State Key Laboratory of Pathogenesis, Prevention, and Treatment of Central Asian High Incidence Diseases, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China.
Xinjiang Key Laboratory of Echinococcosis, WHO-Collaborating Centre, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China.
Antimicrob Agents Chemother. 2018 Dec 21;63(1). doi: 10.1128/AAC.01043-18. Print 2019 Jan.
Cystic echinococcosis is a zoonosis caused by the larval stage of There is an urgent need to develop new drugs for the treatment of this disease. In this study, we identified two new members of mitogen-activated protein kinase (MAPK) cascades, MKK3/6 and MEK1/2 homologs (termed EgMKK1 and EgMKK2, respectively), from Both EgMKK1 and EgMKK2 were expressed at the larval stages. As shown by yeast two-hybrid and coimmunoprecipitation analyses, EgMKK1 interacted with the previously identified Egp38 protein but not with EgERK. EgMKK2, on the other hand, interacted with EgERK. In addition, EgMKK1 and EgMKK2 displayed kinase activity toward the substrate myelin basic protein. When sorafenib tosylate, PD184352, or U0126-ethanol (EtOH) was added to the medium for culture of protoscoleces (PSCs) or cysts, an inhibitory and cytolytic effect was observed via suppressed phosphorylation of EgMKKs and EgERK. Nonviability of PSCs treated with sorafenib tosylate or U0126-EtOH, and not with PD184352, was confirmed through bioassays, i.e., inoculation of treated and untreated protoscoleces into mice. treatment of -infected mice with sorafenib tosylate or U0126-EtOH for 4 weeks demonstrated a reduction in parasite weight, but the results did not show a significant difference. In conclusion, the MAPK cascades were identified as new targets for drug development, and was efficiently inhibited by their inhibitors The translation of these findings into efficacy requires further adjustment of treatment regimens using sorafenib tosylate or, possibly, other kinase inhibitors.
泡球蚴病是一种由幼虫阶段引起的人畜共患病。因此，迫切需要开发新的药物来治疗这种疾病。在这项研究中，我们从细粒棘球蚴中鉴定出两种丝裂原活化蛋白激酶（MAPK）级联反应的新成员，MKK3/6 和 MEK1/2 同源物（分别命名为 EgMKK1 和 EgMKK2）。这两种蛋白均在幼虫阶段表达。酵母双杂交和共免疫沉淀分析表明，EgMKK1 与先前鉴定的 Egp38 蛋白相互作用，但不与 EgERK 相互作用。另一方面，EgMKK2 与 EgERK 相互作用。此外，EgMKK1 和 EgMKK2 对髓鞘碱性蛋白底物表现出激酶活性。当甲苯磺酸索拉非尼、PD184352 或 U0126-乙醇（EtOH）添加到原头节（PSCs）或包囊的培养基中时，EgMKKs 和 EgERK 的磷酸化受到抑制，表现出抑制和细胞溶解作用。甲苯磺酸索拉非尼或 U0126-EtOH 处理的 PSCs 失去活力，但 PD184352 处理的 PSCs 未失去活力，通过生物测定（即接种处理和未处理的原头节到小鼠体内）得到证实。用甲苯磺酸索拉非尼或 U0126-EtOH 治疗感染的小鼠 4 周，显示寄生虫重量减少，但结果未显示出显著差异。总之，MAPK 级联反应被确定为药物开发的新靶点，其抑制剂能有效抑制。将这些发现转化为临床疗效需要进一步调整甲苯磺酸索拉非尼或其他激酶抑制剂的治疗方案。
