Institute for Agro-food Standards and Testing Technology, Laboratory of Quality & Safety Risk Assessment for Agro-products (Shanghai), Ministry of Agriculture and Rural Affairs, Shanghai Academy of Agricultural Sciences, No.1000 Jinqi Road, Shanghai, 201403, PR China; Shanghai Guosen Biotechnology Co., Ltd., Shanghai, 201400, PR China.
Institute for Agro-food Standards and Testing Technology, Laboratory of Quality & Safety Risk Assessment for Agro-products (Shanghai), Ministry of Agriculture and Rural Affairs, Shanghai Academy of Agricultural Sciences, No.1000 Jinqi Road, Shanghai, 201403, PR China; College of Veterinary Medicine, Hunan Agricultural University, No.1 Nongda Road, Changsha, 410128, PR China.
Chemosphere. 2024 Sep;364:143157. doi: 10.1016/j.chemosphere.2024.143157. Epub 2024 Aug 22.
α-amanitin (AMA) is a hepatotoxic mushroom toxin responsible for over 90% of mushroom poisoning fatalities worldwide, seriously endangering human life and health. Few evidences have indicated that AMA leads to inflammatory responses and inflammatory infiltration in vitro and in vivo. However, the molecular mechanism remains unknown. In this study, human hepatocellular carcinomas cells (HepG2) were exposed to AMA at various concentrations for short period of times. Results revealed that AMA increased ROS production and elevated the releases of malondialdehyde (MDA) and lactate dehydrogenase (LDH), resulting in oxidative damage in HepG2 cells. Also, AMA exposure significantly increased the secreted levels of inflammatory cytokines and activated the NLRP3 inflammasome. The inflammatory responses were reversed by NLRP3 inhibitor MCC950 and NF-κB inhibitor Bay11-7082. Additionally, N-acetylcysteine (NAC) blocked the upregulation of the NF-κB/NLRP3 signaling pathway and remarkably alleviated the inflammatory response. These results demonstrated that AMA could induce inflammation through activating the NLRP3 inflammasome triggered by ROS/NF-κB signaling pathway. Our research provides new insights into the molecular mechanism of AMA-induced inflammation damage and may contribute to establish new prevention strategies for AMA hepatotoxicity.
α-鹅膏蕈碱（AMA）是一种肝毒性蘑菇毒素，负责全球超过 90%的蘑菇中毒死亡，严重威胁人类生命和健康。有一些证据表明，AMA 会导致体外和体内的炎症反应和炎症浸润。然而，其分子机制尚不清楚。在这项研究中，用人肝癌细胞（HepG2）在短时间内暴露于不同浓度的 AMA。结果表明，AMA 增加了 ROS 的产生，并提高了丙二醛（MDA）和乳酸脱氢酶（LDH）的释放，导致 HepG2 细胞发生氧化损伤。此外，AMA 暴露显著增加了炎症细胞因子的分泌水平，并激活了 NLRP3 炎性体。NLRP3 抑制剂 MCC950 和 NF-κB 抑制剂 Bay11-7082 逆转了炎症反应。此外，N-乙酰半胱氨酸（NAC）阻断了 NF-κB/NLRP3 信号通路的上调，并显著减轻了炎症反应。这些结果表明，AMA 通过激活 ROS/NF-κB 信号通路引发的 NLRP3 炎性体诱导炎症。我们的研究为 AMA 诱导的炎症损伤的分子机制提供了新的见解，并可能有助于建立 AMA 肝毒性的新预防策略。
