PMID- 36928896 OWN - NLM STAT- MEDLINE DCOM- 20231010 LR - 20240124 IS - 1933-7205 (Electronic) IS - 1933-7191 (Linking) VI - 30 IP - 10 DP - 2023 Oct TI - 6-(7-Nitro-2,1,3-benzoxadiazol-4-ylthio) Hexanol Inhibits Proliferation and Induces Apoptosis of Endometriosis by Regulating Glutathione S-Transferase Mu Class 4. PG - 2945-2961 LID - 10.1007/s43032-023-01207-x [doi] AB - Endometriosis is a chronic disease associated with a disrupted oxidative balance and chronic inflammation. In this study, we investigated the role of glutathione S-transferase Mu class 4 (GSTM4) in endometriosis and determined whether 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio) hexanol (NBDHEX) regulates GSTM4 expression to affect cellular functions and oxidative stress. GSTM4 expression was detected by immunohistochemistry in endometrium from 15 endometriosis patients and 15 healthy controls. Western blotting was used to detect the expression of GSTM4, proliferating cell nuclear antigen (PCNA), matrix metalloproteinase-9 (MMP-9), Survivin, B-cell lymphoma-extra-large (Bcl-XL), Bax, kelch-like ECH-associated protein 1 (Keap1), and nuclear factor-erythroid 2-related factor 2 (Nrf2) in primary endometrial stromal cells with endometriosis (EESC) and normal endometrial stromal cells (NESC). The effects of NBDHEX on cell proliferation, migration, and invasion were evaluated using Cell Counting Kit-8 (CCK8) and Transwell assays. Apoptosis was detected by flow cytometry. The expression of GSTM4 was significantly increased in endometrium from endometriosis patients. Upon NBDHEX treatment, ESC exhibited reduced proliferation, migration and invasion abilities, and increased apoptosis. NBDHEX decreased the expression of endometriosis prognostic markers (PCNA and MMP-9) and anti-apoptotic proteins (Survivin and Bcl-xl), while it increased the expression of the apoptotic protein Bax. It had no effect on Keap1 expression, and it decreased the expression of Nrf2. The effect of siRNA-mediated knockdown of GSTM4 was similar to that of suppressing GSTM4 expression with NBDHEX treatment. These results indicate that GSTM4 is highly expressed in endometriosis and its expression is inhibited by NBDHEX. Decreased expression of GSTM4 inhibits cell growth, migration, and invasion, and negatively regulates Nrf2 to affect oxidative stress-induced apoptosis. Our results suggest that GSTM4 may play a role in ameliorating the progression of endometriosis. NBDHEX may have therapeutic potential in the treatment of endometriosis. CI - (c) 2023. The Author(s), under exclusive licence to Society for Reproductive Investigation. FAU - Liu, Wei AU - Liu W AD - Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China. AD - Department of Obstetrics and Gynecology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical, University, Taiyuan, 030032, Shanxi, China. AD - Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, 250012, Shandong, China. AD - Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. FAU - Cheng, Lei AU - Cheng L AD - Department of Gynecology Oncology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, 266035, China. FAU - Du, Yanbo AU - Du Y AD - Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China. AD - Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, 250012, Shandong, China. FAU - Liu, Xiaoqiang AU - Liu X AD - Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China. AD - Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, 250012, Shandong, China. AD - Reproductive Medicine Center, Qingdao Women and Children's Hospital, Qingdao, 266034, Shandong, China. FAU - Ma, Jinlong AU - Ma J AD - Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China. AD - Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, 250012, Shandong, China. FAU - Yan, Lei AU - Yan L AUID- ORCID: 0000-0003-2156-1483 AD - Center for Reproductive Medicine, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China. yanlei@sdu.edu.cn. AD - Key Laboratory of Reproductive Endocrinology of Ministry of Education, Shandong University, Jinan, 250012, Shandong, China. yanlei@sdu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230316 PL - United States TA - Reprod Sci JT - Reproductive sciences (Thousand Oaks, Calif.) JID - 101291249 RN - 0 (bcl-2-Associated X Protein) RN - EC 2.5.1.18 (Glutathione Transferase) RN - 0 (Hexanols) RN - 0 (Kelch-Like ECH-Associated Protein 1) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) RN - 0 (NF-E2-Related Factor 2) RN - 0 (Proliferating Cell Nuclear Antigen) RN - 0 (Survivin) SB - IM MH - Female MH - Humans MH - Apoptosis MH - bcl-2-Associated X Protein/metabolism MH - Cell Proliferation MH - *Endometriosis/drug therapy/metabolism MH - Endometrium/metabolism MH - Glutathione Transferase/metabolism MH - Hexanols/pharmacology MH - Kelch-Like ECH-Associated Protein 1/metabolism MH - *Matrix Metalloproteinase 9/metabolism MH - NF-E2-Related Factor 2/metabolism MH - Proliferating Cell Nuclear Antigen/metabolism MH - Stromal Cells/metabolism MH - Survivin/metabolism OTO - NOTNLM OT - Apoptosis OT - Endometriosis OT - GSTM4 OT - NBDHEX OT - Nrf2 EDAT- 2023/03/18 06:00 MHDA- 2023/10/09 06:42 CRDT- 2023/03/17 09:36 PHST- 2022/10/13 00:00 [received] PHST- 2023/02/28 00:00 [accepted] PHST- 2023/10/09 06:42 [medline] PHST- 2023/03/18 06:00 [pubmed] PHST- 2023/03/17 09:36 [entrez] AID - 10.1007/s43032-023-01207-x [pii] AID - 10.1007/s43032-023-01207-x [doi] PST - ppublish SO - Reprod Sci. 2023 Oct;30(10):2945-2961. doi: 10.1007/s43032-023-01207-x. Epub 2023 Mar 16.