NADH alleviates anti-tuberculosis drug-induced liver injury and apoptosis in mice through SIRT1/Nrf2 pathway

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Authors:Li Jinfeng, Cui Mengxiang, Long Yifei, Meng Chunyan, Ren Qi, Feng Fumin

Keywords:antituberculosis drug-induced liver injury;apoptosis;inflammation;nicotinamide adenine dinucleotide;silence information regulator 1;nuclear factor erythroid 2-related factor 2

DOI:10.19405/j.cnki.issn1000-1492.2023.12.015

〔Abstract〕 Objective To investigate the mechanism by which Nicotinamide adenine dinucleotide(NADH) regulates anti-tuberculosis drug-induced liver injury and apoptosis in mice through SIRT1/Nrf2 pathway. Methods Twenty-four six-week-old SPF male mice were randomly divided into four groups according to body weight, ADLI group[90 mg/(kg·d) Isoniazid, 135 mg/(kg·d) Rifampicin, 315 mg/(kg·d) Pyrazinamide were given by gavage], control group[thesame volume of saline was given by gavage as antituberculosis drug-induced liver injury(ADLI) group], NADH group(30 mg/kg NADH wasgiven by gavage on the basis of control group) and NADH intervention group(30 mg/kg NADH wasgiven by gavage on the basis of ADLI group), with sixmice in each group. They were gavaged continuously for seven days, and their seruand liver tissues were collected. The mRNA and protein expression of silence information regulator 1(SIRT1), nuclear factor erythroid 2-related factor 2(Nrf2) in SIRT1/Nrf2 pathway, apoptosis indicators B-cell lymphoma-2(Bcl-2), Bcl-2-associated X protein(Bax) and caspase-3 were detected by qRT-PCR and Western blot, respectively. HE staining was performed to observe the morphology of liver tissue. The liver was weighedandthe liver index was obtained by dividingweight by body weight.The levels of glutamate aminotransferase( ALT), aspartate aminotransferase( AST) and lactate dehydrogenase(LDH), which are indicators of liver injury, were detected by microplate method.Results Compared with control group, the protein and mRNA expression of SIRT1, Nrf2decreased significantly in ADLI group. Liver tissue structure wasdisturbed, hepatocytes were obviously swollen, and their boundary was unclear. The weight of mice decreased, but liver index increased. The mRNA and protein expression level of anti-apoptotic factor Bcl-2 decreased,while that of Bax and caspase-3 was raised. The level of ALT, AST and LDH were also elevated. The differences above were statistically significant(P<0. 05). Compared with ADLI group, the protein and mRNA expression of SIRT1, Nrf2 were higher after NADH intervention. Liver tissue structure became clear, and hepatocytes were polygonal. The protein and mRNA expression of anti-apoptosis factor Bcl-2 was elevated and while that of Bax and caspase-3 was lower. The weight of mice increased and liver index decreased. The expression of ALT, AST and LDH decreased. The differences above were statistically significant(P<0. 05).Conclusion NADH may alleviate anti-tuberculosis drug-induced liver injury and apoptosis in mice by regulating SIRT1/Nrf2 pathway.