Singh Sakshi, Subudhi Madhusmita, Moorthy A Vengatachala, Suresh Akash, Sharma Paresh
National Institute of Animal Biotechnology, Hyderabad, 500032, India; Graduate Studies, Regional Centre for Biotechnology (RCB), Faridabad, 121001, India.
National Institute of Animal Biotechnology, Hyderabad, 500032, India.
Int J Parasitol Drugs Drug Resist. 2025 Apr 14;28:100593. doi: 10.1016/j.ijpddr.2025.100593.
This study explores the anti-proliferative and anti-parasitic properties of ursolic acid (UA) in Theileria annulata-infected bovine (TA) cells. Dose-response analyses determined an IC value of approximately 5 μg/mL for UA, demonstrating selective cytotoxicity toward infected cells with minimal impact on healthy cells. UA treatment induced pronounced morphological alterations and apoptosis in TA cells, as evidenced by light microscopy and a time-dependent increase in cell mortality. Notably, UA exhibited consistent efficacy against both buparvaquone (BPQ)-sensitive and BPQ-resistant TA cell lines, highlighting its broad-spectrum anti-parasitic potential. Mechanistic investigations revealed that UA triggers DNA damage, elevates reactive oxygen species (ROS) levels, disrupts mitochondrial function, and induces sub-G1 phase arrest, culminating in apoptosis primarily via the intrinsic pathway. Mass spectrometry-based proteomic profiling identified significant perturbations in host cell pathways, including DNA repair mechanisms, cell cycle regulation, and signaling networks, alongside direct interference with parasite metabolic processes. Western blot analysis further confirmed UA-mediated modulation of host cell signaling pathways and chromatin organization. Given the rising incidence of drug-resistant T. annulata strains, the development of novel therapeutic strategies is imperative. These findings highlight UA's multifaceted mechanism of action, targeting both parasitic and host cellular processes, and position it as a promising candidate for the treatment of bovine theileriosis.
本研究探讨了熊果酸（UA）对环形泰勒虫感染的牛（TA）细胞的抗增殖和抗寄生虫特性。剂量反应分析确定UA的IC值约为5μg/mL，表明其对感染细胞具有选择性细胞毒性，对健康细胞影响最小。UA处理诱导TA细胞出现明显的形态改变和凋亡，光学显微镜观察以及细胞死亡率随时间的增加证明了这一点。值得注意的是，UA对布帕喹（BPQ）敏感和BPQ耐药的TA细胞系均表现出一致的疗效，突出了其广谱抗寄生虫潜力。机制研究表明，UA引发DNA损伤，提高活性氧（ROS）水平，破坏线粒体功能，并诱导亚G1期停滞，最终主要通过内源性途径导致凋亡。基于质谱的蛋白质组学分析确定宿主细胞途径存在显著扰动，包括DNA修复机制、细胞周期调控和信号网络，同时直接干扰寄生虫代谢过程。蛋白质印迹分析进一步证实了UA介导的宿主细胞信号通路和染色质组织的调节。鉴于耐药环形泰勒虫菌株的发病率不断上升，开发新的治疗策略势在必行。这些发现突出了UA多方面的作用机制，靶向寄生虫和宿主细胞过程，并使其成为治疗牛泰勒虫病的有希望的候选药物。
