4-喹啉腙类似物通过诱导细胞凋亡和线粒体依赖途径细胞死亡杀死亚马逊利什曼病(利什曼病)。

IF 3.2 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Juliana da Trindade Granato, Emerson Teixeira da Silva, Ari Sérgio de Oliveira Lemos, Patrícia de Almeida Machado, Victor do Valle Midlej, Luciana Maria Ribeiro Antinarelli, Adolfo Firmino da Silva Neto, Marcus Vinícius Nora Souza, Elaine Soares Coimbra
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引用次数: 0

摘要

尽管做出了努力,但可用于治疗利什曼病的替代药物仍然很少。在这项工作中,我们测试了一类 15 种喹啉腙类似物,并提供了数据,支持在由亚马逊利什曼病引起的皮肤利什曼病中使用活性最强的化合物。总的来说,这些化合物在低浓度下对两种寄生形式都显示出活性(对原生体的活性为 5.33-37.04 μM,对非原生体的活性为 14.31-61.98 μM)。此外,最佳化合物(MHZ15)对寄生虫具有高度选择性。生化研究表明,用 MHZ15 处理原宿主会导致线粒体电位丧失和 ROS 水平升高,这是主要的影响,从而引发脂滴积累、质膜完整性丧失和细胞凋亡标志(包括 DNA 断裂和磷脂酰丝氨酸暴露)。这些效应与细胞内寄生形式类似。然而,在这种寄生形式中,质膜完整性在观察到的处理时间内没有变化,这可能是由于新陈代谢的差异和变形体的恢复能力。此外,还观察到了超微结构的变化,如空泡化,表明存在自噬现象。MHZ15 在皮肤利什曼病实验模型中的体内疗效是在感染了 L. amazonensis 的 BALB/c 株小鼠中进行的。通过穴内途径进行的治疗表明,MHZ15 的作用非常有效,能显著减少受伤爪子和引流淋巴结中的寄生虫数量,而且不会出现临床症状或影响动物福利。此外,还对体内毒性进行了评估,观察到肝脏酶天冬氨酸氨基转移酶和丙氨酸氨基转移酶的水平没有发生变化。本文提供的数据表明,MHZ15 具有一系列有利于开发抗利什曼病药的有利特性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

4-Quinolinylhydrazone analogues kill Leishmania (Leishmania) amazonensis by inducing apoptosis and mitochondria-dependent pathway cell death

4-Quinolinylhydrazone analogues kill Leishmania (Leishmania) amazonensis by inducing apoptosis and mitochondria-dependent pathway cell death

Despite efforts, available alternatives for the treatment of leishmaniasis are still scarce. In this work we tested a class of 15 quinolinylhydrazone analogues and presented data that support the use of the most active compound in cutaneous leishmaniasis caused by Leishmania amazonensis. In general, the compounds showed activity at low concentrations for both parasitic forms (5.33–37.04 μM to promastigotes, and 14.31–61.98 μM to amastigotes). In addition, the best compound (MHZ15) is highly selective for the parasite. Biochemical studies indicate that the treatment of promastigotes with MHZ15 leads the loss of mitochondrial potential and increase in ROS levels as the primary effects, which triggers accumulation of lipid droplets, loss of plasma membrane integrity and apoptosis hallmarks, including DNA fragmentation and phosphatidylserine exposure. These effects were similar in the intracellular form of the parasite. However, in this parasitic form there is no change in plasma membrane integrity in the observed treatment time, which can be attributed to metabolic differences and the resilience of the amastigote. Also, ultrastructural changes such as vacuolization suggesting autophagy were observed. The in vivo effectiveness of MHZ15 in the experimental model of cutaneous leishmaniasis was carried out in mice of the BALB/c strain infected with L. amazonensis. The treatment by intralesional route showed that MHZ15 acted with great efficiency with significantly reduction in the parasite load in the injured paws and draining lymph nodes, without clinical signs of distress or compromise of animal welfare. In vivo toxicity was also evaluated and null alterations in the levels of hepatic enzymes aspartate aminotransferase, and alanine aminotransferase was observed. The data presented herein demonstrates that MHZ15 exhibits a range of favorable characteristics conducive to the development of an antileishmanial agent.

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来源期刊
Chemical Biology & Drug Design
Chemical Biology & Drug Design 医学-生化与分子生物学
CiteScore
5.10
自引率
3.30%
发文量
164
审稿时长
4.4 months
期刊介绍: Chemical Biology & Drug Design is a peer-reviewed scientific journal that is dedicated to the advancement of innovative science, technology and medicine with a focus on the multidisciplinary fields of chemical biology and drug design. It is the aim of Chemical Biology & Drug Design to capture significant research and drug discovery that highlights new concepts, insight and new findings within the scope of chemical biology and drug design.
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