Department of Pharmacy
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Item Isomalto-oligosaccharides, a prebiotic, functionally augment green tea effects against high fat diet-induced metabolic alterations via preventing gut dysbacteriosis in mic(Elsevier, 2017-09) Khare, PragyanshuHigh fat diet (HFD)-induced alterations in gut microbiota and resultant ‘leaky gut’ phenomenon promotes metabolic endotoxemia, ectopic fat deposition, and low-grade systemic inflammation. Here we evaluated the effects of a combination of green tea extract (GTE) with isomalto-oligosaccharide (IMOs) on HFD-induced alterations in mice. Male Swiss albino mice were fed with HFD (58% fat kcal) for 12 weeks. Systemic adiposity, gut derangement parameters and V3-V4 region based 16S rRNA metagenomic sequencing, ectopic fat deposition, liver metabolome analysis, systemic and tissue inflammation, and energy homeostasis markers along with gene expression analysis in multiple tissues were done in mice supplemented with GTE, IMOs or their combination. The combination of GTE and IMOs effectively prevented HFD-induced adiposity and lipid accumulation in liver and muscle while normalizing fasting blood glucose, insulin, glucagon, and leptin levels. Co-administration of GTE with IMOs effectively modulated liver metabolome associated with lipid metabolism. It also prevented leaky gut phenotype and HFD-induced increase in circulating lipopolysaccharides and pro-inflammatory cytokines (e.g. resistin, TNF-α, and IL-1β) and reduction in anti-inflammatory cytokines (e.g. adiponectin and IL-6). Gene expression analysis across multiple tissues further supported these functional outcomes. Most importantly, this combination improved beneficial gut microbiota (Lactobacillus sp., Bifidobacteria, Akkermansia muciniphila, Roseburia spp.) abundances, restored Firmicutes/Bacteriodetes and improved Prevotella/Bacteroides proportions. In particular, a combination of these two agents has shown improved beneficial effects on multiple parameters studied. Data presented herein suggests that strategically chosen food components might be highly effective in the prevention of HFD-induced alterations and may further be developed as functional foods.Item NEXT Neuroprotective Efficacy of Co-Encapsulated Rosiglitazone and Vorinostat Nanoparticle on Streptozotocin Induced Mice Model of Alzheimer Disease(ACS, 2021-04) Chitkara, Deepak; Taliyan, RajeevAnomalies in brain insulin signaling have been demonstrated to be involved in the pathology of Alzheimer disease (AD). In this context, the neuroprotective efficacy of an insulin sensitizer, rosiglitazone, has been confirmed in our previous study. In the present study, we hypothesize that a combination of an epigenetic modulator, vorinostat, along with rosiglitazone can impart improved gene expression of neurotrophic factors and attenuate biochemical and cellular alteration associated with AD mainly by loading these drugs in a surface modified nanocarrier system for enhanced bioavailability and enhanced therapeutic efficacy. Hence, in this study, rosiglitazone and vorinostat were loaded onto a poloxamer stabilized polymeric nanocarrier system and administered to mice in the intracerebroventricular streptozotocin (3 mg/kg) induced model of AD. Treatment with the free drug combination (rosiglitazone 5 mg/kg, vorinostat 25 mg/kg) for 3 weeks attenuated the behavioral, biochemical, and cellular alterations as compared to either treatment alone (rosiglitazone 10 mg/kg, vorinostat 50 mg/kg). Further, the coencapsulated nanoformulation (rosiglitazone 5 mg/kg, vorinostat 25 mg/kg) exerted better neuroprotective efficacy than the free drug combination as evidenced by improved behavioral outcome, reduced oxidative stress, and elevated levels of neurotrophic factors. In conclusion, the synergistic neuroprotective efficacy of rosiglitazone and vorinostat has been increased through the poloxamer stabilized polymeric nanocarrier system.Item Esculetin ameliorates insulin resistance and type 2 diabetic nephropathy through reversal of histone H3 acetylation and H2A lysine 119 monoubiquitination(Elsevier, 2017-08) Gaikwad, Anil BhanudasInsulin resistance (IR) and type 2 diabetic nephropathy (T2DN) are associated with elevated renal expression of monocyte chemo-attractant protein (MCP1) and transforming growth factor-β (TGF-β). Posttranslational histone modifications (PTHMs) play significant role in regulating the expression of such devastating gene expressions. Esculetin, a natural coumarin derivative possesses antioxidant, anti-proliferative and anti-inflammatory potential and has also been reported to revert PTHMs in IR and T2D heart. Thus, we hypothesized that esculetin treatment may show reno-protective effects in high fat diet fed (HFD) and HFD + low dose streptozotocin treated Wistar rats. Our results substantiate that esculetin bestows reno-protection owing to its renin angiotensin system modulating properties and also abrogating the hyper acetylation of histone H3 lysine (K) 14 and 18 and elevated H2AK119 monoubiquitination (Ub). This is the first report demonstrating that esculetin could be attributed to elevation of the occupancy of H2AK119Ub at the promoter regions of Mcp1 and Tgfb1.Item Esculetin reverses histone H2A/H2B ubiquitination, H3 dimethylation, acetylation and phosphorylation in preventing type 2 diabetic cardiomyopathy(Elsevier, 2015-08) Gaikwad, Anil BhanudasPost translational histone modifications (PTHMs) play a pivotal role in pathogenesis of diabetic complications. Esculetin is reported to prevent glomerulosclerosis by reversing PTHMs in diabetic rats, but until now its cardioprotective role is unexplored. Hence, the present study aimed to investigate the effect of esculetin on diabetic cardiomyopathy (DCM) and its associated PTHMs. Insulin resistance (IR) and type 2 diabetic rats' heart had augmented permissive PTHMs which contributed to DCM. Besides this, for the first time we have demonstrated increased histone H2AK119Ub and H2BK120Ub levels in DCM. Esculetin treatment reduced metabolic alterations, hypertension, cardiomyocytes hypertrophy, and fibrosis in the diabetic heart. In addition, esculetin attenuated alteration in the renin–angiotensin system, oxidative stress (Keap1) and cell proliferation (Ki67); thus preventing DCM. Remarkably, esculetin treatment restored normal level of permissive PTHMs and H2A/H2B ubiquitination in IR and diabetic heart which might be the basic mechanism behind its cardioprotective role.Item PPARγ agonists partially restores hyperglycemia induced aggravation of vascular dysfunction to angiotensin II in thoracic aorta isolated from rats with insulin resistance(Elsevier, 2007-05) Gaikwad, Anil BhanudasAltered vascular responses to various vasopressors in animal models of insulin resistance (IR) and diabetes have been well documented. However, the precise mechanisms about vascular responses in IR with or without frank hyperglycemia (prediabetic state) are not available. Moreover, recently the role of peroxisome proliferators activated receptor-γ (PPARγ) has been linked to influence the vascular responses in hypertensive and diabetic state. Hence, the present study was conceived to determine the role of hyperglycemia on angiotensin II (Ang II) mediated vascular responses in the high fat diet (HFD) induced insulin resistance either with mild or frank hyperglycemia [induced by injection of low dose streptozotocin (STZ) to HFD fed rats (HFD + STZ)]. In addition, insulin-sensitizing agent such as rosiglitazone and pioglitazone were also studied on biochemical and vascular responses. Ang II-induced contractions were studied isometrically in thoracic aortic rings isolated from 4 weeks of normal pellet diet (NPD) fed control, HFD and HFD + STZ fed insulin resistant rats. Specific binding of Ang II receptors were carried out using radioligand ([3H]–Ang II) binding studies. After 4 weeks of HFD feeding, rats exhibited characteristics features of insulin resistance such as mild hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia and hypertension; whereas HFD + STZ treated rats showed all above parameters along with frank hyperglycemia. Maximal contractile response (Emax) to Ang II is increased in HFD fed rats as compared to control rats. Moreover, Emax values are further elevated in HFD + STZ group where the frank hyperglycemia was induced by low dose of streptozotocin. Rosiglitazone (5 mg kg−1, p.o.) and pioglitazone (10 mg kg−1, p.o.) treatment significantly lowered the plasma glucose, triglycerides, insulin and cholesterol levels in insulin resistance rats. In addition, it also restored the elevated systolic, mean arterial, diastolic blood pressure and attenuated the enhanced contractile responses to Ang II in thoracic aortic rings obtained from both HFD and HFD + STZ treated rats. Specific binding of [3H]–Ang II is upregulated in HFD-fed and HFD + STZ treated rats. Treatment with pioglitazone and rosiglitazone significantly decreased the AT1R specific binding in HFD fed rats. Our results indicate the role of hyperglycemia in the elevation of Ang II induced vascular responses in thoracic aorta isolated from insulin resistant rats and PPARγ agonists can attenuate these responses.Item Epigenetic Regulation of Mammalian Target of Rapamycin Debilitates Insulin Resistance Associated Alzheimer Disease Condition in Rats(Research Square, 2021) Taliyan, RajeevInsulin resistance (IR) and accumulation of amyloid beta (Aβ) oligomers are potential causative factor for Alzheimer Disease (AD). Simultaneously, enhanced clearance level of these oligomers through autophagy activation bring novel insights into their therapeutic paradigm. Autophagy activation is negatively correlated with mammalian target of rapamycin (mTOR) and dysregulated mTOR level due to epigenetic alterations can further culminate towards AD pathogenesis. Therefore, in the current study we explored the neuroprotective efficacy of rapamycin and vorinostat in-vitro and in-vivo. Aβ1−42 treated SH-SY5Y cells were exposed to rapamycin (20µM) and vorinostat (4µM) to analyse mRNA expression of amyloid precursor protein (APP), brain derived neurotrophic factor (BDNF), glial cell derived neurotrophic factor (GDNF), neuronal growth factor (NGF), beclin-1, microtubule-associated protein 1A/1B-light chain 3-phosphatidylethanolamine conjugate, lysosome-associated membrane protein 2 and microtubule associated protein 2. In order to develop IR condition, rats were fed a high fat diet (HFD) for 8weeks and then subjected to intracerebroventricular Aβ1−42 administration. Subsequently, their treatment was initiated with rapa (1mg/kg, i.p.) and vori (50mg/kg, i.p.) once daily for 28days. Morris water maze was performed to govern cognitive impairment followed by sacrification for subsequent biochemical and histological estimations. For all the measured parameters, a significant improvement was observed amongst the combination treatment group in contrast to that of the HFD + Aβ1−42 group and that of the groups treated with the drugs alone. Outcomes of the present study thus suggest that combination therapy with rapa and vori provide a prospective therapeutic approach to ameliorate AD symptoms exacerbated by IR.Item Epigenetic regulation and autophagy modulation debilitates insulin resistance associated Alzheimer’s disease condition in rats(Springer, 2022-01) Taliyan, Rajeev; Marathe, SandhyaInsulin resistance (IR) and accumulation of amyloid beta (Aβ) oligomers are potential causative factor for Alzheimer’s Disease (AD). Simultaneously, enhanced clearance level of these oligomers through autophagy activation bring novel insights into their therapeutic paradigm. Autophagy activation is negatively correlated with mammalian target of rapamycin (mTOR) and dysregulated mTOR level due to epigenetic alterations can further culminate towards AD pathogenesis. Therefore, in the current study we explored the neuroprotective efficacy of rapamycin (rapa) and vorinostat (vori) in-vitro and in-vivo. Aβ1–42 treated SH-SY5Y cells were exposed to rapa (20 μM) and vori (4 μM) to analyse mRNA expression of amyloid precursor protein (APP), brain derived neurotrophic factor (BDNF), glial cell derived neurotrophic factor (GDNF), neuronal growth factor (NGF), beclin-1, microtubule-associated protein 1A/1B-light chain 3-phosphatidylethanolamine conjugate (LC3), lysosome-associated membrane protein 2 (LAMP2) and microtubule associated protein 2 (MAP2). In order to develop IR condition, rats were fed a high fat diet (HFD) for 8 weeks and then subjected to intracerebroventricular Aβ1–42 administration. Subsequently, their treatment was initiated with rapa (1 mg/kg, i.p.) and vori (50 mg/kg, i.p.) once daily for 28 days. Morris water maze was performed to govern cognitive impairment followed by sacrification for subsequent mRNA, biochemical, western blot and histological estimations. For all the measured parameters, a significant improvement was observed amongst the combination treatment group in contrast to that of the HFD + Aβ1–42 group and that of the groups treated with the drugs alone. Outcomes of the present study thus suggest that combination therapy with rapa and vori provide a prospective therapeutic approach to ameliorate AD symptoms exacerbated by IR.Item Brain insulin resistance linked Alzheimer’s and Parkinson’s disease pathology: An undying implication of epigenetic and autophagy modulation(Springer, 2023-03) Taliyan, RajeevIn metabolic syndrome, dysregulated signalling activity of the insulin receptor pathway in the brain due to persistent insulin resistance (IR) condition in the periphery may lead to brain IR (BIR) development. BIR causes an upsurge in the activity of glycogen synthase kinase-3 beta, increased amyloid beta (Aβ) accumulation, hyperphosphorylation of tau, aggravated formation of Aβ oligomers and simultaneously neurofibrillary tangle formation, all of which are believed to be direct contributors in Alzheimer’s Disease (AD) pathology. Likewise, for Parkinson’s Disease (PD), BIR is associated with alpha-synuclein alterations, dopamine loss in brain areas which ultimately succumbs towards the appearance of classical motor symptoms corresponding to the typical PD phenotype. Modulation of the autophagy process for clearing misfolded proteins and alteration in histone proteins to alleviate disease progression in BIR-linked AD and PD have recently evolved as a research hotspot, as the majority of the autophagy-related proteins are believed to be regulated by histone posttranslational modifications. Hence, this review will provide a timely update on the possible mechanism(s) converging towards BIR induce AD and PD. Further, emphasis on the potential epigenetic regulation of autophagy that can be effectively targeted for devising a complete therapeutic cure for BIR-induced AD and PD will also be reviewed.