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Fisetin, a plant flavonoid ameliorates doxorubicin-induced cardiotoxicity in experimental rats: the decisive role of caspase-3, COX-II, cTn-I, iNOs and TNF-α

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Abstract

Doxorubicin (DOX) is a widely used anthracycline antibiotic for the management of carcinoma. However, it is associated with cardiotoxicity. Fisetin is a plant flavonoid reported to have anti-inflammatory and antiapoptotic potential. To evaluate the cardioprotective potential of fisetin in DOX-induced cardiotoxicity in experimental rats. Sprague–Dawley rats were pre-treated with either fisetin (10, 20 and 40 mg/kg) or sitagliptin (10 mg/kg, p.o.) for 7 days. Cardiac toxicity was induced in rats (except the normal group) by doxorubicin (15 mg/kg i.p.) on 8th day. Various behavioral, biochemical, molecular and histological parameters were assessed in cardiac tissue. DOX-induced alterations in electrocardiographic, hemodynamic and left ventricular function were significantly (p < 0.05) inhibited by fisetin (20 and 40 mg/kg) treatment. Fisetin significantly decrease (p < 0.05) DOX-induced elevated serum CK-MB, LDH, AST, ALT and ALP levels. DOX-induced elevated cardiac oxido-nitrosative (SOD, GSH, MDA and NO) was significantly inhibited (p < 0.05) by fisetin. Up-regulated cardiac caspase-3, COX-II, cTn-I, iNOs, TNF-α, and IL-1β mRNA, as well as protein expressions were significantly decreased (p < 0.05) by fisetin treatment. It also significantly (p < 0.05) attenuated DOX-induced histopathological alterations in cardiac tissue. In conclusion, the fisetin exerts its cardioprotective potential against DOX-induced toxicity via inhibition of multiple pathways including oxidative stress (SOD, GSH, MDA and NO), inflammation (COX-II, TNF-α, and IL-1β), and apoptosis (Caspase-3). Therefore, fisetin can be considered as a potential cardioprotective agent during the management of carcinoma using doxorubicin anthracyclines.

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Abbreviations

ALT:

Alanine transaminase

ALP:

Alkaline phosphatase

ANP:

Atrial natriuretic peptide

AST:

Aspartate aminotransferase

BNP:

Brain natriuretic peptide

BPM:

Blood pressure per minute

cTn-I:

Cardiac troponin I

CK-MB:

Creatine kinase-MB

COX-II:

Cyclooxygenase-II

DNA:

Deoxyribonucleic acid

DBP:

Diastolic blood pressure

iNOs:

Inducible nitric oxide

IL 1β:

Interleukin 1-β

LDH:

Lactate dehydrogenase

LVEDP:

Left ventricular end-diastolic pressure

LVESP:

Left ventricular end-systolic pressure

MABP:

Mean arterial blood pressure

MDA:

Malondialdehyde

NO:

Nitric oxide

ROS:

Reactive oxygen species

GSH:

Reduced glutathione

RT-PCR:

Reverse transcription-polymerase chain reaction

RNA:

Ribonucleic acid

SOD:

Superoxide dismutase

SBP:

Systolic blood pressure

TNF-α:

Tumor necrosis factor-α

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Acknowledgements

The authors would like to acknowledge Dr. S. S. Kadam, Chancellor, and Dr. K. R. Mahadik, Principal, Poona College of Pharmacy, Bharati Vidyapeeth Deemed University, Pune for providing necessary facilities to carry out the study.

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Correspondence to Subhash L. Bodhankar.

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The experimental protocol was approved by the Institutional Animal Ethics Committee (IAEC) of Poona College of Pharmacy, Pune and performed in accordance with the guidelines of Committee for Control and Supervision of Experimentation on Animals, Government of India on animal experimentation.

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Ma, T., Kandhare, A.D., Mukherjee-Kandhare, A.A. et al. Fisetin, a plant flavonoid ameliorates doxorubicin-induced cardiotoxicity in experimental rats: the decisive role of caspase-3, COX-II, cTn-I, iNOs and TNF-α. Mol Biol Rep 46, 105–118 (2019). https://doi.org/10.1007/s11033-018-4450-y

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