Dephosphorylation of Tak1 at Ser412 greatly contributes to the spermatocyte-specific testis toxicity induced by (5R)-5-hydroxytriptolide in C57BL/6 mice
文献类型：期刊论文
| 作者 | Qi, Xinming2 ; Li, Chunzhu2; Wu, Chunyong1; Yu, Cunzhi2; Liu, Mingxia2; Gao, Man2; Li, Chenggang2; Yan, Hong2; Ren, Jin2
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| 刊名 | TOXICOLOGY RESEARCH
 |
| 出版日期 | 2016 |
| 卷号 | 5期号:2页码:594-601 |
| ISSN号 | 2045-452X |
| DOI | 10.1039/c5tx00409h |
| 文献子类 | Article |
| 英文摘要 | (5R)-5-Hydroxytriptolide (LLDT-8), a novel triptolide derivative, will proceed to phase II clinical trials for the treatment of rheumatoid arthritis and cancer. However, the selection of disease and patients is largely limited by the testis toxicity, yet toxicity mechanisms are still poorly understood. In this study, LLDT-8 dose and time-dependently decreased the testes weight, germinal cell layers and induced abnormal spermatid development. Analysis of the germ cell-specific marker showed that spermatocytes were more sensitive to LLDT-8, which was confirmed by the in vitro sensitivity assay with spermatocyte-like GC-2spd and sertoli-like TM4 cells. In GC-2spd, LLDT-8 induced G1/S arrest and apoptosis. MAPK activity screening identified that TGF-beta activated kinase 1 (Tak1) is critical in LLDT-8 induced apoptosis. LLDT-8 reduced the Tak1 protein and dephosphorylated Tak1 at Ser412 in GC-2spd and the testes, but not in TM4. RNAi mediated depletion or pharmacologic inhibition of Tak1 induced apoptosis in GC-2spd. Meanwhile, activating Tak1 rescued up to 50% of the GC-2spd cells from the apoptosis induced by LLDT-8. Altogether, our study firstly revealed the important role of Tak1 in the survival of spermatocytes, and dephosphorylation of Tak1 at Ser412 may contribute to the spermatocyte-specific testis toxicity induced by LLDT-8. |
| WOS关键词 | POLYCYSTIC KIDNEY-DISEASE ; CELL-CYCLE ; CANCER CELLS ; GERM-CELLS ; IN-VIVO ; TRIPTOLIDE ; LLDT-8 ; APOPTOSIS ; SPERMATOGENESIS ; ACTIVATION |
| 资助项目 | National Natural Science Foundation of China[81102496] ; National Key Technologies RD Program[2012ZX09302-003] ; National Key Technologies RD Program[2012ZX09301-001-006] ; Natural Science Foundation of Jiangsu Province[BK2012358] |
| WOS研究方向 | Toxicology |
| 语种 | 英语 |
| 出版者 | ROYAL SOC CHEMISTRY |
| WOS记录号 | WOS:000371613300023 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276245]  |
| 专题 | 药物安全性评价中心 |
| 通讯作者 | Ren, Jin |
| 作者单位 | 1.China Pharmaceut Univ, Sch Pharm, Dept Pharmaceut Anal, Shanghai, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab New Drug Res, Ctr Drug Safety Evaluat & Res, 501 Haike Rd, Shanghai 201203, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Qi, Xinming,Li, Chunzhu,Wu, Chunyong,et al. Dephosphorylation of Tak1 at Ser412 greatly contributes to the spermatocyte-specific testis toxicity induced by (5R)-5-hydroxytriptolide in C57BL/6 mice[J]. TOXICOLOGY RESEARCH,2016,5(2):594-601. |
| APA | Qi, Xinming.,Li, Chunzhu.,Wu, Chunyong.,Yu, Cunzhi.,Liu, Mingxia.,...&Ren, Jin.(2016).Dephosphorylation of Tak1 at Ser412 greatly contributes to the spermatocyte-specific testis toxicity induced by (5R)-5-hydroxytriptolide in C57BL/6 mice.TOXICOLOGY RESEARCH,5(2),594-601. |
| MLA | Qi, Xinming,et al."Dephosphorylation of Tak1 at Ser412 greatly contributes to the spermatocyte-specific testis toxicity induced by (5R)-5-hydroxytriptolide in C57BL/6 mice".TOXICOLOGY RESEARCH 5.2(2016):594-601. |
入库方式： OAI收割
来源：上海药物研究所
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