title: Saffron extracts alleviate cardiomyocytes injury induced by doxorubicin and ischemia-reperfusion in vitro.
abstract: Doxorubicin (DOX), a highly active chemotherapeutic drug, faces limitations in clinical application due to severe cardiotoxic effects (mainly through increased oxidative stress). Therefore, its effect is exacerbated in subjects with ischemic heart disease. We have recently reported that saffron extract (SAF), a natural compound mainly consisting of safranal and corcins, exerts a protective effect against DOX oxidative cytotoxicity in isolated rabbit hearts. Here, we aimed to investigate whether SAF exerts cardioprotection against combined ischemia-reperfusion (I/R) and DOX toxicity in H9c2 cardiomyocytes. H9c2 were subjected to simulated I/R, with or without DOX treatment at reperfusion, in the presence or absence of SAF prior to ischemia or at reperfusion. We evaluated the effects of these treatments by MTT, LDH and western blot analysis. Apoptosis was assessed by Hoechst 33258 staining, tetramethyl rhodamine methyl ester fluorescence and caspase activity. The results showed that I/R and DOX significantly decreased cardiomyocytes viability, inhibited reperfusion injury salvage kinase cardioprotective pathway, reduced contractile proteins (α-Actinine, Troponine C and MLC), increased caspase-3 expression and induced loss of mitochondrial membrane potential. These effects were remarkably inhibited by treatment with SAF (10 μg/mL) at reperfusion. SAF activated AKT/P70S6K and ERK1/2, restored contractile proteins expression, inhibited mitochondrial permeability transition pore and decreased caspase-3 activity. In conclusion, our findings indicate that SAF treatment exerted cardioprotection against I/R and DOX toxicity by reducing oxidative stress (LDH assay). Thereby, SAF offers a potential novel antioxidant therapeutic strategy to counteract I/R and DOX cardiotoxicity, paving the way for future clinical trials.
authors.affiliation: a Physiology Lab , Oxidative Stress and Antioxidant Group, Faculty of Medical Sciences and Doctoral School of Science and Technology, Lebanese University , Hadat , Beirut , Lebanon .|c Signalisation et récepteurs matriciels (SiRMa) UMR CNRS 6237 Lab, Faculty of Sciences, Moulin de la Housse, University of Reims Champagne-Ardenne , France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chahine
authors.affiliation: b Department of Physiological Sciences , College of Medicine, Alfaisal University , Riyadh , KSA , and.
authors.forename: Moni
authors.initials: M
authors.lastname: Nader
authors.affiliation: c Signalisation et récepteurs matriciels (SiRMa) UMR CNRS 6237 Lab, Faculty of Sciences, Moulin de la Housse, University of Reims Champagne-Ardenne , France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Duca
authors.affiliation: c Signalisation et récepteurs matriciels (SiRMa) UMR CNRS 6237 Lab, Faculty of Sciences, Moulin de la Housse, University of Reims Champagne-Ardenne , France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Martiny
authors.affiliation: a Physiology Lab , Oxidative Stress and Antioxidant Group, Faculty of Medical Sciences and Doctoral School of Science and Technology, Lebanese University , Hadat , Beirut , Lebanon .
authors.forename: Ramez
authors.initials: R
authors.lastname: Chahine
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D000975:Antioxidants / Q000302:isolation & purification / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002316:Cardiotonic Agents / Q000302:isolation & purification / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D027622:Crocus / Q000737:chemistry*; D004317:Doxorubicin / Q000633:toxicity*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D033681:Mitochondrial Membrane Transport Proteins / Q000187:drug effects; D000083162:Mitochondrial Permeability Transition Pore; D017202:Myocardial Ischemia / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology*; D051381:Rats; D015427:Reperfusion Injury / Q000150:complications / Q000188:drug therapy
chemical_list: D000903:Antibiotics, Antineoplastic; D000975:Antioxidants; D002316:Cardiotonic Agents; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D010936:Plant Extracts; D004317:Doxorubicin; D053148:Caspase 3
keywords: Antioxidant; H9c2 cells; cardiotoxicity; doxorubicin; free radicals; myocardial ischemia-reperfusion; saffron extract