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Dihydromyricetin protects against liver ischemia/reperfusion induced apoptosis via activation of FOXO3a-mediated autophagy.

ABSTRACT: Liver ischemia and reperfusion (I/R) injury is characterized by defective liver autophagy accompanied by alterations to the endogenous defense system. Dihydromyricetin (DHM) is a natural flavonoid that demonstrates a wide range of physiological functions, and has been implicated as a regulator of autophagy. This study investigates the protective effects of DHM pretreatment on liver injury caused by ischemia/reperfusion (I/R) and elucidates the potential mechanism of DHM-mediated protection. Mice were subjected to 60 minutes of ischemia followed by 5 hours of reperfusion. DHM (100 mg/kg bw/day) or the vehicle was administered daily by gavage 7 days before ischemia and immediately before reperfusion. In this study, DHM markedly decreased serum aminotransferase activity and inhibited liver I/R -stimulated apoptosis. Moreover, DHM exerted hepatoprotective effects by upregulating mRNA levels of various essential autophagy-related genes including ATG5, ATG12, BECN1, and LC3. Autophagy inhibitor chloroquine or Atg5 knockdown blocked DHM -mediated elevation in liver function. Specifically, DHM significantly increased FOXO3a expression, and enhanced FOXO3a nuclear translocation and Ser588 phosphorylation modification. Importantly, the inhibition of FOXO3a with FOXO3a-siRNA in mice decreased DHM-induced autophagy-related genes and diminished the protective effects of DHM against liver I/R injury. In summary, these findings identify DHM as a novel hepatoprotective small molecule by elevating FOXO3a expression and nuclear translocation, stimulating autophagy-related genes and suppressing liver I/R-induced apoptosis, suggesting FOXO3a may have therapeutic value in liver cell protection in liver I/R injury.

SUBMITTER: Chen Y

PROVIDER: S-EPMC5363527 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Dihydromyricetin protects against liver ischemia/reperfusion induced apoptosis via activation of FOXO3a-mediated autophagy.

Chen Yongbiao Y Lv Lizhi L Pi Huifeng H Qin Weijia W Chen Jianwei J Guo Dengfang D Lin Jianyu J Chi Xiaobing X Jiang Zhelong Z Yang Hejun H Jiang Yi Y

Oncotarget 20161101 47

Liver ischemia and reperfusion (I/R) injury is characterized by defective liver autophagy accompanied by alterations to the endogenous defense system. Dihydromyricetin (DHM) is a natural flavonoid that demonstrates a wide range of physiological functions, and has been implicated as a regulator of autophagy. This study investigates the protective effects of DHM pretreatment on liver injury caused by ischemia/reperfusion (I/R) and elucidates the potential mechanism of DHM-mediated protection. Mice ...[more]

PMID: 27793014

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Project description:The present study aimed to evaluate the role of autophagy in the protective effect of dexmedetomidine in lung injury caused by ischemia-reperfusion (IR) in rats. In total 48 adult male Sprague-Dawley rats were randomly divided into 6 groups (n=8) as follows: i) Sham group; ii) the IR group; iii) IR + 1 µg/kg dexmedetomidine preconditioning group (pre-LD); iv) IR + 10 µg/kg dexmedetomidine preconditioning group (pre-HD); v) IR + 1 µg/kg dexmedetomidine postconditioning group (post-LD); and vi) IR + 10 µg/kg dexmedetomidine postconditioning group (post-HD). After the rats were anesthetized, the hilum of the left lung was occluded with a non-invasive microvascular clip for 30 min to induce ischemia. The clip was then removed and the left lung was allowed to regain ventilation and blood for 2 h. The rats were then sacrificed, the left lung removed and the wet/dry (W/D) lung weight ratio was determined. Pathological changes to the lungs were evaluated by light and transmission electron microscopy. Furthermore, the rate of lung cell apoptosis was determined by the TUNEL assay. The expression of hypoxia-inducible factor 1α (HIF-1α), Bcl-2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3), BNIP3 like (BNIP3 L) and microtubule-associated protein 1A/1B light chain 3B (LC3II) was determined by western blotting. Compared with the sham group, a significant increase in the W/D lung weight ratio, and malondialdehyde (MDA), BNIP3, BNIP3 L and LC3II levels were observed in the IR group, and HIF-1α levels and superoxide dismutase (SOD) activity were decreased. Furthermore, the W/D ratio was lower in the pre-LD and pre-HD groups than in the IR group. Additionally, SOD activity was significantly higher and MDA expression was significantly lower in the pre-LD and pre-HD groups compared with the IR group. BNIP3, BNIP3 L and LC3II protein levels were significantly lower in the pre-LD and pre-HD groups compared with the IR group, while HIF-1α was notably upregulated in the pre-LD and pre-HD groups compared with the IR group. In conclusion, the results of the present study indicate that dexmedetomidine preconditioning protects against lung injury induced by IR through inhibition of autophagy and apoptosis.

Dataset Information

Dihydromyricetin protects against liver ischemia/reperfusion induced apoptosis via activation of FOXO3a-mediated autophagy.

Publications

Dihydromyricetin protects against liver ischemia/reperfusion induced apoptosis via activation of FOXO3a-mediated autophagy.

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