Mannan‐binding lectin attenuates acetaminophen‐induced hepatotoxicity by regulating CYP2E1 expression via ROS‐dependent JNK/SP1 pathway

et al. 2022

Microbiol Spectr

Our work revealed that A. muciniphila attenuated APAP-induced liver injury by alleviating oxidative stress and inflammation in the liver, and its hepatoprotective effect was accompanied by activation of the PI3K/Akt pathway and mediated by regulation of the composition and metabolic function of the intestinal microbiota. This finding suggested that the microbial community is a non-negligible impact on drug metabolism and probiotic administration could be a potential therapy for drug-induced liver injury.

Section: Discussionmentioning

confidence: 99%

“…Hepatocyte death caused by APAP hepatotoxicity is a complex process mediated by the coordination of multiple intracellular signal transduction pathways ( 1 , 27 ). A variety of apoptosis-related pathways, such as the AMPK-dependent pathway and SIRT1 pathway, are known to participate in this process.…”

Section: Discussionmentioning

confidence: 99%

Akkermansia muciniphila Ameliorates Acetaminophen-Induced Liver Injury by Regulating Gut Microbial Composition and Metabolism

Xia

et al. 2022

Microbiol Spectr

“…[75,76] Genetic ablation of MBL has been shown to result in excessive ROS production and activation of JNK. [77] The activation of JNK is caused by the mitochondrial ROS generation, reportedly resulting from acetaminophen (APAP)-induced hepatic GSH depletion. [78,79] JNK-activation induced specificity protein 1 (SP1) phosphorylation which could lead to an enhanced ability of SP1 to bind to the CYP2E1 promoter after APAP attack.…”

Section: Cell Death Arising From Regulation Of Signaling Pathwaysmentioning

confidence: 99%

Imbalanced GSH/ROS and sequential cell death

J Biochem & Molecular Tox

Sun

Zhang

et al. 2021

196

Reactive oxygen species (ROS) are produced in cells during metabolic processes.Excessive intracellular ROS may react with large biomolecules, such as DNA, RNA, proteins, and small biomolecules, that is, glutathione (GSH) and unsaturated fatty acids. GSH has physiological functions, including free radical scavenging, antioxidation, and electrophile elimination. The disruption of ROS/GSH balance results in the deleterious oxidation and chemical modification of biomacromolecules, which eventually leads to cell-cycle arrest and proliferation inhibition, and even induces cell death. Imbalanced ROS/GSH may result from a direct increase of ROS, consumption of GSH, intracellular oxidoreductase interference, or thioredoxin activity reduction. Some chemicals including arsenic trioxide (ATO), pyrogallol (PG), and carbobenzoxy-Leu-Leu-leucinal (MG132) could also disrupt the balance of GSH and ROS. This article reviews the occurrence and consequences of the imbalance between GSH and ROS and introduces factors responsible for the disruption of cellular ROS and GSH balance, resulting in cell death. "GSH" and "ROS" were used as keywords to search the relevant literaturess.

“…Also, attenuated activities of ALT and LDH were found in sera obtained from E2-injected fat-1 mice compared to those from WT counterparts after the APAP challenge (Figures 2(b) and 2(c) ). Moreover, we evaluated the effect of estrogen on n-3 PUFA-mediated regulation of APAP toxicity in human HepaRG cells, a reliable model to study mechanisms of APAP hepatotoxicity in humans [ 27 ]. The result showed that DHA alone accelerated APAP-induced cell death, but DHA plus estrogen treatment strongly attenuated the APAP hepatotoxicity ( Figure 2(d) ).…”

Section: Resultsmentioning

confidence: 99%

Gender Difference on the Effect of Omega-3 Polyunsaturated Fatty Acids on Acetaminophen-Induced Acute Liver Failure

Oxidative Medicine and Cellular Longevity

Chen

Xie

et al. 2020

Self Cite

Acetaminophen (APAP) toxicity is the leading cause of drug-induced liver failure, which is closely related to mitochondrial dysfunction and oxidative damage. Studies in clinical trials and in animal models have shown that omega-3 polyunsaturated fatty acids (n-3 PUFAs) affect the progression of various types of liver damage. Interestingly, the sex-dependent effect of n-3 PUFAs on human health has also been well documented. However, it is unknown whether supplementation of n-3 PUFAs modulates the pathogenesis of APAP-induced liver failure with sex-specificity. Our results showed that both endogenous and exogenous n-3 PUFAs significantly aggravated the APAP-induced liver injury in male mice, whereas the opposite effects were observed in females. In vivo and in vitro studies demonstrated that estrogen contributes to the gender difference in the regulation of n-3 PUFAs on APAP overdose. We found that n-3 PUFA-mediated regulation of hepatic oxidative stress response and autophagy upon APAP challenge is distinct between male and female mice. Moreover, we provided evidence that β-catenin signaling activation is responsible for the sex-dependent regulation of APAP hepatotoxicity by n-3 PUFAs. Together, these findings indicated that supplementation with n-3 PUFAs displays sex-differential effect on APAP hepatotoxicity and could have profound significance in the clinical management for drug-induced liver injury.