Mitochondrial dysfunction on Leishmania (Leishmania) amazonensis induced by ketoconazole: insights into drug mode of action.
Mitochondrial dysfunction on Leishmania (Leishmania) amazonensis induced by ketoconazole: insights into drug mode of action.
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DOI：
10.1590/0074-02760210157
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发表时间：
2022
影响因子：
2.8
通讯作者：
Geraldo Yoneyama, Kelly Aparecida
中科院分区：
文献类型：
--
作者：
de Oliveira Silva Nunes, Debora Cristina;Costa, Monica Soares;Bispo-da-Silva, Luiz Borges;Vieira Ferro, Eloisa Amalia;Pereira Zoia, Mariana Alves;Goulart, Luiz Ricardo;Rodrigues, Renata Santos;Rodrigues, Veridiana de Melo;Geraldo Yoneyama, Kelly Aparecida
利什曼原虫寄生虫引起利什曼病，范围从自限性皮肤病变到更严重的疾病形式。以生化和代谢途径为重点的潜在药物靶标的寻找表明，甾醇生物合成抑制剂（SBI）是一种有前途的方法。此类抑制剂中包括酮康唑，它是 14α-甲基甾醇 14-去甲基酶的经典抑制剂。 本研究旨在更好地了解亚马逊利什曼原虫（Leishmania）前鞭毛体在酮康唑治疗后在细胞水平上的生物学反应。 在此，使用荧光测定法、流式细胞术、荧光显微镜、电子显微镜和扫描显微镜等技术来研究细胞结构并鉴定受酮康唑处理影响的细胞器。 该研究首次证明了酮康唑对亚马逊 L. (L.) 前鞭毛体（IFLA/BR/67/PH8 株）线粒体功能的影响及其与细胞周期和死亡的可能关系。 酮康唑诱导的线粒体损伤导致这种单一细胞器的超极化和自噬空泡的形成，作为寄生虫的生存策略。这些损害并不直接反映在寄生虫细胞周期上，而是导致寄生虫死亡，使它们在体外模型中对酮康唑治疗敏感。
Leishmania parasites cause leishmaniasis that range from self-limiting cutaneous lesions to more serious forms of the disease. The search for potential drug targets focusing on biochemical and metabolic pathways revealed the sterol biosynthesis inhibitors (SBIs) as a promising approach. In this class of inhibitors is found ketoconazole, a classical inhibitor of 14α-methysterol 14-demethylase. The present study aimed to better understand the biological response of Leishmania (Leishmania) amazonensis promastigotes at the cellular level after ketoconazole treatment. Herein, techniques, such as fluorimetry, flow cytometry, fluorescence microscopy, electron and scanning microscopy were used to investigate the cellular structures and to identify organelles affected by ketoconazole treatment. The study demonstrated, for the first time, the effect of ketoconazole on mitochondrion functioning and its probable relationship to cell cycle and death on L. (L.) amazonensis promastigotes (IFLA/BR/67/PH8 strain). Ketoconazole-induced mitochondrial damages led to hyperpolarisation of this single organelle and autophagic vacuoles formation, as a parasite survival strategy. These damages did not reflect directly on the parasite cell cycle, but drove the parasites to death, making them susceptible to ketoconazole treatment in in vitro models.
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影响因子：
3.7
作者：
Kessler RL;Soares MJ;Probst CM;Krieger MA
通讯作者：
Krieger MA
影响因子：
3.2
作者：
Guzzo, M. F.;Carvalho, L. R.;Bronstein, M. D.
通讯作者：
Bronstein, M. D.
水杨酸钌 (II) 复合物通过靶向硫氧还蛋白还原酶诱导 ROS 介导的细胞凋亡
影响因子：
3.9
作者：
Chen, Jin-can;Zhang, Yao;Chen, Lan-mei
通讯作者：
Chen, Lan-mei
影响因子：
0.5
作者：
Hoffmann, Aline Rafaeli;Navarro, Italmar Teodorico;Pereira, Patricia Mendes
通讯作者：
Pereira, Patricia Mendes
影响因子：
--
作者：
Lepesheva, Galina I.;Villalta, Fernando;Waterman, Michael R.
通讯作者：
Waterman, Michael R.