Pterostilbene Reduces Acetaminophen-Induced Liver Injury by Activating the Nrf2 Antioxidative Defense System via the AMPK/Akt/GSK3β Pathway

Abstract

Background/Aims: Pterostilbene (Pts), a natural dimethylated analog of resveratrol from blueberries, exerts antioxidative and anti-apoptotic effects in various diseases. This study aims to investigate the protective effects and mechanism of Pts against acetaminophen (APAP)-induced hepatotoxicity in vivo. Methods: C57BL/6 mice were treated with APAP or APAP+Pts. HepG2 cells were used to further explore the underlying mechanisms in vitro. The effects of Pts on hepatotoxicity were measured by commercial kits, Hematoxylin and Eosin (H&E) straining, TUNEL assay, Western blot analysis, and Flow cytometry assay. Results: In vivo, Pts treatment effectively protected against APAP-induced severe liver injury by decreasing the lethality rate, the serum alanine transaminase (ALT) and aspartate aminotransferase (AST) levels, liver histological injury, liver malondialdehyde (MDA) formation and myeloperoxidase (MPO) levels and by increasing liver glutathione (GSH) and superoxide dismutase (SOD) levels. Moreover, in Pts-treated mice, the nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway was activated; however, APAP-induced c-Jun NH2-terminal kinase (JNK) activation, mitochondrial Bcl-2 Associated X Protein (Bax) translocation, apoptosis-inducing factor (AIF) levels and cytochrome c release were attenuated. In vitro, Pts was found to reverse hydrogen peroxide (H₂O₂) -induced cytotoxicity, reactive oxygen species (ROS) production and apoptosis that depended on Nrf2 activation. Moreover, Pts induced a dose-dependent increase in the phosphorylation of AMP-activated protein kinase (AMPK), serine/threonine kinase (Akt), and glycogen synthase kinase 3β (GSK3β) in HepG2 cells. Moreover, Pts protect against APAP or H₂O₂-induced toxicity were effectively attenuated or abolished in HepG2 Nrf2-/- cells and Nrf2-/- mice. Conclusion: Our data suggest that Pts protects against APAP-induced toxicity by activating Nrf2 via the AMPK/Akt/GSK3β pathway.

Cinnamon oil against acetaminophen-induced acute liver toxicity by attenuating inflammation, oxidative stress and apoptosis

“…Increased content of LPO and diminish enzymes activities such as SOD, CAT, GR, GPx and level of GSH were noticed in APAP group. In support of our data, previously reported work showed that APAP encourages oxidative stress and impairment of the antioxidant system of the liver [ 42 , 43 ]. While rats treated with CO reveal remarkable improvement in the activity of the antioxidant enzymes, GSH level and suppresses high level LPO in APAP group.…”

Pterostilbene Prevents Early Diabetic Retinopathy Alterations in a Rabbit Experimental Model

“…The antioxidant capability of Pter has been previously shown in several experimental models [37,38,[55][56][57][58] and our results well agree with the previously reported effect of Pter on NRF2 activation [37,38,57], one of the main redox homeostasis regulators and an appealing therapeutic target for DR [59]. Under physiological conditions, NRF2 is sequestered mostly in the cytosol and degraded through ubiquitination.…”

“…Moreover, as Pter administration does not influence body weight and blood glucose levels, any beneficial effects should be attributed to a direct effect of Pter on the retina. The demise of retinal neural cells may be induced by hyperglycaemia-generated hydrogen peroxide [54], and Pter reduces its cytotoxicity, oxidative stress and apoptosis in different cellular models like HepG2 cells [55]. According to our results, Pter decreased the hydrogen peroxide production induced by high glucose levels in vivo ( Figure 3D) and in vitro ( Figure 5C).…”

Hepatoprotective Effect of Baicalein Against Acetaminophen-Induced Acute Liver Injury in Mice

“…AKT is a crucial metabolic regulation enzyme that participates in the maintenance of regulating cellular metabolism to cellular energy homeostasis. It plays a protective role in an APAP-induced mouse model by promoting cell survival, oxidative stress responses, and energy generation [54,55]. mTOR is a master kinase regulating the synthesis and metabolism of protein and lipid.…”