Identification of Functional MKK3/6 and MEK1/2 Homologs from Echinococcus granulosus and Investigation of Protoscolecidal Activity of Mitogen-Activated Protein Kinase Signaling Pathway Inhibitors In Vitro and In Vivo
Identification of Functional MKK3/6 and MEK1/2 Homologs from Echinococcus granulosus and Investigation of Protoscolecidal Activity of Mitogen-Activated Protein Kinase Signaling Pathway Inhibitors In Vitro and In Vivo
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细粒棘球绦虫功能性 MKK3/6 和 MEK1/2 同源物的鉴定以及丝裂原激活蛋白激酶信号通路抑制剂体外和体内杀原头球菌活性的研究
DOI：
10.1128/aac.01043-18
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发表时间：
2018-10
影响因子：
4.9
通讯作者：
Renyong Lin
中科院分区：
文献类型：
--
作者：
Chuanshan Zhang;Jing Li;Tuerganaili Aji;Liang Li;Xiaojuan Bi;Ning Yang;Zhide Li;Hui Wang;Rui Mao;Guodong Lü;Yingmei Shao;Dominique A Vuitton;Hao Wen;Renyong Lin
囊状棘球蚴病是一种人畜共患病，由广义细粒棘球蚴的幼虫阶段引起。迫切需要开发治疗这种疾病的新药。囊型棘球蚴病是由广义细粒棘球蚴幼虫引起的人畜共患病。迫切需要开发治疗这种疾病的新药。在本研究中，我们从大肠杆菌中鉴定了两个新的丝裂原活化蛋白激酶（MAPK）级联反应成员，MKK 3/6和MEK 1/2同源物（分别称为EgMKK 1和EgMKK 2）。严格意义上的颗粒体EgMKK 1和EgMKK 2均在幼虫期表达。如酵母双杂交和免疫共沉淀分析所示，EgMKK 1与先前鉴定的Egp 38蛋白相互作用，但不与EgERK相互作用。另一方面，EgMKK 2与EgERK相互作用。此外，EgMKK 1和EgMKK 2对底物髓鞘碱性蛋白表现出激酶活性。当在培养基中加入甲苯磺酸索拉非尼、PD 184352或U 0126-乙醇（EtOH）进行E.在颗粒状原核细胞（PSC）或包囊中，通过抑制EgMKK和EgERK的磷酸化观察到抑制和细胞溶解作用。通过生物测定证实了用甲苯磺酸索拉非尼或U 0126-EtOH处理而不用PD 184352处理的PSC的无活力，即，将处理的和未处理的原球茎接种到小鼠中。体内处理E.用甲苯磺酸索拉非尼或U 0126-EtOH感染严格意义上的细粒棘球绦虫4周的小鼠显示寄生虫重量减少，但结果未显示显著差异。总之，MAPK级联被确定为药物开发的新靶点，E。在体外，它们的抑制剂有效地抑制了颗粒细胞。将这些发现转化为体内疗效需要使用甲苯磺酸索拉非尼或可能的其他激酶抑制剂进一步调整治疗方案。
Cystic echinococcosis is a zoonosis caused by the larval stage of Echinococcus granulosus sensu lato. There is an urgent need to develop new drugs for the treatment of this disease. ABSTRACT Cystic echinococcosis is a zoonosis caused by the larval stage of Echinococcus granulosus sensu lato. 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 E. granulosus sensu stricto. 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 in vitro culture of E. granulosus 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. In vivo treatment of E. granulosus sensu stricto-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 E. granulosus was efficiently inhibited by their inhibitors in vitro. The translation of these findings into in vivo efficacy requires further adjustment of treatment regimens using sorafenib tosylate or, possibly, other kinase inhibitors.
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影响因子：
2.1
作者：
Brumlik, Michael J.;Nkhoma, Standwell;Kious, Mark J.;Thompson, George R., III;Patterson, Thomas F.;Siekierka, John J.;Anderson, Tim J. C.;Curiel, Tyler J.
通讯作者：
Curiel, Tyler J.
影响因子：
5.4
作者：
Hemer S;Konrad C;Spiliotis M;Koziol U;Schaack D;Förster S;Gelmedin V;Stadelmann B;Dandekar T;Hemphill A;Brehm K
通讯作者：
Brehm K
影响因子：
64.8
作者：
Kato N;Comer E;Sakata-Kato T;Sharma A;Sharma M;Maetani M;Bastien J;Brancucci NM;Bittker JA;Corey V;Clarke D;Derbyshire ER;Dornan GL;Duffy S;Eckley S;Itoe MA;Koolen KM;Lewis TA;Lui PS;Lukens AK;Lund E;March S;Meibalan E;Meier BC;McPhail JA;Mitasev B;Moss EL;Sayes M;Van Gessel Y;Wawer MJ;Yoshinaga T;Zeeman AM;Avery VM;Bhatia SN;Burke JE;Catteruccia F;Clardy JC;Clemons PA;Dechering KJ;Duvall JR;Foley MA;Gusovsky F;Kocken CH;Marti M;Morningstar ML;Munoz B;Neafsey DE;Sharma A;Winzeler EA;Wirth DF;Scherer CA;Schreiber SL
通讯作者：
Schreiber SL
影响因子：
6.8
作者：
Rauch, Nora;Rukhlenko, Oleksii S.;Kholodenko, Boris N.
通讯作者：
Kholodenko, Boris N.
DOI：
10.1096/fj.00-0102rev
发表时间：
2000-11
期刊：
The FASEB Journal
影响因子：
--
作者：
M. Wilkinson;J. Millar
通讯作者：
M. Wilkinson;J. Millar