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Exploring Esculetin's Protective Role: Countering Doxorubicin-Induced Oxidative Stress in Rat Heart

Yıl 2024, Cilt: 4 Sayı: 1, 44 - 52, 29.03.2024
https://doi.org/10.5281/zenodo.10892230

Öz

Doxorubicin (DOX) and other anthracyclines are potent chemotherapy drugs used against cancer; however, their clinical application is linked to significant and potentially life-threatening cardiotoxicity. Despite extensive research over many years, the available treatment choices are still constrained. DOX is typically believed to primarily affect mitochondria, and the characteristic feature of DOX-induced cardiotoxicity is mitochondrial dysfunction. In this study was designed to explore the protective effects of esculetin against DOX-induced cardiotoxicity in Sprague-Dawley rats, considering its known properties. Cardiotoxicity was induced by administering DOX via intraperitoneal injection at a weekly dosage of 5 mg/kg body weight for two consecutive weeks. Rats receiving DOX injections were simultaneously supplemented with esculetin at doses of 50 and 100 mg/kg body weight through intraperitoneal administration over the same period. The investigation, oxidative stress enzymes in heart tissue employed biochemical and molecular methods. Enzyme activities and expression levels of catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) were assessed in heart tissues.Intoxication with DOX resulted in a reduction in antioxidant status, affecting CAT and GPx and SOD. Both enzyme activity and mRNA expression decreased in the DOX group. There was an increase in DOX and esculetin combined groups. The present study proposes that DOX-induced detrimental effects on heart tissue are potentially mitigated by esculetin via modulation of oxidative stress.

Etik Beyan

Ethics committee approval was received for this study from the ethics committee of Atatürk University (Protocol Number: 2021/4–123).

Proje Numarası

Ardahan Üniversitesi BAP birimi Proje No: 2021-003

Kaynakça

  • Abdelghffar, E. A., Obaid, W. A., Elgamal, A. M., Daoud, R., Sobeh, M., & El Raey, M. A. (2021). Pea (Pisum sativum) peel extract attenuates DOX-induced oxidative myocardial injury. Biomedicine and pharmacotherapy, 143, 112120.
  • Aebi H. (1984). Catalase in vitro. Methods in Enzymology, 105, 121–126.
  • Bradford M. M. (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical Biochemistry, 72, 248–254.
  • Ceylan, H., Budak, H., Kocpinar, E. F., Baltaci, N. G., & Erdogan, O. (2019). Examining the link between dose-dependent dietary iron intake and Alzheimer's disease through oxidative stress in the rat cortex. Journal of Trace Elements in Medicine and Biology, 56, 198–206.
  • Childs, A. C., Phaneuf, S. L., Dirks, A. J., Phillips, T., & Leeuwenburgh, C. (2002). Doxorubicin treatment in vivo causes cytochrome C release and cardiomyocyte apoptosis, as well as increased mitochondrial efficiency, superoxide dismutase activity, and Bcl-2:Bax ratio. Cancer Research, 62(16), 4592–4598.
  • Dai, G. F., Wang, Z., & Zhang, J. Y. (2018). Octreotide protects doxorubicin-induced cardiac toxicity via regulating oxidative stress. European Review for Medical and Pharmacological Sciences, 22(18), 6139–6148.
  • De Geest, B., & Mishra, M. (2022). Role of oxidative stress in diabetic cardiomyopathy. Antioxidants, 11(4), 784.
  • Jiang, Q., Chen, X., Tian, X., Zhang, J., Xue, S., Jiang, Y., Liu, T., Wang, X., Sun, Q., Hong, Y., Li, C., Guo, D., Wang, Y., & Wang, Q. (2022). Tanshinone I inhibits doxorubicin-induced cardiotoxicity by regulating Nrf2 signaling pathway. Phytomedicine, 106, 154439.
  • Kadakol, A., Sharma, N., Kulkarni, Y. A., & Gaikwad, A. B. (2016). Esculetin: A phytochemical endeavor fortifying effect against non-communicable diseases. Biomedicine and Pharmacotherapy 84, 1442–1448.
  • Karagac, M. S., & Ceylan, H. (2023). Neuroprotective potential of tannic acid against neurotoxic outputs of monosodium glutamate in rat cerebral cortex. Neurotoxicity Research, 41(6), 670–680.
  • Kong, C. Y., Guo, Z., Song, P., Zhang, X., Yuan, Y. P., Teng, T., Yan, L., & Tang, Q. Z. (2022). Underlying the Mechanisms of Doxorubicin-Induced Acute Cardiotoxicity: Oxidative Stress and Cell Death. International Journal of Biological Sciences, 18(2), 760–770.
  • Lee, S. Y., Lim, T. G., Chen, H., Jung, S. K., Lee, H. J., Lee, M. H., Kim, D. J., Shin, A., Lee, K. W., Bode, A. M., Surh, Y. J., & Dong, Z. (2013). Esculetin suppresses proliferation of human colon cancer cells by directly targeting β-catenin. Cancer Prevention Research, 6(12), 1356–1364.
  • Lei, F. J., Chiang, J. Y., Chang, H. J., Chen, D. C., Wang, H. L., Yang, H. A., Wei, K. Y., Huang, Y. C., Wang, C. C., Wei, S. T., & Hsieh, C. H. (2023). Cellular and exosomal GPx1 are essential for controlling hydrogen peroxide balance and alleviating oxidative stress in hypoxic glioblastoma. Redox Biology, 65, 102831.
  • Marques, G. L., Neto, F. F., Ribeiro, C. A., Liebel, S., de Fraga, R., & Bueno, R. daR. (2015). Oxidative Damage in the Aging Heart: an Experimental Rat Model. The Open Cardiovascular Medicine Journal, 9, 78–82.
  • Minotti, G., Menna, P., Salvatorelli, E., Cairo, G., & Gianni, L. (2004). Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacological Reviews, 56(2), 185-229.
  • Nandi, A., Yan, L. J., Jana, C. K., & Das, N. (2019). Role of Catalase in Oxidative Stress- and Age-Associated Degenerative Diseases. Oxidative Medicine and Cellular Longevity, 2019, 9613090.
  • Ojha, S., Al Taee, H., Goyal, S., Mahajan, U. B., Patil, C. R., Arya, D. S., & Rajesh, M. (2016). Cardioprotective potentials of plant-derived small molecules against doxorubicin associated cardiotoxicity. Oxidative medicine and cellular longevity, 2016.
  • Palma, F. R., He, C., Danes, J. M., Paviani, V., Coelho, D. R., Gantner, B. N., & Bonini, M. G. (2020). Mitochondrial Superoxide Dismutase: What the Established, the Intriguing, and the Novel Reveal About a Key Cellular Redox Switch. Antioxidants and Redox Signaling, 32(10), 701–714.
  • Psotová, J., Chlopcíková, S., Miketová, P., Hrbác, J., & Simánek, V. (2004). Chemoprotective effect of plant phenolics against anthracycline-induced toxicity on rat cardiomyocytes. Part III. Apigenin, baicalelin, kaempherol, luteolin and quercetin. Phytotherapy Research, 18(7), 516–521.
  • Qiu, Y., Jiang, P., & Huang, Y. (2023). Anthracycline-induced cardiotoxicity: mechanisms, monitoring, and prevention. Frontiers in Cardiovascular Medicine, 10, 1242596.
  • Rawat, P. S., Jaiswal, A., Khurana, A., Bhatti, J. S., & Navik, U. (2021). Doxorubicin-induced cardiotoxicity: An update on the molecular mechanism and novel therapeutic strategies for effective management. Biomedicine and Pharmacotherapy, 139, 111708.
  • Shi, S., Chen, Y., Luo, Z., Nie, G., & Dai, Y. (2023). Role of oxidative stress and inflammation-related signaling pathways in doxorubicin-induced cardiomyopathy. Cell Communication and Signaling, 21(1), 61.
  • Shi, W., Deng, H., Zhang, J., Zhang, Y., Zhang, X., & Cui, G. (2018). Mitochondria-Targeting Small Molecules Effectively Prevent Cardiotoxicity Induced by Doxorubicin. Molecules, 23(6), 1486.
  • Sohail, M., Sun, Z., Li, Y., Gu, X., & Xu, H. (2021). Research progress in strategies to improve the efficacy and safety of doxorubicin for cancer chemotherapy. Expert Review of Anticancer Therapy, 21(12), 1385-1398.
  • Sun, Y., Oberley, L. W., & Li, Y. (1988). A simple method for clinical assay of superoxide dismutase. Clinical Chemistry, 34(3), 497–500.
  • Tadokoro, T., Ikeda, M., Ide, T., Deguchi, H., Ikeda, S., Okabe, K., Ishikita, A., Matsushima, S., Koumura, T., Yamada, K. I., Imai, H., & Tsutsui, H. (2023). Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity. JCI insight, 8(6), e169756.
  • Wendel A. (1981). Glutathione peroxidase. Methods in Enzymology, 77, 325–333.
  • Wu, Y. Z., Zhang, L., Wu, Z. X., Shan, T. T., & Xiong, C. (2019). Berberine Ameliorates Doxorubicin-Induced Cardiotoxicity via a SIRT1/p66Shc-Mediated Pathway. Oxidative Medicine and Cellular Longevity, 2019, 2150394.
  • Yang, Y., Sun, B., Zuo, S., Li, X., Zhou, S., Li, L., Luo, C., Liu, H., Cheng, M., Wang, Y., Wang, S., He, Z., & Sun, J. (2020). Trisulfide bond-mediated doxorubicin dimeric prodrug nanoassemblies with high drug loading, high self-assembly stability, and high tumor selectivity. Science advances, 6(45), 1725.
  • Yesilkent, E. N., & Ceylan, H. (2022). Investigation of the multi-targeted protection potential of tannic acid against doxorubicin-induced kidney damage in rats. Chemico-Biological Interactions, 365, 110111.
  • Yun, E. S., Park, S. S., Shin, H. C., Choi, Y. H., Kim, W. J., & Moon, S. K. (2011). p38 MAPK activation is required for esculetin-induced inhibition of vascular smooth muscle cells proliferation. Toxicology In Vitro, 25(7), 1335-1342.
  • Zhang, L., Xie, Q., & Li, X. (2022). Esculetin: A review of its pharmacology and pharmacokinetics. Phytotherapy research, 36(1), 279–298.

Eskuletin'in Koruyucu Rolünü Keşfetmek: Sıçan Kalbinde Doksorubisinin Neden Olduğu Oksidatif Stresle Mücadele

Yıl 2024, Cilt: 4 Sayı: 1, 44 - 52, 29.03.2024
https://doi.org/10.5281/zenodo.10892230

Öz

Doksorubisin (DOX) ve diğer antrasiklinler kansere karşı kullanılan güçlü kemoterapi ilaçlarıdır; ancak klinik uygulamaları önemli ve potansiyel olarak yaşamı tehdit eden kardiyotoksisite ile bağlantılıdır. Uzun yıllar süren kapsamlı araştırmalara rağmen, mevcut tedavi seçenekleri hala kısıtlıdır. DOX'un tipik olarak öncelikle mitokondriyi etkilediğine inanılır ve DOX kaynaklı kardiyotoksisitenin karakteristik özelliği mitokondriyal disfonksiyondur. Bu çalışma, bilinen özellikleri göz önünde bulundurularak Sprague-Dawley sıçanlarında DOX kaynaklı kardiyotoksisiteye karşı esculetin'in koruyucu etkilerini araştırmak üzere tasarlanmıştır. Kardiyotoksisite, DOX'un intraperitoneal enjeksiyon yoluyla haftalık 5 mg/kg vücut ağırlığı dozunda iki ardışık hafta boyunca uygulanmasıyla indüklenmiştir. DOX enjeksiyonu yapılan sıçanlara aynı süre boyunca 50 ve 100 mg/kg vücut ağırlığı dozlarında intraperitoneal uygulama yoluyla eş zamanlı olarak esculetin takviyesi yapılmıştır. Kalp dokusundaki oksidatif stres enzimlerinin araştırılmasında biyokimyasal ve moleküler yöntemler kullanılmıştır. Kalp dokularında katalaz (CAT), glutatyon peroksidaz (GPx) ve süperoksit dismutaz (SOD) enzim aktiviteleri ve ekspresyon seviyeleri değerlendirildi.DOX ile intoksikasyon, CAT ve GPx ve SOD'yi etkileyerek antioksidan durumda bir azalmaya neden oldu. DOX grubunda hem enzim aktivitesi hem de mRNA ekspresyonu azalmıştır. DOX ve esculetin kombine gruplarında ise artış görülmüştür. Bu çalışma, kalp dokusu üzerinde DOX'un neden olduğu zararlı etkilerin, oksidatif stresin modülasyonu yoluyla esculetin tarafından potansiyel olarak hafifletildiğini öne sürmektedir.

Etik Beyan

Ethics committee approval was received for this study from the ethics committee of Atatürk University (Protocol Number: 2021/4–123).

Proje Numarası

Ardahan Üniversitesi BAP birimi Proje No: 2021-003

Kaynakça

  • Abdelghffar, E. A., Obaid, W. A., Elgamal, A. M., Daoud, R., Sobeh, M., & El Raey, M. A. (2021). Pea (Pisum sativum) peel extract attenuates DOX-induced oxidative myocardial injury. Biomedicine and pharmacotherapy, 143, 112120.
  • Aebi H. (1984). Catalase in vitro. Methods in Enzymology, 105, 121–126.
  • Bradford M. M. (1976). A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical Biochemistry, 72, 248–254.
  • Ceylan, H., Budak, H., Kocpinar, E. F., Baltaci, N. G., & Erdogan, O. (2019). Examining the link between dose-dependent dietary iron intake and Alzheimer's disease through oxidative stress in the rat cortex. Journal of Trace Elements in Medicine and Biology, 56, 198–206.
  • Childs, A. C., Phaneuf, S. L., Dirks, A. J., Phillips, T., & Leeuwenburgh, C. (2002). Doxorubicin treatment in vivo causes cytochrome C release and cardiomyocyte apoptosis, as well as increased mitochondrial efficiency, superoxide dismutase activity, and Bcl-2:Bax ratio. Cancer Research, 62(16), 4592–4598.
  • Dai, G. F., Wang, Z., & Zhang, J. Y. (2018). Octreotide protects doxorubicin-induced cardiac toxicity via regulating oxidative stress. European Review for Medical and Pharmacological Sciences, 22(18), 6139–6148.
  • De Geest, B., & Mishra, M. (2022). Role of oxidative stress in diabetic cardiomyopathy. Antioxidants, 11(4), 784.
  • Jiang, Q., Chen, X., Tian, X., Zhang, J., Xue, S., Jiang, Y., Liu, T., Wang, X., Sun, Q., Hong, Y., Li, C., Guo, D., Wang, Y., & Wang, Q. (2022). Tanshinone I inhibits doxorubicin-induced cardiotoxicity by regulating Nrf2 signaling pathway. Phytomedicine, 106, 154439.
  • Kadakol, A., Sharma, N., Kulkarni, Y. A., & Gaikwad, A. B. (2016). Esculetin: A phytochemical endeavor fortifying effect against non-communicable diseases. Biomedicine and Pharmacotherapy 84, 1442–1448.
  • Karagac, M. S., & Ceylan, H. (2023). Neuroprotective potential of tannic acid against neurotoxic outputs of monosodium glutamate in rat cerebral cortex. Neurotoxicity Research, 41(6), 670–680.
  • Kong, C. Y., Guo, Z., Song, P., Zhang, X., Yuan, Y. P., Teng, T., Yan, L., & Tang, Q. Z. (2022). Underlying the Mechanisms of Doxorubicin-Induced Acute Cardiotoxicity: Oxidative Stress and Cell Death. International Journal of Biological Sciences, 18(2), 760–770.
  • Lee, S. Y., Lim, T. G., Chen, H., Jung, S. K., Lee, H. J., Lee, M. H., Kim, D. J., Shin, A., Lee, K. W., Bode, A. M., Surh, Y. J., & Dong, Z. (2013). Esculetin suppresses proliferation of human colon cancer cells by directly targeting β-catenin. Cancer Prevention Research, 6(12), 1356–1364.
  • Lei, F. J., Chiang, J. Y., Chang, H. J., Chen, D. C., Wang, H. L., Yang, H. A., Wei, K. Y., Huang, Y. C., Wang, C. C., Wei, S. T., & Hsieh, C. H. (2023). Cellular and exosomal GPx1 are essential for controlling hydrogen peroxide balance and alleviating oxidative stress in hypoxic glioblastoma. Redox Biology, 65, 102831.
  • Marques, G. L., Neto, F. F., Ribeiro, C. A., Liebel, S., de Fraga, R., & Bueno, R. daR. (2015). Oxidative Damage in the Aging Heart: an Experimental Rat Model. The Open Cardiovascular Medicine Journal, 9, 78–82.
  • Minotti, G., Menna, P., Salvatorelli, E., Cairo, G., & Gianni, L. (2004). Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacological Reviews, 56(2), 185-229.
  • Nandi, A., Yan, L. J., Jana, C. K., & Das, N. (2019). Role of Catalase in Oxidative Stress- and Age-Associated Degenerative Diseases. Oxidative Medicine and Cellular Longevity, 2019, 9613090.
  • Ojha, S., Al Taee, H., Goyal, S., Mahajan, U. B., Patil, C. R., Arya, D. S., & Rajesh, M. (2016). Cardioprotective potentials of plant-derived small molecules against doxorubicin associated cardiotoxicity. Oxidative medicine and cellular longevity, 2016.
  • Palma, F. R., He, C., Danes, J. M., Paviani, V., Coelho, D. R., Gantner, B. N., & Bonini, M. G. (2020). Mitochondrial Superoxide Dismutase: What the Established, the Intriguing, and the Novel Reveal About a Key Cellular Redox Switch. Antioxidants and Redox Signaling, 32(10), 701–714.
  • Psotová, J., Chlopcíková, S., Miketová, P., Hrbác, J., & Simánek, V. (2004). Chemoprotective effect of plant phenolics against anthracycline-induced toxicity on rat cardiomyocytes. Part III. Apigenin, baicalelin, kaempherol, luteolin and quercetin. Phytotherapy Research, 18(7), 516–521.
  • Qiu, Y., Jiang, P., & Huang, Y. (2023). Anthracycline-induced cardiotoxicity: mechanisms, monitoring, and prevention. Frontiers in Cardiovascular Medicine, 10, 1242596.
  • Rawat, P. S., Jaiswal, A., Khurana, A., Bhatti, J. S., & Navik, U. (2021). Doxorubicin-induced cardiotoxicity: An update on the molecular mechanism and novel therapeutic strategies for effective management. Biomedicine and Pharmacotherapy, 139, 111708.
  • Shi, S., Chen, Y., Luo, Z., Nie, G., & Dai, Y. (2023). Role of oxidative stress and inflammation-related signaling pathways in doxorubicin-induced cardiomyopathy. Cell Communication and Signaling, 21(1), 61.
  • Shi, W., Deng, H., Zhang, J., Zhang, Y., Zhang, X., & Cui, G. (2018). Mitochondria-Targeting Small Molecules Effectively Prevent Cardiotoxicity Induced by Doxorubicin. Molecules, 23(6), 1486.
  • Sohail, M., Sun, Z., Li, Y., Gu, X., & Xu, H. (2021). Research progress in strategies to improve the efficacy and safety of doxorubicin for cancer chemotherapy. Expert Review of Anticancer Therapy, 21(12), 1385-1398.
  • Sun, Y., Oberley, L. W., & Li, Y. (1988). A simple method for clinical assay of superoxide dismutase. Clinical Chemistry, 34(3), 497–500.
  • Tadokoro, T., Ikeda, M., Ide, T., Deguchi, H., Ikeda, S., Okabe, K., Ishikita, A., Matsushima, S., Koumura, T., Yamada, K. I., Imai, H., & Tsutsui, H. (2023). Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity. JCI insight, 8(6), e169756.
  • Wendel A. (1981). Glutathione peroxidase. Methods in Enzymology, 77, 325–333.
  • Wu, Y. Z., Zhang, L., Wu, Z. X., Shan, T. T., & Xiong, C. (2019). Berberine Ameliorates Doxorubicin-Induced Cardiotoxicity via a SIRT1/p66Shc-Mediated Pathway. Oxidative Medicine and Cellular Longevity, 2019, 2150394.
  • Yang, Y., Sun, B., Zuo, S., Li, X., Zhou, S., Li, L., Luo, C., Liu, H., Cheng, M., Wang, Y., Wang, S., He, Z., & Sun, J. (2020). Trisulfide bond-mediated doxorubicin dimeric prodrug nanoassemblies with high drug loading, high self-assembly stability, and high tumor selectivity. Science advances, 6(45), 1725.
  • Yesilkent, E. N., & Ceylan, H. (2022). Investigation of the multi-targeted protection potential of tannic acid against doxorubicin-induced kidney damage in rats. Chemico-Biological Interactions, 365, 110111.
  • Yun, E. S., Park, S. S., Shin, H. C., Choi, Y. H., Kim, W. J., & Moon, S. K. (2011). p38 MAPK activation is required for esculetin-induced inhibition of vascular smooth muscle cells proliferation. Toxicology In Vitro, 25(7), 1335-1342.
  • Zhang, L., Xie, Q., & Li, X. (2022). Esculetin: A review of its pharmacology and pharmacokinetics. Phytotherapy research, 36(1), 279–298.
Toplam 32 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Biyokimya ve Hücre Biyolojisi (Diğer)
Bölüm Araştırma Makaleleri
Yazarlar

Neslihan Öztürk 0000-0002-9119-1206

Medine Sibel Karağaç 0000-0002-8064-1195

Esra Nur Yeşilkent 0000-0001-9468-2679

Murat Isıyel 0000-0003-4157-2729

Hilal Tosun 0009-0000-7020-9668

Habibe Karadaş 0009-0001-6786-006X

Hamid Ceylan 0000-0003-3781-4406

Yeliz Demir 0000-0003-3216-1098

Proje Numarası Ardahan Üniversitesi BAP birimi Proje No: 2021-003
Yayımlanma Tarihi 29 Mart 2024
Gönderilme Tarihi 29 Ocak 2024
Kabul Tarihi 12 Mart 2024
Yayımlandığı Sayı Yıl 2024 Cilt: 4 Sayı: 1

Kaynak Göster

EndNote Öztürk N, Karağaç MS, Yeşilkent EN, Isıyel M, Tosun H, Karadaş H, Ceylan H, Demir Y (01 Mart 2024) Exploring Esculetin’s Protective Role: Countering Doxorubicin-Induced Oxidative Stress in Rat Heart. Laboratuvar Hayvanları Bilimi ve Uygulamaları Dergisi 4 1 44–52.

Content of this journal is licensed under a Creative Commons Attribution NonCommercial 4.0 International License

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