Upregulation of Nrf2-related cytoprotective genes expression by acetaminophen-induced acute hepatotoxicity in mice and the protective role of betaine

Abstract

Overdose of acetaminophen (APAP) is the main reason for acute liver failure. Oxidative stress is associated with hepatotoxicity caused by APAP. Betaine is a methyl donor and S-adenosylmethionine precursor. The present study investigated the effect of betaine and the role of nuclear factor-erythroid-2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) genes in hepatotoxicity induced by APAP in mice. In this study, male Naval Medical Research Institute (NMRI) mice were treated with 500 mg/kg of betaine for 5 days followed with a single dose of APAP 300 mg/kg on the fifth day. Biochemical, histological, immunohistochemical, Western blot, and real-time polymerase chain reaction (PCR) analyses were then conducted. The results of the present study showed that betaine pretreatment improved hepatotoxicity through the reduction of serum ALT and AST levels and ameliorating histopathological finding. Betaine pretreatment also increased glutathione level and decreased malondialdehyde level. Importantly, the results of immunohistochemical, Western blot and real-time PCR showed that the APAP increased the expression of the genes and proteins of Nrf2 and HO-1. While betaine decreased Nrf2 and HO-1 expression in comparison with the APAP group. The findings of this study demonstrated that the increased expression of Nrf2 and HO-1 genes and proteins by APAP is a compensatory mechanism to combat acute liver toxicity. While the protective effect of betaine against acute liver injury induced by APAP is independent on the Nrf2 and HO-1 genes but occurs via modifying cysteine supply as a precursor of glutathione in the transsulfuration pathway in the liver.

Betaine supplementation alleviates dextran sulfate sodium-induced colitis via regulating the inflammatory response, enhancing the intestinal barrier, and altering gut microbiota

“…25 It is worth noting that 800 mg kg −1 betaine was chosen as a suitable treatment dose, which was based on previous studies. [26][27][28] Therefore, betaine might have acted as an osmotic agent to increase intestinal permeability and relieve mouse colitis in our study.…”

Fisetin Attenuates Paracetamol-Induced Hepatotoxicity by Regulating CYP2E1 Enzyme

“…We have seen that fisetin reduces the levels of TNF-α and NF-κB. The important parameters in the evaluation of general liver damage and paracetamol toxicity are liver enzymes (Khodayar et al 2020). For this purpose, we firstly detected ALT, AST and ALP serum levels, which are biomarkers of liver damage.…”

Metabolomics reveals that chronic restraint stress alleviates carbon tetrachloride-induced hepatic fibrosis through the INSR/PI3K/AKT/AMPK pathway

“…Betaine is an important nutrient that is synthesized through the choline metabolic pathway and is an endogenous metabolite [19] . In recent years, a large amount of literature has reported that betaine has good preventive and therapeutic effects on a variety of liver diseases, in addition to maintaining normal physiological functions [20][21][22][23][24] . It is worth mentioning that a number of studies have shown that betaine has signi cant anti brotic effects on CCl 4 -induced liver brosis in vitro and in vivo [25][26][27] .Our results showed that CRS increased betaine levels in liver tissue of mice with HF and that there was no signi cant difference in betaine levels between the normal and CRS groups (Fig.…”