Nicotinic Acid against Acetaminophen-Induced Hepatotoxicity via Sirt1/Nrf2 Antioxidative Pathway in Mice

Abstract

Acetaminophen (N-acetyl-p-aminophenol, APAP) overdose causes hepatotoxicity, even liver failure, and oxidative stress plays pivotal role in its pathogenesis. Nicotinic acid (NA) is one form of vitamin B3, which has been used to treat a series of diseases in clinic for decades. To date, several studies have evidenced that NA has anti-oxidative property. Therefore, NA may have the hepatoprotective potential against APAP-induced toxicity. Here, our aim was to investigate the beneficial effect of NA against hepatotoxicity induced by APAP and its mechanism in vivo. BALB/c mice were intraperitoneally injected with NA (100 mg/kg) 3 times at 24, 12 and 1 h before APAP (600 mg/kg or 400 mg/kg) challenge. The results showed that pretreatment of NA markedly improved the survival rate, alleviated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and mitigated the histopathological injuries compared to APAP-exposed mice. Furthermore, NA significantly elevated the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) content, while reduced malondialdehyde (MDA) level. Finally, the signaling pathway was probed. The western blot revealed that NA up-regulated Sirtuin1 (Sirt1), nuclear factor erythroid 2-related factor 2 (Nrf2) and NAD(P)H quinone dehydrogenase-1 (NQO-1) expression and down-regulated Kelch-like ECH-associated protein 1 (Keap1) level in liver followed APAP exposure, implying Sirt1/Nrf2 axis exerted an essential role in the protective mechanism of NA on APAP toxicity. In brief, pretreatment of NA effectively protects liver against hepatotoxicity due to overdose of APAP through an antioxidant dependent manner modulated by Sirt1/Nrf2 signaling pathway.

Phytic acid attenuates acetaminophen-induced hepatotoxicity via modulating iron-mediated oxidative stress and SIRT-1 expression in mice

“…The APAP group showed a significant decrease in SIRT-1 expression level compared to the control group. This finding was in accordance with previously reported results ( Wang et al, 2020 ; Hu et al, 2021 ). On the other hand, PA administration significantly increased SIRT-1 expression levels in APAP-induced hepatotoxicity.…”

Recommendations for the use of the acetaminophen hepatotoxicity model for mechanistic studies and how to avoid common pitfalls

“…Taken together, these strategies establish bona fide NRF2 activation and a potential direct mechanism conferring protection. Current work suggesting that slight increases in protein/gene levels of NRF2 or an increased ratio of NRF2/KEAP1 does not provide sufficient evidence to state that NRF2 activation is responsible for the observed protection 199 .…”

Ferulic acid and berberine, via Sirt1 and AMPK, may act as cell cleansing promoters of healthy longevity

“…The discovery that ferulic acid is a Sirt1 inducer may offer important insight into its effects on Nrf2 and NF-kappaB activities. Sirt1 promotes antioxidant phase 2 induction by deacetylating and enhancing the transcriptional activity of Nrf213–15; this effect likely contributes to the phase 2-inducing activity of ferulic acid, although activation of Erk1/2 is also thought to contribute in this regard 16–18. Ferulic acid-mediated induction of Sirt1 would also be expected to combat inflammation by reversing the acetylation of p65 on Lys310 required for optimal transactivation activity of the NF-kappaB complex 15 19.…”