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阿扑吗啡通过抑制铁死亡来抑制脂肪性肝炎的进展。

Apomorphine Suppresses the Progression of Steatohepatitis by Inhibiting Ferroptosis.

作者信息

Maeda Hiroshi, Miura Kouichi, Aizawa Kenichi, Bat-Erdene Oyunjargal, Sashikawa-Kimura Miho, Noguchi Eri, Watanabe Masako, Yamada Naoya, Osaka Hitoshi, Morimoto Naoki, Yamamoto Hironori

机构信息

Department of Medicine, Division of Gastroenterology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke 329-0498, Tochigi, Japan.

Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke 329-0498, Tochigi, Japan.

出版信息

Antioxidants (Basel). 2024 Jul 2;13(7):805. doi: 10.3390/antiox13070805.

Abstract

The role of ferroptosis in steatohepatitis development is largely unknown. We investigated (1) whether hepatocyte ferroptosis occurs in a gene-modified steatohepatitis model without modifying dietary components, (2) whether ferroptosis occurs at an early stage of steatohepatitis, and (3) whether apomorphine, recently reported as a ferroptosis inhibitor, can ameliorate steatohepatitis. Hepatocyte-specific PTEN KO mice were used. Huh 7 and primary cultured hepatocytes isolated from the mice were used in this study. The number of dead cells increased in 10-week-old PTEN KO mice. This cell death was suppressed by the administration of ferroptosis inhibitor ferrostatin-1 for 2 weeks. Apomorphine also ameliorated the severity of steatohepatitis. Treatment with ferroptosis inhibitors, including apomorphine, decreases the level of lipid peroxidase. Apomorphine suppressed cell death induced by RSL-3 (a ferroptosis inducer), which was not suppressed by apoptosis or necroptosis inhibitors. Apomorphine showed a radical trapping capacity with much more potent activity than ferrostatin-1 and Trolox, a soluble form of vitamin E. In addition, apomorphine activated nrf2 and its downstream genes, including HO-1 and xCT. In conclusion, ferroptosis occurs in steatohepatitis from an early stage in PTEN KO mice. In addition, apomorphine ameliorates the severity of steatohepatitis by inhibiting ferroptosis.

摘要

铁死亡在脂肪性肝炎发展中的作用很大程度上尚不清楚。我们研究了:(1)在不改变饮食成分的基因修饰脂肪性肝炎模型中,肝细胞铁死亡是否发生;(2)铁死亡是否发生在脂肪性肝炎的早期阶段;(3)最近报道作为铁死亡抑制剂的阿扑吗啡是否能改善脂肪性肝炎。使用了肝细胞特异性PTEN基因敲除小鼠。本研究使用了从小鼠分离出的Huh 7细胞和原代培养肝细胞。10周龄的PTEN基因敲除小鼠中死亡细胞数量增加。给予铁死亡抑制剂铁抑素-1 2周可抑制这种细胞死亡。阿扑吗啡也改善了脂肪性肝炎的严重程度。包括阿扑吗啡在内用铁死亡抑制剂治疗可降低脂质过氧化物酶水平。阿扑吗啡抑制了由RSL-3(一种铁死亡诱导剂)诱导的细胞死亡,而凋亡或坏死性凋亡抑制剂不能抑制这种细胞死亡。阿扑吗啡表现出自由基捕获能力,其活性比铁抑素-1和维生素E的可溶形式Trolox更强。此外,阿扑吗啡激活了nrf2及其下游基因,包括HO-1和xCT。总之,铁死亡在PTEN基因敲除小鼠脂肪性肝炎的早期阶段就已发生。此外,阿扑吗啡通过抑制铁死亡改善了脂肪性肝炎严重程度。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/33df/11273851/6dbcb603ec35/antioxidants-13-00805-g001.jpg

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本文引用的文献

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Apomorphine is a potent inhibitor of ferroptosis independent of dopaminergic receptors.
Sci Rep. 2024 Feb 27;14(1):4820. doi: 10.1038/s41598-024-55293-1.
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Int J Biol Sci. 2023 Jul 31;19(12):3937-3950. doi: 10.7150/ijbs.85883. eCollection 2023.
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A multisociety Delphi consensus statement on new fatty liver disease nomenclature.
J Hepatol. 2023 Dec;79(6):1542-1556. doi: 10.1016/j.jhep.2023.06.003. Epub 2023 Jun 24.
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ATF4 suppresses hepatocarcinogenesis by inducing SLC7A11 (xCT) to block stress-related ferroptosis.
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