Therapeutic potential of nicorandil beyond anti-anginal drug: A review on current and future perspectives.

Nicorandil (NIC) is a well-known anti-anginal agent, which has been recommended as one of the second-line treatments for chronic stable angina as justified by the European guidelines. It shows an efficacy equivalent to that of classic anti-anginal agents. NIC has also been used clinically in various cardiovascular diseases such as variant or unstable angina and reperfusion-induced damage following coronary angioplasty or thrombolysis. Different mechanisms have been involved in the protective effects of nicorandil in various diseases, including opening of adenosine triphosphate-sensitive potassium (KATP) channel and donation of nitric oxide (NO). In recent years, NIC has been found to show numerous pharmacological activities such as neuroprotective, nephroprotective, hepatoprotective, cardioprotective, and testicular protective effects, among other beneficial effects on the body. The present review dwells on the pharmacological potentials of NIC beyond its anti-anginal action.

Assessing and Prioritizing Zoonotic Diseases in Punjab, India: A One Health Approach.

Zoonotic diseases have a significant impact on both human and animal health globally. The present study was planned to prioritize the zoonoses in Punjab state of India. To develop a zoonotic disease prioritization scoring system, a comprehensive approach has been taken, including literature review, key person interviews with animal health experts (n = 12) and medical professionals (n = 7), and nine focus group discussions (FGDs) with veterinary academicians, medical professionals, and field veterinary doctors. The scoring system comprises of seven major criteria, each assigned a weightage score (ws): prevalence/incidence of the disease (ws = 0.20), severity of illnesses in humans (ws = 0.18), epidemic potential (ws = 0.16), socio-economic burden (ws = 0.16), availability of effective control and prevention measures (ws = 0.15), inter-sectoral collaborations (ws = 0.1), and bioterrorism potential (ws = 0.05). The finalized scoring system, accompanied by a list of 15 selected zoonotic diseases, was implemented among a group of 23 professionals engaged in zoonoses research (n = 7), animal health (n = 10), and medical health (n = 6) to determine their prioritization. The zoonotic diseases prioritized for the Punjab (India) included, Brucellosis (0.70) > Rabies (0.69) > Anthrax (0.64) > Leptospirosis (0.62) = Toxoplasmosis (0.62) = Highly Pathogenic Avian Influenza (HPAI) (0.62) > Bovine tuberculosis (0.61) > Q fever (0.60) > Cysticercosis (0.59) > Listeriosis (0.58) > Crimean-Congo haemorrhagic fever (CCHF) (0.57) > Japanese encephalitis (0.56) = Echinococcosis (0.56) > Dermatophytosis (0.53) > and Scrub typhus (0.48), respectively. Higher priority is suggested for endemic zoonoses (e.g., brucellosis and rabies) as compared to those with epidemic potential (e.g., CCHF, HPAI etc.) in Punjab. Results of the current study will help in the development of targeted control and prevention strategies for zoonotic diseases in Punjab and other geographical regions facing similar challenges.

Opportunities and challenges in application of artificial intelligence in pharmacology.

Artificial intelligence (AI) is a machine science that can mimic human behaviour like intelligent analysis of data. AI functions with specialized algorithms and integrates with deep and machine learning. Living in the digital world can generate a huge amount of medical data every day. Therefore, we need an automated and reliable evaluation tool that can make decisions more accurately and faster. Machine learning has the potential to learn, understand and analyse the data used in healthcare systems. In the last few years, AI is known to be employed in various fields in pharmaceutical science especially in pharmacological research. It helps in the analysis of preclinical (laboratory animals) and clinical (in human) trial data. AI also plays important role in various processes such as drug discovery/manufacturing, diagnosis of big data for disease identification, personalized treatment, clinical trial research, radiotherapy, surgical robotics, smart electronic health records, and epidemic outbreak prediction. Moreover, AI has been used in the evaluation of biomarkers and diseases. In this review, we explain various models and general processes of machine learning and their role in pharmacological science. Therefore, AI with deep learning and machine learning could be relevant in pharmacological research.

Ecological and human health risk assessment of metals in soils and wheat along Sutlej river (India).

Heavy metal (HMs) entry into soil affects the food chain, which is of great worry for human well-being hazards. In order to study the association of HMs in soil-plant system, surface (0-0.15 m) soil and wheat grain samples were collected within five km buffer zone of Sutlej river in Punjab (India). These samples were analysed for total arsenic (As), cadmium (Cd), chromium (Cr), copper (Cu), cobalt (Co), iron (Fe), manganese (Mn), nickle (Ni), lead (Pb), and zinc (Zn). Among all the HMs in soil and grain samples, the concentration of total Fe was maximum and As was minimum. The HM contamination of soils was assessed using contamination factor (CF), enrichment factor (EF), potential ecological risk (Er) and modified potential ecological risk (mEr). The CF, EF, Er and mEr were highest for Cd in soils. The bioaccumulation metal factor was highest for Zn and lowest for Ni in wheat grain. There was a significant (p < 0.05) positive relationship between HM concentration in soils and wheat grains indicating the health risk due to consumption of wheat cultivated around the five km buffer of the Sutlej river. The carcinogenic and non-carcinogenic risk due to ingestion of wheat grain were higher from Cd and Pb, respectively. These results are helpful for devising the remediation approaches to decrease the multi-metal contamination in soils and plants, and the epidemiological ways to preclude the human health risk from HM contamination.

Diabetic Neuropathy: A Repercussion of Vitamin D Deficiency.

Diabetes mellitus is a crucial health issue worldwide. The worldwide ubiquity is 8.8% among adults, which is predicted to rise to 10.4% by 2040. Diabetic neuropathy is a long-term complication associated with the diabetes mellitus condition, which primarily targets Schwann cells, peripheral axons and cell bodies (perikarya) in DRG (dorsal root ganglia). It can be accompanied by different factors such as metabolic factors such as insulin resistance, hypertension, obesity, low HDL level, and hypertriglyceridemia. The etiology of DPN is multifactorial. It is caused by hyperglycemia, micro-angiopathy, HbA1c, duration of diabetes, smoking status, high-density lipoprotein cholesterol and hypertension. Also, increased glucose conditions decrease vitamin D levels. Vitamin D, which is involved in neurotrophins such as NGF (nerve growth factor) and NCH (neuronal calcium homeostasis), plays a neuroprotective role in peripheral nerves. Depletionleads to vitamin D deficiency which further develops peripheral neuropathy in diabetic patients. Accumulation of AGEs (advanced glycation end product) plays a significant role in the pathogenesis of sensory neuronal damage. It contributes to microangiopathy and endoneurial vascular dysfunction in peripheral nerves. With vitamin D supplementation, the neuropathy pain scores were improved.

Snail maintains the stem/progenitor state of skin epithelial cells and carcinomas through the autocrine effect of matricellular protein Mindin.

Preservation of a small population of cancer stem cells (CSCs) within a heterogeneous carcinoma serves as a paradigm to understand how select cells in a tissue maintain their undifferentiated status. In both embryogenesis and cancer, Snail has been correlated with stemness, but the molecular underpinning of this phenomenon remains largely ill-defined. In models of cutaneous squamous cell carcinoma (cSCC), we discovered a non-epithelial-mesenchymal transition function for the transcription factor Snail in maintaining the stemness of epidermal keratinocytes. Snail-expressing cells secrete the matricellular protein Mindin, which functions in an autocrine fashion to activate a Src-STAT3 pathway to reinforce their stem/progenitor phenotype. This pathway is activated by the engagement of Mindin with the leukocyte-specific integrin, CD11b (ITGAM), which is also unexpectedly expressed by epidermal keratinocytes. Interestingly, disruption of this signaling module in human cSCC attenuates tumorigenesis, suggesting that targeting Mindin would be a promising therapeutic approach to hinder cancer recurrence.

Phytoavailability and human risk assessment of heavy metals in soils and food crops around Sutlej river, India.

We assessed the phytoavailability of heavy metals in wheat and rice grown on soils along flood plains of Sutlej river (India) and its effects on human health. Surface soil samples along with wheat (pre-monsoon season) and rice (post-monsoon season) grain samples were collected during the years 2017 and 2018. Soil samples were analysed for total and DTPA-extractable metals and, wheat and rice grains samples for total metals. There were no significant (p < 0.05) changes in total metal concentration during both the years, but the concentration of DTPA-extractable metals was higher during pre-monsoon than post-monsoon season. The concentration of Pb, Cd, and Co in wheat grains, whereas the concentration of Cr, Co, Pb and Cd in rice grains surpassed their safe limits. Both DTPA-extractable metals (water soluble plus exchangeable) and non-exchangeable fractions explained more than 80% of the variations in metal uptake by plants. The bioaccumulation factor for DTPA-extractable metals (BCF) was above one, but Pollution Load Index for these metals (PLI) was less than one. The carcinogenic risks due to ingestion of wheat and rice grains were higher for Cd. The BAF, PLI and health risks were higher along transboundary of the river. These results suggest that exchangeable and non-exchangeable fractions are contributing towards metals uptake by wheat and rice along flood plain soils of the Sutlej river and the present study may act as a model for carrying out similar studies to find out the risks of heavy metals and it effect on human health in future.

Impact assessment of metal contamination in surface water of Sutlej River (India) on human health risks.

The Sutlej river in Indian Punjab is getting contaminated by industrial waste, sewage, and agricultural runoff. Most of the previous studies on metal contamination of water are mainly confined to the small stretch of river. Therefore, a systematic study was carried out to assess the spatial and temporal variability of metal contamination in water from the entry point of Sutlej River in Indian Punjab to its tail end when it leaves the country. The likelihood of cancer risk was also estimated though human health risk assessment. The water samples (between 76 and 91) were collected from Sutlej river during pre- (April) and post-monsoon (September-October) seasons of the years 2017 and 2018. There samples were analyzed for 10 metals (Zn, Cu, Fe, Mn, Ni, Cd, Pb, Co, Cr and As) using Atomic Absorption Spectrophotometer. Results showed that metal concentration in water was higher along the transboundary during both the seasons. The concentration of metals in water was higher in pre-monsoon season than post-monsoon season. Multivariate analysis in different seasons showed that biophysical variables and social drivers (including anthropogenic activities) have great influence on the concentration of metals. Spatial distribution of all the metals in water and heavy metal pollution index showed that metal contamination was higher along the transboundary followed by the area from the confluence of contaminated drain with river to transboundary along with localized spots in the river flowing in Indian Punjab. The likelihood of cancer risk due to ingestion of metals through water was in the order: Cd > Ni > Cr > As and the risk is higher in the areas along the transboundary. These results are useful for formulating the action plan to improve the water quality of Sutlej river and its environs including water-soil-plant continuum which affect human health.

Pesticide Residues in Peri-Urban Bovine Milk from India and Risk Assessment: A Multicenter Study.

Pesticides residue poses serious concerns to human health. The present study was carried out to determine the pesticide residues of peri-urban bovine milk (n = 1183) from five different sites (Bangalore, Bhubaneswar, Guwahati, Ludhiana and Udaipur) in India and dietary exposure risk assessment to adults and children. Pesticide residues were estimated using gas chromatography with flame thermionic and electron capture detectors followed by confirmation on gas chromatography-mass spectrometer. The results noticed the contamination of milk with hexachlorocyclohexane (HCH), dichloro-diphenyl trichloroethane (DDT), endosulfan, cypermethrin, cyhalothrin, permethrin, chlorpyrifos, ethion and profenophos pesticides. The residue levels in some of the milk samples were observed to be higher than the respective maximum residue limits (MRLs) for pesticide. Milk samples contamination was found highest in Bhubaneswar (11.2%) followed by Bangalore (9.3%), Ludhiana (6.9%), Udaipur (6.4%) and Guwahati (6.3%). The dietary risk assessment of pesticides under two scenarios i.e. lower-bound scenario (LB) and upper-bound (UB) revealed that daily intake of pesticides was substantially below the prescribed acceptable daily intake except for fipronil in children at UB. The non-cancer risk by estimation of hazard index (HI) was found to be below the target value of one in adults at all five sites in India. However, for children at the UB level, the HI for lindane, DDT and ethion exceeded the value of one in Ludhiana and Udaipur. Cancer risk for adults was found to be in the recommended range of United States environment protection agency (USEPA), while it exceeded the USEPA values for children.

Coriandrum sativum improve neuronal function via inhibition of oxidative/nitrosative stress and TNF-α in diabetic neuropathic rats.

ETHNOPHRAMACOLOGICAL RELEVANCE: Coriandrum sativum L. is traditionally acknowledged for its use in inflammatory disorders, altered blood lipid levels, respiratory and digestive problems. AIM OF THE STUDY: The present study investigates possible role of hydro-alcoholic extract of C. sativum (CHA) seeds in the attenuation of indices of diabetic peripheral neuropathy (DPN). MATERIALS AND METHODS: Phytochemical analysis was carried out by employing chromatographic, spectroscopic as well as spectrometric techniques. Diabetes was induced by a single i.p. injection of freshly prepared STZ (65 mg/kg). The indexed markers of DPN, i.e., thermal and mechanical hyperalgesia were found to be prominent on the 60th day of STZ administration. Administration of CHA (100, 200, and 400 mg/kg, p.o.) for 30 days was started on the substantiation of DPN onset. Molecular docking study was performed by targeting TNF-α. RESULTS: Phytochemical analysis revealed the presence of flavonoids, terpenoids, and phenolic acids. Oral administration of CHA considerably attenuated hyperglycemia and decreased pain threshold in diabetic rats as well as modulated oxidative-nitrosative stress. Docking study suggested good affinity of flavonoids when docked into the binding site of TNF-α. CONCLUSION: In conclusion, using STZ model, it was successfully predicted that CHA might be beneficial in diabetes-induced neuropathic pain by inhibiting oxidative/nitrosative stress and inflammatory cytokine.

A Fyn biosensor reveals pulsatile, spatially localized kinase activity and signaling crosstalk in live mammalian cells.

Cell behavior is controlled through spatio-temporally localized protein activity. Despite unique and often contradictory roles played by Src-family-kinases (SFKs) in regulating cell physiology, activity patterns of individual SFKs have remained elusive. Here, we report a biosensor for specifically visualizing active conformation of SFK-Fyn in live cells. We deployed combinatorial library screening to isolate a binding-protein (F29) targeting activated Fyn. Nuclear-magnetic-resonance (NMR) analysis provides the structural basis of F29 specificity for Fyn over homologous SFKs. Using F29, we engineered a sensitive, minimally-perturbing fluorescence-resonance-energy-transfer (FRET) biosensor (FynSensor) that reveals cellular Fyn activity to be spatially localized, pulsatile and sensitive to adhesion/integrin signaling. Strikingly, growth factor stimulation further enhanced Fyn activity in pre-activated intracellular zones. However, inhibition of focal-adhesion-kinase activity not only attenuates Fyn activity, but abolishes growth-factor modulation. FynSensor imaging uncovers spatially organized, sensitized signaling clusters, direct crosstalk between integrin and growth-factor-signaling, and clarifies how compartmentalized Src-kinase activity may drive cell fate.

Coriandrum sativum seeds extract mitigate progression of diabetic nephropathy in experimental rats via AGEs inhibition.

Inthe present study, we have demonstrated the phytochemical composition of petroleum ether extract of C. sativum (CPE) seeds by using chromatographic, spectroscopic as well spectrometric analysis. CPE was evaluated for its possible role in mitigation of diabetic nephropathy (DN) in Streptozotocin (STZ)-nicotinamide (NAD) induced type 2 diabetes model. Administration of CPE at doses of 100, 200, and 400 mg/kg for 45 days has produced significant attenuation of elevated biochemical parameters including serum glucose, lipid and creatinine levels. CPE has also reserved albuminuria and elevated creatinine clearance in treated diabetic rats. Advanced glycation end products (AGEs) formation in kidneyswas also considerably reduced along with noteworthy increase in level of superoxide dismutase (SOD), glutathione (GSH), and decrease in lipid peroxidation in terms of thiobarbituric acid reactive species (TBARS). Molecular docking studies were also employed to reveal out the possible mechanism. In conclusion, using STZ-NAD model, we have successfully predicted that by assets of bioactive constituents CPE might inhibit the progression of DN. C. sativum may act as potential adjuvant for antidiabetic therapy and needs to be investigated further.

Drug metabolizing enzymes and their inhibitors' role in cancer resistance.

Despite continuous research on chemotherapeutic agents, different mechanisms of resistance have become a major pitfall in cancer chemotherapy. Although, exhaustive efforts are being made by several researchers to target resistance against chemotherapeutic agents, there is another class of resistance mechanism which is almost carrying on unattended. This class of resistance includes pharmacokinetics resistance such as efflux by ABC transporters and drug metabolizing enzymes. ABC transporters are the membrane bound proteins which are responsible for the movement of substrates through the cell membrane. Drug metabolizing enzymes are an integral part of phase-II metabolism that helps in the detoxification of exogenous, endogenous and xenobiotics substrates. These include uridine diphospho-glucuronosyltransferases (UGTs), glutathione-S-transferases (GSTs), dihydropyrimidine dehydrogenases (DPDs) and thiopurine methyltransferases (TPMTs). These enzymes may affect the role of drugs in both positive as well negative manner, depending upon the type of tissue and cells present and when present in tumors, can result in drug resistance. However, the underlying mechanism of resistance by drug metabolizing enzymes is still not clear. Here, we have tried to cover various aspects of these enzymes in relation to anticancer drugs.

Unusual presentation of uncommon disease: anorexia nervosa presenting as wernicke-korsakoff syndrome-a case report from southeast Asia.

Anorexia nervosa presenting as Wernicke-Korsakoff syndrome is rare. The causes of Wernicke-Korsakoff syndrome are multiple like alcohol abuse, thyrotoxicosis, haemodialysis, severe malnutrition because of gastric carcinoma and pyloric obstruction, hyperemesis gravidarum, and prolonged parenteral feeding. We report a case of anorexia nervosa, who presented with Wernicke's encephalopathy and progressed to Korsakoff's syndrome. Knowledge, awareness, and early intervention of anorexia nervosa by mental health professionals can prevent development of Wernicke-Korsakoff syndrome.

Imidazoles as promising scaffolds for antibacterial activity: a review.

In the last few decades, a lot of work has been done on heterocycles, especially the imidazole ring, to obtain a scaffold with potential pharmacological properties such as antibacterial, antifungal, anticancer, antiviral, antidiabetic and others, with lesser side effects. The search for new biologically active imidazoles continues to be an interesting area of investigation in medicinal chemistry. The present paper aims to bring together and discuss the wealth of information on antibacterial profile of imidazoles. So it can be employed for future development to obtain new potent drug molecules.

Management of diabetic complications: a chemical constituents based approach.

ETHNOPHARMACOLOGICAL RELEVANCE: Long term hyperglycemia leads to development of complications associated with diabetes. Diabetic complications are now a global health problem without effective therapeutic approach. Hyperglycemia and oxidative stress are important components for the development of diabetic complications. Over the past few decades, herbal medicines have attracted much attention as potential therapeutic agents in the prevention and treatment of diabetic complications due to their multiple targets and less toxic side effects. This review aims to assess the current available knowledge of medicinal herbs for attenuation and management of diabetic complications and their underlying mechanisms. MATERIAL AND METHODS: Bibliographic investigation was carried out by scrutinizing classical text books and peer reviewed papers, consulting worldwide accepted scientific databases (SCOPUS, PUBMED, SCIELO, NISCAIR, Google Scholar) to retrieve available published literature. The inclusion criteria for the selection of plants were based upon all medicinal herbs and their active compounds with attributed potentials in relieving diabetic complications. Moreover, plants which have potential effect in ameliorating oxidative stress in diabetic animals have been included. RESULTS: Overall, 238 articles were reviewed for plant literature and out of the reviewed literature, 127 articles were selected for the study. Various medicinal plants/plant extracts containing flavonoids, alkaloids, phenolic compounds, terpenoids, saponins and phytosterol type chemical constituents were found to be effective in the management of diabetic complications. This effect might be attributed to amelioration of persistent hyperglycemia, oxidative stress and modulation of various metabolic pathways involved in the pathogenesis of diabetic complications. CONCLUSION: Screening chemical candidate from herbal medicine might be a promising approach for new drug discovery to treat the diabetic complications. There is still a dire need to explore the mechanism of action of various plant extracts and their toxicity profile and to determine their role in therapy of diabetic complications. Moreover, a perfect rodent model which completely mimics human diabetic complications should be developed.

Effect of modulating the allosteric sites of N-methyl-D-aspartate receptors in ischemia-reperfusion induced acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is one of the major health problems in developed as well as developing countries. The literature regarding the role of N-methyl-D-aspartate receptors (NMDAR) and the impact of the modulation of its allosteric sites on renal function is inadequate. The present study investigated the effect of modulating allosteric sites of NMDAR in ischemia-reperfusion-induced AKI. MATERIALS AND METHODS: We subjected rats to bilateral renal ischemia for 40 min followed by reperfusion for 24 h to induce AKI. We measured blood urea nitrogen, serum creatinine, uric acid, and lactate dehydrogenase to assess kidney injury. We assayed the thiobarbituric acid-reactive substances, reduced glutathione level, and myeloperoxidase and catalase activity to assess oxidative stress in renal tissue, and used hematoxylin-eosin staining to observe histopathologic changes. RESULTS: Ischemia-reperfusion induced AKI, as demonstrated by an increase in serum parameters, oxidative stress and histopathologic changes in renal tissue. The NMDA agonist glutamic acid and polyamine binding site agonist spermidine significantly aggravated oxidative stress and ischemia-reperfusion-induced AKI. Various NMDA receptor antagonists, including glycine binding site inhibitor kynurenic acid, polyamine binding site inhibitor ketamine, and channel blocking agent magnesium sulfate, attenuated ischemia-reperfusion-induced AKI and significantly reduced oxidative stress, which suggests a role for NMDA receptors and the importance of regulating its allosteric sites in AKI. CONCLUSIONS: Acute kidney injury is associated with the activation of NMDA receptors, as well as significant oxidative stress. The antagonism of various allosteric sites of NMDA receptors affords significant benefit against ischemia-reperfusion-induced AKI.

Impact of obesity on hypertension-induced cardiac remodeling: role of oxidative stress and its modulation by gemfibrozil treatment in rats.

This study investigated the possible synergistic role of obesity in hypertension-induced cardiac remodeling and its modulation by gemfibrozil treatment in rats. Male Wistar rats were fed a high-fat diet (HFD) for 90 days. Normal rats were subjected to hypertension by partial abdominal aortic constriction (PAAC) for 28 days. In the HFD+PAAC control group, rats on HFD were subjected to PAAC on the 62nd day and were sacrificed on the 90th day. HFD and PAAC individually resulted in significant cardiac hypertrophy and fibrosis along with increased oxidative stress and mean arterial blood pressure (MABP) in rats as evidenced by various morphological, biochemical, and histological parameters. Moreover, the HFD + PAAC control group showed marked cardiac remodeling compared to rats subjected to HFD or PAAC alone. The HFD+gemfibrozil and HFD+PAAC+gemfibrozil groups showed significant reduction in cardiac remodeling along with reduction in oxidative stress and MABP. Hence, it may be concluded that oxidative stress plays a key role in obesity-mediated synergistic effects on induction and progression of PAAC-induced cardiac remodeling, and its deleterious effects could be reversed by gemfibrozil treatment in rats through its antioxidant activity.

Modulation of impact of high fat diet in pathological and physiological left ventricular cardiac hypertrophy by fluvastatin.

The male Wistar rats were kept at high fat diet for 90 days and subjected to partial abdominal aortic constriction (PAAC) at 62nd and continued up to 90th day. Similarly, rats were kept at high fat diet for 90 days and subjected to chronic swimming training (CST) at 46th day and continued up to 90th day. Obesity was assessed by % age change in body weight, WHR ratio and adiposity index whereas cardiac hypertrophy was assessed by using index of cardiac hypertrophy, i.e., left ventricular weight, left ventricular weight to body weight, (LVW/BW), left ventricular wall thickness (LVWT), cardiomyocyte diameter, LV, protein content and collagen content. Further, mean arterial blood pressure (MABP) was also recorded. Oxidative stress was assessed by measuring the levels of thiobarbituric acid reactive species (TBARS), levels of superoxide anion generation and levels of reduced glutathione in left ventricular tissue. The PAAC and CST increased the index of cardiac hypertrophy. Moreover, PAAC has significantly increased MABP. Fluvastatin, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, significantly attenuated PAAC induced left ventricular cardiac hypertrophy and MABP whereas no significant change was observed in CST-induced cardiac hypertrophy. Furthermore, fluvastatin significantly attenuated the oxidative stress by decreasing the levels of TBARS and superoxide anion generation and increasing the levels of reduced glutathione. These results suggest that fluvastatin prevented the PAAC-induced cardiac hypertrophy.

Molecular targets and regulators of cardiac hypertrophy.

Cardiac hypertrophy is one of the main ways in which cardiomyocytes respond to mechanical and neurohormonal stimuli. It enables myocytes to increase their work output, which improves cardiac pump function. Although cardiac hypertrophy may initially represent an adaptive response of the myocardium, ultimately, it often progresses to ventricular dilatation and heart failure which is one of the leading causes of mortality in the western world. A number of signaling modulators that influence gene expression, apoptosis, cytokine release and growth factor signaling, etc. are known to regulate heart. By using genetic and cellular models of cardiac hypertrophy it has been proved that pathological hypertrophy can be prevented or reversed. This finding has promoted an enormous drive to identify novel and specific regulators of hypertrophy. In this review, we have discussed the various molecular signal transduction pathways and the regulators of hypertrophic response which includes calcineurin, cGMP, NFAT, natriuretic peptides, histone deacetylase, IL-6 cytokine family, Gq/G11 signaling, PI3K, MAPK pathways, Na/H exchanger, RAS, polypeptide growth factors, ANP, NO, TNF-alpha, PPAR and JAK/STAT pathway, microRNA, Cardiac angiogenesis and gene mutations in adult heart. Augmented knowledge of these signaling pathways and their interactions may potentially be translated into pharmacological therapies for the treatment of various cardiac diseases that are adversely affected by hypertrophy. The purpose of this review is to provide the current knowledge about the molecular pathogenesis of cardiac hypertrophy, with special emphasis on novel researches and investigations.