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  • Heme oxygenase-1 regulates autophagy through carbon-oxygen to alleviate deoxynivalenol-induced hepatic damage.

Heme oxygenase-1 regulates autophagy through carbon-oxygen to alleviate deoxynivalenol-induced hepatic damage.

Archives of toxicology (2019-12-19)
Zhao Peng, Yuxiao Liao, Xiaoqian Wang, Liangkai Chen, Liangliang Wang, Chenyuan Qin, Zhenting Wang, Mengyao Cai, Jiawei Hu, Dan Li, Ping Yao, Andreas K Nüssler, Liegang Liu, Wei Yang
ABSTRACT

Deoxynivalenol (DON) cannot be totally removed due to its stable chemical characteristics and chronic exposure to low doses of DON causes significant toxic effects in humans and animals. However, the potential hazard of such low-dose exposure in target organs still remains not completely understood, especially in liver, which is mainly responsible for detoxification of DON. In the present study, we demonstrated for the first time that estimated human daily DON exposure (25 μg/kg bw) for 30 and 90 days caused low-grade inflammatory infiltration around hepatic centrilobular veins, elevated systemic IL-1β, IL-6 and TNF-α and impaired liver function evidenced by increased serum ALT activity. At the molecular level, expressions of autophagy-related proteins as well as Cleaved Caspase-3 and Cleaved Caspase-7 were upregulated during DON exposure, which indicated the activation of autophagy and apoptosis. Importantly, AAV-mediated liver-specific overexpression of HO-1 reversed DON-induced liver damages, upregulated autophagy and attenuated apoptosis in liver, while AAV-mediated HO-1 silence aggravated DON-induced liver damages, inhibited autophagy and increased apoptosis. Furthermore, in vitro experiments demonstrated that lentivirus-mediated HO-1 overexpression in Hepa 1-6 cells prolonged the duration of autophagy and delayed the onset of apoptosis. HO-1 silence in Hepa 1-6 cells inhibited activation of autophagy and accelerated occurrence of apoptosis, and these could be recovered by CO pre-treatment. Therefore, we suppose that HO-1 might be a potential research target to protect human and animal from liver injuries induced by low dose of DON exposure.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
6-Diazo-5-oxo-L-norleucine, crystalline
Millipore
Immobilon-NC Transfer Membrane, 1 roll, 33 cm x 3 m, 0.45 µm pore size, Triton-free, mixed cellulose esters transfer membrane
Sigma-Aldrich
CORM-A1, ≥95% (NMR)
Sigma-Aldrich
N-(3-Hydroxytetradecanoyl)-DL-homoserine lactone, ≥96% (HPLC), carbon 64.7-67.3 %