青蒿素通过靶向Adcy5-Gch1轴触发大鼠BH4和多巴胺级联产生来缓解帕金森病

IF 10.1 1区 生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Xin-xing Yang, Guo-qing Wang, Qian Wen, Yu-jia Zhao, Dai-di Li, Feng Zhang
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引用次数: 0

摘要

帕金森氏症是一种非常普遍的神经退行性疾病。多巴胺(DA)分泌减少是帕金森病病理的最终结果。不幸的是,缺乏安全有效的治疗药物。酪氨酸羟化酶是合成DA的限速酶,可以将酪氨酸羟化生成左旋多巴,而四氢生物蝶呤(BH4)是必不可少的辅酶。此外,BH4被证实具有抗帕金森病的神经保护作用。因此,调控BH4的合成被证实是治疗帕金森病的一种有前景的治疗策略。我们证明青蒿素在大鼠中有效地产生抗帕金森病的神经保护作用。中脑蛋白质组学和非靶向代谢组学综合分析表明,青蒿素可能通过靶向腺苷酸环化酶5 (Adcy5)提高GTP环水解酶1 (Gch1, BH4合成酶)的表达,进一步促进BH4的合成。为了验证这一假设,分子对接实验证明ART可以直接结合Adcy5。青蒿素在体内和体外均增加Adcy5和Gch1的表达和BH4的产生。进一步的救援实验表明,在体外抑制Adcy5或Gch1后,青蒿素产生的DA神经保护作用和DA和BH4的高分泌消失。此外,Adcy5的抑制加重了帕金森病的表现,减少了中脑DA和BH4的产生,下调了体内Gch1的表达。青蒿素通过调节Adcy5-Gch1-BH4轴介导大鼠帕金森病的神经保护作用。这些发现为将来应用青蒿素治疗帕金森病提供了有益的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Artemisinin alleviates Parkinson’s disease by targeting Adcy5-Gch1 axis to trigger a cascade generation of BH4 and dopamine in rats
Parkinson’s disease is a highly prevalent neurodegenerative disorder. Hyposecretion of dopamine (DA) is the end result in the pathology of Parkinson’s disease. Unfortunately, safe and efficient therapeutic drugs are deficient. Tyrosine hydroxylase is the rate-limiting enzyme for DA synthesis, could hydroxylate tyrosine and generate levodopa with tetrahydrobiopterin (BH4) as an indispensable coenzyme. Furthermore, BH4 was confirmed to confer neuroprotection against Parkinson’s disease. Thus, regulation of BH4 synthesis was verified to become a promising therapeutic strategy for Parkinson’s disease. We demonstrate that artemisinin effectively produced neuroprotection against Parkinson’s disease in rats. Integrated analysis of midbrain proteomics and non-targeted metabolomics suggests that artemisinin might target adenylate cyclase 5 (Adcy5) to increase GTP cyclohydrolase 1 (Gch1, BH4 synthetase) expression to further boost BH4 synthesis. To verify this hypothesis, molecular docking experiments demonstrate that ART could directly bind to Adcy5. Artemisinin increases Adcy5 and Gch1 expressions and BH4 production both in vivo and in vitro. Further rescue experiments demonstrate that artemisinin-generated DA neuroprotection and hypersecretion of DA and BH4 disappears after inhibition of Adcy5 or Gch1 in vitro. Additionally, suppression of Adcy5 aggravates Parkinson’s disease manifestation, decreases midbrain DA and BH4 production and down-regulated Gch1 expression in vivo. Artemisinin mediates neuroprotection against Parkinson’s disease via regulation of Adcy5-Gch1-BH4 axis in rats. These findings present a beneficial potential for future application of artemisinin on Parkinson’s disease treatment.
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来源期刊
Genome Biology
Genome Biology Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
21.00
自引率
3.30%
发文量
241
审稿时长
2 months
期刊介绍: Genome Biology stands as a premier platform for exceptional research across all domains of biology and biomedicine, explored through a genomic and post-genomic lens. With an impressive impact factor of 12.3 (2022),* the journal secures its position as the 3rd-ranked research journal in the Genetics and Heredity category and the 2nd-ranked research journal in the Biotechnology and Applied Microbiology category by Thomson Reuters. Notably, Genome Biology holds the distinction of being the highest-ranked open-access journal in this category. Our dedicated team of highly trained in-house Editors collaborates closely with our esteemed Editorial Board of international experts, ensuring the journal remains on the forefront of scientific advances and community standards. Regular engagement with researchers at conferences and institute visits underscores our commitment to staying abreast of the latest developments in the field.
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