INVESTIGATING THE IN VIVO EFFECTS OF COPPER COORDINATION COMPOUNDS WITH THIOSEMICARBAZONES ON ERYTHROCYTE REDOX BALANCE
DOI:
https://doi.org/10.47743/jemb-2025-236Keywords:
thiol-disulfide metabolism, erythrocytes, copper coordination compounds with thiosemicarbazonesAbstract
Thiol-disulfide homeostasis plays a vital role in cellular and systemic functions, regulating biosynthetic reactions, growth, transport, repair, and redox signaling through the dynamic interplay between thiol (-SH) and disulfide (-S-S-) states. This study evaluated the effects of copper coordination compounds with thiosemicarbazones (CCTs) on thiol-disulfide metabolism in 120 rats (Rattus norvegicus Albicans). The animals were divided into 10 groups by sex, with the control group receiving saline and experimental groups (Groups 2–10) administered specific CCTs (10 µg/kg, subcutaneously) for 30 days. CCTs, known for their medicinal potential, particularly as anticancer agents, enhanced antioxidant defenses by increasing total and reduced glutathione (tGSH, rGSH) and decreasing oxidized glutathione (GSSG). These findings underscore the potential of CCTs in modulating redox balance and their promise in therapeutic applications, including cancer treatment.
References
Arthur JR. 2000. The glutathione peroxidases. Cell Mol Life Sci. 57(13-14):1825-35. doi: 10.1007/pl00000664
Brülisauer L, Gauthier MA, Leroux JC. 2014. Disulfide-containing parenteral delivery systems and their redox-biological fate. J Control Release. 195:147-54. doi: 10.1016/j.jconrel.2014.06.012
Byrnes RW, Mohan M, Antholine WE, Xu RX, Petering DH. 1990. Oxidative stress induced by a copper-thiosemicarbazone complex. Biochemistry. 29(30):7046-53. doi: 10.1021/bi00482a014
Chen W, Zhao Y, Seefeldt T, Guan X. 2008. Determination of thiols and disulfides via HPLC quantification of 5-thio-2-nitrobenzoic acid. J Pharm Biomed Anal. 48(5):1375-80. doi: 10.1016/j.jpba.2008.08.033
D'Autréaux B, Toledano MB. 2007. ROS as signalling molecules: mechanisms that generate specificity in ROS homeostasis. Nat Rev Mol Cell Biol. 8(10):813-24. doi: 10.1038/nrm2256
Dalle-Donne I, Rossi R, Colombo G, Giustarini D, Milzani A. 2009. Protein S-glutathionylation: a regulatory device from bacteria to humans. Trends Biochem Sci. 34(2):85-96. doi: 10.1016/j.tibs.2008.11.002
Ellgaard L, Sevier CS, Bulleid NJ. 2018. How Are Proteins Reduced in the Endoplasmic Reticulum? Trends Biochem Sci. 43(1):32-43. doi: 10.1016/j.tibs.2017.10.006
Fernández-Checa JC, Kaplowitz N, García-Ruiz C, Colell A, Miranda M, Marí M, Ardite E, Morales A. 1997. GSH transport in mitochondria: defense against TNF-induced oxidative stress and alcohol-induced defect. Am J Physiol. 273 (1 Pt 1):G7-17. doi: 10.1152/ajpgi.1997.273.1.G7
Forman HJ, Zhang H, Rinna A. 2009. Glutathione: overview of its protective roles, measurement, and biosynthesis. Mol Aspects Med. 30(1-2):1-12. doi: 10.1016/j.mam.2008.08.006
Garcia-Ruiz C, Fernandez-Checa JC. 2006. Mitochondrial glutathione: hepatocellular survival-death switch. J Gastroenterol Hepatol. Suppl 3:S3-6. doi: 10.1111/j.1440-1746.2006.04570.x
Gulea A, Poirier D, Roy J, Stavila V, Bulimestru I, Tapcov, V., Birca, M., and Popovschi, L. 2008. In vitro antileukemia, antibacterial and antifungal activities of some 3d metal complexes: chemical synthesis and structure - activity relationships. J Enzyme Inhib Med Chem. 23(6):806-18. doi: 10.1080/14756360701743002
Halliwell B, Gutteridge JM. 1984. Lipid peroxidation, oxygen radicals, cell damage, and antioxidant therapy. Lancet. 1(8391):1396-7. doi: 10.1016/s0140-6736(84)91886-5
Hancock CN, Stockwin LH, Han B, Divelbiss RD, Jun JH, Malhotra SV, Hollingshead MG, Newton DL. 2011. A copper chelate of thiosemicarbazone NSC 689534 induces oxidative/ER stress and inhibits tumor growth in vitro and in vivo. Free Radic Biol Med. 50(1):110-21. doi: 10.1016/j.freeradbiomed.2010.10.696
Jin Y, Yu C, Denman RJ, Zhang W. 2013. Recent advances in dynamic covalent chemistry. Chem Soc Rev. 42(16):6634-54. doi: 10.1039/c3cs60044k
Jones DP. 2002. Redox potential of GSH/GSSG couple: assay and biological significance. Methods Enzymol. 348:93-112. doi: 10.1016/s0076-6879(02)48630-2
Jones DP, Go YM, Anderson CL, Ziegler TR, Kinkade JM Jr, Kirlin WG. 2004. Cysteine/cystine couple is a newly recognized node in the circuitry for biologic redox signaling and control. FASEB J. 18(11):1246-8. doi: 10.1096/fj.03-0971fje
Jones DP, Jr. Mody VC, Carlson JL, Lynn MJ, Jr. Sternberg P. 2002. Redox analysis of human plasma allows separation of pro-oxidant events of aging from decline in antioxidant defenses. Free Radic Biol Med. 33(9):1290-300. doi: 10.1016/s0891-5849(02)01040-7
Kirlin WG, Cai J, Thompson SA, Diaz D, Kavanagh TJ, Jones DP. 1999. Glutathione redox potential in response to differentiation and enzyme inducers. Free Radic Biol Med. 27(11-12):1208-18. doi: 10.1016/s0891-5849(99)00145-8
Kosower NS, Kosower EM. 1978. The glutathione status of cells. Int Rev Cytol. 54:109-60. doi: 10.1016/s0074-7696(08)60166-7
Leichner C, Jelkmann M, Bernkop-Schnürch A. 2019. Thiolated polymers: Bioinspired polymers utilizing one of the most important bridging structures in nature. Adv Drug Deliv Rev. 151-152:191-221. doi: 10.1016/j.addr.2019.04.007
Liu RM, Gaston Pravia KA. 2010. Oxidative stress and glutathione in TGF-beta-mediated fibrogenesis. Free Radic Biol Med. 48(1):1-15. doi: 10.1016/j.freeradbiomed.2009.09.026
Lu SC. 1999. Regulation of hepatic glutathione synthesis: current concepts and controversies. FASEB J. 13(10):1169-83.
Lu SC. 2009. Regulation of glutathione synthesis. Mol Aspects Med. 30(1-2):42-59. doi: 10.1016/j.mam.2008.05.005
Meister A, Anderson ME. 1983. Glutathione. Annu Rev Biochem. 52:711-60. doi: 10.1146/annurev.bi.52.070183.003431
Meister A. 1988. Glutathione metabolism and its selective modification. J Biol Chem. 263(33):17205-8.
Meister A. 1991. Glutathione deficiency produced by inhibition of its synthesis, and its reversal; applications in research and therapy. Pharmacol Ther. 51(2):155-94. doi: 10.1016/0163-7258(91)90076-x
Nkabyo YS, Ziegler TR, Gu LH, Watson WH, Jones D. 2002. Glutathione and thioredoxin redox during differentiation in human colon epithelial (Caco-2) cells. Am J Physiol Gastrointest Liver Physiol. 283(6):G1352-9. doi: 10.1152/ajpgi.00183.2002
Pantea V, Popa V, Tagadiuc O, Andronache L, Gudumac V. 2022. Changes of oxidative stress indices and antioxidant system in the liver tissue on the administration of some coordination compound of copper, derivatives of thiosemicarbazide. Revista de Ştiinţe ale Sănătăţii din Moldova. 3(29):7-12. doi: 10.52645/MJHS.2022.3.02
Pantea V, Andronache L, Globa P, Pavlovschi E, Gulya A, Tagadiuc O, Gudumac V. 2023. Copper coordination compounds with thiosemicarbazones: in vitro assessment of their potential in inhibiting glioma viability and proliferation. Archives of the Balkan Medical Union. 58:234-244. doi: 10.31688/ABMU.2023.58.3.02
Pantea V. 2023. The metabolic effects of native bioactive compounds with antitumor activity. https://anacec.md/files/Pantea_teza.pdf
Rinaldi R, Eliasson E, Swedmark S, Morgenstern R. 2002. Reactive intermediates and the dynamics of glutathione transferases. Drug Metab Dispos. 30(10):1053-8. doi: 10.1124/dmd.30.10.1053
Sánchez-Rodríguez MA, Mendoza-Núñez VM. 2019. Oxidative Stress Indexes for Diagnosis of Health or Disease in Humans. Oxid Med Cell Longev. 2019:4128152. doi: 10.1155/2019/4128152
Wada K, Fujibayashi Y, Yokoyama A. 1994. Copper(II)[2,3-butanedionebis(N4-methylthiosemicarbazone)], a stable superoxide dismutase-like copper complex with high membrane penetrability. Arch Biochem Biophys. 310(1):1-5. doi: 10.1006/abbi.1994.1132
Watson WH, Chen Y, Jones DP. 2003. Redox state of glutathione and thioredoxin in differentiation and apoptosis. Biofactors. 17(1-4):307-14. doi: 10.1002/biof.5520170130
Yang Y, Karakhanova S, Werner J, Bazhin AV. 2013. Reactive oxygen species in cancer biology and anticancer therapy. Curr Med Chem. 20(30):3677-92. doi: 10.2174/0929867311320999165
Yi MC, Khosla C. 2016. Thiol-Disulfide Exchange Reactions in the Mammalian Extracellular Environment. Annu Rev Chem Biomol Eng. 7:197-222. doi: 10.1146/annurev-chembioeng-080615-033553
Downloads
Published
How to Cite
License
Copyright (c) 2025 Valeriana Pantea, Ecaterina Pavlovschi, Veronica Sardari, Svetlana Protopop, Vasile Macari, Ala Ambros, Sergiu Curlat, Tatiana Timercan, Olga Tagadiuc

This work is licensed under a Creative Commons Attribution 4.0 International License.
This journal provides immediate open access to its content on the principle that making research freely available to the public supports a greater global exchange of knowledge. The journal allows readers to read, download, copy, distribute, print, search, link to the full texts or use the articles for any other lawful purpose.
The authors are the sole copyright owners of the published articles. The articles are distributed under the CC BY 4.0 license to the readers.
The readers are free to:
Share — copy and redistribute the material in any medium or format
Adapt — remix, transform, and build upon the material for any purpose, even commercially
Under the following terms:
Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.
No additional restrictions — you may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.






