Department of Pharmacy
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Item SET7, a lysine-specific methyl transferase: An intriguing epigenetic target to combat diabetic nephropathy(Elsevier, 2023-10) Paul, Atish TulshiramDiabetic nephropathy (DN) is a dreadful complication of diabetes that affects ∼50% of diabetics and is a leading cause of end-stage renal disease (ESRD). Studies have linked aberrant expression of lysine methyltransferases (KMTs) to the onset and progression of DN. SET7 is a KMT that methylates specific lysine residues of the histone and nonhistone proteins. It plays an important role in the transforming growth factor-β (TGF-β)-induced upregulation of extracellular matrix (ECM)-associated genes that are responsible for the inflammatory cascade observed in DN. Inhibiting SET7 has potential to attenuate renal disorders in animal studies. This review will focus on the role of SET7 in DN and its potential as a therapeutic target to combat DN.Item Hidden targets of ubiquitin proteasome system: To prevent diabetic nephropathy(Elsevier, 2017-06) Gaikwad, Anil BhanudasDiabetic nephropathy (DN) is the major cause of end stage renal failure. Although, several therapeutic targets have emerged to prevent the progression of DN, the number of people with DN still continues to rise worldwide, suggesting an urgent need of novel targets to prevent DN completely. Currently, the role of ubiquitin proteasome system (UPS) has been highlighted in the pathogenesis and progression of various diseases like obesity, insulin resistance, atherosclerosis, cancers, neurodegerative disorders and including secondary complications of diabetes. UPS mainly involves in protein homeostatis through ubiquitination (post translational modification) and proteasomal degradation of various proteins. Ubiquitination, not only involves in proteasomal degradation, but also directs the substrate proteins to participate in multitude of cell signalling pathways. However, very little is known about ubiquitination and UPS in the progression of DN. This review mainly focuses on UPS and its components including E2 conjugating enzymes, E3 ligases and deubiquitinases (DUBs) in the development of DN and thus may help us to find novel therapeutic targets with in UPS to prevent DN completely in future.Item AT2 receptor agonist Compound 21: A silver lining for diabetic nephropathy(Elsevier, 2017-11) Gaikwad, Anil BhanudasThe currently available therapies for diabetic nephropathy, one of the leading causes of renal failure globally are based on inhibition of renin angiotensin system. However, recently, the focus has shifted towards activation of its protective arm rather than the inhibition of deteriorative axis, using specific agonists. Compound 21 (C21), a novel non-peptide Angiotensin II type 2 receptor (AT2) agonist, recently granted orphan drug status for the treatment of a rare disease, idiopathic pulmonary fibrosis has also shown a potent anti-inflammatory, anti-fibrotic, antioxidant and anti-apoptotic potential in various diseases including heart failure, myocardial infarction, chronic inflammatory diseases, and neurological diseases such as ischemic stroke. A pool of evidences suggest that C21, either alone or in combination with angiotensin receptor blockers could be extremely beneficial in the treatment of diabetic nephropathy, a chronic inflammatory condition sharing its pathogenesis with aforementioned diseases. The review analyses the new therapeutic tool, C21, its mechanisms of action for renoprotection in diabetic nephropathy, and its future perspectives and thereby provides an insight into the potential application of C21 as a novel therapeutic tool in the eradication of diabetic nephropathy.Item Histone Acetylation Regulates Natriuretic Peptides and Neprilysin Gene Expressions in Diabetic Cardiomyopathy and Nephropathy(Bentham Science, 2019) Gaikwad, Anil BhanudasNatriuretic peptide system (NPS) alterations are involved in pathogenesis of diabetic cardiomyopathy (DCM) and nephropathy (DN), however its epigenetic regulation is still unclear. Interestingly, histone acetylation epigenetically regulates neprilysin expression in Alzheimer's disease.Item Concurrent neprilysin inhibition and renin-angiotensin system modulations prevented diabetic nephropathy(Elsevier, 2019-03) Gaikwad, Anil BhanudasRenin-angiotensin system (RAS) and natriuretic peptides system (NPS) perturbations govern the development of diabetic nephropathy (DN). Hence, in search of a novel therapy against DN, present study targeted both, NPS and RAS simultaneously using a neprilysin inhibitor (NEPi) in combination with either angiotensin receptor blocker (ARB) or angiotensin-converting enzyme 2 (ACE2) activator.Item Gallotannin ameliorates the development of streptozotocin‐induced diabetic nephropathy by preventing the activation of PARP(Wiley, 2008-08) Gaikwad, Anil BhanudasPoly(ADP-ribose) polymerase (PARP) is known to be activated under conditions of oxidative stress and/or radiation exposure. The role of this enzyme has been well demonstrated in the streptozotocin (STZ) induced model of diabetes. Inhibition of PARP by specific inhibitors is known to prevent the development of STZ induced diabetic nephropathy by reduction in oxidative stress induced apoptosis. This study shows for the first time the role of poly(ADP-ribose) glycohydrolase (PARG) inhibitors as an alternative approach for inhibition of PARP. Gallotannin (20 mg/kg/day, i.p.) treatment for 4 weeks led to a significant reduction in the levels of plasma creatinine which is a well known marker for diabetic nephropathy. Treatment with gallotannin resulted in protection up to a certain level of glomerular damage, suggesting compensatory glomerular hypertrophy. As a PARG inhibitor gallotannin treatment also showed protection in PARP cleavage which is a hallmark for apoptotic cell death signifying the protective role of gallotannin in cell death signaling.Item Telmisartan and thiorphan combination treatment attenuates fibrosis and apoptosis in preventing diabetic cardiomyopathy(Oxford, 2018-09) Gaikwad, Anil BhanudasLCZ696, a first-generation dual angiotensin receptor-neprilysin inhibitor (ARNi), is effective in treating heart failure patients. However, the role of ARNis in treating diabetic cardiomyopathy is poorly understood. This study evaluates the efficacy of a novel combination of telmisartan [angiotensin receptor blocker (ARB)] and thiorphan [neprilysin inhibitor (NEPi)] in ameliorating diabetic cardiomyopathy while, at the same time, exploring the relevant underlying molecular mechanism(s).Item Diabetic nephropathy: The regulatory interplay between epigenetics and microRNAs(Elsevier, 2019-03) Gaikwad, Anil Bhanudas; Gaikwad, Anil BhanudasDiabetic nephropathy (DN) is still one of the leading causes of end-stage renal disease despite the emergence of different therapies to counter the metabolic, hemodynamic and fibrotic pathways, implicating a prominent role of genetic and epigenetic factors in its progression. Epigenetics is the study of changes in the expression of genes which may be inheritable and does not involve a change in the genome sequence. Thrust areas of epigenetic research are DNA methylation and histone modifications. Noncoding RNAs (ncRNAs), particularly microRNAs (miRNAs) control the expression of genes via post-transcriptional mechanisms. However, the regulation by epigenetic mechanisms and miRNAs are not completely distinct. A number of emerging reports have revealed the interplay between epigenetic machinery and miRNA expression, particularly in cancer. Further research has proved that a feedback loop exists between miRNA expression and epigenetic regulation in disorders including DN. Studies showed that different miRNAs (miR-200, miR-29 etc.) were found to be regulated by epigenetic mechanisms viz. DNA methylation and histone modifications. Conversely, miRNAs (miR-301, miR-449 etc.) themselves modulated levels of DNA methyltranferases (DNMTs) and Histone deacetylases (HDACs), enzymes vital to epigenetic modifications. With already few FDA approved epigenetic -modulating drugs (Vorinostat, Decitabine) in the market and miRNA therapeutic drugs under clinical trial it becomes imperative to analyze the possible interaction between the two classes of drugs in the modulation of a disease process. The purpose of this review is to articulate the interplay between miRNA expression and epigenetic modifications with a particular focus on its impact on the development and progression of DN.Item Diminazene aceturate prevents nephropathy by increasing glomerular ACE2 and AT2 receptor expression in a rat model of type1 diabetes(Wiley, 2017-07) Gaikwad, Anil BhanudasOne of the protective actions of angiotensin converting enzyme-2 (ACE2) is the inactivation of angiotensin II. Expression and activity of ACE2 was reduced in glomeruli of diabetic patients and in animal models of diabetes. Recently the potential role of recombinant ACE2 administration in preventing diabetic nephropathy (DN) has been shown. Here we have tested the effects of the ACE2 activator, diminazene aceturate (DIZE), in a model of DN.Item Epigenetic changes and alteration of Fbn1 and Col3A1 gene expression under hyperglycaemic and hyperinsulinaemic conditions(Portland Press, 2010-11) Gaikwad, Anil BhanudasLittle is known regarding the role of hyperglycaemia on histone H3 modifications and, in turn, altering the expression of genes during the development of diabetes-associated complications. In the present study, we have investigated the hyperinsulinaemia/hyperglycaemia-induced epigenetic changes and alteration of Fbn1 (fibrillin 1) and Col3A1 (collagen type III α1) gene expression. Insulin resistance and Type 2 diabetes in male Sprague–Dawley rats was developed by feeding rats an HFD (high-fat diet) and administering a low dose of STZ (streptozotocin). Hyperglycaemia induced deacetylation and dephosphorylation of histone H3 in the heart and kidneys of diabetic rats. Furthermore, mRNA expression of Fbn1 and Col3A1 increased in the kidneys and decreased in the heart under hyperglycaemic/hyperinsulinaemic conditions. Similar to mRNA expression, chromatin immunoprecipitation also showed an increase in the level of histone H3 acetylation of the Fbn1 gene, but not of the Col3A1 gene. Our present findings suggests that the change in expression of the Fbn1 gene is epigenetically regulated, but the expression of the Col3A1 gene may either be independent of epigenetic regulation or may involve other histone modifications. We provide the first evidence regarding the role of hyperglycaemia/hyperinsulinaemia in altering histone H3 modifications, which may result in the alteration of extracellular matrix gene expression.