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  • In order to further explore whether the cytoprotective

    2024-02-23

    In order to further explore whether the cytoprotective effect of isogarcinol against oxidative stress in H2O2-induced HepG2 Danazol is a consequence of the breakdown of the endogenous antioxidant defence mechanism, we measured the LDH release, MDA levels, GSH levels and SOD activity. A large body of evidence indicates that oxidative stress increases LDH release and MDA levels and reduces SOD, CAT, GPx activities, and GSH levels in H2O2-treated cells (Martín et al., 2011, Kong et al., 2016). MDA levels can reflect the extent of cell damage resulting from oxidative stress, leading to lipid peroxidation (Parthasarathi et al., 2015). In our study, we observed a reduction of LDH release and MDA levels following exposure to isogarcinol and VE (Fig. 4A and B); moreover, isogarcinol significantly increased intracellular SOD activity and GSH levels (Fig. 4C and D), suggesting that H2O2-induced HepG2 cellular injury is due to ROS generated by oxidative stress. Previous studies have shown that ROS are mainly by-products of mitochondrial respiration, and high levels of ROS lead to lipid peroxidation, damage to mitochondrial membranes and release of mitochondrial pro-apoptotic factors into the cytoplasm, followed by caspase activation and, finally, apoptosis. (Ma et al., 2016). Caspase-3 plays a central role in the execution of apoptosis (Shao, Huang, Yan, Jin, & Ren, 2016). Hence, to see whether isogarcinol protected against H2O2-induced oxidative stress by inhibiting apoptosis, we measured the expression of caspase-3 by Western blotting. Isogarcinol markedly up-regulated pro-caspase-3 and down-regulated cleaved caspase-3 (Fig. 5A and B). The presence of an isopentenyl group will greatly enhance the lipophilicity of the compounds, and such compounds can more easily pass through the lipid-soluble cell membrane and combine with target protein (Chen et al., 2017). Therefore, our results may be explained by the ability of isogarcinol to protect pro-caspase-3 against fragmentation into active caspase-3 (cleaved caspase-3) by interacting with pro-caspase-3. However, the exact functional mechanism of isogarcinol requires further exploration. In a word, isogarcinol protected HepG2 cells against H2O2-induced mitochondrial-dependent apoptosis.
    Conclusion Isogarcinol has strong antioxidant activity and reduces oxidative damage induced by H2O2 in HepG2 cells. It is not cytotoxic and genotoxic to HepG2 cells in the range of concentrations tested. It alleviates oxidative stress by reducing ROS generation and blocking the ROS-induced mitochondrial apoptosis pathway. At the same time, isogarcinol decreases LDH release, MDA level and increases GSH level and SOD activity in a concentration-dependent manner. It may be of use for treating a variety of diseases associated with free radical and oxidative damage.
    Acknowledgements Thanks for Youth Foundation Project of National Natural Science Foundation of Hainan province, China and the National Natural Science Foundation of China (31460120, 31760170, 81660584).
    INTRODUCTION Within each cell of the body, metabolic processes generate free radicals, and antioxidant systems are in place to effectively disarm them. However, this homeostatic balance can be altered due to excess free radical production, antioxidant depletion, or both. When the controls fail, cells are exposed to high levels of free radicals [reactive oxygen (ROS), reactive nitrogen, or reactive sulfur species]. Oxidative stress ensues, leading to cell injury such as protein and lipid peroxidation, DNA strand breakage, racemization or decarboxylation of AA, enzyme dysfunction, and oxidative breakdown of carbohydrates (d'Ischia et al., 2006; Li et al., 2015). Sustained oxidative stress is considered a causative agent of neurodegenerative disorders (Gilgun-Sherki et al., 2001; Klein and Ackerman, 2003), cancer (Waris and Ahsan, 2006), liver injury (Li et al., 2015), aging (Lee et al., 2004), and appears to aggravate diabetes (Rochette et al., 2014), cystic fibrosis (Galli et al., 2012), chronic pancreatitis (Zhou et al., 2015), and cardiovascular disease (Sugamura and Keaney, 2011; Lönn et al., 2012). Cells protect themselves from oxidative damage by (1) prevention, (2) repair, (3) antioxidant production, or (4) uptake of dietary antioxidants or their precursors (Valko et al., 2007; Niki, 2010). Endogenous antioxidants include the intracellular enzymes superoxide dismutase (SOD) and catalase (CAT). The metal-binding enzyme, SOD, converts superoxide anion to hydrogen peroxide plus oxygen, whereas CAT converts hydrogen peroxide to water (Weydert and Cullen, 2010). The cytosolic Cys tripeptide γ-glutamyl-cysteinyl-glycine reduces hydroperoxides to alcohols and hydrogen peroxide to water by converting from its reduced (GSH) to its oxidized form. Well-documented dietary antioxidants include ascorbic acid (vitamin C), α-tocopherol (vitamin E), polyphenols, and carotenoids (Fiedor and Burda, 2014).