Akbari Ziba, Seyfouri KeyKavoos, Mirzazadeh Roghayeh, Jamali Elena, Zamani Zahra, Arjmand Mohammad
Metabolomics Laboratory. Pasteur Institute of Iran, Tehran, Iran.
Department of Pathology, Loghman Hakim Hospital, Shahid Beheshti University of Medical Science, Tehran, Iran.
Iran J Pharm Res. 2021 Fall;20(4):59-70. doi: 10.22037/ijpr.2021.114937.15122.
Cutaneous leishmaniasis is caused by protozoa of the genus and spread by sandflies. The standard therapy for this ailment is the first-line medication of pentavalent antimonial and the second drug line of pentamidine amphotericin B. All are practiced over the years and exhibit adverse toxicity effects. Herbal product-derived medicine is a promising potential source for treating parasitic diseases. Xanthatin, a xanthanolide sesquiterpene lactone, is isolated from L. treats several ailments in many countries. In the present study, we investigated the leishmanicidal activity of the xanthatin by using a metabolomics-based analysis in J774 macrophages and amastigotes phases in . Xanthatin was isolated and identified by NMR spectroscopy. Macrophage toxicity of xanthatin performed by MTT assay. Macrophages infected by the promastigote stationary phase, the infection rate (IR), and multiplication index (MI) were calculated. Axenic amastigotes were treated with xanthatin. Cell quenching and metabolite extraction were performed, and the metabolome profile was analyzed with NMR spectroscopy. Outliers were classified by using multivariate statistical analysis software, and relevant metabolites and pathways were worked out. The xanthatin IC rate defined 0.75 µg/mL base on macrophages viability and also activity of xanthatin on amastigotes showed the best leishmanicidal activity in IR and MI values of 53% and 62.5%, respectively. Xanthatin altered amino sugars and nucleotide sugars metabolism, starch and sucrose metabolism, cyanoamino acid, and galactose metabolism. Our finding revealed that the main target of xanthatin is carbon metabolism, which is an essential step for amastigotes virulence.
皮肤利什曼病由利什曼原虫属的原生动物引起，通过白蛉传播。这种疾病的标准疗法是一线药物五价锑剂和二线药物喷他脒、两性霉素B。多年来一直在使用这些药物，但它们都有不良毒性作用。草药衍生药物是治疗寄生虫病的一个有前景的潜在来源。山柑子萜内酯是一种黄原醇化物倍半萜内酯，从 中分离得到，在许多国家用于治疗多种疾病。在本研究中，我们通过基于代谢组学的分析，研究了山柑子萜内酯在J774巨噬细胞和 中的无鞭毛体阶段的杀利什曼原虫活性。通过核磁共振光谱法分离并鉴定了山柑子萜内酯。通过MTT法检测山柑子萜内酯对巨噬细胞的毒性。计算被前鞭毛体静止期感染的巨噬细胞的感染率（IR）和增殖指数（MI）。用山柑子萜内酯处理无菌无鞭毛体。进行细胞淬灭和代谢物提取，并用核磁共振光谱法分析代谢组图谱。使用多变量统计分析软件对异常值进行分类，并找出相关代谢物和代谢途径。基于巨噬细胞活力，山柑子萜内酯的IC率定义为0.75μg/mL，山柑子萜内酯对无鞭毛体的活性在IR和MI值分别为53%和62.5%时显示出最佳的杀利什曼原虫活性。山柑子萜内酯改变了氨基糖和核苷酸糖代谢、淀粉和蔗糖代谢、氰基氨基酸和半乳糖代谢。我们的研究结果表明，山柑子萜内酯的主要靶点是碳代谢，这是无鞭毛体毒力的一个关键步骤。
