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Regulation of Sirt1/Nrf2/TNF-? signaling pathway by luteolin is critical to attenuate acute mercuric chloride exposure induced hepatotoxicity.

ABSTRACT: Inorganic mercury, though a key component of pediatric vaccines, is an environmental toxicant threatening human health via accumulating oxidative stress in part. Luteolin has been of great interest because of its antiinflammatory, anticarcinogenic and antioxidative effects. Here we hypothesized that luteolin would attenuate hepatotoxicity induced by acute inorganic mercury exposure. Kunming mice were treated with luteolin (100?mg/kg) 24?h after administration of 4?mg/kg mercuric chloride (HgCl₂). The results showed that luteolin ameliorated HgCl₂ induced anemia and hepatotoxicity, regulating radical oxygen species (ROS) production and hepatocyte viability in vitro and oxidative stress and apoptosis in vivo. Furthermore, luteolin reversed the changes in levels of inflammation- and apoptosis-related proteins involving NF-?B, TNF-?, Sirt1, mTOR, Bax, p53, and Bcl-2, and inhibited p38 MAPK activation. Luteolin enhanced antioxidant defense system based on Keap1, Nrf2, HO-1, NQO1, and KLF9. Moreover, luteolin did not affect miRNA-146a expression. Collectively, our findings, for the first time, elucidate a precise mechanism for attenuation of HgCl₂-induced liver dysfunction by dietary luteolin via regulating Sirt1/Nrf2/TNF-? signaling pathway, and provide a foundation for further study of luteolin as a novel therapeutic agent against inorganic mercury poisoning.

SUBMITTER: Yang D

PROVIDER: S-EPMC5112569 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Regulation of Sirt1/Nrf2/TNF-α signaling pathway by luteolin is critical to attenuate acute mercuric chloride exposure induced hepatotoxicity.

Yang Daqian D Tan Xiao X Lv Zhanjun Z Liu Biying B Baiyun Ruiqi R Lu Jingjing J Zhang Zhigang Z

Scientific reports 20161117

Inorganic mercury, though a key component of pediatric vaccines, is an environmental toxicant threatening human health via accumulating oxidative stress in part. Luteolin has been of great interest because of its antiinflammatory, anticarcinogenic and antioxidative effects. Here we hypothesized that luteolin would attenuate hepatotoxicity induced by acute inorganic mercury exposure. Kunming mice were treated with luteolin (100 mg/kg) 24 h after administration of 4 mg/kg mercuric chloride (HgCl<s ...[more]

PMID: 27853236

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Project description:The abundant use of lead (Pb; toxic heavy metal) worldwide has increased occupational and ecosystem exposure, with subsequent negative health effects. The flavonoid luteolin (LUT) found in many natural foodstuffs possesses antioxidant and anti-inflammatory properties. Herein, we hypothesized that LUT could mitigate liver damage induced by exposure to lead acetate (PbAc). Male Wistar rats were allocated to four groups: control group received normal saline, LUT-treated group (50 mg/kg, oral, daily), PbAc-treated group (20 mg/kg, i.p., daily), and LUT+PbAc-treated group (received the aforementioned doses via the respective routes of administration); the rats were treated for 7 days. The results revealed that PbAc exposure significantly increased hepatic Pb residue and serum activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin value. Oxidative reactions were observed in the liver tissue following PbAc intoxication, characterized by the depletion and downregulation of antioxidant proteins (glutathione, glutathione reductase, glutathione peroxidase, superoxide dismutase, catalase, nuclear factor erythroid 2-related factor 2, and heme oxygenase-1), and an increase in oxidants (malondialdehyde and nitric oxide). Additionally, PbAc increased the release and expression of the pro-inflammatory cytokines (tumor necrosis factor alpha and interleukin-1 beta), inducible nitric oxide synthase, and nuclear factor kappa B. Moreover, PbAc enhanced hepatocyte loss by increasing the expression of pro-apoptotic proteins (Bax and caspase-3) and downregulating the anti-apoptotic protein (Bcl-2). The changes in the aforementioned parameters were further confirmed by noticeable histopathological lesions. LUT supplementation significantly reversed all of the tested parameters in comparison with the PbAc-exposed group. In conclusion, our findings describe the potential mechanisms involved in the alleviation of PbAc-induced liver injury by luteolin via its potent anti-inflammatory, antioxidant, and anti-apoptotic properties.

Dataset Information

Regulation of Sirt1/Nrf2/TNF-? signaling pathway by luteolin is critical to attenuate acute mercuric chloride exposure induced hepatotoxicity.

Publications

Regulation of Sirt1/Nrf2/TNF-α signaling pathway by luteolin is critical to attenuate acute mercuric chloride exposure induced hepatotoxicity.

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