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Isoniazid prevents Nrf2 translocation by inhibiting ERK1 phosphorylation and induces oxidative stress and apoptosis.

ABSTRACT: Isoniazid is used either alone or in combination with other drugs for the treatment of tuberculosis. It is also used for the prevention of tuberculosis. Chronic treatment of Isoniazid may cause severe liver damage leading to acute liver failure. The mechanism through which Isoniazid causes liver damage is investigated. Isoniazid treatment generates reactive oxygen species and induces apoptosis in Hep3B cells. It induces antioxidative and apoptotic genes leading to increase in mRNA expression and protein levels in Hep3B cells. Whole genome expression analysis of Hep3B cells treated with Isoniazid has resulted in differential expression of various genes playing prime role in regulation of apoptotic, antioxidative, DNA damage, cell signaling, cell proliferation and differentiation pathways. Isoniazid increased cytosolic Nrf2 protein level while decreased nuclear Nrf2 protein level. It also decreased ERK1 phosphorylation and treatment of Hep3B cells with ERK inhibitor followed by Isoniazid resulting in increased apoptosis in these cells. Two dimensional gel electrophoresis results have also shown differential expression of various protein species including heat shock proteins, proteins playing important role in oxidative stress, DNA damage, apoptosis, cell proliferation and differentiation. Results suggest that Isoniazid induces apoptosis through oxidative stress and also prevents Nrf2 translocation into the nucleus by reducing ERK1 phosphorylation thus preventing cytoprotective effect.

SUBMITTER: Verma AK

PROVIDER: S-EPMC4522592 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Isoniazid prevents Nrf2 translocation by inhibiting ERK1 phosphorylation and induces oxidative stress and apoptosis.

Verma Ajeet Kumar AK Yadav Arti A Dewangan Jayant J Singh Sarvendra Vikram SV Mishra Manisha M Singh Pradhyumna Kumar PK Rath Srikanta Kumar SK

Redox biology 20150708

Isoniazid is used either alone or in combination with other drugs for the treatment of tuberculosis. It is also used for the prevention of tuberculosis. Chronic treatment of Isoniazid may cause severe liver damage leading to acute liver failure. The mechanism through which Isoniazid causes liver damage is investigated. Isoniazid treatment generates reactive oxygen species and induces apoptosis in Hep3B cells. It induces antioxidative and apoptotic genes leading to increase in mRNA expression and ...[more]

PMID: 26202867

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Project description:BACKGROUND:Exposure to cold weather is associated with infaust cardiovascular responses, including myocardial infarction and arrhythmias. However, the exact mechanisms of these adverse changes in the myocardium under cold stress are unknown. This study was designed to investigate the mechanisms of cardiac injury induced by cold stress in mice. METHODS:The mice were randomly divided into three groups, normal control (no handling), 1-week cold stress and 2-week cold stress. We observed physiological changes of the mice and morphological changes of myocardium tissues, and we measured the changes of 3'-nitrotyrosine and 4-hydroxynonenal, the expression levels of superoxide dismutase-1, superoxide dismutase-2, Bax, Bad, Bcl-2, Nuclear factor erythroid-derived 2-like 2 (Nrf2) and Kelch like-ECH-associated protein 1 (Keap1) in myocardium by western blot. Besides, we detected mRNA of superoxide dismutase-1, superoxide dismutase-2, Bax, Bad, Bcl-2, Nrf2 and Keap1 by real-time PCR. One-way analysis of variance, followed by LSD-t test, was used to compare each variable for differences among the groups. RESULTS:Echocardiography analyses demonstrated left ventricle dysfunction in the groups receiving cold stress. Histological analyses witnessed inflammation, vacuolar and eosinophilic degeneration occurred in left ventricle tissues. Western blotting results showed increased 3'-nitrotyrosine and 4-hydroxynonenal and decreased antioxidant enzymes (superoxide dismutase-1 and superoxide dismutase-2) in the myocardium. Expression of Nrf2 and Keap1 followed a downward trend under cold exposure, as indicated by western blotting and real-time PCR. Expression of anti-apoptotic protein Bcl-2 also showed the same trend. In contrast, expression of pro-apoptotic proteins Bax and Bad followed an upward trend under cold exposure. The results of real-time PCR were consistent with those of western blotting. CONCLUSIONS:These findings were very significant, showing that cold exposure induced cardiac injury by inhibiting the Nrf2-Keap1 signaling pathway.

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Isoniazid prevents Nrf2 translocation by inhibiting ERK1 phosphorylation and induces oxidative stress and apoptosis.

Publications

Isoniazid prevents Nrf2 translocation by inhibiting ERK1 phosphorylation and induces oxidative stress and apoptosis.

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