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Toxicol Appl Pharmacol. 2018 Dec 1;360:141-149. doi: 10.1016/j.taap.2018.10.002. Epub 2018 Oct 2.

Salinomycin ameliorates oxidative hepatic damage through AMP-activated protein kinase, facilitating autophagy.

Author information

1
Korean Medicine Application Center, Korea Institute of Oriental Medicine, Daegu 41062, Republic of Korea.
2
College of Oriental Medicine, Daegu Haany University, Gyeongsan 38610, Republic of Korea.
3
Department of Pathology, Kyungpook National University School of Medicine, Daegu 41944, Republic of Korea.
4
College of Oriental Medicine, Dongguk University, Gyeongju 38066, Republic of Korea.
5
Pusan National University School of Medicine, Yangsan 50612, Republic of Korea.
6
College of Pharmacy, Yeungnam University, Gyeongsan 38541, Republic of Korea.
7
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
8
Korean Medicine Application Center, Korea Institute of Oriental Medicine, Daegu 41062, Republic of Korea. Electronic address: kipark@kiom.re.kr.
9
College of Oriental Medicine, Daegu Haany University, Gyeongsan 38610, Republic of Korea. Electronic address: ywkim@dhu.ac.kr.

Abstract

Salinomycin, a monocarboxylic ionophore in Streptomyces albus, has been studied as an anti-cancer agent. However, we wondered whether salinomycin has another effect such as an anti-oxidant and hepatic protectant, because some chemical drugs treating human diseases were sometimes related with their toxic effects. Therefore, this study was conducted to examine the effects of salinomycin against oxidative stress and mitochondrial impairment in vivo and in vitro as well as the cellular mechanisms of action. In hepatocyte, salinomycin inhibited arachidonic acid (AA) + iron-induced apoptosis, mitochondrial dysfunction and ROS production. As a molecular mechanism, salinomycin induced autophagy through AMP-activated protein kinase (AMPK) activation, as assessed by the accumulation of acidic vesicle organelles, p62 and LC3-II. Moreover, these protective effects were blocked by AMPK inhibition, which indicates the importance of AMPK in the process of salinomycin's effects. In mice, oral administration of salinomycin protected against carbon tetrachloride (CCl4)-induced oxidative stress and liver injury, and also activated AMPK as well as autophagy-related proteins in the liver. Collectively, salinomycin had the ability to protect hepatocytes against AA+iron-induced reactive oxygen species production and mitochondrial dysfunction, as well as CCl4-induced liver injury. Although this beneficial effect was demonstrated under severe oxidative stress, this study showed that salinomycin protected the liver against the oxidative stress and liver damage through AMPK and autophagy, and suggest that salinomycin has a possibility to treat a broad range of diseases.

KEYWORDS:

AMP-activated protein kinase; Autophagy; Liver injury; Oxidative stress; Salinomycin

PMID:
30290169
DOI:
10.1016/j.taap.2018.10.002
[Indexed for MEDLINE]

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