Hyperoside Protected Against Oxidative Stress-Induced Liver Injury via the PHLPP2-AKT-GSK-3β Signaling Pathway In Vivo and In Vitro

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 3b (GSK-3b) signaling pathway in tert-butylhydroquinone (t-BHP)-treated liver cells, e.g., Hyperoside reduced PHLPP2 expression to activate AKT phosphorylation, induce GSK-3b 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-3b 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-3b signaling pathway in vivo and in vitro.

Alpinetin inhibits macrophage infiltration and atherosclerosis by improving the thiol redox state: Requirement of GSk3β/Fyn‐dependent Nrf2 activation

“…On the contrary, reports have demonstrated that inhibitory phosphorylation of GSK‐3β at Ser9 by the Ser/Thr kinase protein, p‐Akt (Ser473), enhances Nrf2 nuclear accumulation 15 . Upregulation of the Akt (Ser473)/GSK‐3 (Ser9)/Fyn/Nrf2 axis has been shown to alleviate oxidative stress‐induced liver injury and myocardial infarction and cardiotoxicity 17–19 …”

“…15 Upregulation of the Akt (Ser473)/GSK-3 (Ser9)/Fyn/Nrf2 axis has been shown to alleviate oxidative stress-induced liver injury and myocardial infarction and cardiotoxicity. [17][18][19] Alpinetin (7-hydroxy-5-methoxyflavanone) is a natural flavonoid isolated from the seeds of Alpinia katsumadai Hayata. Alpinetin has anti-inflammatory and antioxidative activities, and it is commonly used in traditional Chinese medicine for therapeutic applications.…”

Crm1-Dependent Nuclear Export of Bach1 is Involved in the Protective Effect of Hyperoside on Oxidative Damage in Hepatocytes and CCl4-induced Acute Liver Injury

“…Our previous study revealed that Hyp was able to downregulate PHLPP2 expression, induce AKT phosphorylation and inactivate GSK-3β, and thereby, promoted Nrf2 nuclear translocation. 15 Hyp could enhance the cellular antioxidant defense system through Nrf2 signaling pathway to upregulate HO-1 expression. In this study, we further dissect the mechanism that Hyp control Bach1 regulation.…”

“…Our previous study showed that Hyp attenuates H 2 O 2 -induced hepatic L02 cell oxidative damage via MAPK-dependent Keap1-Nrf2-ARE signaling pathway to upregulate HO-1 expression and enhance intracellular antioxidant activity, and Hyp could protect against oxidative stress-induced liver injury by regulating the PHLPP2-AKT-GSK-3β signaling pathway in vivo and in vitro. 14 , 15 However, rarely research reports the effect of Hyp on the oxidative liver injury model animal. The influence of Hyp on the expression and distribution of Bach1, and the relationship of Hyp’s antioxidative effect and the influence of Bach1 remain unclear.…”

Hyperoside promotes pollen tube growth by regulating the depolymerization effect of actin-depolymerizing factor 1 on microfilaments in okra

“…Hyperoside is a major pharmacologically active component in A. esculentus . Many studies have already shown that hyperoside has pharmacological effects, such as relieving oxidative stress injury in cells and anticancer properties 13 – 15 .…”