Ivermectin confers its cytotoxic effects by inducing AMPK/mTOR-mediated autophagy and DNA damage
CHEMOSPHERE
Authors: Zhang, Ping; Ni, Hongfei; Zhang, Yang; Xu, Wenping; Gao, Jufang; Cheng, Jiagao; Tao, Liming
Abstract
Ivermectin (IVM), a broad-spectrum antiparasitic drug, is widely used in agriculture and animal husbandry. Due to widespread use and little metabolism in animals, the toxicity of IVM has received increasing attention. The accumulation of IVM in animal tissues and the excretion of urine and feces in the environment is the major source of potential toxicity. Human consumption of meat or milk contaminated with livestock can result in exposure to high levels of IVM exposure. The aim of this study was to reveal the cytotoxic mechanism of IVM in model cell HeLa in vitro, in order to provide a theoretical basis for the safe and rational use of IVM. Here we observed the gamma H2AX and 8-oxodG foci to detect the DNA damage in HeLa cells. As expected, we found that IVM can induce oxidative double-stranded damage in HeLa cells, indicating that IVM has potential genotoxicity to human health. In addition, we observed the formation of LC3-B in HeLa cells, the accumulation of Beclin1, the degradation of p62 and the activation of the AMPK/mTOR signal transduction pathway. This suggests that IVM confers cytotoxicity through autophagy mediated by the AMPK/mTOR signaling pathway. We conclude that IVM produces genotoxicity and cytotoxicity by inducing DNA damage and AMPK/mTOR-mediated autophagy, thereby posing a potential risk to human health. (C) 2020 Elsevier Ltd. All rights reserved.
Cessation of electrically-induced muscle contraction activates autophagy in cultured myotubes
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Authors: Yoshioka, Kiyoshi; Sasai, Nobuaki; Kurogi, Yuko; Hayakawa, Kimihide; Itoh, Yuta; Agata, Nobuhide; Murakami, Taro; Inoue-Miyazu, Masumi; Sokabe, Masahiro; Kawakami, Keisuke
Abstract
Exercise is known to improve skeletal muscle function. The mechanism involves muscle contraction-induced activation of the mTOR pathway, which plays a central role in protein synthesis. However, mTOR activation blocks autophagy, a recycling mechanism with a critical role in cellular maintenance/homeostasis. These two responses to muscle contraction look contradictory to the functional improvement of exercise. Herein, we investigate these paradoxical muscle responses in a series of active-inactive phases in a cultured myotube model receiving electrical stimulation to induce intermittent muscle contraction. Our model shows that (1) contractile activity induces mTOR activation and muscle hypertrophy but blocks autophagy, resulting in the accumulation of damaged proteins, while (2) cessation of muscle contraction rapidly activates autophagy, removing damaged protein, yet a prolonged inactive state results in muscle atrophy. Our findings provide new insights into muscle biology and suggest that not only muscle contraction, but also the subsequent cessation of contraction plays a substantial role for the improvement of skeletal muscle function. (C) 2020 Elsevier Inc. All rights reserved.
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