Curcumin attenuates isoniazid‐induced hepatotoxicity by upregulating the SIRT1/PGC‐1α/NRF1 pathway

Abstract

As a serious infectious disease, tuberculosis threatens global public health. Isoniazid is the first-line drug not only in active tuberculosis but also in its prevention. Severe hepatotoxicity greatly limits its use. Curcumin, extracted from turmeric, has been found to relieve isoniazid-induced hepatotoxicity. However, the mechanism of isoniazid-induced hepatotoxicity and the protective effects of curcumin are not yet understood completely. We established both cell and animal models about isoniazidinduced hepatotoxicity and investigated the new mechanism of curcumin against isoniazid-induced liver injury. The experimental data in our study demonstrated that curcumin ameliorated isoniazid-mediated liver oxidative stress. The protective effects of curcumin were demonstrated and confirmed to be correlated with upregulating SIRT1/PGC-1α/NRF1 pathway. Western blot revealed that while inhibiting SIRT1 by the siRNA1 (a SIRT1 inhibitor), the expressions of SIRT1, PGC-1α/Ac-PGC-1α, and NRF1 decreased, and the protective effect that curcumin exerted on isoniazidtreated L-02 cells was significantly attenuated. Furthermore, curcumin improved liver functions and reduced necrosis of the isoniazid-treated BALB/c mice, accompanied by downregulating oxidative stress and inflammation in liver. Western blot revealed that curcumin treatment activates the SIRT1/PGC-1α/NRF1 pathway in the isoniazid-treated BALB/c mice. In conclusion, we found one mechanism of isoniazidinduced hepatotoxicity downregulating the SIRT1/PGC-1α/NRF1 pathway, and curcumin attenuated this hepatotoxicity by activating it. Our study provided a novel approach and mechanism for the treatment of isoniazid-induced hepatotoxicity.

Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family in physiological and pathophysiological process and diseases

“…Pre-clinical studies of PGC-1s in non-cancer diseases treatment Medical treatment: The medical treatments targeting PGC-1s, mainly PGC-1α, have exhibited immense potential in various disease models in preclinical studies. Since a comprehensive presentation of all is too verbose, we will concentrate on a couple of natural products, such as resveratrol, [642][643][644][645][646][647][648][649] curcumin, [650][651][652][653][654] berberine, 517,[655][656][657][658][659][660] quercetin, [661][662][663][664][665][666][667][668][669] or clinical drugs, which have been extensively investigated in different pathological models. Other representative compounds, including astragaloside IV, [670][671][672] baicalin, [673][674][675][676] dihydromyricetin, [676][677][678][679][680][681] isoliquiritigenin, 682,683 astragalus ...…”

Quercetin Reprograms Immunometabolism of Macrophages via the SIRT1/PGC-1α Signaling Pathway to Ameliorate Lipopolysaccharide-Induced Oxidative Damage

“…The SIRT1/PGC-1a signaling pathway is closely related to the regulation of cellular oxidative stress and inflammation [ 42 , 43 ]. To investigate the mechanism by which quercetin exerts its antioxidant effects in inflammatory macrophages, the expression of SIRT1 and PGC-1α proteins was measured.…”

Nutritional intervention is promising in alleviating liver injury during tuberculosis treatment: a review

“…In addition, curcumin can decrease the levels of protoporphyrin IX, an endogenous liver toxicant, which can alleviate isoniazid- and rifampicin-induced liver injury ( 44 ). Curcumin can also alleviate the isoniazid-induced liver injury by activating the SIRT1/peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α)/nuclear respiratory factor 1 (NRF1) pathway ( 45 ).…”

“…Li et al ( 45 ) treated rats with 100 mg/kg body weight isoniazid and 100 mg/kg body weight curcumin for 28 days. Curcumin alleviated the liver injury caused by isoniazid.…”

“…Curcumin significantly reduced the abnormal increase of liver function biomarkers including TBil, AST, ALP and ALT. Li et al ( 45 ). also treated the L-02 cells with 40 mmol/L isoniazid and different doses of curcumin.…”