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.

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Acetaminophen (APAP) overdose causes acute liver injury (ALI). Nicotinamide adenine dinucleotide (NAD) is an essential coenzyme, and NAD+ is oxidized type which synthesized from nicotinamide (NAM). The present study aimed to investigate the role of NAD+ in ALI and protective property of NAM. The mice were subjected to different doses APAP. After 8 hours, the serum activities of alaninetransaminase (ALT) and aspartate aminotransferase (AST), the hepatic NAD+ level and nicotinamide phosphoribosyltransferase (NAMPT) expression were determined. Then, the mice were pretreated with NAM (800 mg/kg), the hepatoprotective effects and the key antioxidative molecules were evaluated. Our findings indicated that APAP resulted in remarkable NAD+ depletion in a dose-dependent manner accompanied by NAMPT downregulation, and NAM pretreatment significantly elevated the NAD+ decline due to upregulation of NAMPT. Moreover, the downregulated Kelch-like ECH-associated protein-1 (Keap1), upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) and its translocation activation after NAM administration were confirmed, which were in accordance with improved superoxide dismutase (SOD) and glutathione (GSH) levels. Finally, NAM dramatically exhibited hepatoprotective effects by reducing the liver index and necrotic area. This study has suggested that APAP impairs liver NAD+ level and NAM is able to improve hepatic NAD+ to activate antioxidant pathway against APAP-induced ALI.

The aim of this study was to investigate the protective effect of nicotinamide adenine dinucleotide (NAD+) against acute liver injury (ALI) induced by acetaminophen (APAP) overdose in mice. First, serum transaminases were used to assess the protective effect of NAD+, and the data revealed that NAD+ mitigated the APAP-induced ALI in a dose-dependent manner. Then, we performed hematoxylin–eosin staining of liver tissues and found that NAD+ alleviated the abnormalities of histopathology. Meanwhile, increase in the malondialdehyde content and decrease in glutathione, superoxide dismutase (SOD), and glutathione peroxidase were identified in the APAP group, which were partially prevented by the NAD+ pretreatment. Moreover, compared with the mice treated with APAP only, the expression of poly ADP-ribose polymerase 1 (PARP1), Sirtuin1 (Sirt1), SOD2, nuclear factor erythroid 2-related factor 2 (Nrf2), and hemoxygenase-1 was upregulated, while Kelch-like ECH-associated protein 1 and histone H2AX phosphorylated on Ser-139 were downregulated by NAD+ in NAD+ + APAP group. Conversely, NAD+ could not correct the elevated expression of phospho-Jun N-terminal kinase and phospho-extracellular signal-regulated kinase induced by APAP. Taken together, these findings suggest that NAD+ confers an anti-ALI effect to enhance the expression of PARP1 and Sirt1, and to simultaneously stimulate the Nrf2 anti-oxidant signaling pathway.