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Tryptanthrin prevents oxidative stress-mediated apoptosis through AMP-activated protein kinase-dependent p38 mitogen-activated protein kinase activation

Jung, Eun Hye, Jung, Ji Yun, Ko, Hae Li, Kim, Jae Kwang, Park, Sang Mi, Jung, Dae Hwa, Park, Chung A, Kim, Young Woo, Ku, Sae Kwang, Cho, Il Je, Kim, Sang Chan
Archives of pharmacal research 2017 v.40 no.9 pp. 1071-1086
AMP-activated protein kinase, alanine transaminase, apoptosis, arachidonic acid, aspartate transaminase, bilirubin, blood serum, cytotoxicity, glutathione, hepatocytes, human cell lines, iron, liver diseases, medicinal properties, mice, mitochondria, mitochondrial membrane, mitogen-activated protein kinase, models, mutants, oxidative stress, phosphorylation, proteins, reactive oxygen species, tissues, transfection
Tryptanthrin (6,12-dihydro-6,12-dioxoindolo-(2,1-b)-quinazoline) has been reported to have a variety of pharmacological activities. Present study investigated the cytoprotective effects of tryptanthrin on arachidonic acid (AA) + iron-mediated oxidative stress and the molecular mechanisms responsible. In HepG2 cells, pretreatment with tryptanthrin inhibited the cytotoxic effect of AA + iron in a concentration-dependent manner. In addition, tryptanthrin prevented the changes in the levels of apoptosis-related proteins, and attenuated reactive oxygen species production, glutathione depletion, and mitochondrial membrane impairment induced by AA + iron. Mechanistic investigations showed that tryptanthrin increased the phosphorylations of AMP-activated protein kinase (AMPK) and of p38 mitogen-activated protein kinase (p38). Furthermore, inhibition of AMPK or p38 reduced the ability of tryptanthrin to prevent AA + iron-induced cell death and mitochondrial dysfunction. Transfection experiments using AMPK mutants indicated that p38 phosphorylation by tryptanthrin was dependent on AMPK activation. In a phenylhydrazine-induced acute liver injury model, tryptanthrin decreased serum levels of alanine aminotransferase, aspartate aminotransferase, and bilirubin in mice. Additionally, tryptanthrin reduced numbers of degenerating hepatocytes, infiltrating inflammatory cells, 4-hydroxynonenal-, and nitrotyrosine-positive cells in hepatic tissues. Thus, these results suggest tryptanthrin has therapeutic potential to protect cells from oxidative injury via AMPK-dependent p38 activation.