Laboratory of Experimental Protozoology, Department of Pathological Sciences, Center of Biological Sciences, State University of Londrina, PR, Brazil.
Laboratory of Biotransformation and Phytochemistry, Department of Chemistry, Center of Exact Sciences, State University of Londrina, PR, Brazil.
Phytomedicine. 2018 Jul 15;46:11-20. doi: 10.1016/j.phymed.2018.06.010. Epub 2018 Jun 13.
BACKGROUND: American tegumentary leishmaniasis (ATL) is a zoonotic disease caused by protozoa of the genus Leishmania. The high toxicity, high costs and resistance of some strains to current drugs has prompted the search for therapeutic alternatives for the management of this disease. Sphagneticola trilobata is a plant that has diterpenes as main constituents, including grandiflorenic acid (GFA) that has antiinflammatory, antiprotozoal, antibacterial and antinociceptive activity. PURPOSE: The aim of our study was to determine the effect of GFA on both the promastigotes and the amastigotes of Leishmania amazonensis. METHODS: Isolation by chromatographic methods and chemical identification of GFA, then evaluation of the in vitro leishmanicidal activity of this compound against Leishmania amazonensis promastigotes and L. amazonensis infected peritoneal Balb/c macrophages, as well its action and microbicide mechanisms. RESULTS: GFA treatment significantly inhibited the proliferation of promastigotes. This antiproliferative effect was accompanied by morphological changes in the parasite with 25 nM GFA. Afterwards, we investigated the mechanisms involved in the death of the protozoan; there was an increase in the production of reactive oxygen species (ROS), phosphatidylserine exposure, permeabilization of the plasma membrane and decreased mitochondrial depolarization. In addition, we observed that the treatment caused a reduction in the percentage of infected cells and the number of amastigotes per macrophage, without showing cytotoxicity in low doses to peritoneal macrophages and sheep erythrocytes. GFA increased IL-10 and total iron bound to transferrin in infected macrophages. Our results showed that GFA treatment acts on promastigote forms through an apoptosis-like mechanism and on intracellular amastigote forms, dependent of regulatory cytokine IL-10 modulation with increase in total iron bound to transferrin. CONCLUSION: GFA showed in vitro antileishmanial activity on L. amazonensis promastigotes forms and on L. amazonensis-infected macrophages.
背景：美洲皮肤利什曼病（ATL）是一种由利什曼原虫属原生动物引起的人畜共患疾病。一些菌株的高毒性、高成本和耐药性促使人们寻找治疗这种疾病的替代方法。三叶鬼针草是一种植物，其主要成分为二萜类化合物，包括大花酸（GFA），具有抗炎、抗原生动物、抗菌和抗伤害作用。
目的：本研究旨在确定 GFA 对利什曼原虫前鞭毛体和无鞭毛体的影响。
方法：通过色谱方法分离和化学鉴定 GFA，然后评估该化合物对利什曼原虫前鞭毛体和利什曼原虫感染的腹腔 Balb/c 巨噬细胞的体外杀利什曼原虫活性，以及其作用和杀微生物机制。
结果：GFA 处理显著抑制了前鞭毛体的增殖。这种抗增殖作用伴随着寄生虫形态的变化，用 25 nM GFA 处理。之后，我们研究了参与原生动物死亡的机制；活性氧（ROS）的产生增加，磷脂酰丝氨酸暴露，质膜通透性增加，线粒体去极化减少。此外，我们观察到治疗导致感染细胞的百分比和每个巨噬细胞内的无鞭毛体数量减少，而在低剂量对腹腔巨噬细胞和绵羊红细胞没有细胞毒性。GFA 增加了感染巨噬细胞中 IL-10 和总铁结合转铁蛋白的含量。我们的结果表明，GFA 处理通过类似于细胞凋亡的机制作用于前鞭毛体形式，并作用于细胞内无鞭毛体形式，依赖于调节细胞因子 IL-10 的调节，增加总铁结合转铁蛋白。
结论：GFA 对 L. amazonensis 前鞭毛体形式和 L. amazonensis 感染的巨噬细胞表现出体外抗利什曼原虫活性。
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