Leishmaniasis is a neglected tropical disease caused by the flagellated protozoa of the genus Leishmania that affects millions of people around the world. Drugs employed in the treatment of leishmaniasis have limited efficacy and induce local and systemic side effects to the patients. Natural products are an interesting alternative to treat leishmaniasis, because some purified molecules are selective toward parasites and not to the host cells. Thus, the aim of the present study was to compare the in vitro antileishmanial activity of the triterpenes betulin (Be), lupeol (Lu), and ursolic acid (UA); analyze the physiology and morphology of affected organelles; analyze the toxicity of selected triterpenes in golden hamsters; and study the therapeutic activity of triterpenes in hamsters infected with L. (L.) infantum as well as the cellular immunity induced by studied molecules. The triterpenes Lu and UA were active on promastigote ( and  μM, respectively) and amastigote forms ( and  μM, respectively) of L. (L.) infantum, and their selectivity indexes (SI) toward amastigote forms were higher (≥13.4 and 14, respectively) than SI of miltefosine (2.7). L. (L.) infantum promastigotes treated with Lu and UA showed cytoplasmic degradation, and in some of these areas, cell debris were identified, resembling autophagic vacuoles, and parasite mitochondria were swelled, fragmented, and displayed membrane potential altered over time. Parasite cell membrane was not affected by studied triterpenes. Studies of toxicity in golden hamster showed that Lu did not alter blood biochemical parameters associated with liver and kidney functions; however, a slight increase of aspartate aminotransferase level in animals treated with 2.5 mg/kg of UA was detected. Lu and UA triterpenes eliminated amastigote forms in the spleen (87.5 and 95.9% of reduction, respectively) and liver of infected hamster (95.9 and 99.7% of reduction, respectively); and UA showed similar activity at eliminating amastigote forms in the spleen and liver than amphotericin B (99.2 and 99.8% of reduction). The therapeutic activity of both triterpenes was associated with the elevation of IFN-γ and/or iNOS expression in infected treated animals. This is the first comparative work showing the in vitro activity, toxicity, and therapeutic activity of Lu and UA in the chronic model of visceral leishmaniasis caused by L. (L.) infantum; additionally, both triterpenes activated cellular immune response in the hamster model of visceral leishmaniasis.

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相关的五环三萜在慢性实验性内脏利什曼病中具有免疫调节活性

利什曼病是一种被忽视的热带疾病，由利什曼原虫属的鞭毛原生动物引起，影响全世界数百万人。用于治疗利什曼病的药物疗效有限，并且会对患者产生局部和全身副作用。天然产物是治疗利什曼病的一种有趣的替代方法，因为一些纯化的分子对寄生虫而非宿主细胞具有选择性。因此，本研究的目的是比较体外三萜类桦木脑 (Be)、羽扇豆醇 (Lu) 和熊果酸 (UA) 的抗利什曼原虫活性；分析受影响细胞器的生理和形态；分析选定的三萜对金黄仓鼠的毒性；并研究三萜对感染L. ( L. ) infantum 的仓鼠的治疗活性以及所研究分子诱导的细胞免疫。三萜类 Lu 和 UA 对前鞭毛体有活性（ 和  μ M，分别）和无鞭毛体形式（ 和  L. ( L. ) infantum分别为μ M ) ，它们对无鞭毛体形式的选择性指数 (SI) 比米替福新 (2.7) 的 SI 更高（分别≥13.4 和 14）。L. ( L. )婴儿用 Lu 和 UA 处理的前鞭毛体表现出细胞质降解，在其中一些区域，鉴定出细胞碎片，类似于自噬液泡，寄生虫线粒体膨胀、破碎，并显示出随时间改变的膜电位。寄生虫细胞膜不受所研究的三萜的影响。对金仓鼠的毒性研究表明，Lu 不会改变与肝肾功能相关的血液生化参数；然而，在用 2.5 mg/kg UA 处理的动物中检测到天冬氨酸转氨酶水平略有增加。Lu 和 UA 三萜消除了受感染仓鼠的脾脏（分别减少了 87.5% 和 95.9%）和肝脏（分别减少了 95.9% 和 99.7%）中的无鞭毛体形式；和 UA 在消除脾脏和肝脏中的无鞭毛体形式方面表现出与两性霉素 B 相似的活性（减少 99.2% 和 99.8%）。两种三萜的治疗活性都与 IFN-α 的升高有关。受感染的治疗动物中的γ和/或 iNOS 表达。这是第一个比较性工作，显示Lu 和 UA 在由L. ( L. )婴儿引起的内脏利什曼病慢性模型中的体外活性、毒性和治疗活性；此外，两种三萜类在内脏利什曼病的仓鼠模型中都激活了细胞免疫反应。