Department of Pharmacy

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Author: search.filters.author.Gaikwad, Anil BhanudasSubject: search.filters.subject.Insulin resistance (IR)

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    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 Bhanudas
    Insulin 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.
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    Esculetin reverses histone H2A/H2B ubiquitination, H3 dimethylation, acetylation and phosphorylation in preventing type 2 diabetic cardiomyopathy
    (Elsevier, 2015-08) Gaikwad, Anil Bhanudas
    Post 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.
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    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 Bhanudas
    Altered 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.