088)] and had a stronger association with childhood asthma exacerbation at long lags [OR (95% CI):1.060 (1.039, 1.082)]. A low heterogeneity and no publication bias were detected. Conclusion: Exposure to UFPs may increase the risk of asthma exacerbation and may be strongly associated with childhood asthma exacerbation at long lags.

Increasing interest in vascular pseudo-ossification has alarmed the modern atherosclerotic society. High phosphate is one of the key factors in vascular pseudo ossification, also known as vascular calcification. The active process of deposition of the phosphate crystals in vascular tissues results in arterial stiffness. High phosphate condition is mainly observed in chronic kidney disease patients. However, prolonged exposure with high phosphate enriched foods such as canned drinks, dietary foods, etc. can be considered as modifiable risk factors for vascular complication in a population regardless of chronic kidney disease. High intake of vitamin K regulates the vascular calcification by exerting its anti-calcification effect. The changes in serum phosphate and vitamin K levels in a normal individual with high phosphate intake are not well investigated. This review summarised the underlying mechanisms of high phosphate induced vascular pseudo ossification such as vascular transdifferentiation, vascular apoptosis and phosphate uptake by sodium-dependent co-transporters. Pubmed, Science Direct, Scopus, ISI Web of Knowledge and Google Scholar were searched using the terms ‘vitamin K’, ‘vascular calcification, ‘phosphate’, ‘transdifferentiation’ and ‘vascular pseudoossification’. Vitamin K certainly activates the matrix GIA protein and inhibits vascular transition and apoptosis in vascular pseudo-ossification. The present view highlighted the possible therapeutic linkage between vitamin K and the disease. Understanding the role of vitamin K will be considered as potent prophylaxis agent against the vascular disease in near future.

Hypertension is usually associated with deficient nitric oxide (NO) bioavailability, and therefore stimulating NO activity is an important antihypertensive strategy. Recently, many studies have shown that both nitrite and nitrate anions are not simple products of NO metabolism and indeed may be reduced back to NO. While enzymes with nitrite-reductase activity capable of generating NO from nitrite may contribute to antihypertensive effects of nitrite, another mechanism involving the generation of NO-related species in the stomach from nitrite has been validated. Under the acidic conditions of the stomach, nitrite generates NO-related species that form S-nitrosothiols. Conversely, drugs that increase gastric pH may impair the gastric formation of S-nitrosothiols, which may mediate antihypertensive effects of oral nitrite or nitrate. Therefore, it is now becoming clear that promoting gastric formation of S-nitrosothiols may result in effective antihypertensive responses, and this mechanism opens a window of opportunity in the therapy of hypertension. In this review, we discuss the recent studies supporting the gastric generation of S-nitrosothiols as a potential antihypertensive mechanism of oral nitrite. We also highlight some drugs that increase S-nitrosothiols bioavailability, which may also improve the responses to nitrite/nitrate therapy. This new approach may result in increased nitrosation of critical pharmacological receptors and enzymes involved in the pathogenesis of hypertension, which tend to respond less to their activators resulting in lower blood pressure.

Sesquiterpene lactones, secondary metabolites of plants, present in a large number of species mostly from the Asteracea family, are used in the traditional medicine of many countries for the treatment of various pathological conditions. They exert a broad range of activities, including antiinflammatory, anti-bacterial and anti-cancer properties. The best-known sesquiterpene lactones which are already used as drugs or are used in clinical trials are artemisinin, thapsigargin and parthenolide. Yet another sesquiterpene lactone, helenalin, an active component of Arnica montana, known for its strong anti-inflammatory activity, has been used for centuries in folk medicine to treat minor injuries. Unfortunately, helenalin's ability to cause allergic reactions and its toxicity to healthy tissues prevented so far the development of this sesquiterpene lactone as an anticancer or anti-inflammatory drug. Recently, the new interest in the biological properties, as well as in the synthesis of helenalin analogs has been observed. This review describes helenalin's major biological activities, molecular mechanisms of action, its toxicity and potential for further research.

Cyclin Dependent Kinase 9 (CDK9) as a serine/threonine kinase belongs to a great number of CDKs. CDK9 is the main core of PTEF-b complex and phosphorylates RNA polymerase (RNAP) II besides other transcription factors which regulate gene transcription elongation in numerous physiological processes. Multi-functional nature of CDK9 in diverse cellular pathways proposes that it is as an appealing target. In this review, we summarized the recent findings on the molecular interaction of CDK9 with critical participant molecules to modulate their activity in various diseases. Furthermore, the presented review provides a rationale supporting the use of CDK9 as a therapeutic target in clinical developments for crucial diseases; particularly cancers will be reviewed.

Disintegrins are non-enzymatic proteins that interfere on cell–cell interactions and signal transduction, contributing to the toxicity of snake venoms and play an essential role in envenomations. Most of their pharmacological and toxic effects are the result of the interaction of these molecules with cell surface ligands, which has been widely described and studied. These proteins may act on platelets, leading to hemorrhage, and may also induce apoptosis and cytotoxicity, which highlights a high pharmacological potential for the development of thrombolytic and antitumor agents. Additionally, these molecules interfere with the functions of integrins by altering various cellular processes such as migration, adhesion and proliferation. This review gathers information on functional characteristics of disintegrins isolated from snake venoms, emphasizing a comprehensive view of the possibility of direct use of these molecules in the development of new drugs, or even indirectly as structural models.