Sabbir Khan

Sodium butyrate, a HDAC inhibitor ameliorates eNOS, iNOS and TGF-β1-induced fibrogenesis, apoptosis and DNA damage in the kidney of juvenile diabetic rats.

Recent reports highlighted the role of histone deacetylases (HDACs) in the pathogenesis of diabetic nephropathy (DN), but the exact molecular mechanisms by which HDAC inhibitors ameliorate DN still remain unclear. The present study was aimed to investigate the renoprotective effects of sodium butyrate (NaB) in diabetes-induced renal damages, apoptosis and fibrosis in juvenile rats. Diabetes was induced by single injection of STZ (60mg/kg), whereas NaB (500mg/kg/day) was administrated for 21days by i.p. route in a pre- and post-treatment schedule. End-points of evaluation included biochemical estimation, histology, protein expression as well as apoptosis and DNA damage examinations. Post-treatment with NaB significantly decreased plasma glucose, creatinine, urea, histological alterations including the fibrosis and collagen deposition as well as decreased the HDACs activity, expression of eNOS, iNOS, α-SMA, collagen I, fibronectin, TGFβ-1, NFκB, apoptosis and DNA damage in the diabetic kidney. These results showed that NaB treatment improved the renal function and ameliorated the histological alterations, fibrosis, apoptosis and DNA damage in the kidney of juvenile rats.

Sodium valproate ameliorates diabetes-induced fibrosis and renal damage by the inhibition of histone deacetylases in diabetic rat

Recent reports emphasize the contribution of histone deacetylases (HDACs) in the pathogenesis of diabetic renal injury and fibrosis. Valproic acid (VPA) is a first-line drug used for the treatment of epilepsy and migraine as well as established as a HDAC inhibitor. The present study was aimed to evaluate the anti-fibrotic and renoprotective effects of VPA in diabetic nephropathy (DN). Diabetes was induced by single injection of STZ (50mg/kg), whereas VPA at the doses of 150 and 300mg/kg/day was administered for 8 consecutive weeks by oral route in Sprague Dawley rats. The renal injuries and fibrosis were assessed by histology, fibrosis specific staining and fibroblast activation by a transmission electron microscope, while expression of proteins of interest was evaluated by western blotting and immunohistochemistry. VPA treatment ameliorated the histological alterations as well as fibrosis, and decreased the expression of TGF-β1, CTGF, α-SMA, fibronectin, collagen I, COX-2, ICAM-1 and HDAC4/5/7. Further, VPA treatment significantly increased histone H3 acetylation and MMP-2 expression. The present study clearly established that VPA treatment ameliorates the renal injury and fibrosis in diabetic kidney by preventing the myofibroblast activation and fibrogenesis by HDAC inhibition and associated mechanisms, thereby improving the profibrotic and anti-fibrotic protein balance.

Zinc protects cyclophosphamide-induced testicular damage in rat: involvement of metallothionein, tesmin and Nrf2.

The role of zinc (Zn) in the protection of germ cells against testicular toxicants has long been elucidated, but the exact molecular mechanisms have not yet been explored. Cyclophosphamide (CP), one of the most commonly used anticancer drugs survived ages of treatment, but the unwanted toxicity limits its clinical usage. The present investigation was aimed to explore the role of Zn and its associated pathways in CP-induced testicular toxicity in S.D. rat. CP was administered in saline 30 mg/kg 5× weekly for 3 weeks (total dose of 450 mg/kg) by i.p. route, while Zn was supplemented by oral route at the doses of 1, 3, 10mg/kg/day for 3 weeks. CP significantly reduced Zn levels in serum and testes, body and testicular weight, sperm count and motility, spermiogenic cells, plasma testosterone and significantly increased the oxidative stress, sperm head abnormalities, sperm DNA damage with decreased chromatin and acrosome integrity; while Zn supplementation ameliorated the same. The present results demonstrated that Zn supplementation protected against CP-induced testicular damages by modulating metallothionein (MT), tesmin and Nrf2 associated pathways. Thus Zn supplementation during anticancer therapy might be potentially beneficial in reducing the off target effects associated with oxidative stress.

The role of butyrate, a histone deacetylase inhibitor in diabetes mellitus: experimental evidence for therapeutic intervention

The contribution of epigenetic mechanisms in diabetes mellitus (DM), β-cell reprogramming and its complications is an emerging concept. Recent evidence suggests that there is a link between DM and histone deacetylases (HDACs), because HDAC inhibitors promote β-cell differentiation, proliferation, function and improve insulin resistance. Moreover, gut microbes and diet-derived products can alter the host epigenome. Furthermore, butyrate and butyrate-producing microbes are decreased in DM. Butyrate is a short-chain fatty acid produced from the fermentation of dietary fibers by microbiota and has been proven as an HDAC inhibitor. The present review provides a pragmatic interpretation of chromatin-dependent and independent complex signaling/mechanisms of butyrate for the treatment of Type 1 and Type 2 DM, with an emphasis on the promising strategies for its drugability and therapeutic implication.

Valproic Acid Improves Glucose Homeostasis by Increasing Beta-Cell Proliferation, Function, and Reducing its Apoptosis through HDAC Inhibition in Juvenile Diabetic Rat.

Recent evidence highlighted that there is a link between type‐1 diabetes mellitus and histone deacetylases (HDACs) due to their involvement in beta‐cell differentiation, proliferation, and function. The present study aimed to investigate the protective role of valproic acid (VPA) on beta‐cell proliferation, function, and apoptosis in juvenile diabetic rat. Diabetes was induced in juvenile Sprague–Dawley rats by streptozotocin (75 mg/kg, i.p.) and VPA was administered at the doses of 150 and 300 mg/kg/day for 3 weeks by oral route. Various biochemical parameters, cellular alterations, and protein expression as well as apoptosis were assessed using different assays. VPA treatment significantly decreased plasma glucose, beta‐cell damage, and apoptosis as well as increased the beta‐cell function, insulin level/expression. The present study demonstrated that VPA improves beta‐cell proliferation and function as well as reduces beta‐cell apoptosis through HDAC inhibition. Our findings provide evidence that VPA may be useful for the treatment of juvenile diabetes.

Role of Zinc Supplementation in Testicular and Epididymal Damages in Diabetic Rat: Involvement of Nrf2, SOD1, and GPX5

Zinc (Zn) is one of the most important trace elements required for several biological processes. Diabetes negatively affects many organs, and diabetic patients are often hypozincemic. The present study aims to investigate the role of Zn supplementation in the testes, epididymis, and sperms of streptozotocin (STZ)-induced diabetic rat. Serum, testicular, and sperm Zn contents were found to be altered in diabetic rat. Biochemical, histopathological, and protein expression profiles were determined to decipher the role of Zn in protecting the cellular perturbations. Further, histopathological analyses of testes and epididymis showed deranged architecture along with other noted abnormalities. Diabetic testes showed decreased Nrf2, HO-1, SOD1, PCNA, and Bcl-2 expressions whereas increased COX-2, NF-κB, MT, IL-6, and p-ERK levels. SOD1 and GPX5 were decreased in the epididymis of diabetic rat, whereas Zn supplementation attenuated these changes. The present results demonstrate the beneficial role of Zn supplementation in diabetes-associated testicular alterations of rat.

Sodium Butyrate Ameliorates l-Arginine-Induced Pancreatitis and Associated Fibrosis in Wistar Rat: Role of Inflammation and Nitrosative Stress

Several reports indicated that histone deacetylases (HDACs) play a crucial role in inflammation and fibrogenesis. Sodium butyrate (SB) is a short‐chain fatty acid having HDAC inhibition potential. The present study aimed to evaluate the protective effect of SB against l‐arginine (l‐Arg)‐induced pancreatic fibrosis in Wistar rats. Pancreatic fibrosis was induced by twice intraperitoneal (i.p.) injections of 20% l‐Arg (250 mg/100 g) at 2‐h interval on day 1, 4, 7, and 10, whereas SB (800 mg/kg/day) was administrated for 10 days. At the end of the study, biochemical estimations, histological alterations, DNA damage, and the expression of various proteins were evaluated. Posttreatment of SB decreased l‐Arg‐induced oxidative and nitrosative stress, DNA damage, histological alterations, and fibrosis. Interestingly, posttreatment of SB significantly decreased the expression of α‐smooth muscle actin, interleukin‐1β, inducible nitric oxide synthase, and 3‐nitrotyrosine. The present study demonstrated that posttreatment of SB alleviates l‐Arg‐induced pancreatic damage and fibrosis in rat.

3-Aminobenzamide – a PARP inhibitor enhances the sensitivity of peripheral blood micronucleus and comet assays in mice

Abstract Context: DNA repair is an essential outcome of DNA damage, which may compromise the end point of various in vitro and in vivo test systems of the genotoxicity evaluation. poly(ADP-ribose) polymerase (PARP) enzymes have an essential role in DNA repair. Here, we investigated the effect of 3-AB, a PARP inhibitor on the sensitivity of comet and PBMN assays. Objective: This study aimed to enhance the sensitivity of the comet and peripheral blood micronucleus (PBMN) assays using 3-aminobenzamide (3-AB), a well-characterized PARP inhibitor. Materials and methods: Cyclophosphamide (CP, 50 mg/kg), 5-flourouracil (5-FU, 25 mg/kg), zidovudine (AZT, 400 mg/kg) and furosemide (FUR, 60 mg/kg) were selected as genotoxins. 3-AB was given every 8 h with the first dose given 2 h before the genotoxin treatment. For the PBMN assay, small amount of blood was taken from the tail tip of each animal and smears were prepared. The comet assay was performed in PBL, bone marrow and liver. Results: In the comet as well as PBMN assay, 3-AB pre-treatment enhanced the extent of DNA damage in all the combination groups (3-AB + CP, 3-AB + 5-FU and 3-AB + AZT) compared to CP, 5-FU and AZT per se. 3-AB also enhanced the DNA damage caused by FUR in the bone marrow and liver. Discussion: This study results clearly demonstrate that the pretreatment with 3-AB (30 mg/kg) significantly enhances the sensitivity of the PBMN and comet assays. This model may be useful for the detection of marginally active DNA damaging agents.

Role of autophagy and histone deacetylases in diabetic nephropathy: Current status and future perspectives

The prevalence of diabetes and its complications is increasing at an alarming rate in both developed and deve1oping nations. The emerging evidences highlighted that both genetic and epigenetic mechanisms including histone modifications play a significant role in the pathogenesis of diabetic nephropathy (DN). Histone deacetylases (HDACs) and acetylation are involved in the regulation of autophagy as well as pathogenesis of DN. Both HDACs and histone acetyltransferases (HATs) play a key role in chromatin remodeling and affect the transcription of various genes involved in the cellular homeostasis, apoptosis, immunity and angiogenesis. Further, HDAC inhibitors are exert the renoprotective effects in DN and other diabetic complications. Thus, the cellular acetylation plays a crucial role in the regulation of autophagy and can be explored as a new therapeutic target for the treatment of DN. This review aimed to delineate the role of HDACs and associated molecular signaling/pathways in the regulation of autophagy with an emphasis on promising targets for the treatment of DN.

Anti-fibrotic effects of valproic acid: role of HDAC inhibition and associated mechanisms

Tissue injuries and pathological insults produce oxidative stress, genetic and epigenetic alterations, which lead to an imbalance between pro- and anti-fibrotic molecules, and subsequent accumulation of extracellular matrix, thereby fibrosis. Various molecular pathways play a critical role in fibroblasts activation, which promotes the extracellular matrix production and accumulation. Recent reports highlighted that histone deacetylases (HDACs) are upregulated in various fibrotic disorders and play a central role in fibrosis, while HDAC inhibitors exert antifibrotic effects. Valproic acid is a first-line anti-epileptic drug and a proven HDAC inhibitor. This review provides the current research and novel insights on antifibrotic effects of valproic acid in various fibrotic conditions with an emphasis on the possible strategies for treatment of fibrosis.