Teixeira Samuel Cota, Paschoalino Marina, de Souza Guilherme, Rosini Alessandra Monteiro, de Lima Junior Joed Pires, Luz Luana Carvalho, Fajardo Martínez Aryani Felixa, Alves Rosiane Nascimento, Almeida Marcos Paulo Oliveira, Damasceno Jaqueline Lopes, Silva Marcelo José Barbosa, Ietta Francesca, Barbosa Bellisa Freitas, Ferro Eloisa Amália Vieira, Gomes Martins Carlos Henrique
Laboratory of Immunophysiology of Reproduction, Institute of Biomedical Sciences, Universidade Federal de Uberlândia, Uberlândia, MG, Brazil.
Department of Agricultural and Natural Sciences, Universidade do Estado de Minas Gerais, Ituiutaba, MG, Brazil.
Chem Biol Interact. 2023 Oct 1;384:110716. doi: 10.1016/j.cbi.2023.110716. Epub 2023 Sep 16.
Congenital toxoplasmosis, caused by the opportunistic protozoan parasite T. gondii, can cause stillbirths, miscarriages and fetal abnormalities, as well as encephalitis and chorioretinitis in newborns. Available treatment options rely on antiparasitic drugs that have been linked to serious side effects, high toxicity and the development of drug-resistant parasites. The search for alternative therapeutics to treat this disease without acute toxicity for the mother and child is essential for the advancement of current therapeutic procedures. The present study aimed to unravel the mode of the anti-T. gondii action of Rottlerin, a natural polyphenol with multiple pharmacological properties described. Herein, we further assessed the antiparasitic activity of Rottlerin against T. gondii infection on the human trophoblastic cells (BeWo cells) and, for the first time, on human villous explants. We found that non-cytotoxic doses of Rottlerin impaired early and late steps of parasite infection with an irreversible manner in BeWo cells. Rottlerin caused parasite cell cycle arrest in G1 phase and compromised the ability of tachyzoites to infect new cells, thus highlighting the possible direct action on parasites. An additional and non-exclusive mechanism of action of Rottlerin involves the modulation of host cell components, by affecting lipid droplet formation, mitochondrial function and upregulation of the IL-6 and MIF levels in BeWo cells. Supporting our findings, Rottlerin also controlled T. gondii proliferation in villous explants with low toxicity and reduced the IL-10 levels, a cytokine associated with parasite susceptibility. Collectively, our results highlighted the potential use of Rottlerin as a promising tool to prevent and/or treat congenital toxoplasmosis.
先天性弓形虫病由机会性原生动物寄生虫刚地弓形虫引起，可导致死产、流产和胎儿畸形，以及新生儿脑炎和脉络膜视网膜炎。现有的治疗选择依赖于抗寄生虫药物，这些药物与严重的副作用、高毒性以及耐药寄生虫的产生有关。寻找对母婴无急性毒性的替代疗法来治疗这种疾病对于当前治疗方法的进步至关重要。本研究旨在揭示具有多种药理特性的天然多酚rottlerin抗刚地弓形虫的作用模式。在此，我们进一步评估了rottlerin对人滋养层细胞（BeWo细胞）以及首次对人绒毛外植体的弓形虫感染的抗寄生虫活性。我们发现，非细胞毒性剂量的rottlerin以不可逆的方式损害了BeWo细胞中寄生虫感染的早期和晚期步骤。rottlerin导致寄生虫细胞周期停滞在G1期，并损害速殖子感染新细胞的能力，从而突出了其对寄生虫可能的直接作用。rottlerin的另一种非排他性作用机制涉及通过影响脂质小滴形成、线粒体功能以及上调BeWo细胞中IL-6和MIF水平来调节宿主细胞成分。支持我们的研究结果的是，rottlerin还以低毒性控制了绒毛外植体中弓形虫的增殖，并降低了与寄生虫易感性相关的细胞因子IL-10的水平。总体而言，我们的结果突出了rottlerin作为预防和/或治疗先天性弓形虫病的有前途工具的潜在用途。
