Online ISSN: 2149-3189
2015
Monthly
Nicaea Medical Publishing
Türkiye

In Vivo Evaluation of [Gly14]-Humanin's Protective Effect Against Cisplatin-Induced Ototoxicity

Murat Yaşar, Sedat Gökmen, Fatma Atalay, İrfan Çınar, Yusuf Aydin, Musa Tatar
DOI
https://doi.org/10.18621/eurj.1803088
Abstract
Objectives: This study aimed to evaluate in vivo the potential protective effects of [Gly14]-humanin against cisplatin-induced ototoxicity (CIO) and its modulatory effects against oxidative stress, inflammatory, and apoptotic markers
Methods: Thirty-five male Balb/c mice were randomly divided into five groups: control, cisplatin, cisplatin + [Gly14]-humanin (3 mg/kg), cisplatin + (6 mg/kg), and vitamin E. Cisplatin (10 mg/kg, b.w.) was administered as a single dose. [Gly14]-humanin was administered intraperitoneally for 14 days. Biochemical analyses (Superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA)), gene expression levels (TNF-α, IL-1β, IL-6, CASP-3, CASP-9, Bcl-2/Bax), and histopathological examinations (PARP1, PARP2 immunoreactivity) were performed in cochlear tissue samples to evaluate oxidative stress, inflammation, and apoptosis.
Results: Cisplatin decreased SOD and GSH levels and increased MDA levels in the cochlear tissue (P<0.05). With the application of [Gly14]-humanin, these parameters approached their normal levels. Cisplatin increased the values of pro-inflammatory and pro-apoptotic markers (TNF-α, IL-1β, IL-6, Caspase-3 (CAS-3), Caspase-9 (CAS-9)) significantly while reducing the Bcl-2/Bax ratio (P<0.05). [Gly14]-humanin administration reversed these effects in a dose-dependent manner. Histological analysis also revealed decreased PARP1 and PARP2 immunoreactivity in [Gly14]-humanin treated groups, comparable to the positive control (vitamin E).
Conclusions: The findings of this study show that [Gly14]-humanin exhibits important protective effects against CIO by attenuating oxidative stress, inflammation, and apoptosis in cochlear tissues. Further studies evaluating the clinical efficacy and reliability of [Gly14]-humanin are now needed.
Keywords
[Gly14]-Humanin, Cisplatin, Ototoxicity, Oxidative Stress, Cochlear Protection
References

1. Tang Q, Wang X, Jin H, et al. Cisplatin-induced ototoxicity: Updates on molecular mechanisms and otoprotective strategies. Eur J Pharm Biopharm. 2021;163:60-71. doi: 10.1016/j.ejpb.2021.03.008.

2. Rybak LP, Whitworth CA, Mukherjea D, Ramkumar V. Mechanisms of cisplatin-induced ototoxicity and prevention. Hear Res. 2007;226(1-2):157-67. doi: 10.1016/j.heares.2006.09.015.

3. Nagy JL, Adelstein DJ, Newman CW, Rybicki LA, Rice TW, Lavertu P. Cisplatin ototoxicity: the importance of baseline audiometry. Am J Clin Oncol. 1999;22(3):305-308. doi: 10.1097/00000421-199906000-00020.

4. Dai D, Chen C, Lu C, Guo Y, Li Q, Sun C. Apoptosis, autophagy, ferroptosis, and pyroptosis in cisplatin-induced ototoxicity and protective agents. Front Pharmacol. 2024;15:1430469. doi: 10.3389/fphar.2024.1430469.

5. Sheth S, Mukherjea D, Rybak LP, Ramkumar V. Mechanisms of Cisplatin-Induced Ototoxicity and Otoprotection. Front Cell Neurosci. 2017;11:338. doi: 10.3389/fncel.2017.00338.

6. Liu Z, Zhang H, Hong G, et al. Inhibition of Gpx4-mediated ferroptosis alleviates cisplatin-induced hearing loss in C57BL/6 mice. Mol Ther. 2024;32(5):1387-1406. doi: 10.1016/j.ymthe.2024.02.029.

7. Xu B, Li J, Chen X, Kou M. Puerarin attenuates cisplatin-induced apoptosis of hair cells through the mitochondrial apoptotic pathway. Biochim Biophys Acta Mol Cell Res. 2022;1869(4):119208. doi: 10.1016/j.bbamcr.2021.119208.

8. Lu X, Deng T, Dong H, et al. Novel Application of Eupatilin for Effectively Attenuating Cisplatin-Induced Auditory Hair Cell Death via Mitochondrial Apoptosis Pathway. Oxid Med Cell Longev. 2022;2022:1090034. doi: 10.1155/2022/1090034.

9. Ramkumar V, Mukherjea D, Dhukhwa A, Rybak LP. Oxidative Stress and Inflammation Caused by Cisplatin Ototoxicity. Antioxidants (Basel). 2021;10(12):1919. doi: 10.3390/antiox10121919.

10. Finkel T. Signal transduction by reactive oxygen species. J Cell Biol. 2011;194(1):7-15. doi: 10.1083/jcb.201102095.

11. Sies H, Belousov VV, Chandel NS, et al. Defining roles of specific reactive oxygen species (ROS) in cell biology and physiology. Nat Rev Mol Cell Biol. 2022;23(7):499-515. doi: 10.1038/s41580-022-00456-z.

12. Gentilin E, Simoni E, Candito M, Cazzador D, Astolfi L. Cisplatin-Induced Ototoxicity: Updates on Molecular Targets. Trends Mol Med. 2019;25(12):1123-1132. doi: 10.1016/j.molmed.2019.08.002.

13. Wang X, Zhou Y, Wang D, et al. Cisplatin-induced ototoxicity: From signaling network to therapeutic targets. Biomed Pharmacother. 2023;157:114045. doi: 10.1016/j.biopha.2022.114045.

14. Kim KH. Intranasal delivery of mitochondrial protein humanin rescues cell death and promotes mitochondrial function in Parkinson's disease. Theranostics. 2023;13(10):3330-3345. doi: 10.7150/thno.84165.

15. Alqahtani SM, Al-Kuraishy HM, Al-Gareeb AI, et al. The neuroprotective role of Humanin in Alzheimer's disease: The molecular effects. Eur J Pharmacol. 2025;998:177510. doi: 10.1016/j.ejphar.2025.177510.

16. Thiankhaw K, Chattipakorn K, Chattipakorn SC, Chattipakorn N. Roles of humanin and derivatives on the pathology of neurodegenerative diseases and cognition. Biochim Biophys Acta Gen Subj. 2022;1866(4):130097. doi: 10.1016/j.bbagen.2022.130097.

17. Karachaliou CE, Livaniou E. Neuroprotective Action of Humanin and Humanin Analogues: Research Findings and Perspectives. Biology (Basel). 2023;12(12):1534. doi: 10.3390/biology12121534.

18. Zhu S, Hu X, Bennett S, Xu J, Mai Y. The Molecular Structure and Role of Humanin in Neural and Skeletal Diseases, and in Tissue Regeneration. Front Cell Dev Biol. 2022;10:823354. doi: 10.3389/fcell.2022.823354.

19. Zapała B, Kaczyński Ł, Kieć-Wilk B, et al. Humanins, the neuroprotective and cytoprotective peptides with antiapoptotic and anti-inflammatory properties. Pharmacol Rep. 2010;62(5):767-777. doi: 10.1016/s1734-1140(10)70337-6.

20. Jin H, Liu T, Wang WX, et al. Protective effects of [Gly14]-Humanin on beta-amyloid-induced PC12 cell death by preventing mitochondrial dysfunction. Neurochem Int. 2010;56(3):417-423. doi: 10.1016/j.neuint.2009.11.015.

21. Hazafa A, Batool A, Ahmad S, et al. Humanin: A mitochondrial-derived peptide in the treatment of apoptosis-related diseases. Life Sci. 2021;264:118679. doi: 10.1016/j.lfs.2020.118679.

22. Li M, Liu Z, Cao X, et al. [Gly14]-Humanin ameliorates high glucose-induced endothelial senescence via SIRT6. Sci Rep. 2024;14(1):30924. doi: 10.1038/s41598-024-81878-x.

23. Liu Y, Feng Q, Zou L, Zhu C, Xia W. Oligoasthenozoospermia is alleviated in a mouse model by [Gly14]-humanin-mediated attenuation of oxidative stress and ferroptosis. Andrology. 2025;13(6):1541-1555. doi: 10.1111/andr.13786.

24. Wang XL, Lin FL, Xu W, Wang C, Wang QQ, Jiang RW. Silybin B exerts protective effect on cisplatin-induced neurotoxicity by alleviating DNA damage and apoptosis. J Ethnopharmacol. 2022;288:114938. doi: 10.1016/j.jep.2021.114938.

25. Aissous I, Benrebai M, Ameddah S, et al. The preventive effects of Centaurea maroccanaBall. extract against oxidative stress induced by cisplatin in mice brains: in vitro and in vivostudies. Drug Chem Toxicol. 2023;46(6):1162-1175. doi: 10.1080/01480545.2022.2139841.

26. Gelen V, Sengul E, Yildirim S, Cinar İ. The role of GRP78/ATF6/IRE1 and caspase-3/Bax/Bcl2 signaling pathways in the protective effects of gallic acid against cadmium-induced liver damage in rats. Iran J Basic Med Sci. 2023;26(11):1326-1333. doi: 10.22038/IJBMS.2023.71343.15525.

27. Çınar İ, Gıdık B, Dirican E. Determination of anti-cancer effects of Nigella sativa seed oil on MCF7 breast and AGS gastric cancer cells. Mol Biol Rep. 2024;51(1):491. doi: 10.1007/s11033-024-09453-1.

28. Tatar M, Tüfekci KK. An investigation of the distributions of ferroptosis and necroptosis mediators in the maternal-fetal interface at different days of rat pregnancy. Anat Histol Embryol. 2024;53(1):e12991. doi: 10.1111/ahe.12991.

29. Tatar M, Tüfekci KK, Uslu S. A determination of the main regulators of necroptosis in testicular tissue under different heat stresses. J Mol Histol. 2025;56(1):74. doi: 10.1007/s10735-024-10350-x.

30. Cinar I, Sirin B, Aydin P, Toktay E, Cadirci E, Halici I, Halici Z. Ameliorative effect of gossypin against acute lung injury in experimental sepsis model of rats. Life Sci. 2019;221:327-334. doi: 10.1016/j.lfs.2019.02.039.

31. Cai H, Liu Y, Men H, Zheng Y. Protective Mechanism of Humanin Against Oxidative Stress in Aging-Related Cardiovascular Diseases. Front Endocrinol (Lausanne). 2021;12:683151. doi: 10.3389/fendo.2021.683151.

32. Klein LE, Cui L, Gong Z, Su K, Muzumdar R. A humanin analog decreases oxidative stress and preserves mitochondrial integrity in cardiac myoblasts. Biochem Biophys Res Commun. 2013;440(2):197-203. doi: 10.1016/j.bbrc.2013.08.055.

There are 32 references in total.
How to Cite
1.
Yaşar M, Gökmen S, Atalay F, Çınar İrfan, Aydin Y, Tatar M. In Vivo Evaluation of [Gly14]-Humanin’s Protective Effect Against Cisplatin-Induced Ototoxicity. Eur Res J. 2026;12(1):119-128. doi:10.18621/eurj.1803088
License
Creative Commons License

Copyright (c) 2026 The European Research Journal
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

View Volume 12 - Issue 1 (January 2026)

Volume 12 - Issue 1 (January 2026)

Article Information

  • File Downloads 204
  • Abstract Views 180
  • Altmetrics
  • Share
Download data is not yet available.