👤 S Chhabra

Hypertrophic cardiomyopathy (HCM), associated with left ventricular hypertrophy, can lead to significant morbidity. Given the hereditary association, identifying population-specific genetic markers and gender disparities could enable better screening and management strategies. The study aimed to observe the genetic patterns of HCM and investigate its gender associations among the Indian population. A prospective analysis was performed based on the medical records of patients with HCM. Genetic testing was conducted among those with a family history of HCM or sudden cardiac death. Genetic testing results, echocardiography, and clinical outcomes were documented. The prevalence of HCM types and genetic abnormalities were estimated in the study population and were compared between the two genders. The study included 103 patients with a mean age of 56.3 ± 13.9 years. Genetic analysis was conducted in 48/103 individuals based on the hereditary linkage. Only 50% of the 48 individuals had known genes associated with HCM. About 48% had apical or midapical HCM, and 31.1% had reverse curvature HCM. About 38% of apical and 60% of neutral or reverse curvature were associated with genetic abnormalities. The more commonly associated genes were MYBPC3 and MYH7. The current study also identified genetic variants in several emerging genes in Indian HCM patients. Our study findings indicate that the prevalence of different types of HCM is different in the Indian population. With only 50% of the hereditary HCM linked to known genes, the study calls for further screening of genes associated with HCM in the Indian population. Show less

In this study, comparative analysis of skeletal muscle transcriptome was carried out for four biological replicates of Aseel, a fighter type breed and Punjab Brown, a meat type breed of India. The profusely expressed genes in both breeds were related to muscle contraction and motor activity. Differential expression analysis identified 961 up-regulated and 979 down-regulated genes in Aseel at a threshold of log Show less

Melanocortin 4 receptor (MC4R) mutation is the most common cause of known monogenic obesity in humans. Unexpectedly, humans and rodents with MC4R deficiency do not develop hyperglycaemia despite chronic obesity and insulin resistance. To explain the underlying mechanisms for this phenotype, we determined the role of MC4R in glucose homeostasis in the presence and absence of obesity in mice. We used global and hypothalamus-specific MC4R-deficient mice to investigate the brain regions that contribute to glucose homeostasis via MC4R. We performed oral, intraperitoneal and intravenous glucose tolerance tests in MC4R-deficient mice that were either obese or weight-matched to their littermate controls to define the role of MC4R in glucose regulation independently of changes in body weight. To identify the integrative pathways through which MC4R regulates glucose homeostasis, we measured renal and adrenal sympathetic nerve activity. We also evaluated glucose homeostasis in adrenaline (epinephrine)-deficient mice to investigate the role of adrenaline in mediating the effects of MC4R in glucose homeostasis. We employed a graded [ We found that obese and weight-matched MC4R-deficient mice exhibited improved glucose tolerance due to elevated glucosuria, not enhanced beta cell function. Moreover, MC4R deficiency selectively in the paraventricular nucleus of the hypothalamus (PVH) is responsible for reducing the renal threshold for glucose as measured by graded [ These findings define a previously unrecognised function of hypothalamic MC4R in glucose reabsorption mediated by adrenaline and renal GLUT2. Taken together, our findings indicate that elevated glucosuria due to low sympathetic tone explains why MC4R deficiency does not cause hyperglycaemia despite inducing obesity and insulin resistance. Graphical abstract. Show less

Life-threatening hypoglycemia is a major limiting factor in the management of diabetes. While it is known that counterregulatory responses to hypoglycemia are impaired in diabetes, molecular mechanisms underlying the reduced responses remain unclear. Given the established roles of the hypothalamic proopiomelanocortin (POMC)/melanocortin 4 receptor (MC4R) circuit in regulating sympathetic nervous system (SNS) activity and the SNS in stimulating counterregulatory responses to hypoglycemia, we hypothesized that hypothalamic POMC as well as MC4R, a receptor for POMC derived melanocyte stimulating hormones, is required for normal hypoglycemia counterregulation. To test the hypothesis, we induced hypoglycemia or glucopenia in separate cohorts of mice deficient in either POMC or MC4R in the arcuate nucleus (ARC) or the paraventricular nucleus of the hypothalamus (PVH), respectively, and measured their circulating counterregulatory hormones. In addition, we performed a hyperinsulinemic-hypoglycemic clamp study to further validate the function of MC4R in hypoglycemia counterregulation. We also measured Pomc and Mc4r mRNA levels in the ARC and PVH, respectively, in the streptozotocin-induced type 1 diabetes mouse model and non-obese diabetic (NOD) mice to delineate molecular mechanisms by which diabetes deteriorates the defense systems against hypoglycemia. Finally, we treated diabetic mice with the MC4R agonist MTII, administered stereotaxically into the PVH, to determine its potential for restoring the counterregulatory response to hypoglycemia in diabetes. Stimulation of epinephrine and glucagon release in response to hypoglycemia or glucopenia was diminished in both POMC- and MC4R-deficient mice, relative to their littermate controls. Similarly, the counterregulatory response was impaired in association with decreased hypothalamic Pomc and Mc4r expression in the diabetic mice, a phenotype that was not reversed by insulin treatment which normalized glycemia. In contrast, infusion of an MC4R agonist in the PVH restored the counterregulatory response in diabetic mice. In conclusion, hypothalamic Pomc as well as Mc4r, both of which are reduced in type 1 diabetic mice, are required for normal counterregulatory responses to hypoglycemia. Therefore, enhancing MC4R function may improve hypoglycemia counterregulation in diabetes. Show less

Melanoma is an aggressive skin cancer that can rapidly metastasize to become fatal, if not diagnosed early. Despite recent therapeutic advances, management of melanoma remains difficult. Therefore, novel molecular targets and strategies are required to manage this neoplasm. This study was undertaken to determine the role of the sirtuin SIRT6 in melanoma. Employing a panel of human melanoma cells and normal human melanocytes, we found significant SIRT6 mRNA and protein upregulation in melanoma cells. Further, using a tissue microarray coupled with quantitative Vectra analysis, we demonstrated significant SIRT6 overexpression in human melanoma tissues. Lentiviral short hairpin RNA-mediated knockdown of SIRT6 in A375 and Hs 294T human melanoma cells significantly decreased cell growth, viability, and colony formation, induced G1-phase arrest and increased senescence-associated beta-galactosidase staining. As autophagy is important in melanoma and is associated with SIRT6, we used a qPCR array to study SIRT6 knockdown in A375 cells. We found significant modulation in several genes and/or proteins (decreases in AKT1, ATG12, ATG3, ATG7, BAK1, BCL2L1, CLN3, CTSB, CTSS, DRAM2, HSP90AA1, IRGM, NPC1, SQSTM1, TNF, and BECN1; increases in GAA, ATG10). Our data suggests that increased SIRT6 expression may contribute to melanoma development and/or progression, potentially via senescence-and autophagy-related pathways. Show less

Various population studies have reported the association of rare S2 allele of apolipoprotein C3 (APOC3) SstI polymorphism with hypertriglyceridemia (HTG) and coronary artery disease (CAD). We were the first to report an association of S2 allele with high triglyceride (TG) levels in healthy volunteers from Northern India. Since HTG is suggested to be a predominant risk factor for CAD among Indians, we have elucidated the relationship of APOC3 SstI polymorphism with the lipid profile and CAD. A total of 158 patients with > or = 70% stenosis in one or more coronary artery (angiographically proven CAD patients), 35 subjects with < 70% stenosis (NCAD) and 151 normal controls (free of heart disease) from Northern plains of India were recruited in the study. DNA samples were analyzed by polymerase chain reaction (PCR) followed by SstI digestion. Lipid profile was estimated by enzymatic kit. We found a strong association of S2 allele with high TG levels, which was more significant in patients. Prevalence of S2 allele in normal controls and CAD patients were comparable, despite the fact that mean TG level was significantly higher in patients. A greater insight into this observation revealed that the prevalence of high TG, if not coupled with other risk factors (like high total cholesterol, low HDL), was comparable in patients and controls. Thus, our study reveals that rare S2 allele may be employed as a susceptibility marker for high TG. However, high TG or S2 allele alone may not contribute to the etiology of CAD. Show less

Several studies including a small case-control (hypertriglyceridemic/normotriglyceridemic individuals) study by us revealed close association between rare S2 allele ofAPOC3 Sstl polymorphism and hypertriglyceridemia. With the understanding that Asian Indians are highly vulnerable to the adverse effects of hypertriglyceridemia, we extended the investigation and studied the frequency distribution of this polymorphism in 216 healthy volunteers from Northern plains of India. We found that more than 50% of the study population had one or two S2 allele. This may suggest that a larger fraction of this population is genetically predisposed to hypertriglyceridemia. Show less

A close association between Sst I polymorphism in the 3' untranslated region of the apolipoproteinC3 (APOC3) gene and levels of plasma triglycerides (TG) had been reported by different investigators. Hypertriglyceridemia(HTG) is a known risk factor for coronary artery disease (CAD) in the context of Asian Indians. We conducted a study on the relationship between APOC3 SstI polymorphism (S1S1, S1S2 and S2S2 genotypes) and plasma TG levels in a group of 139 male healthy volunteers from Northern India. DNA samples were analyzed by polymerase chain reaction (PCR) followed by SstI digestion. Digested PCR products were run on 3% agarose gel and visualized by ethidium bromide staining. Rare S2 allele was highly prevalent in our study population (0.313) as compared to the Caucasians (0.00-0.11). The genotypic distribution was in agreement with Hardy-Weinberg equilibrium. S2 allele was almost two times more prevalent in the HTG group (N = 34) as compared to NTG group (N = 105) (p = 0.001). Multiple logistic regression revealed S1S2 individuals had age-adjusted odds ratio of 2.43 (95%CI = 0.99-6.01, p = 0.054) and S2S2 had 9.9 (95%CI = 2.66-37.29, p = 0.0006) for developing HTG in comparison to S1S1 genotype. Our study shows a significant association between rare S2 allele and HTG in Asian Indians. Show less