Ukr.Biochem.J. 2025; Volume 97, Issue 1, Jan-Feb, pp. 51-61
doi: https://doi.org/10.15407/ubj97.01.051
Biomarkers of apoptosis and endoplasmic reticulum stress in cardiomyocytes of rats under chronic ethanol consumption and germanium-nicotinic acid complex administration
I. V. Nizhenkovska1, O. V. Kuznetsova1,
V. P. Narokha1, D. O. Labudzynskyi2*
1Department of Medicinal Chemistry and Toxicology,
Bogomolets National Medical University, Kyiv, Ukraine;
2Department of Vitamins and Coenzyme Biochemistry,
Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv;
*e-mail: labudzinskidmytro@gmail.com
Received: 11 November 2024; Revised: 03 February 2025;
Accepted: 21 February 2025; Available on-line: 03 March 2025
Chronic ethanol consumption is associated with a range of harmful effects on different systems of the body, including the heart. Coordination complexes of bioactive compounds based on non-toxic metals are attracting interest in biomedical research due to their potential therapeutic properties. The study aimed to evaluate the influence of the germanium-nicotinic acid complex (MIGU-1) on apoptosis and endoplasmic reticulum (ER) stress indicators in the myocardium of rats under chronic alcohol exposure. Female Wistar rats were divided into three groups of 6 animals each: intact animals; rats that received 20% ethanol as the sole source of liquid for 110 days; animals with chronic consumption of 20% ethanol, which from the 90th day until the end of the experiment were intraperitoneally administered MIGU-1 solution (10 mg/kg/day). Biomarkers related to apoptosis, ER stress autophagy were assessed by Western blot analysis. It was shown that chronic ethanol consumption significantly activated apoptotic pathways in rat myocardium tissue, evidenced by increased levels of cleaved caspase-3 and BAX proteins alongside Beclin-1 level elevation, indicating enhanced autophagy. A significant decrease in the content of the protein IRE1 and its phosphorylated form in myocardial with no changes in GRP78 protein level was detected. Treatment with MIGU-1 resulted in both ethanol-induced apoptosis reduction and ER stress attenuation in cardiomyocytes with the level of Beclin-1 and GRP78 proteins remaining unchanged. Our findings demonstrate that the MIGU-1 complex promotes cardiomyocyte survival by balancing apoptosis and unfolded protein response, thus preventing alcohol-related cardiac injury.
Keywords: alcohol intoxication, apoptosis, autophagy, ER stress, germanium, MIGU-1, nicotinic acid, rat cardiomyocytes
References:
- Le Daré B, Lagente V, Gicquel T. Ethanol and its metabolites: update on toxicity, benefits, and focus on immunomodulatory effects. Drug Metab Rev. 2019;51(4):545-561. PubMed, CrossRef
- Wong B, Ryan C, Fagbamigbe A, Bray JJ, McNamee B, Niranjan V, Zhou S, Bogdanet D, Reddin C, McDonald K, Ledwidge M. Alcohol consumption and heart failure: a dose-response meta-analysis. Cochrane Database Syst Rev. 2024;8(8):CD015398. PubMed, PubMedCentral, CrossRef
- Hyun J, Han J, Lee C, Yoon M, Jung Y. Pathophysiological Aspects of Alcohol Metabolism in the Liver. Int J Mol Sci. 2021;22(11):5717. PubMed, PubMedCentral, CrossRef
- Fernández-Solà J, Planavila Porta A. New Treatment Strategies for Alcohol-Induced Heart Damage. Int J Mol Sci. 2016;17(10):1651. PubMed, PubMedCentral, CrossRef
- Rungratanawanich W, Qu Y, Wang X, Essa MM, Song BJ. Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury. Exp Mol Med. 2021;53(2):168-188. PubMed, PubMedCentral, CrossRef
- Fernández-Solà J. The effects of ethanol on the heart: alcoholic cardiomyopathy. Nutrients. 2020;12(2):572. PubMed, PubMedCentral, CrossRef
- Ji C. Mechanisms of alcohol-induced endoplasmic reticulum stress and organ injuries. Biochem Res Int. 2012;2012:216450. PubMed, PubMedCentral, CrossRef
- Luo X, Sun J, Kong D, Lei Y, Gong F, Zhang T, Shen Z, Wang K, Luo H, Xu Y. The role of germanium in diseases: exploring its important biological effects. J Transl Med. 2023;21(1):795. PubMed, PubMedCentral, CrossRef
- Abdel Gaber SA, Hamza AH, Tantawy MA, Toraih EA, Ahmed HH. Germanium dioxide nanoparticles mitigate biochemical and molecular changes characterizing Alzheimer’s disease in rats. Pharmaceutics. 2023;15(5):1386. PubMed, PubMedCentral, CrossRef
- Feng C, Ouyang J, Tang Z, Kong N, Liu Y, Fu L, Ji X, Xie T, Farokhzad OC, Tao W. Germanene-based theranostic materials for surgical adjuvant treatment: inhibiting tumor recurrence and wound infection. Matter. 2020;3(1):127-144. CrossRef
- Ying W, Alano CC, Garnier P, Swanson RA. NAD+ as a metabolic link between DNA damage and cell death. J Neurosci Res. 2005;79(1-2):216-223. PubMed, CrossRef
- Zou L, Collins HE, Young ME, Zhang J, Wende AR, Darley-Usmar VM, Chatham JC. The identification of a novel calcium-dependent link between NAD+ and glucose deprivation-induced increases in protein O-GlcNAcylation and ER stress. Front Mol Biosci. 2021;8:780865. PubMed, PubMedCentral, CrossRef
- Mandal A, Rai R, Saha S, Kushwaha R, Wei L, Gogoi H, Mandal AA, Yadav AK, Huang H, Dutta A, Dhar P, Banerjee S. Polypyridyl-based Co(III) complexes of vitamin B6 Schiff base for photoactivated antibacterial therapy. Dalton Trans. 2023;52(46):17562-17572. PubMed, CrossRef
- Hadjiadamou I, Vlasiou M, Spanou S, Simos Y, Papanastasiou G, Kontargiris E, Dhima I, Ragos V, Karkabounas S, Drouza C, Keramidas AD. Synthesis of vitamin E and aliphatic lipid vanadium(IV) and (V) complexes, and their cytotoxic properties. J Inorg Biochem. 2020;208:111074. PubMed, CrossRef
- Harihar S, Mone N, Satpute SK, Chadar D, Chakravarty D, Weyhermüller T, Butcher RJ, Salunke-Gawali S. Metal complexes of a pro-vitamin K3 analog phthiocol (2-hydroxy-3-methylnaphthalene-1,4-dione): synthesis, characterization, and anticancer activity. Dalton Trans. 2022;51(45):17338-17353. PubMed, CrossRef
- Cunningham CL, Pina MM. Alcohol Preference Tests. In: Stolerman IP, Price LH. (eds). Encyclopedia of Psychopharmacology. Springer, Berlin, Heidelberg, 2015. P. 79-83. CrossRef
- Lukyanchuk VD, Kravets DS, Tchadova LV. Toxicometry of potential cerebroprotector MIGU-1. Integr Anthropol. 2008;(1(11)):46-49. (In Ukrainian).
- Seifullina II, Martsinko EE, Khristova NM, Chebanenko EA. Molecular complexes of germanium tetrachloride with niacin, nicotinic amide, isonicotinic hydrazide and their pharmacological actions. Odesa Nat Univ Herald. Chemistry. 2016;21(2(58)):18-28. CrossRef
- Pillai-Kastoori L, Schutz-Geschwender AR, Harford JA. A systematic approach to quantitative Western blot analysis. Anal Biochem. 2020;593:113608. PubMed, CrossRef
- Gerber GB, Léonard A. Mutagenicity, carcinogenicity and teratogenicity of germanium compounds. Mutat Res. 1997;387(3):141-146. PubMed, CrossRef
- Sabbioni E, Fortaner S, Bosisio S, Farina M, Del Torchio R, Edel J, Fischbach M. Metabolic fate of ultratrace levels of GeCl(4) in the rat and in vitro studies on its basal cytotoxicity and carcinogenic potential in Balb/3T3 and HaCaT cell linesdagger. J Appl Toxicol. 2010;30(1):34-41. PubMed, CrossRef
- Nizhenkovska I, Kuznetsova O, Narokha V. Intensity of endoplasmic reticulum stress, autophagy, and apoptosis in the cerebral cortex of rats with chronic ethanol consumption under the influence of the complex compound of germanium with nicotinic acid. ScienceRise: Pharm Sci. 2023;6(46)):70-78. CrossRef
- Lin Q, Zuo W, Liu Y, Wu K, Liu Q. NAD+ and cardiovascular diseases. Clin Chim Acta. 2021;515:104-110. PubMed, CrossRef
- Hetz C, Zhang K, Kaufman RJ. Mechanisms, regulation and functions of the unfolded protein response. Nat Rev Mol Cell Biol. 2020;21(8):421-438. PubMed, PubMedCentral, CrossRef
- Chen X, Shi C, He M, Xiong S, Xia X. Endoplasmic reticulum stress: molecular mechanism and therapeutic targets. Signal Transduct Target Ther. 2023;8(1):352. PubMed, PubMedCentral, CrossRef
- Urra H, Dufey E, Avril T, Chevet E, Hetz C. Endoplasmic reticulum stress and the hallmarks of cancer. Trends Cancer. 2016;2(5):252-262. PubMed, CrossRef
- Ibrahim IM, Abdelmalek DH, Elfiky AA. GRP78: A cell’s response to stress. Life Sci. 2019;226:156-163. PubMed, PubMedCentral, CrossRef
- Liu Z, Liu G, Ha DP, Wang J, Xiong M, Lee AS. ER chaperone GRP78/BiP translocates to the nucleus under stress and acts as a transcriptional regulator. Proc Natl Acad Sci USA. 2023;120(31):e2303448120. PubMed, PubMedCentral, CrossRef
- Bashir S, Banday M, Qadri O, Bashir A, Hilal N, Nida-I-Fatima, Rader S, Fazili KM. The molecular mechanism and functional diversity of UPR signaling sensor IRE1. Life Sci. 2021;265:118740. PubMed, CrossRef
- Read A, Schröder M. The Unfolded Protein Response: An Overview. Biology (Basel). 2021;10(5):384. PubMed, PubMedCentral, CrossRef
- Bhardwaj M, Leli NM, Koumenis C, Amaravadi RK. Regulation of autophagy by canonical and non-canonical ER stress responses. Semin Cancer Biol. 2020;66:116-128. PubMed, PubMedCentral, CrossRef
- Zhu H, He L. Beclin 1 biology and its role in heart disease. Curr Cardiol Rev. 2015;11(3):229-237. PubMed, PubMedCentral, CrossRef
- Maejima Y, Isobe M, Sadoshima J. Regulation of autophagy by Beclin 1 in the heart. J Mol Cell Cardiol. 2016;95:19-25. PubMed, PubMedCentral, CrossRef
- Prerna K, Dubey VK. Beclin1-mediated interplay between autophagy and apoptosis: New understanding. Int J Biol Macromol. 2022;204:258-273. PubMed, CrossRef
- Djavaheri-Mergny M, Maiuri MC, Kroemer G. Cross talk between apoptosis and autophagy by caspase-mediated cleavage of Beclin 1.
Oncogene. 2010;29(12):1717-1719. PubMed, CrossRef - Naseer MI, Ullah N, Ullah I, Koh PO, Lee HY, Park MS, Kim MO. Vitamin C protects against ethanol and PTZ-induced apoptotic neurodegeneration in prenatal rat hippocampal neurons. Synapse. 2011;65(7):562-571. PubMed, CrossRef
- Biswas U, Roy R, Ghosh S, Chakrabarti G. The interplay between autophagy and apoptosis: its implication in lung cancer and therapeutics. Cancer Lett. 2024;585:216662. PubMed, CrossRef
- Dong Y, Chen H, Gao J, Liu Y, Li J, Wang J. Molecular machinery and interplay of apoptosis and autophagy in coronary heart disease.
J Mol Cell Cardiol. 2019;136:27-41. PubMed, CrossRef - Digby JE, Lee JM, Choudhury RP. Nicotinic acid and the prevention of coronary artery disease. Curr Opin Lipidol. 2009;20(4):321-326. PubMed, CrossRef
- Narokha VP. The effect of the germanium complex with nicotinic acid on oxidative modification of cardiac and hepatic proteins in the experimental chronic intoxication with doxorubicin in rats. Clin Pharm. 2016;20(4):35-38. CrossRef
- Litwiniuk A, Kalisz M, Domańska A, Chmielowska M, Martyńska L, Baranowska-Bik A, Bik W. Nicotinic acid attenuates amyloid β1-42-induced mitochondrial dysfunction and inhibits the mitochondrial pathway of apoptosis in differentiated SH-SY5Y cells. Neurochem Int. 2024;178:105772. PubMed, CrossRef
- Kamat JP, Devasagayam TP. Nicotinamide (vitamin B3) as an effective antioxidant against oxidative damage in rat brain mitochondria. Redox Rep. 1999;4(4):179-184. PubMed, CrossRef
- Ali MM. Germanium l-Cysteine Alpha-Tocopherol Complex as Stimulator to Antioxidant Defense System. In: Kretsinger RH, Uversky VN, Permyakov EA. (eds) Encyclopedia of Metalloproteins. Springer, New York, NY, 2013. P. 836-841. CrossRef
