Abstract
Hydrogen peroxide (H2O2) mediated oxidative stress leading to hepatocyte apoptosis plays a pivotal role in the pathophysiology of several chronic liver diseases. This study demonstrates that S-allyl cysteine (SAC) renders cytoprotective effects on H2O2 induced oxidative damage and apoptosis in HepG2 cells. Cell viability assay showed that SAC protected HepG2 cells from H2O2 induced cytotoxicity. Further, SAC treatment dose dependently inhibited H2O2 induced apoptosis via decreasing the Bax/Bcl-2 ratio, restoring mitochondrial membrane potential (∆Ψm), inhibiting mitochondrial cytochrome c release, and inhibiting proteolytic cleavage of caspase-3. SAC protected cells from H2O2 induced oxidative damage by inhibiting reactive oxygen species accumulation and lipid peroxidation. The mechanism underlying the antiapoptotic and antioxidative role of SAC is the induction of the heme oxygenase-1 (HO-1) gene in an NF-E2-related factor-2 (Nrf-2) and Akt dependent manner. Specifically SAC was found to induce the phosphorylation of Akt and enhance the nuclear localization of Nrf-2 in cells. Our results were further confirmed by specific HO-1 gene knockdown studies which clearly demonstrated that HO-1 induction indeed played a key role in SAC mediated inhibition of apoptosis and ROS production in HepG2 cells, thus suggesting a hepatoprotective role of SAC in combating oxidative stress mediated liver diseases.
Highlights
Oxidative stress in liver hepatocytes underlies various liver diseases [1]
In order to determine the cytoprotective concentrations of S-allyl cysteine (SAC), HepG2 cells were treated with different concentrations of SAC followed by treatment with H2O2
We found that 1 mM H2O2 treatment induced cell death in a time dependent manner beginning from 6 h and SAC posttreatment reversed this effect
Summary
Hydrogen peroxide (H2O2) plays a major role in inducing liver oxidative stress, by disrupting the cellular redox circuitry that depends on the redox state of various signaling molecules behaving as redox sensitive molecular switches, or by directly damaging cellular macromolecules including DNA, proteins, and lipids. This alters many fundamental cellular functions including proliferation, differentiation, migration and adhesion [1] and eventually results in sustained hepatocyte apoptosis, a pathological condition frequently associated with the progression of several liver diseases such as hepatic ischemia-reperfusion (I/R) injury, alcoholic liver disease, nonalcoholic fatty liver disease, and hepatitis [2, 3]. It has been shown that HO-1 plays a role in cellular defense mechanism against oxidative stress induced apoptotic cell death [5,6,7]
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