Saurabh Bharti

All India Institute of Medical Sciences, New Dilli, NCT, India

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Publications (33)94.52 Total impact

  • Saurabh Bharti, Neha Rani, D.S. Arya
    The American Journal of Cardiology 03/2015; 115. DOI:10.1016/j.amjcard.2015.01.062 · 3.43 Impact Factor
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    ABSTRACT: Pharmacological stimulation of peroxisome proliferator-activated receptor-gamma (PPAR-γ) has been recognized as a molecular switch in alleviating myocardial injury through modulating oxidative, inflammatory and apoptotic signaling pathways. This study was designed to elucidate the effect of chrysin, a novel PPAR-γ agonist and its functional interaction with TGF-β/MAPKs in isoproterenol-challenged myocardial injury in rats. Male Wistar Albino rats were either subjected to vehicle (1.5 mL/kg, p.o.) or chrysin (15-60 mg/kg, p.o.) for 28 days. Isoproterenol (85 mg/kg, s.c.) was administered to rats on 27(th) and 28(th) day to induce myocardial injury. Chrysin dose dependently improved ventricular (±LVdP/dtmax and LVEDP) and hemodynamic (SAP, MAP and DAP) dysfunction in isoproterenol-insulted rats. This beneficial effect of chrysin was well supported with increased expression of PPAR-γ and decreased expression of TGF-β as evidenced by western blotting and immunohistochemistry analysis. Moreover, downstream signaling pathway of TGF-β viz. P-ERK½/ERK½ activation and P-JNK/JNK, P-p38/p38 and MMP-2 inhibition were also observed. Chrysin also attenuated NF-κBp65 and IKK-β expressions, TNF-α level and TUNEL positivity thereby validating its anti-inflammatory and anti-apoptotic properties. Additionally, chrysin in a dose dependent fashion improved NO level, redox status of the myocardium (GSH and MDA levels and SOD, GSHPx and CAT activities), cardiac injury markers (CK-MB and LDH levels) and oxidative DNA damage marker (8-OHdG level) and displayed preservation of subcellular and ultrastructural components. We established that activation of PPAR-γ and inhibition of TGF-β via MAPKs dependent mechanism is critical for cardioprotective effect of chrysin.
    Nutrition & Metabolism 03/2015; 12(1):11. DOI:10.1186/s12986-015-0004-7 · 3.36 Impact Factor
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    ABSTRACT: Recent studies have proposed the potential role of 5-HT2B receptor (5-HT2BR) blockade in alleviating myocardial dysfunction; hitherto, the regulatory pathway for its protective effect has remained enigmatic. In the present study, we sought to investigate the role of SB-204741, a 5-HT2BR blocker in isoproterenol-induced myocardial remodeling in rats and its cross-talk with apoptosis and mitogen activated protein kinase (MAPKs)/heat shock proteins (HSPs) pathway. To assess this hypothesis, we measured the effect of SB-204741 (0.25-1.0 mg/kg/day, i.p.) in isoproterenol (85 mg/kg/day, s.c.)-induced myocardial remodeling in rats. SB-204741 dose dependently improved hemodynamic and ventricular functions following isoproterenol-induced myocardial injury. This amelioration was well substantiated with reduced expression of 5-HT2B, inflammatory proteins (NF-κBp65, IKK-β, TNF-α, IL-6, and Cox-2), MAPKs (p-p38/p38 and p-JNK/JNK ratio) accompanied with increased protein expression of HSPs (αB-crystallin, Hsp27 and Hsp70), autophagy (LC3 and Beclin-1) and p-ERK/ERK ratio. Additionally, SB-204741 inhibited apoptotic signaling pathway as there was decreased DAPI/TUNEL positivity and protein expression of cytochrome c, Bax, and caspase-3 along with increased Bcl-2 expression. Preservation of histopathological and ultrastructural components, normalization of nitric oxide level, endogenous antioxidants and myocyte injury marker enzymes were also observed. In conclusion, inhibition of apoptosis via modulation of MAPKs/HSPs is essential for 5-HT2BR blockade mediated cardioprotective effect.
    APOPTOSIS 12/2014; 20(4). DOI:10.1007/s10495-014-1083-z · 3.61 Impact Factor
  • N Rani, S Bharti, D S Arya
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    ABSTRACT: Purpose: Chrysin (5,7-dihydroxylflavone), an agonist of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has been shown to possess antioxidant and anti-inflammatory properties. Here, we investigated whether chrysin (60 mg/kg/day) can improve the pathophysiology of myocardial infarction in diabetes partially through the PPAR-gamma pathway by assessing a variety of indices, e.g., hemodynamic, biochemical, histoarchitectural changes, and apoptosis. Methods: Diabetes was induced by a single dose of streptozotocin (70 mg/kg, i.p.). Diabetic rats received either chrysin (60 mg/kg/day, orally), PPAR-gamma antagonist GW9662 (1 mg/kg/day, i.p.) or both for 28 days with concurrent administration of isoproterenol (85 mg/kg, SC) on days 27th and 28th. Results: Compared with diabetic controls, diabetic rats with myocardial infarction exhibited altered hemodynamic profiles (MAP, LVEDP, ±LVdP/dtmax) and reduction in the activities of creatine kinase-MB isoenzyme, lactate dehydrogenase, superoxide dismutase, catalase, and glutathione level along with increased level of malondialdehyde. Further, diabetic animals with myocardial infarction exhibited increased myonecrosis, edema, and apoptotic cell death. Treatment with chrysin significantly improved the redox status of the myocardium with subsequent cardiac functional recovery. However, significant effects were lowered in animals treated with chrysin plus GW9662. Chrysin markedly inhibited Bax expression, TUNEL-positive cells, and increased Bcl2 expression. Moreover, down-regulated PPAR-gamma expression in myocardial infarcted diabetic hearts was also increased by chrysin. Conclusion: Chrysin improves myocardial infarction in diabetic rats through a pathway involving PPAR- gamma.
    Cardiovascular Research 07/2014; 103(suppl 1):S81. DOI:10.1093/cvr/cvu091.121 · 5.81 Impact Factor
  • S Bharti, N Rani, D S Arya
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    ABSTRACT: Purpose: We established previously that Crocus sativus and its carotenoid crocin protects the myocardium via augmenting the endogenous antioxidant defense system. Since, heat shock protein70 (Hsp70) actively participates in shielding the cell from oxidative stress, programmed or necrotic cell deaths; we hypothesized that Hsp70 might be the actual mediator behind the cardioprotective effects of crocin. Methods: To document this interplay between crocin and Hsp70, we administered crocin (20mg/kg/day, p.o.) and Hsp70 inhibitor, KNK437 (25mg/kg/day, i.p.) for 14 days followed by left anterior descending coronary artery ligation for 45 minutes and reperfusion for 60 minutes on the 15th day. Results: Intriguingly, crocin pretreatment significantly ameliorated (P<0.05) hemodynamic status, myocardial architecture and decreased infarct size in ischemia-reperfusion challenged myocardium. This improvement in functional and morphological changes were corroborated with suppression of inflammatory (IKK-beta/NF-kappaB and TNF-alpha), apoptotic (TUNEL positivity and Bax expression) and cardiac injury markers (CK-MB, LDH and BNP), along with upregulation of Hsp70 protein expression. In addition, crocin bolstered the antioxidant defense system as manifested by augmented activities of GSH, GSHPx and overexpression of MnSOD protein expression levels. Surprisingly, co-treatment with KNK437 abrogated the crocin-induced cardioprotection with significant amplification in infarct size, inflammation, apoptosis and oxidative stress markers. Conclusion: For the first time, present study unravels that crocin attenuates ischemia-reperfusion injury through augmenting Hsp70 expression and could be developed as a nutriment for alleviating acute myocardial infarction.
    Cardiovascular Research 07/2014; 103(suppl 1):S24. DOI:10.1093/cvr/cvu082.78 · 5.81 Impact Factor
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    ABSTRACT: Canagliflozin (CFZ) is a member of new class of glucose lowering agents, sodium-glucose co-transporter (SGLT) inhibitors, which got approval by food and drug administration. It has insulin independent action by blocking the transporter protein SGLT2 in the kidneys, resulting in urinary glucose excretion and reduction in blood glucose levels. In clinical trials, CFZ significantly decreased HbA1c level when administered either as monotherapy or as combined therapy with other anti-diabetic drugs. Intriguingly, it showed additional benefits like weight reduction and lowering of blood pressure. The commonly observed side effects were urinary and genital infections. It has exhibited favorable pharmacokinetic and pharmacodynamic profiles even in patients with renal and hepatic damage. Hence, this review purports to outline CFZ as a newer beneficial drug for type 2 diabetes mellitus.
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    ABSTRACT: Naringin, chemically 4',5,7- trihydroxyflavanone-7-rhamnoglucoside, is a major flavanone glycoside obtained from tomatoes, grapefruits, and many other citrus fruits. It has been experimentally documented to possess numerous biological properties such as antioxidant, anti-inflammatory, and antiapoptotic activities. In vitro and in vivo studies have further established the usefulness of naringin in various preclinical models of atherosclerosis, cardiovascular disorders, diabetes mellitus, neurodegenerative disorders, osteoporosis, and rheumatological disorders. Apart from this, naringin has also exerted chemopreventive and anticancer attributes in various models of oral, breast, colon, liver, lung, and ovarian cancer. This wide spectrum of biological expediency has been documented to be a result of either the upregulation of various cell survival proteins or the inhibition of inflammatory processes, or a combination of both. Due to the scarcity of human studies on naringin, this review focuses on the various established activities of naringin in in vitro and in vivo preclinical models, and its potential therapeutic applications using the available knowledge in the literature. Additionally, it also encompasses the pharmacokinetic properties of naringin and its inhibition of CYP isoenzymes, and the subsequent drug interactions. Moreover, further clinical research is evidently needed to provide significant insights into the mechanisms underlying the effects of naringin in humans.
    Planta Medica 04/2014; DOI:10.1055/s-0034-1368351 · 2.34 Impact Factor
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    ABSTRACT: Naringin has antioxidant properties that could improve redox-sensitive myocardial ischemia reperfusion (IR) injury. This study was designed to investigate whether naringin restores the myocardial damage and dysfunction in vivo after IR and the mechanisms underlying its cardioprotective effects. Naringin (20-80 mg/kg/day, p.o.) or saline were administered to rats for 14 days and the myocardial IR injury was induced on 15(th) day by occluding the left anterior descending coronary artery for 45 min and subsequent reperfusion for 60 min. Post-IR rats exhibited pronounced cardiac dysfunction as evidenced by significantly decreased mean arterial pressure, heart rate, +LVdP/dt max (inotropic state), -LVdP/dt max (lusitropic state) and increased left ventricular end diastolic pressure as compared to sham group, which was improved by naringin. Further, on histopathological and ultrastructural assessments myocardium and myocytes appeared more normal in structure and the infarct size was reduced significantly in naringin 40 and 80 mg/kg/day group. This amelioration of post-IR-associated cardiac injury by naringin was accompanied by increased nitric oxide (NO) bioavailability, decreased NO inactivation to nitrotyrosine, amplified protein expressions of Hsp27, Hsp70, β-catenin and increased p-eNOS/eNOS, p-Akt/Akt, and p-ERK/ERK ratio. In addition, IR-induced TNF-α/IKK-β/NF-κB upregulation and JNK phosphorylation were significantly attenuated by naringin. Moreover, western blotting and immunohistochemistry analysis of apoptotic signaling pathway further established naringin cardioprotective potential as it upregulated Bcl-2 expression and downregulated Bax and Caspase-3 expression with reduced TUNEL positivity. Naringin also normalized the cardiac injury markers (lactate dehydrogenase and creatine kinase-MB), endogenous antioxidant activities (superoxide dismutase, reduced glutathione and glutathione peroxidase) and lipid peroxidation levels. Thus, naringin restored IR injury by preserving myocardial structural integrity and regulating Hsp27, Hsp70, p-eNOS/p-Akt/p-ERK signaling and inflammatory response.
    PLoS ONE 12/2013; 8(12):e82577. DOI:10.1371/journal.pone.0082577 · 3.53 Impact Factor
  • Experimental and toxicologic pathology: official journal of the Gesellschaft fur Toxikologische Pathologie 11/2012; 65(5). DOI:10.1016/j.etp.2012.09.004 · 2.01 Impact Factor
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    FEBS Letters 06/2012; 586(13):1832. DOI:10.1016/j.febslet.2012.05.032 · 3.34 Impact Factor
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    ABSTRACT: Syzygium cumini (SC) is well known for its anti-diabetic potential, but the mechanism underlying its amelioration of type 2 diabetes is still elusive. Therefore, for the first time, we investigated whether SC aqueous seed extract (100, 200, or 400 mg/kg) exerts any beneficial effects on insulin resistance (IR), serum lipid profile, antioxidant status, and/or pancreatic β-cell damage in high-fat diet / streptozotocin-induced (HFD-STZ) diabetic rats. Wistar albino rats were fed with HFD (55% of calories as fat) during the experiment to induce IR and on the 10th day were injected with STZ (40 mg/kg, i.p.) to develop type 2 diabetes. Subsequently, after confirmation of hyperglycemia on the 14th day (fasting glucose level > 13.89 mM), diabetic rats were treated with SC for the next 21 days. Diabetic rats showed increased serum glucose, insulin, IR, TNF-α, dyslipidemia, and pancreatic thiobarbituric acid-reactive substances with a concomitant decrease in β-cell function and pancreatic superoxide dismutase, catalase, and glutathione peroxidase antioxidant enzyme activities. Microscopic examination of their pancreas revealed pathological changes in islets and β-cells. These alterations reverted to near-normal levels after treatment with SC at 400 mg/kg. Moreover, hepatic tissue demonstrated increased PPARγ and PPARα protein expressions. Thus, our study demonstrated the beneficial effect of SC seed extract on IR and β-cell dysfunction in HFD-STZ-induced type 2 diabetic rats.
    Journal of Pharmacological Sciences 06/2012; 119(3):205-13. · 2.11 Impact Factor
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    ABSTRACT: This article has been withdrawn at the request of the editors. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.
    Biochimica et Biophysica Acta 05/2012; DOI:10.1016/j.bbadis.2012.05.011 · 4.66 Impact Factor
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    ABSTRACT: Increased oxidative stress and inflammation in obesity are the central and causal components in the pathogenesis and progression of cardiometabolic syndrome (CMetS). The aim of the study was to determine the potential role of sesamol (a natural powerful antioxidant and anti-inflammatory phenol derivative of sesame oil) in chronic high-cholesterol/high-fat diet (HFD)-induced CMetS in rats and to explore the molecular mechanism driving this activity. Rats were fed with HFD (55% calorie from fat and 2% cholesterol) for 60 days to induce obesity, dyslipidemia, insulin resistance (IR), hepatic steatosis and hypertension. On the 30th day, rats with total cholesterol >150 mg/dl were considered hypercholesterolemic and administered sesamol 2, 4 and 8 mg/kg per day for the next 30 days. Sesamol treatment decreased IR, hyperinsulinemia, hyperglycemia, dyslipidemia, TNF-α, IL-6, leptin, resistin, highly sensitive C-reactive protein (hs-CRP), hepatic transaminases and alkaline phosphatase, along with normalization of adiponectin, nitric oxide and arterial pressures in a dose-dependent fashion. Increased TBARS, nitrotyrosine and decreased antioxidant enzyme activities were also amended in HFD rats. Similarly, sesamol normalized hepatic steatosis and ultrastructural pathological alteration in hepatocytes, although the effect was more pronounced at 8 mg/kg. Furthermore, hepatic PPARγ, PPARα and e-NOS protein expressions were increased, whereas LXRα, SERBP-1c, P-JNK and NF-κB expression were decreased by sesamol treatment. These results suggest that sesamol attenuates oxidative stress, inflammation, IR, hepatic steatosis and hypertension in HFD-fed rats via modulating PPARγ, NF-κB, P-JNK, PPARα, LXRα, SREBP-1c and e-NOS protein expressions, thereby preventing CMetS. Thus, the present study demonstrates the therapeutic potential of sesamol in alleviating CMetS.
    The Journal of nutritional biochemistry 03/2012; 23(11):1482-9. DOI:10.1016/j.jnutbio.2011.09.011 · 4.59 Impact Factor
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    ABSTRACT: Protecting myocardium from ischaemia-reperfusion (I-R) injury is important to reduce the complication of myocardial infarction (MI) and interventional revascularization procedures. In the present study, the cardioprotective potential of hydroalcoholic extract of Andrographis paniculata was evaluated against left anterior descending coronary artery (LADCA) ligation-induced I-R injury of myocardium in rats. MI was induced in rats by LADCA ligation for 45 min followed by reperfusion for 60 min. The rats were divided into five experimental groups viz., sham (saline treated, but LADCA was not ligated), I-R control (saline treated + I-R), benazepril (30 mg/kg + I-R), A. paniculata (200 mg/kg per se) and A. paniculata (200 mg/kg + I-R). A. paniculata was administered orally for 31 days. On day 31, rats were subjected to the I-R and cardiac function parameters were recorded. Further, rats were sacrificed and heart was excised for biochemical and histopathological studies. In I-R control group, LADCA ligation resulted in significant cardiac dysfunction evidenced by reduced haemodynamic parameters; mean arterial pressure (MAP) and heart rate (HR). The left ventricular contractile function was also altered. In I-R control group, I-R caused decline in superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and reduced glutathione (GSH) as well as leakage of myocytes injury marker enzymes, creatine phosphokinase-MB (CK-MB) isoenzyme and lactate dehydrogenase (LDH), and enhanced lipid peroxidation product, malonaldialdehyde (MDA). However, rats pretreated with A. paniculata 200 mg/kg showed favourable modulation of haemodynamic and left ventricular contractile function parameters, restoration of the myocardial antioxidants and prevention of depletion of myocytes injury marker enzymes along with inhibition of lipid peroxidation. Histopathological observations confirmed the protective effects of A. paniculata. The cardioprotective effects of A. paniculata were found comparable to that of benazepril treatment. Interpretation & Our results showed the cardioprotective effects of A. paniculata against I-R injury likely result from the suppression of oxidative stress and preserved histoarchitecture of myofibrils along with improved haemodynamic and ventricular functions.
    The Indian Journal of Medical Research 03/2012; 135(3):414-21. · 1.66 Impact Factor
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    ABSTRACT: Metabolic syndrome (MetS) is defined as a cluster of numerous cardiovascular risk factors, which encompasses obesity, dyslipidaemia, insulin resistance and hypertension. Patients with MetS are more prone to developing cardiovascular events than other patients. To date, several approaches such as physical exercise, dietary control and invasive and non-invasive therapeutic interventions for dyslipidaemia, hypertension and insulin resistance have been used to manage MetS. However, there is a progressive elevation in the incidence of fatal and non-fatal cardiovascular events due to the increased prevalence of obesity and diabetes. Percutaneous coronary intervention has emerged over the last few years as an effective revascularisation strategy for those with coronary artery disease, in parallel with the development of effective anti-platelet medications and newer drug-eluting stents. In recent years, considerable research efforts have been undertaken to elucidate the pathophysiology of re-stenosis and develop strategies to prevent re-stenosis following percutaneous transluminal coronary angioplasty and stent implantation. Although the rate of stent re-stenosis and target-lesion revascularisation has been reduced, there is little information in the literature on the outcome of MetS in the pathophysiology of re-stenosis. In this review article, we summarise the recent development and progress on re-stenosis and the role of drug-eluting stents, particularly in MetS.
    Diabetes & Vascular Disease Research 01/2012; 9(3):177-88. DOI:10.1177/1479164111430336 · 3.04 Impact Factor
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    ABSTRACT: Objectives: Increased oxidative stress and inflammation in obesity are the central and causal components in the pathogenesis and progression of cardiometabolic syndrome (CMetS). The aim of the study was to determine the potential role of sesamol (a natural powerful antioxidant and anti-inflammatory phenol derivative of sesame oil) in chronic high-cholesterol/high-fat diet (HFD)-induced CMetS in rats and to explore the molecular mechanism. Design and methods: Rats were fed with HFD (55% calorie from fat and 2% cholesterol) for 60 days to induce obesity, dyslipidemia, insulin resistance (IR), hepatic steatosis and hypertension. On the 30th day, rats with total cholesterol>150 mg/dl were considered hypercholesterolemic and administered sesamol 2, 4 and 8 mg/kg per day for the next 30 days. Results: Sesamol treatment decreased IR, hyperinsulinemia, hyperglycemia, dyslipidemia, TNF-[alpha], IL-6, leptin, resistin, highly sensitive C-reactive protein (hs-CRP), hepatic transaminases and alkaline phosphatase, along with normalization of adiponectin, nitric oxide and arterial pressures in a dose-dependent fashion. Increased TBARS, nitrotyrosine and decreased antioxidant enzyme activities were also amended in HFD rats. Similarly, sesamol normalized hepatic steatosis and ultrastructural pathological alteration in hepatocytes, although the effect was more pronounced at 8 mg/kg. Furthermore, hepatic PPAR[gamma], PPAR[alpha] and e-NOS protein expressions were increased, whereas LXR[alpha], SERBP-1c, P-JNK and NF-[kappa]B expression were decreased by sesamol treatment. Conclusions: These results suggest that sesamol attenuates oxidative stress, inflammation, IR, hepatic steatosis and hypertension in HFD-fed rats via modulating PPAR[gamma], NF-[kappa]B, PJNK, PPAR[alpha], LXR[alpha], SREBP-1c and e-NOS protein expressions, thereby preventing CMetS. Thus, the present study demonstrates the therapeutic potential of sesamol in alleviating CMetS.
    Journal of Hypertension 01/2012; 30:e272. DOI:10.1097/01.hjh.0000420461.40489.5a · 4.22 Impact Factor
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    ABSTRACT: Present study evaluated the cardioprotective effect of Andrographis paniculata (100, 200 or 400 mg/kg) against isoproterenol (85 mg/kg, b.w.)-induced cardiotoxicity referred as myocardial infarction in rats. Isoproterenol significantly (p < 0.05) decreased mean arterial pressure, heart rate, contractility and relaxation and increased left ventricular end diastolic pressure. Isoproterenol also significantly (p < 0.05) decreased antioxidants, superoxide dismutase, catalase, glutathione peroxidase, glutathione and increased leakage of cardiac injury markers; creatine phosphokinase-MB isoenzyme, lactate dehydrogenase concomitant to increased lipid peroxidation and histopathological perturbations. However, pretreatment with A. paniculata favorably restored hemodynamic parameters and left ventricular function and significantly (p < 0.05) prevented the depletion of endogenous antioxidants and myocyte marker enzymes as well as inhibited lipid peroxidation. Significant (p < 0.05) reversal of almost all the hemodynamic, biochemical and histopathological parameters by A. paniculata pretreatment in isoproterenol-induced cardiotoxicity depicted the cardioprotective effect of A. paniculata. Results showed that A. paniculata protected heart against cardiotoxic effects of isoproterenol by boosting endogenous antioxidant network, restoring ventricular function and maintaining structural integrity of heart.
    Acta poloniae pharmaceutica 01/2012; 69(2):269-78. · 0.69 Impact Factor
  • Journal of Pharmacological Sciences 01/2012; 119(3):205-213. DOI:10.1254/jphs.11184FP · 2.11 Impact Factor
  • Journal of Hypertension 01/2012; 30:e263-e264. DOI:10.1097/01.hjh.0000420453.32865.74 · 4.22 Impact Factor
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    ABSTRACT: Herein, we studied the cross talk between 5-HT(2B) receptor blocker (SB-204741) and GSK-3β inhibitor (SB-216763) in isoproterenol-induced cardiac hypertrophy for 28 days. SB-204741 treatment significantly ameliorated (P<0.05) myocardial dysfunction, myocyte area, fibrosis and myocardial architecture in isoproterenol insulted myocardium. Moreover, this improvement in functional and morphological changes was associated with suppression of hypertrophic (BNP and CK-MB), inflammatory (IKK-β/NF-κB/TNF-α and CRP), and apoptotic markers (TUNEL positivity and Bax expression) along with phosphorylation of Akt/GSK-3β/β-catenin/eNOS. Intriguingly, co-treatment with GSK-3β inhibitor (P<0.01) further amplified the anti-hypertrophic effect of SB-204741 (P<0.05) such that the effect was indistinguishable from that of vehicle treated rats. Thus, 5-HT(2B) receptor blockade mediated anti-hypertrophic effect is atleast in part is governed through phosphorylation of Akt/GSK-3β/β-catenin/eNOS via attenuating inflammatory and apoptotic pathways.
    FEBS letters 12/2011; 586(2):180-5. DOI:10.1016/j.febslet.2011.12.015 · 3.34 Impact Factor