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Nitish R Mahapatra
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Nitish R Mahapatra
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Nitish R Mahapatra
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Mahapatra, N. R.
Mahapatra, Nitish R.
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30 results
Now showing 1 - 10 of 30
- PublicationChromogranin A: A novel susceptibility gene for essential hypertension(01-03-2010)
;Sahu, Bhavani S. ;Sonawane, Parshuram J.Chromogranin A (CHGA) is ubiquitously expressed in secretory cells of the endocrine, neuroendocrine, and neuronal tissues. Although this protein has long been known as a marker for neuroendocrine tumors, its role in cardiovascular disease states including essential hypertension (EH) has only recently been recognized. It acts as a prohormone giving rise to bioactive peptides such as vasostatin-I (human CHGA1-76) and catestatin (human CHGA352-372) that exhibit several cardiovascular regulatory functions. CHGA is over-expressed but catestatin is diminished in EH. Moreover, genetic variants in the promoter, catestatin, and 3'-untranslated regions of the human CHGA gene alter autonomic activity and blood pressure. Consistent with these findings, targeted ablation of this gene causes severe arterial hypertension and ventricular hypertrophy in mice. Transgenic expression of the human CHGA gene or exogenous administration of catestatin restores blood pressure in these mice. Thus, the accumulated evidence establishes CHGA as a novel susceptibility gene for EH. - PublicationIntegrated computational and experimental analysis of the neuroendocrine transcriptome in genetic hypertension identifies novel control points for the cardiometabolic syndrome(01-08-2012)
;Friese, Ryan S. ;Ye, Chun ;Nievergelt, Caroline M. ;Schork, Andrew J.; ;Rao, Fangwen ;Napolitan, Philip S. ;Waalen, Jill ;Ehret, Georg B. ;Munroe, Patricia B. ;Schmid-Schönbein, Geert W. ;Eskin, EleazarO'Connor, Daniel T.Background: Essential hypertension, a common complex disease, displays substantial genetic influence. Contemporary methods to dissect the genetic basis of complex diseases such as the genomewide association study are powerful, yet a large gap exists betweens the fraction of population trait variance explained by such associations and total disease heritability. Methods and Results: We developed a novel, integrative method (combining animal models, transcriptomics, bioinformatics, molecular biology, and trait-extreme phenotypes) to identify candidate genes for essential hypertension and the metabolic syndrome. We frst undertook transcriptome profiling on adrenal glands from blood pressure extreme mouse strains: the hypertensive BPH (blood pressure high) and hypotensive BPL (blood pressure low). Microarray data clustering revealed a striking pattern of global underexpression of intermediary metabolism transcripts in BPH. The MITRA algorithm identified a conserved motif in the transcriptional regulatory regions of the underexpressed metabolic genes, and we then hypothesized that regulation through this motif contributed to the global underexpression. Luciferase reporter assays demonstrated transcriptional activity of the motif through transcription factors HOXA3, SRY, and YY1. We finally hypothesized that genetic variation at HOXA3, SRY, and YY1 might predict blood pressure and other metabolic syndrome traits in humans. Tagging variants for each locus were associated with blood pressure in a human population blood pressure extreme sample with the most extensive associations for YY1 tagging single nucleotide polymorphism rs11625658 on systolic blood pressure, diastolic blood pressure, body mass index, and fasting glucose. Meta-analysis extended the YY1 results into 2 additional large population samples with significant effects preserved on diastolic blood pressure, body mass index, and fasting glucose. Conclusions: The results outline an innovative, systematic approach to the genetic pathogenesis of complex cardiovascular disease traits and point to transcription factor YY1 as a potential candidate gene involved in essential hypertension and the cardiometabolic syndrome. © 2012 American Heart Association, Inc. - PublicationCatestatin: A master regulator of cardiovascular functions(01-01-2018)
;Mahata, Sushil K. ;Kiranmayi, MalapakaBackground: Cardiovascular disease (CVD), the most common cause of death globally, accounts for ~30% of all deaths worldwide. Hypertension is a common contributor to morbidity and mortality from CVD. Methods and Results: The plasma concentration of chromogranin A (CgA) is elevated in patients with CVD as well as patients with established human essential hypertension and heart failure (HF). In contrast, the plasma level of the CgA-derived peptide catestatin (CST) is diminished in human essential hypertension. Low conversion of CgA-to-CST has been associated with increased mortality in patients hospitalized with acute HF. Consistent with human findings, the lack of CST in CgA knockout (Chga-KO) mice eventuates in the development of hypertension and supplementation of CST to Chga-KO mice restores blood pressure, implicating CST as a key player in regulating hypertension. In the peripheral system, CST decreases blood pressure by stimulating histamine release, inhibiting catecholamine secretion, or causing vasodilation. Centrally, CST improves baroreflex sensitivity (BRS) and heart rate variability (HRV) by exciting GABAergic neurons in the caudal ventrolateral medulla (CVLM) and pyramidal neurons of the central amygdala; CST also decreases BRS by exciting glutamatergic rostral ventrolateral medulla (RVLM) neurons. In addition, CST provides cardioprotection by inhibiting inotropy and lusitropy; activating mitochondrial KATP channels, and stimulating reperfusion injury salvage kinase (RISK) and survivor activating factor enhancement (SAFE) pathways and consequent inhibition of mitochondrial permeability transition pore (mPTP). CST modulates cardiomyocyte Ca2+ levels by direct inhibition of Ca2+/calmodulin-dependent protein kinase IIδ (CaMKIIδ) activity and consequent reduction in phosphorylation of phospholamban and ryanodine receptor 2, thereby providing support for a direct functional role of CST in the failing myocardium. Conclusion: These multitude of effects establish CST as a master regulator of cardiovascular functions. - PublicationMolecular interactions of the physiological anti-hypertensive peptide catestatin with the neuronal nicotinic acetylcholine receptor(01-06-2012)
;Sahu, Bhavani S. ;Mohan, Jagan ;Sahu, Giriraj ;Singh, Pradeep K. ;Sonawane, Parshuram J. ;Sasi, Binu K. ;Allu, Prasanna K.R. ;Maji, Samir K.; ; - PublicationBio-effective disease control and plant growth promotion in lentil by two pesticide degrading strains of Bacillus sp.(01-12-2018)
;Roy, Tina ;Bandopadhyay, Anuradha ;Sonawane, Parshuram J. ;Majumdar, Sukanta; ;Alam, SharifulDas, NirmalenduAntagonistic bacteria are common soil inhabitants with potential to control several soil-borne diseases of various crops. In this study, two methomyl degrading Bacillus sp. were screened for their antagonistic potential against soil borne pathogen identified as Alternaria sp. which causes leaf spot and blight disease in lentil. Both the strains produced non-volatile and volatile organic compounds, extracellular enzymes, siderophore, indole acetic acid and solubilized phosphate which ascribed to the mechanism of bio-control and plant growth promotion. These bacterial strains produced indole acetic acid, chitinase and solubilized phosphate even in presence of pesticides (namely methomyl, carbendazim and imidacloprid). The production of chitinase increased by 51–140% in presence of different tested pesticides by the bacterial strains. However, phosphate solublization was only increased up to 79% in B. cereus and 87% in B. safensis in presence of methomyl. Both strains promoted plant growth and suppressed leaf spot and the incidence of blight in lentil plants under controlled conditions in green house. Application of B. cereus and B. safensis isolates to sterile rhizospheric soil increased the dry weight of plants by 40.8% and 43.2%, respectively as compared to control. In similar set of experiments the disease incidence was reduced by 67.7–81.6% in B. cereus and 57.2–78.8% in B. safensis in sterile condition and by 51.4–76.5% and 48.6–63.4%, respectively in non-sterile condition. The present investigation shows both B. cereus and B. safensis as potential plant growth promoting rhizobacteria that can be exploited as efficient bio-control organisms against soil borne plant pathogens as well as can be applied in plant growth enhancement even in pesticide infested soil. - PublicationGlobal metabolic consequences of the chromogranin A-null model of hypertension: Transcriptomic detection, pathway identification, and experimental verification(01-02-2010)
;Friese, Ryan S. ;Gayen, Jiaur R.; ;Schmid-Schönbein, Geert W. ;O'Connor, Daniel T.Mahata, Sushil K.Chromogranin A (CHGA) has a crucial role in formation of regulated secretory granules in neuroendocrine tissues and is also a prohormone that is proteolytically processed into peptides with diverse and complex actions. CHGA and several of its peptide products, including catestatin and pancreastatin, are implicated in pathogenesis of essential hypertension, insulin resistance, and the metabolic syndrome. The Chga knockout mouse (Chga KO) displays severe hypertension coupled with reduction in size, number, and density of regulated secretory granules. We performed genome-wide transcriptome profiling in Chga KO adrenal gland and liver for insight into biochemical and physiological systems altered in this monogenic mouse model of hypertension. Adrenal gene expression pathway prediction of enhanced insulin sensitivity (P = 0.03) in Chga KO was confirmed with glucose, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) measurements: blood glucose was normal in Chga KO, blood insulin was reduced 4.5-fold (P < 0.0001), and HOMA-IR was decreased 3.8-fold (P < 0.002). Remarkably, such observations conclusively dissociate fundamental features of the metabolic syndrome in this monogenic hypertension model. Exogenous pancreastatin treatment restored insulin sensitivity in the Chga KO to near-normal levels. Gene expression predictions of decreased adrenal cholesterol biosynthesis (P < 0.001) and increased hepatic cholesterol biosynthesis (P < 0.001) were verified with tissue total cholesterol assays: Chga KO adrenal cholesterol decreased 1.8-fold (P = 0.039) and hepatic cholesterol increased 1.8-fold (P = 0.018). Transcriptional regulatory network prediction identified sets of transcription factors that may provide insight into the unclear mechanistic links among CHGA, cholesterol, insulin sensitivity, and the metabolic syndrome. These experiments demonstrate, for the first time, that genetic variation at the CHGA locus impacts insulin sensitivity and tissue cholesterol levels in an intact, living organism. The Chga KO may constitute a unique model for studying the relationship between the CHGA locus and disease phenotypes of the metabolic syndrome. - PublicationFunctional genetic variants of the catecholamine-release-inhibitory peptide catestatin in an Indian population: Allele-specific effects on metabolic traits(21-12-2012)
;Sahu, Bhavani S. ;Obbineni, Jagan M. ;Sahu, Giriraj ;Allu, Prasanna K.R. ;Subramanian, Lakshmi ;Sonawane, Parshuram J. ;Singh, Pradeep K. ;Sasi, Binu K.; ;Maji, Samir K.; ;Gomathi, Balashankar S. ;Mullasari, Ajit S.Catestatin (CST), a chromogranin A (CHGA)-derived peptide, is a potent inhibitor of catecholamine release from adrenal chromaffin cells and postganglionic sympathetic axons. We resequenced the CST region of CHGA in an Indian population (n = 1010) and detected two amino acid substitution variants: G364S and G367V. Synthesized CST variant peptides (viz. CST-Ser-364 and CST-Val-367) were significantly less potent than the wild type peptide (CST-WT) to inhibit nicotine-stimulated catecholamine secretion from PC12 cells. Consistently, the rank-order of blockade of nicotinic acetylcholine receptor (nAChR)-stimulated inward current and intracellular Ca2+ rise by these peptides in PC12 cells was: CST-WT > CST-Ser-364 > CST-Val-367. Structural analysis by CD spectroscopy coupled with molecular dynamics simulations revealed the following order of α-helical content: CST-WT > CST-Ser-364 > CST-Val-367; docking of CST peptides onto a major human nAChR subtype and molecular dynamics simulations also predicted the above rank order for their binding affinity with nAChR and the extent of occlusion of the receptor pore, providing a mechanistic basis for differential potencies. The G364S polymorphism was in strong linkage disequilibrium with several common CHGA genetic variations. Interestingly, the Ser-364 allele (detected in ∼15% subjects) was strongly associated with profound reduction (up to ∼2.1-fold) in plasma norepinephrine/epinephrine levels consistent with the diminished nAChR desensitization-blocking effect of CST-Ser-364 as compared with CST-WT. Additionally, the Ser-364 allele showed strong associations with elevated levels of plasma triglyceride and glucose levels. In conclusion, a common CHGA variant in an Indian population influences several biochemical parameters relevant to cardiovascular/metabolic disorders. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. - PublicationPost-Transcriptional Regulation of Renalase Gene by MIR-29 and MIR-146 MicroRNAs: Implications for Cardiometabolic Disorders(14-08-2015)
;Kalyani, Ananthamohan ;Sonawane, Parshuram J. ;Khan, Abrar Ali ;Subramanian, Lakshmi ;Ehret, Georg B. ;Mullasari, Ajit S.Renalase, a recently identified oxidoreductase, is emerging as a novel regulator of cardiovascular and metabolic disease states. The mechanism of regulation of renalase gene, especially at the post-transcriptional level, is completely unknown. We set out to investigate the possible role of microRNAs in regulation of renalase gene in this study. Computational predictions using multiple algorithms coupled with systematic functional analysis revealed specific interactions of miR-29a/b/c and miR-146a/b with mouse and human renalase 3′-UTR (untranslated region) in cultured cells. Next, we estimated miR-29b and miR-146a, as well as renalase expression, in genetically hypertensive blood pressure high and genetically hypotensive blood pressure low mice. Kidney tissues from blood pressure high mice showed diminished (∼ 1.6- to 1.8-fold) renalase mRNA/protein levels and elevated (∼ 2.2-fold) miR-29b levels as compared to blood pressure low mice. A common single nucleotide polymorphism in human renalase 3′-UTR (C/T; rs10749571) creates a binding site for miR-146a; consistently, miR-146a down-regulated human renalase 3′-UTR/luciferase activity in case of the T allele suggesting its potential role in regulation of renalase in humans. Indeed, genome-wide association studies revealed directionally concordant association of rs10749571 with diastolic blood pressure, glucose and triglyceride levels in large human populations (n ≈ 58,000-96,000 subjects). This study provides evidence for post-transcriptional regulation of renalase gene by miR-29 and miR-146 and has implications for inter-individual variations on cardiometabolic traits. - PublicationNaturally occurring variants of the dysglycemic peptide pancreastatin: Differential potencies for multiple cellular functions and structure-function correlation(14-02-2014)
;Allu, Prasanna K.R. ;Chirasani, Venkat R. ;Ghosh, Dhiman ;Mani, Anitha; ;Maji, Samir K.; ;Mullasari, Ajit S.Background: Pancreastatin is a potent physiological regulator of plasma glucose/insulin. Results: We discovered two human variants of pancreastatin that are profoundly more potent than the wild-type peptide. Conclusion: Higher potencies of the variants correlate well with their enhanced propensity to adopt longer helical structures than the wild-type peptide. Significance: These findings provide new insights into the mechanism of human metabolic diseases. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.. - PublicationCoordinated transcriptional regulation of hspa1a gene by multiple transcription factors: Crucial roles for HSF-1, NF-Y, NF-κB, and CREB(09-01-2014)
;Sasi, Binu K. ;Sonawane, Parshuram J. ;Gupta, Vinayak ;Sahu, Bhavani S.Although the transcript level of inducible heat shock protein 70.3 (Hsp70.3, also known as Hspa1a) is altered in various disease states, its transcriptional regulation remains incompletely understood. Here, we systematically analyzed the Hspa1a promoter to identify major cis elements and transcription factors that may govern the constitutive/inducible gene expression. Computational analyses coupled with extensive in vitro (promoter-reporter activity and electrophoretic mobility shift assays) and in vivo (chromatin immunoprecipitation assays) revealed interaction of several transcription factors with Hspa1a promoter motifs: HSF-1 (heat shock factor 1) at - 114/- 97 bp and - 788/- 777 bp, NF-Y (nuclear transcription factor Y) at - 73/- 58 bp, NF-κB (nuclear factor kappa B) at - 133/- 124 bp, and CREB (cAMP response element binding protein) at - 483/- 476 bp. Consistently, siRNA (small interfering RNA)-mediated down-regulation of each of these transcription factors caused substantial reduction of endogenous Hspa1a expression. Heat-shock-induced activation of Hspa1a was coordinately regulated by HSF-1 and NF-Y/NF-κB. The Hspa1a expression was augmented by TNF-α (tumor necrosis factor-alpha) and forskolin in NF-κB and CREB-dependent manners, respectively. NF-κB and CREB also activated Hspa1a transcription in cardiac myoblasts upon exposure to ischemia-like conditions. Taken together, this study discovered previously unknown roles for NF-κB and CREB to regulate Hspa1a expression and a coordinated action by several transcription factors for Hspa1a transactivation under heat-shock/ischemia-like conditions and thereby provided new insights into the mechanism of Hspa1a regulation. © 2013 Elsevier Ltd.
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