Turkish Propolis Mitigates Oxidative Stress and Endoplasmic Reticulum Stress in Cardiac Damage Caused by Doxorubicin in Rats
Year 2025,
Volume: 9 Issue: 2, 299 - 308, 31.05.2025
Selma Cırrık
,
Emel Kabartan Çökeli
,
Gulay Hacıoğlu
,
Emine Gülçeri Güleç Peker
References
-
Wu BB, Leung KT, Poon EN. Mitochondrial-targeted therapy for doxorubicin-induced cardiotoxicity. Int J Mol Sci 2022;23:1912.
-
Christidi E, Brunham LR. Regulated cell death pathways in doxorubicin-induced cardiotoxicity. Cell Death Dis 2021;12:339.
-
Songbo M, Lang H, Xinyong C, Bin X, Ping Z, Liang S. Oxidative stress injury in doxorubicin-induced cardiotoxicity. Toxicol Lett 2019;307:41-48.
-
Abdel-Daim MM, Kilany OE, Khalifa HA, Ahmed AAM. Allicin ameliorates doxorubicin-induced cardiotoxicity in rats via suppression of oxidative stress, inflammation and apoptosis. Cancer Chemother Pharmacol 2017;80:745-753.
-
Tabas I, Ron D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol 2011;13:184-190.
-
Malhotra JD, Kaufman RJ. Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxid Redox Signal 2007;9:2277-2293.
-
Yarmohammadi F, Rezaee R, Karimi G. Natural compounds against doxorubicin-induced cardiotoxicity: A review on the involvement of Nrf2/ARE signaling pathway. Phytother Res 2021;35:1163-1175.
-
Razavi-Azarkhiavi K, Iranshahy M, Sahebkar A, Shirani K, Karimi G. The protective role of phenolic compounds against doxorubicin-induced cardiotoxicity: a comprehensive review. Nutr Cancer 2016;68:892-917.
-
Huang S, Zhang CP, Wang K, Li GQ, Hu FL. Recent advances in the chemical composition of propolis. Molecules 2014;19:19610-19632.
-
Mohamed EK, Osman AA, Moghazy AM, Abdel Rahman AAS. Propolis protective effects against doxorubicin-induced multi-organ toxicity via suppression of oxidative stress, inflammation, apoptosis, and histopathological alterations in female albino rats. Biointerface Res Appl Chem 2022;12:1762-1777.
-
Alyane M, Kebsa LB, Boussenane H, Rouibah H, Lahouel M. Cardioprotective effects and mechanism of action of polyphenols extracted from propolis against doxorubicin toxicity. Pak J Pharm Sci 2008;21:201-209.
-
Chopra S, Pillai KK, Husain SZ, Giri DK. Propolis protects against doxorubicin-induced myocardiopathy in rats. Exp Mol Pathol 1995;62: 190-198.
-
Zhang Y, Kong D, Han H, Cao Y, Zhu H, Cui G. Caffeic acid phenethyl ester protects against doxorubicin-induced cardiotoxicity and increases chemotherapeutic efficacy by regulating the unfolded protein response. Food Chem Toxicol 2022;159:112770.
-
Hirata Y, Motoyama M, Kimura S, Takashima M, Ikawa T, Oh-Hashi K, et al. Artepillin C, a major component of Brazilian green propolis, inhibits endoplasmic reticulum stress and protein aggregation. Eur J Pharmacol 2021;912:174572.
-
Izuta H, Shimazawa M, Tazawa S, Araki Y, Mishima S, Hara H. Protective effects of Chinese propolis and its component, chrysin, against neuronal cell death via inhibition of mitochondrial apoptosis pathway in SH-SY5Y cells. J Agric Food Chem 2008;56:8944-53.
-
Guzelmeric E, Yuksel PI, Yaman BK, Sipahi H, Celik C, Kırmızıbekmez H, et al. Comparison of antioxidant and anti-inflammatory activity profiles of various chemically characterized Turkish propolis sub-types: Which propolis type is a promising source for pharmaceutical product development? J Pharm Biomed Anal 2021;203: 114196.
-
Fathi Hafshejani S, Lotfi S, Rezvannejad E, Mortazavi M, Riahi-Madvar A. Correlation between total phenolic and flavonoid contents and biological activities of 12 ethanolic extracts of Iranian propolis. Food Sci Nutr 2023;11:4308-4325.
-
Kubiliene L, Laugaliene V, Pavilonis A, Maruska A, Majiene D, Barcauskaite K, et al. Alternative preparation of propolis extracts: comparison of their composition and biological activities. BMC Complement Altern Med 2015;15:156.
-
Bankova V, Trusheva B, Popova M. Propolis extraction methods: a review. J Apic Res 2021;60:734-743.
-
Mataix J, Ochoa JJ, Quiles JL. Olive oil and mitochondrial oxidative stress. Int J Vitam Nutr Res 2006;76:178-83.
-
Utarı AU, Djabir YY, Palinggi BP. A Combination of virgin coconut oil and extra virgin olive oil elicits superior protection against doxorubicin cardiotoxicity in rats. Turk J Pharm Sci 2022;19:138-144.
-
Cirrik S, Kabartan Cokeli E, Gulec Peker EG, Hacioglu G. The effects of propolis on doxorubicin-induced hepatorenal damage: a comparison of ethanolic and oily extracts of propolis. CyTA-Journal of Food 2023;21:666-673
-
Altaee MF. Cytogenetic analysis for the effect of alcoholic and water extracts of iraqi propolis in mice. Curr Res Microbiol Biotechnol 2014; 2: 310-315.
-
Kelleni MT, Amin EF, Abdelrahman AM. Effect of metformin and sitagliptin on doxorubicin-induced cardiotoxicity in rats: impact of oxidative stress, inflammation, and apoptosis. J Toxicol 2015; 2015:424813.
-
Buege JA, Aust SD. Microsomal lipid peroxidation. Methods Enzymol 1978;52:302-10.
-
Aykaç G, Uysal M, Yalçin AS, Koçak-Toker N, Sivas A, Oz H. The effect of chronic ethanol ingestion on hepatic lipid peroxide, glutathione, glutathione peroxidase and glutathione transferase in rats. Toxicology 1985;36:71-6.
-
Aebi H. Catalase in vitro. Methods Enzymol 1984; 105: 121-6.
-
Zhang J, Cui L, Han X, Zhang Y, Zhang X, Chu X, et al. Protective effects of tannic acid on acute doxorubicin-induced cardiotoxicity: Involvement of suppression in oxidative stress, inflammation, and apoptosis. Biomed Pharmacother 2017;93:1253-1260.
-
Upadhyay S, Gupta KB, Mantha AK, Dhiman M. A short review: Doxorubicin and its effect on cardiac proteins. J Cell Biochem 2021:122;153-165.
-
Kim BS, Park IH, Lee AH, Kim HJ, Lim YH, Shin JH. Sacubitril/valsartan reduces endoplasmic reticulum stress in a rat model of doxorubicin-induced cardiotoxicity. Arch Toxicol 2022;96:1065-1074.
-
Wang F, Han L. Upregulation of serum and glucocorticoid-regulated kinase 1 (SGK1) ameliorates doxorubicin-induced cardiotoxic injury, apoptosis, inflammation and oxidative stress by suppressing glucose regulated protein 78 (GRP78)-mediated endoplasmic reticulum stress. Bioengineered 2022;13:844-855.
-
Karabulut D, Ozturk E, Kaymak E, Akin AT, Yakan B. Thymoquinone attenuates doxorubicin-cardiotoxicity in rats. J Biochem Mol Toxicol 2021; 35: e22618.
-
Lou Y, Wang Z, Xu Y, Zhou P, Cao J, Li Y, et al. Resveratrol prevents doxorubicin-induced cardiotoxicity in H9c2 cells through the inhibition of endoplasmic reticulum stress and the activation of the Sirt1 pathway. Int J Mol Med 2015;36:873-80.
-
Yang N, Shi JJ, Wu FP, Li M, Zhang X, Li YP, et al. Caffeic acid phenethyl ester up-regulates antioxidant levels in hepatic stellate cell line T6 via an Nrf2-mediated mitogen activated protein kinases pathway. World J Gastroenterol 2017;23:1203-1214.
-
Kamiya T, Nishihara H, Hara H, Adachi T. Ethanol extract of Brazilian red propolis induces apoptosis in human breast cancer MCF-7 cells through endoplasmic reticulum stress. J Agric Food Chem 2012;60:11065-11070.
-
Demir S, Aliyazicioglu Y, Turan I, Misir S, Mentese A, Yaman SO, et al. Antiproliferative and proapoptotic activity of Turkish propolis on human lung cancer cell line. Nutr Cancer 2016; 68:165-72.
-
Ryu S, Bazer FW, Lim W, Song G. Chrysin leads to cell death in endometriosis by regulation of endoplasmic reticulum stress and cytosolic calcium level. J Cell Physiol 2019;234:2480-2490.
-
Cırrık S, Kabartan E, Hacıoğlu G, Peker EGG. The Effects of Prunus Laurocerasus Fruit Extract on Oxidative and Endoplasmic Reticulum Stress Responses in Doxorubicin-induced Cardiac Damage. J Acad Res Med 2024;14(1):34-9.
-
Chang WT, Lin YW, Ho CH, Chen ZC, Liu PY, Shih JY. Dapagliflozin suppresses ER stress and protects doxorubicin-induced cardiotoxicity in breast cancer patients. Arch Toxicol 2021;95(2):659-671.
Turkish Propolis Mitigates Oxidative Stress and Endoplasmic Reticulum Stress in Cardiac Damage Caused by Doxorubicin in Rats
Year 2025,
Volume: 9 Issue: 2, 299 - 308, 31.05.2025
Selma Cırrık
,
Emel Kabartan Çökeli
,
Gulay Hacıoğlu
,
Emine Gülçeri Güleç Peker
Abstract
Purpose: This study examined the effects of propolis extracted with ethanol (EPE) or olive oil (OPE) on the endoplasmic reticulum (ER) and oxidative stress in doxorubicin (DXR)-induced cardiac damage in rats.
Materials and Methods: Six groups of Sprague‒Dawley rats were used in this research: Control, EPE, OPE, DXR, EPE+DXR, and OPE+DXR. The extracts were administered orally for two weeks (50 mg/kg/day), and DXR was injected 48 hours before sacrifice (15 mg/kg). Cardiac malondialdehyde (MDA) and glutathione (GSH) levels and catalase (CAT) activity were assayed spectrophotometrically, while cardiac glucose-regulated protein (GRP)-78, pro-caspase 12, and serum troponin I levels were determined via ELISA.
Results: The DXR group presented elevated serum troponin I, indicating cardiac injury, increased MDA, decreased CAT activity, and reduced GSH, indicating oxidative stress, along with elevated GRP78 and decreased pro-caspase 12, indicating ER stress. Pretreatment with EPE or OPE significantly prevented DXR-induced increases in troponin I and MDA, as well as decreases in GSH, CAT activity, and pro-caspase 12, but did not significantly alter cardiac GRP78 levels. Compared with the EPE+DXR group, the OPE+DXR group presented higher levels of CAT activity (p<0.01).
Conclusion: Pretreatment with EPE or OPE may provide protection against DXR-induced cardiotoxicity by suppressing both oxidative and ER stress.
Ethical Statement
This study was reviewed and approved by the Institutional Animal Experiments Ethics Committee of Ordu University (Date: 11.01.2023, Decision No: 2023/09).
Supporting Institution
Ordu University
References
-
Wu BB, Leung KT, Poon EN. Mitochondrial-targeted therapy for doxorubicin-induced cardiotoxicity. Int J Mol Sci 2022;23:1912.
-
Christidi E, Brunham LR. Regulated cell death pathways in doxorubicin-induced cardiotoxicity. Cell Death Dis 2021;12:339.
-
Songbo M, Lang H, Xinyong C, Bin X, Ping Z, Liang S. Oxidative stress injury in doxorubicin-induced cardiotoxicity. Toxicol Lett 2019;307:41-48.
-
Abdel-Daim MM, Kilany OE, Khalifa HA, Ahmed AAM. Allicin ameliorates doxorubicin-induced cardiotoxicity in rats via suppression of oxidative stress, inflammation and apoptosis. Cancer Chemother Pharmacol 2017;80:745-753.
-
Tabas I, Ron D. Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol 2011;13:184-190.
-
Malhotra JD, Kaufman RJ. Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxid Redox Signal 2007;9:2277-2293.
-
Yarmohammadi F, Rezaee R, Karimi G. Natural compounds against doxorubicin-induced cardiotoxicity: A review on the involvement of Nrf2/ARE signaling pathway. Phytother Res 2021;35:1163-1175.
-
Razavi-Azarkhiavi K, Iranshahy M, Sahebkar A, Shirani K, Karimi G. The protective role of phenolic compounds against doxorubicin-induced cardiotoxicity: a comprehensive review. Nutr Cancer 2016;68:892-917.
-
Huang S, Zhang CP, Wang K, Li GQ, Hu FL. Recent advances in the chemical composition of propolis. Molecules 2014;19:19610-19632.
-
Mohamed EK, Osman AA, Moghazy AM, Abdel Rahman AAS. Propolis protective effects against doxorubicin-induced multi-organ toxicity via suppression of oxidative stress, inflammation, apoptosis, and histopathological alterations in female albino rats. Biointerface Res Appl Chem 2022;12:1762-1777.
-
Alyane M, Kebsa LB, Boussenane H, Rouibah H, Lahouel M. Cardioprotective effects and mechanism of action of polyphenols extracted from propolis against doxorubicin toxicity. Pak J Pharm Sci 2008;21:201-209.
-
Chopra S, Pillai KK, Husain SZ, Giri DK. Propolis protects against doxorubicin-induced myocardiopathy in rats. Exp Mol Pathol 1995;62: 190-198.
-
Zhang Y, Kong D, Han H, Cao Y, Zhu H, Cui G. Caffeic acid phenethyl ester protects against doxorubicin-induced cardiotoxicity and increases chemotherapeutic efficacy by regulating the unfolded protein response. Food Chem Toxicol 2022;159:112770.
-
Hirata Y, Motoyama M, Kimura S, Takashima M, Ikawa T, Oh-Hashi K, et al. Artepillin C, a major component of Brazilian green propolis, inhibits endoplasmic reticulum stress and protein aggregation. Eur J Pharmacol 2021;912:174572.
-
Izuta H, Shimazawa M, Tazawa S, Araki Y, Mishima S, Hara H. Protective effects of Chinese propolis and its component, chrysin, against neuronal cell death via inhibition of mitochondrial apoptosis pathway in SH-SY5Y cells. J Agric Food Chem 2008;56:8944-53.
-
Guzelmeric E, Yuksel PI, Yaman BK, Sipahi H, Celik C, Kırmızıbekmez H, et al. Comparison of antioxidant and anti-inflammatory activity profiles of various chemically characterized Turkish propolis sub-types: Which propolis type is a promising source for pharmaceutical product development? J Pharm Biomed Anal 2021;203: 114196.
-
Fathi Hafshejani S, Lotfi S, Rezvannejad E, Mortazavi M, Riahi-Madvar A. Correlation between total phenolic and flavonoid contents and biological activities of 12 ethanolic extracts of Iranian propolis. Food Sci Nutr 2023;11:4308-4325.
-
Kubiliene L, Laugaliene V, Pavilonis A, Maruska A, Majiene D, Barcauskaite K, et al. Alternative preparation of propolis extracts: comparison of their composition and biological activities. BMC Complement Altern Med 2015;15:156.
-
Bankova V, Trusheva B, Popova M. Propolis extraction methods: a review. J Apic Res 2021;60:734-743.
-
Mataix J, Ochoa JJ, Quiles JL. Olive oil and mitochondrial oxidative stress. Int J Vitam Nutr Res 2006;76:178-83.
-
Utarı AU, Djabir YY, Palinggi BP. A Combination of virgin coconut oil and extra virgin olive oil elicits superior protection against doxorubicin cardiotoxicity in rats. Turk J Pharm Sci 2022;19:138-144.
-
Cirrik S, Kabartan Cokeli E, Gulec Peker EG, Hacioglu G. The effects of propolis on doxorubicin-induced hepatorenal damage: a comparison of ethanolic and oily extracts of propolis. CyTA-Journal of Food 2023;21:666-673
-
Altaee MF. Cytogenetic analysis for the effect of alcoholic and water extracts of iraqi propolis in mice. Curr Res Microbiol Biotechnol 2014; 2: 310-315.
-
Kelleni MT, Amin EF, Abdelrahman AM. Effect of metformin and sitagliptin on doxorubicin-induced cardiotoxicity in rats: impact of oxidative stress, inflammation, and apoptosis. J Toxicol 2015; 2015:424813.
-
Buege JA, Aust SD. Microsomal lipid peroxidation. Methods Enzymol 1978;52:302-10.
-
Aykaç G, Uysal M, Yalçin AS, Koçak-Toker N, Sivas A, Oz H. The effect of chronic ethanol ingestion on hepatic lipid peroxide, glutathione, glutathione peroxidase and glutathione transferase in rats. Toxicology 1985;36:71-6.
-
Aebi H. Catalase in vitro. Methods Enzymol 1984; 105: 121-6.
-
Zhang J, Cui L, Han X, Zhang Y, Zhang X, Chu X, et al. Protective effects of tannic acid on acute doxorubicin-induced cardiotoxicity: Involvement of suppression in oxidative stress, inflammation, and apoptosis. Biomed Pharmacother 2017;93:1253-1260.
-
Upadhyay S, Gupta KB, Mantha AK, Dhiman M. A short review: Doxorubicin and its effect on cardiac proteins. J Cell Biochem 2021:122;153-165.
-
Kim BS, Park IH, Lee AH, Kim HJ, Lim YH, Shin JH. Sacubitril/valsartan reduces endoplasmic reticulum stress in a rat model of doxorubicin-induced cardiotoxicity. Arch Toxicol 2022;96:1065-1074.
-
Wang F, Han L. Upregulation of serum and glucocorticoid-regulated kinase 1 (SGK1) ameliorates doxorubicin-induced cardiotoxic injury, apoptosis, inflammation and oxidative stress by suppressing glucose regulated protein 78 (GRP78)-mediated endoplasmic reticulum stress. Bioengineered 2022;13:844-855.
-
Karabulut D, Ozturk E, Kaymak E, Akin AT, Yakan B. Thymoquinone attenuates doxorubicin-cardiotoxicity in rats. J Biochem Mol Toxicol 2021; 35: e22618.
-
Lou Y, Wang Z, Xu Y, Zhou P, Cao J, Li Y, et al. Resveratrol prevents doxorubicin-induced cardiotoxicity in H9c2 cells through the inhibition of endoplasmic reticulum stress and the activation of the Sirt1 pathway. Int J Mol Med 2015;36:873-80.
-
Yang N, Shi JJ, Wu FP, Li M, Zhang X, Li YP, et al. Caffeic acid phenethyl ester up-regulates antioxidant levels in hepatic stellate cell line T6 via an Nrf2-mediated mitogen activated protein kinases pathway. World J Gastroenterol 2017;23:1203-1214.
-
Kamiya T, Nishihara H, Hara H, Adachi T. Ethanol extract of Brazilian red propolis induces apoptosis in human breast cancer MCF-7 cells through endoplasmic reticulum stress. J Agric Food Chem 2012;60:11065-11070.
-
Demir S, Aliyazicioglu Y, Turan I, Misir S, Mentese A, Yaman SO, et al. Antiproliferative and proapoptotic activity of Turkish propolis on human lung cancer cell line. Nutr Cancer 2016; 68:165-72.
-
Ryu S, Bazer FW, Lim W, Song G. Chrysin leads to cell death in endometriosis by regulation of endoplasmic reticulum stress and cytosolic calcium level. J Cell Physiol 2019;234:2480-2490.
-
Cırrık S, Kabartan E, Hacıoğlu G, Peker EGG. The Effects of Prunus Laurocerasus Fruit Extract on Oxidative and Endoplasmic Reticulum Stress Responses in Doxorubicin-induced Cardiac Damage. J Acad Res Med 2024;14(1):34-9.
-
Chang WT, Lin YW, Ho CH, Chen ZC, Liu PY, Shih JY. Dapagliflozin suppresses ER stress and protects doxorubicin-induced cardiotoxicity in breast cancer patients. Arch Toxicol 2021;95(2):659-671.