دورية أكاديمية
أعرض في EDS

Triptolide induced spermatogenesis dysfunction via ferroptosis activation by promoting K63-linked GPX4 polyubiquitination in spermatocytes.

التفاصيل البيبلوغرافية
العنوان: Triptolide induced spermatogenesis dysfunction via ferroptosis activation by promoting K63-linked GPX4 polyubiquitination in spermatocytes.
المؤلفون: Li J; School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 210009, People's Republic of China., Chen D; School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 210009, People's Republic of China., Suo J; School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 210009, People's Republic of China., Li J; School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 210009, People's Republic of China., Zhang Y; School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 210009, People's Republic of China., Wang Y; School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 210009, People's Republic of China., Deng Z; School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 210009, People's Republic of China., Zhang Q; School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 210009, People's Republic of China. Electronic address: nancyzhang03@hotmail.com., Ma B; School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 210009, People's Republic of China. Electronic address: mabo201012@njtech.edu.cn.
المصدر: Chemico-biological interactions [Chem Biol Interact] 2024 Aug 25; Vol. 399, pp. 111130. Date of Electronic Publication: 2024 Jul 02.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Country of Publication: Ireland NLM ID: 0227276 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-7786 (Electronic) Linking ISSN: 00092797 NLM ISO Abbreviation: Chem Biol Interact Subsets: MEDLINE
أسماء مطبوعة: Publication: Limerick : Elsevier
Original Publication: Amsterdam, Elsevier.
مواضيع طبية MeSH: Phenanthrenes*/pharmacology , Spermatogenesis*/drug effects , Diterpenes*/pharmacology , Epoxy Compounds*/toxicity , Phospholipid Hydroperoxide Glutathione Peroxidase*/metabolism , Phospholipid Hydroperoxide Glutathione Peroxidase*/genetics , Ferroptosis*/drug effects , Spermatocytes*/drug effects , Spermatocytes*/metabolism , Ubiquitination*/drug effects, Male ; Animals ; Mice ; Testis/drug effects ; Testis/metabolism ; Testis/pathology ; Cell Line ; Reactive Oxygen Species/metabolism ; Membrane Potential, Mitochondrial/drug effects ; DNA Damage/drug effects ; Lysine/metabolism ; Lipid Peroxidation/drug effects
مستخلص: Triptolide (TP) is a major bioactive compound derived from Tripterygium wilfordii Hook. F. (TwHF) known for its medicinal properties, but it also exhibits potential toxic effects. It has been demonstrated to induce severe male reproductive toxicity, yet the precise mechanism behind this remains unclear, which limits its broad clinical application. This study aimed to investigate the mechanisms underlying testicular damage and spermatogenesis dysfunction induced by TP in mice, using both mouse models and the spermatocyte-derived cell line GC-2spd. In the present study, it was found that TP displayed significant testicular microstructure damaged and spermatogenesis defects including lower concentration and abnormal morphology by promoting ROS formation, MDA production and restraining GSH level, glutathione peroxidase 4 (GPX4) expression in vivo. Furthermore, Ferrostatin-1 (FER-1), a ferroptosis inhibitor, was found to significantly reduce the accumulation of lipid peroxidation, alleviate testicular microstructural damage, and enhance spermatogenic function in mice. Besides, notably decreased cell viability, collapsed mitochondrial membrane potential, and elevated DNA damage were observed in vitro. The above-mentioned phenomenon could be reversed by pre-treatment of FER-1, indicating that ferroptosis participated in the TP-mediated spermatogenesis dysfunction. Mechanistically, TP could enhance GPX4 ubiquitin degradation via triggering K63-linked polyubiquitination of GPX4, thereby stimulating ferroptosis in spermatocytes. Functionally, GPX4 deletion intensified ferroptosis and exacerbated DNA damage in GC-2 cells, while GPX4 overexpression mitigated ferroptosis induced by TP. Overall, these findings for the first time indicated a vital role of ferroptosis in TP induced-testicular injury and spermatogenic dysfunction through promoting GPX4 K63-linked polyubiquitination, which hopefully offers a potential therapeutic avenue for TP-related male reproductive damage. In addition, this study also provides a theoretical foundation for the improved clinical application of TP or TwHF in the future.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
فهرسة مساهمة: Keywords: Ferroptosis; GPX4; Male reproductive toxicity; Spermatogenesis dysfunction; Triptolide; Ubiquitination
المشرفين على المادة: 0 (Phenanthrenes)
19ALD1S53J (triptolide)
0 (Diterpenes)
0 (Epoxy Compounds)
EC 1.11.1.12 (Phospholipid Hydroperoxide Glutathione Peroxidase)
EC 1.11.1.9 (glutathione peroxidase 4, mouse)
0 (Reactive Oxygen Species)
K3Z4F929H6 (Lysine)
تواريخ الأحداث: Date Created: 20240703 Date Completed: 20240731 Latest Revision: 20240731
رمز التحديث: 20240801
DOI: 10.1016/j.cbi.2024.111130
PMID: 38960301
قاعدة البيانات: MEDLINE
الوصف
تدمد:1872-7786
DOI:10.1016/j.cbi.2024.111130