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Background: Madhuca indica J. F. Gmel. (Sapotaceae) is widely used ethnobotanically as anti-diabetic, antipyretic, hepatoprotective, anti-inflammatory and analgesic. It was shown to possess potent anti-apoptotic property., The Aim of the Study: To evaluate the possible mechanism of action of isolated phytoconstituent from Madhuca indica Leaves methanolic extract (MI-ALC) on arsenic-induced cardiotoxicity in rats., Materials and Methods: The 3,5,7,3',4'-Pentahydroxy flavone (QTN) was isolated and characterized by using HPTLC, 1 H NMR, and LC-MS from MI-ALC. QTN (5, 10 and 20mg/kg, p.o.) was administered in arsenic intoxicated rats (5mL/kg, p.o.) for 28days and evaluated for various behavioral, biochemical, molecular and ultra-histological changes., Results: Treatment with QTN (10 and 20mg/kg, p.o.) significantly inhibited (p<0.05) arsenic-induced electrocardiographic, hemodynamic and left ventricular function alterations. Elevated levels of cardiac markers (LDH, CK-MB, AST, ALT, and ALP), altered lipid metabolism (total cholesterol, triglyceride, LDL, HDL, and VLDL) was significantly restored (p<0.05) by QTN. It also significantly inhibited (p<0.05) altered cardiac oxido-nitrosative stress, Na-K-ATPase level and mitochondrial enzymes (I-IV) activity after arsenite administration. QTN significantly increased (p<0.05) myocardial Nrf-2, PPAR-γ and significantly decreased (p<0.05) myocardial c-fos and c-jun mRNA expressions. Flow cytometric analysis showed that treatment with QTN (10 and 20mg/kg) significantly inhibited (p<0.05) arsenite-induce ROS and apoptosis. It also reduced ultra-histological aberrations induced by sodium arsenite., Conclusion: Administration of 3,5,7,3',4'- Pentahydroxy flavone (i.e. Quercetin (QTN)) isolated from MI-ALC showed significant protection against arsenic-induced oxido-nitrosative stress and myocardial injury via modulation of Nrf2, PPAR-γ, and apoptosis., (Copyright © 2017. Published by Elsevier B.V.)