Abstract
Oxidative stress and mitochondrial dysfunction are involved in the mechanisms of cardiac toxicity induced by aluminum phosphide (AlP). AlP-induced cardiotoxicity leads to cardiomyocyte death, cardiomyopathy, cardiac dysfunction, and eventually severe heart failure and death. Importantly, protecting cardiomyocytes from death resulting from AlP is vital for improving survival. It has been reported that flavonoids such as myricetin (Myr) act as modifiers of mitochondrial function and prevent mitochondrial damage resulting from many insults and subsequent cell dysfunction. In this study, the ameliorative effect of Myr, as an important antioxidant and mitochondrial protective agent, was investigated in cardiomyocytes and mitochondria isolated from rat heart against AlP-induced toxicity, oxidative stress, and mitochondrial dysfunction. Treatment of AlP (20 μg/ml) significantly increased cytotoxicity; reduced glutathione (GSH) depletion, cellular reactive oxygen species (ROS) formation, malondialdehyde (MDA) level, ATP depletion, caspase-3 activation, mitochondrial membrane potential (ΔΨm) collapse, and lysosomal dysfunction; and decreased the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in intact cardiomyocytes. Also, treatment of AlP (20 μg/ml) significantly increased mitochondrial dysfunction and swelling in isolated mitochondria. Myr (80 µM) appeared to ameliorate AlP-induced cytotoxicity in isolated cardiomyocytes; significantly lessened the AlP-stimulated intracellular ROS and MDA production and depletion of GSH; and increased the activities of SOD, CAT, and GSH-Px. Furthermore, Myr (40 and 80 µM) lowered AlP-induced lysosomal/mitochondrial dysfunction, ATP depletion, and caspase-3 activation. In the light of these findings, we concluded that Myr through antioxidant potential and inhibition of mitochondrial permeability transition (MPT) pore exerted an ameliorative role in AlP-induced toxicity in isolated cardiomyocytes and mitochondria, and it would be valuable to examine its in vivo effects.
Highlights
Pesticide poisoning is a global public health problem, and onethird of the suicides in the world is due to self-poisoning (Gunnell et al, 2007)
Mitochondrial dysfunction and oxidative stress are the major mechanisms in performed experimental studies (Valmas et al, 2008; Kariman et al, 2012; Anand et al, 2013; Sciuto et al, 2016)
Oxidative stress and mitochondrial damages induced by Aluminum phosphide (AlP) have been demonstrated in nematodes, insects, mammalian cell lines, and animals (Valmas et al, 2008; Sciuto et al, 2016)
Summary
Pesticide poisoning is a global public health problem, and onethird of the suicides in the world is due to self-poisoning (Gunnell et al, 2007). Due to its low-cost availability, AlP is extensively used as suicidal poison In developing countries such as Iran and India, AlP is emerging as a common selfpoisoning agent (Etemadi-Aleagha et al, 2015; Mehrpour et al, 2018). Phosphine gas induces oxidative stress through mitochondrial dysfunction, inhibition of cytochrome c oxidase in mitochondria and enzymatic antioxidants such as reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) (Bumbrah et al, 2012). Mitochondrial dysfunction, inhibition of cellular respiration, and antioxidant enzymes such as CAT, GR, and SOD can produce free radicals, lipid peroxidation, and oxidative stress. These alterations will lead to cellular injury and cytotoxicity via oxidative stress in different tissues.
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