Isatin Improves Oligoasthenospermia Caused by Busulfan by Regulating GSH/GPX4 Axis to Inhibit Ferroptosis

Overview

Journal Front Pharmacol

Date 2024 Nov 15

PMID 39545065

Authors

Chengniu Wang

Weizhen Wang

Jin Dong

Xiaoran Li

Taowen Ye

Fanshuo Zeng

Mingyu Jiang

Jianwu Shi

Xiaorong Wang

Lei Zhang

Affiliations

Soon will be listed here.

Abstract

Introduction: Ferroptosis, induced by iron overload and an imbalance in redox homeostasis, promotes the generation of reactive oxygen species (ROS), leading to iron-dependent lipid peroxides (LPO) and oxidative stress. Lipid peroxidation induced by reactive oxygen species is essential for the progression of spermatogenesis. However, its imbalance can lead to reproductive system damage and oligoasthenospermia, a critical cause of oligoasthenospermia. Isatin (ISA) is a naturally occurring compound that is widely distributed in lobsters, crustaceans, shellfish and various plants. It exhibits significant antioxidant and anti-aging properties, suggesting its potential as a therapeutic agent for the treatment of oligoasthenospermia. This study aimed to investigate the effects and mechanisms of ISA on oligoasthenospermia and to elucidate the underlying molecular pathways.

Methods: All mice were divided into normal group, model group and treatment group. Both model group and treatment group received a single intraperitoneal injection of 30 mg/kg BUS to create the model of oligoasthenospermia. After 2 weeks, the treatment group received different doses of 25, 50 and 100 mg/kg ISA by gavage for 28 days, and then mice were sacrificed and tested.

Results: The results demonstrated that ISA effectively reversed busulfan-induced reproductive system damage in mice. This included the restoration of testicular histomorphology, improvement in sperm concentration and motility, regulation of serum sex hormone levels, and normalization of various oxidative indices in testicular tissue. Furthermore, ISA successfully reversed testicular ferroptosis by restraining the translocation of nuclear factor erythroid 2-related factor 2 (NRF2) into the nucleus and improved oligoasthenospermia through the glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis.

Discussion: ISA was found to effectively ameliorate oligoasthenospermia in mice, presenting a potential therapeutic option for patients with this condition.

References

Storey B . Biochemistry of the induction and prevention of lipoperoxidative damage in human spermatozoa. Mol Hum Reprod. 1997; 3(3):203-13. DOI: 10.1093/molehr/3.3.203. View

Zhao X, Sang M, Han P, Gao J, Liu Z, Li H . Peptides from the croceine croaker () swim bladder attenuate busulfan-induced oligoasthenospermia in mice. Pharm Biol. 2022; 60(1):319-325. PMC: 8843205. DOI: 10.1080/13880209.2022.2034895. View

Tawfik N, Mohamed W, Mahmoud H, Alqarni M, Naguib I, Fahmy A . Isatin Counteracts Diethylnitrosamine/2-Acetylaminofluorene-Induced Hepatocarcinogenesis in Male Wistar Rats by Upregulating Anti-Inflammatory, Antioxidant, and Detoxification Pathways. Antioxidants (Basel). 2022; 11(4). PMC: 9027254. DOI: 10.3390/antiox11040699. View

Zheng J, Conrad M . The Metabolic Underpinnings of Ferroptosis. Cell Metab. 2020; 32(6):920-937. DOI: 10.1016/j.cmet.2020.10.011. View

Gil-Turnes M, Hay M, Fenical W . Symbiotic marine bacteria chemically defend crustacean embryos from a pathogenic fungus. Science. 1989; 246(4926):116-8. DOI: 10.1126/science.2781297. View

Dai X, Zhang Q, Yu Z, Sun W, Wang R, Miao D . Deficient Mice Exhibit Male Infertility. Int J Biol Sci. 2018; 14(3):358-368. PMC: 5859480. DOI: 10.7150/ijbs.23325. View

Hou L, Ju C, Zhang J, Song J, Ge Y, Yue W . Antitumor effects of Isatin on human neuroblastoma cell line (SH-SY5Y) and the related mechanism. Eur J Pharmacol. 2008; 589(1-3):27-31. DOI: 10.1016/j.ejphar.2008.04.061. View

Sriram D, Bal T, Yogeeswari P . Design, synthesis and biological evaluation of novel non-nucleoside HIV-1 reverse transcriptase inhibitors with broad-spectrum chemotherapeutic properties. Bioorg Med Chem. 2004; 12(22):5865-73. DOI: 10.1016/j.bmc.2004.08.028. View

Gan B . ACSL4, PUFA, and ferroptosis: new arsenal in anti-tumor immunity. Signal Transduct Target Ther. 2022; 7(1):128. PMC: 9033814. DOI: 10.1038/s41392-022-01004-z. View

10.

Shen L, Zhang J, Zheng Z, Yang F, Liu S, Wu Y . PHGDH Inhibits Ferroptosis and Promotes Malignant Progression by Upregulating SLC7A11 in Bladder Cancer. Int J Biol Sci. 2022; 18(14):5459-5474. PMC: 9461664. DOI: 10.7150/ijbs.74546. View

11.

Zhao Y, Zhang P, Ge W, Feng Y, Li L, Sun Z . Alginate oligosaccharides improve germ cell development and testicular microenvironment to rescue busulfan disrupted spermatogenesis. Theranostics. 2020; 10(7):3308-3324. PMC: 7053202. DOI: 10.7150/thno.43189. View

12.

Wang D, Zhou X, Yuan Y, Zheng X . Optimal dose of busulfan for depleting testicular germ cells of recipient mice before spermatogonial transplantation. Asian J Androl. 2009; 12(2):263-70. PMC: 3739084. DOI: 10.1038/aja.2009.67. View

13.

Metzendorf C, Lind M . Drosophila mitoferrin is essential for male fertility: evidence for a role of mitochondrial iron metabolism during spermatogenesis. BMC Dev Biol. 2010; 10:68. PMC: 2905335. DOI: 10.1186/1471-213X-10-68. View

14.

Rochdi C, Ouadrhiri M, Allai L, Bellajdel I, Mamri S, Taheri H . Beneficial effects of oral antioxidant supplementation on semen quality parameters, reproductive hormones, and sperm DNA integrity in men with idiopathic oligoasthenoteratozoospermia. Clin Exp Reprod Med. 2024; 51(2):135-141. PMC: 11140257. DOI: 10.5653/cerm.2023.06555. View

15.

Yang R, Gao W, Wang Z, Jian H, Peng L, Yu X . Polyphyllin I induced ferroptosis to suppress the progression of hepatocellular carcinoma through activation of the mitochondrial dysfunction via Nrf2/HO-1/GPX4 axis. Phytomedicine. 2023; 122:155135. DOI: 10.1016/j.phymed.2023.155135. View

16.

Liu S, Gao Z, He W, Wu Y, Liu J, Zhang S . The gut microbiota metabolite glycochenodeoxycholate activates TFR-ACSL4-mediated ferroptosis to promote the development of environmental toxin-linked MAFLD. Free Radic Biol Med. 2022; 193(Pt 1):213-226. DOI: 10.1016/j.freeradbiomed.2022.10.270. View

17.

Laird A, Vajkoczy P, Shawver L, Thurnher A, Liang C, Mohammadi M . SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. Cancer Res. 2000; 60(15):4152-60. View

18.

Alahmar A . The Effect of Selenium Therapy on Semen Parameters, Antioxidant Capacity, and Sperm DNA Fragmentation in Men with Idiopathic Oligoasthenoteratospermia. Biol Trace Elem Res. 2023; 201(12):5671-5676. DOI: 10.1007/s12011-023-03638-8. View

19.

Lahimer M, Gherissi O, Ben Salem N, Ben Mustapha H, Bach V, Khorsi-Cauet H . Effect of Micronutrients and L-Carnitine as Antioxidant on Sperm Parameters, Genome Integrity, and ICSI Outcomes: Randomized, Double-Blind, and Placebo-Controlled Clinical Trial. Antioxidants (Basel). 2023; 12(11). PMC: 10669279. DOI: 10.3390/antiox12111937. View

20.

Chen L, Ma Y, Ma X, Liu L, Jv X, Li A . TFEB regulates cellular labile iron and prevents ferroptosis in a TfR1-dependent manner. Free Radic Biol Med. 2023; 208:445-457. DOI: 10.1016/j.freeradbiomed.2023.09.004. View