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脱氢紫堇灵对克氏锥虫的促氧化剂机制的新认识。

New insights into the pro-oxidant mechanism of dehydroleucodine on Trypanosoma cruzi.

机构信息

Instituto de Histología y Embriología, IHEM-CONICET, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo (UNCuyo), 5500, Mendoza, Argentina.

Facultad de Química, Bioquímica y Farmacia, Instituto de Investigación en Tecnología Química, INTEQUI-CONICET., Universidad Nacional de San Luis, 5700, San Luis, Argentina.

出版信息

Sci Rep. 2024 Aug 14;14(1):18875. doi: 10.1038/s41598-024-69201-0.

DOI:10.1038/s41598-024-69201-0
PMID:39143185
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11324952/
Abstract

Chagas disease, caused by Trypanosoma cruzi (T. cruzi), is one of the most important neglected diseases in Latin America. The limited use of the current nitro-derivative-based chemotherapy highlights the need for alternative drugs and the identification of their molecular targets. In this study, we investigated the trypanocidal effect of the sesquiterpene lactone dehydroleucodine (DhL) and its derivatives, focusing on the antioxidative defense of the parasites. DhL and two derivatives, at lesser extent, displayed antiproliferative effect on the parasites. This effect was blocked by the reducing agent glutathione (GSH). Treated parasites exhibited increased intracellular ROS concentration and trypanothione synthetase activity, accompanied by mitochondrial swelling. Although molecular dynamics studies predicted that GSH would not interact with DhL, H-NMR analysis confirmed that GSH could protect parasites by interacting with the lactone. When parasites overexpressing mitochondrial tryparedoxin peroxidase were incubated with DhL, its effect was attenuated. Overexpression of cytosolic tryparedoxin peroxidase also provided some protection against DhL. These findings suggest that DhL induces oxidative imbalance in T. cruzi, offering new insights into potential drug targets against this parasite.

摘要

克氏锥虫（T. cruzi）引起的恰加斯病是拉丁美洲最重要的被忽视疾病之一。目前基于硝基衍生物的化疗方法的应用有限，这突出表明需要替代药物，并确定其分子靶标。在这项研究中，我们研究了倍半萜内酯脱氢苦马豆素（DhL）及其衍生物的杀锥虫作用，重点关注寄生虫的抗氧化防御。DhL 和两种衍生物在较小程度上对寄生虫表现出抗增殖作用。这种作用被还原剂谷胱甘肽（GSH）阻断。用药物处理的寄生虫表现出细胞内 ROS 浓度和转硫酶活性增加，伴随着线粒体肿胀。尽管分子动力学研究预测 GSH 不会与 DhL 相互作用，但 H-NMR 分析证实 GSH 可以通过与内酯相互作用来保护寄生虫。当过表达线粒体硫氧还蛋白过氧化物酶的寄生虫与 DhL 孵育时，其作用被减弱。细胞溶质硫氧还蛋白过氧化物酶的过表达也对 DhL 提供了一定的保护。这些发现表明，DhL 在克氏锥虫中诱导氧化失衡，为针对这种寄生虫的潜在药物靶标提供了新的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b85/11324952/c08f360dfac0/41598_2024_69201_Fig11_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b85/11324952/2248d5f55ffa/41598_2024_69201_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b85/11324952/020328720d73/41598_2024_69201_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b85/11324952/f7fca9a34b94/41598_2024_69201_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b85/11324952/993c394efc55/41598_2024_69201_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b85/11324952/5d3876889189/41598_2024_69201_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b85/11324952/2b8a604fa750/41598_2024_69201_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b85/11324952/b70de5869553/41598_2024_69201_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b85/11324952/6fec8ee151ca/41598_2024_69201_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0b85/11324952/c08f360dfac0/41598_2024_69201_Fig11_HTML.jpg

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