Abstract
Hyperoside, isolated from Drosera rotundifolia L., seeds of Cuscuta chinensis Lam., or Hypericum perforatum L., originally showed to possess an antifungal and antibacterial activity, while recently showed the protective effects against oxidative stress-induced liver injury. This study investigated such a protective effect of hyperoside and the underlying molecular mechanisms in vitro and in carbon tetrachloride (CCl4)-injured rat livers. The data showed that hyperoside was able to prevent the oxidative stress-induced liver morphological changes and CCl4-induced rat liver injury. Hyperoside reversed the decrease of superoxidase dismutase (SOD) level and the increase of malondialdehyde (MDA) level in vivo. Moreover, hyperoside regulated the pleckstrin homology (PH) domain leucine-rich repeat protein phosphatase 2 (PHLPP2)-protein kinase B (AKT)-glycogen synthase kinase 3β (GSK-3β) signaling pathway in tert-butylhydroquinone (t-BHP)-treated liver cells, e.g., Hyperoside reduced PHLPP2 expression to activate AKT phosphorylation, induce GSK-3β phosphorylation, and then increased nuclear factor erythroid-2-related factor 2 (Nrf2) nuclear translocation, reduced nuclear translocation of phosphorylated Fyn, and promoted heme oxygenase-1 (HO-1) expression in vivo and in vitro. In contrast, siRNA-mediated knockdown of PHLPP2 expression enhanced hyperoside-mediated activation of the AKT-GSK-3β kinase pathway in liver cells. In conclusion, the present study demonstrated that hyperoside could protect against oxidative stress-induced liver injury by regulating the PHLPP2-AKT-GSK-3β signaling pathway in vivo and in vitro.
Highlights
Oxidative stress contributes to the pathophysiological processes of alcoholic liver disease, non-alcoholic fatty liver disease, drug-induced liver disease, and other liver diseases by producing excessive reactive oxygen species (ROS), destroying mitochondrial structure and function, and reducing the level and activity of superoxide dismutase (SOD) and other cytoprotective proteins (Ivanov et al, 2017)
Hyp treatments protect the rats from changes in the liver enzymes, i.e., the ALT and aspartate transaminase (AST) levels significantly increased in the model group, but Hyp treatment reversed their changes (Figures 1B, C)
We found that CCl4 injection reduced heme oxygenase-1 (HO-1) expression, but induced p-nuclear factor erythroid-2-related factor 2 (Nrf2) level, both cytoplasmic and nuclear p-Fyn expressions in the liver tissues (Figure 2), whereas Hyp treatment (60 mg/kg) reversed these changes in the liver tissues (P < 0.05 vs. control or vs. CCl4)
Summary
Oxidative stress contributes to the pathophysiological processes of alcoholic liver disease, non-alcoholic fatty liver disease, drug-induced liver disease, and other liver diseases by producing excessive reactive oxygen species (ROS), destroying mitochondrial structure and function, and reducing the level and activity of superoxide dismutase (SOD) and other cytoprotective proteins (Ivanov et al, 2017). Hepatic ROS is thought to be central in the pathogenesis of liver injury, and antioxidants including vitamin C and phenolic compounds have been extensively investigated to determine their ability to confer liver protection (Chougule and Kekunnaya, 2019; Fan et al, 2019; Su et al, 2019). Hyp exhibits an anti-oxidative activity against a series of diseases or conditions, such as carbon tetrachloride (CCl4)-induced liver injury (Zou et al, 2017), and hepatic and renal ischemiareperfusion injury (Shi et al, 2019; Wu et al, 2019). The exact mechanisms involved in Hyp-mediated protection of the oxidative damaged liver are not completely understood
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