Abstract
Amaç: Bu çalışmada, sıçanlarda MTX ile indüklenen kardiyak toksisitede timokinonun kardiyak doku üzerindeki etkisinin çeşitli parametrelerle değerlendirilmesi amaçlanmıştır.
Gereç ve Yöntem: Grup I'e (n=8) 10 gün boyunca intraperitoneal salin uygulandı. Grup II'ye (n=8) 10 gün boyunca intraperitoneal zeytinyağı uygulandı. Grup III (n=8) 10 gün boyunca 10 mg/kg timokinon (THQ) intraperitoneal olarak almıştır. Grup IV'e (n=8) deneyin 1. gününde tek doz 20 mg/kg Metotreksat (MTX), 500 mg/20 ml, intraperitoneal olarak uygulandı. Metotreksat sıvı formda olduğu için herhangi bir çözücü kullanılmamıştır. Grup V (n=8) MTX: 1. gün 20 mg/kg tek doz intraperitoneal; THQ: 10mg/kg i.p. 10 gün boyunca uygulandı. Deney süresinin sonunda sıçanlar kalp dokusu analizi için sakrifiye edilmiştir. Kalp dokusunun yapısı hematoksilen-eozin boyama ile değerlendirildi. İmmünohistokimyasal olarak, konneksin-43, HSP90 ve HIF-1α antikorları ile boyandı.
Bulgular: Grup IV’ün histopatolojisinde bozulmalar olduğu belirlendi, THQ’nun bu bozulmayı iyileştirdiği görüldü. Bunun yanı sıra, diğer gruplara göre; konneksin-43 immunureaktivitesi, Grup IV’de: 108.5±7.4 ile en düşük, HSP90 immunureaktivitesi diğer gruplara göre, Grup IV’de: 103.6±10.4 en yüksek, HIF-1α immunureaktivitesi diğer gruplara göre Grup IV’de: 95.2 ±9.1 en yüksek değerlerdeydi.
Sonuç: Timokinon, MTX toksisitesine karşı interkalar disklerde iletimi sağlayan proteinlerden biri olan konneksin-43, hücre içindeki şaperonlardan biri olan HSP90 ve HIF-1α ekspresyonu üzerine olumlu etki göstermektedir. Aynı zamanda THQ, kalp dokusunda histopatolojik olarak kardiyoprotektif etki göstererek anlamlı bir iyileşme sağlamaktadır.
Keywords
Supporting Institution
Yozgat Bozok Üniversitesi BAP
Project Number
21/036
References
- Genestier L, Paillot R, Quemeneur L, Izeradjene K, Revillard JP. Mechanisms of action of methotrexate. Immunopharmacology. 2000;47:247-57.
- Perez-Verdia A, Angulo F, Hardwicke FL, Nugent KM. Acute cardiac toxicity associated with high-dose intravenous methotrexate therapy: case report and review of the literature. Pharmacother J Hum Pharmacol Drug Ther. 2005;25:1271-6.
- Al-Taher AY, Morsy MA, Rifaai RA, Zenhom NM, Abdel-Gaber SA. Paeonol attenuates methotrexate-induced cardiac toxicity in rats by inhibiting oxidative stress and suppressing TLR4-induced NF-κB inflammatory pathway. Mediators Inflamm. 2020;2020:8641026.
- Abdel-Daim MM, Khalifa HA, Abushouk AI, Dkhil MA, Al-Quraishy SA. Diosmin attenuates methotrexate-induced hepatic, renal, and cardiac injury: a biochemical and histopathological study in mice. Oxid Med Cell Longev. 2017;2017:3281670.
- Johnson RD, Camelliti P. Role of non-myocyte gap junctions and connexin hemichannels in cardiovascular health and disease: novel therapeutic targets? Int J Mol Sci. 2018;19:866.
- Severs NJ, Bruce AF, Dupont E, Rothery S. Remodelling of gap junctions and connexin expression in diseased myocardium. Cardiovasc Res. 2008;80:9-19.
- Ko YS, Yeh HI, Ko YL, Hsu YC, Chen CF, Wu S et al. Three-dimensional reconstruction of the rabbit atrioventricular conduction axis by combining histological, desmin, and connexin mapping data. Circulation. 2004;109:1172-9.
- Desplantez T. Cardiac Cx43, Cx40 and Cx45 co-assembling: Involvement of connexins epitopes in formation of hemichannels and Gap junction channels. BMC Cell Biol. 2017;18:1-13.
- Yu X, Mao M, Liu X, Shen T, Li T, Yu H et al. A cytosolic heat shock protein 90 and co-chaperone p23 complex activates RIPK3/MLKL during necroptosis of endothelial cells in acute respiratory distress syndrome. J Mol Med. 2020;98:569-83.
- Minet E, Mottet D, Michel G, Roland I, Raes M, Remacle J et al. Hypoxia-induced activation of HIF-1: role of HIF-1α-Hsp90 interaction. FEBS Lett. 1999;460:251-6.
- Isaacs JS, Jung YJ, Mimnaugh EG, Martinez A, Cuttitta F, Neckers LM. Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1α-degradative pathway. J Biol Chem. 2002;277:29936-44.
- Park SY, Jang WJ, Yi EY, Jang JY, Jung Y, Jeong JW et al. Melatonin suppresses tumor angiogenesis by inhibiting HIF-1α stabilization under hypoxia. J Pineal Res. 2010;48:178-84.
- Schmid T, Zhou J, Brüne B. HIF-1 and p53: communication of transcription factors under hypoxia. J Cell Mol Med. 2004;8:423-31.
- Yeo EJ, Chun YS, Park JW. New anticancer strategies targeting HIF-1. Biochem Pharmacol. 2004;68:1061-9.
- Alrashedi M. The protective role of thymoquinone against drugs toxicity : a review. 2018;24:1-11.
- Farooq J, Sultana R, Taj T, Asdaq SMB, Alsalman AJ, Mohaini MA et al. Insights into the protective effects of thymoquinone against toxicities induced by chemotherapeutic agents. Molecules. 2022;27:226.
- Sonmez MF, Cılenk KT, Karabulut D, Unalmıs S, Deligonul E, Ozturk I et al. Protective effects of propolis on methotrexate-induced testis injury in rat. Biomed Pharmacother. 2016;79: 44-51.
- Yildirim AB, Karabulut D, Dundar M, Ulusoy HB, Sonmez MF. Expression of Ghrelin and GHSR-1a in Long Term Diabetic Rat’s Kidney. Braz Arch Biol Technol. 2016;59:150312.
- Michela P, Velia V, Aldo P, Ada P. Role of connexin 43 in cardiovascular diseases. Eur J Pharmacol. 2015;768:71-6.
- Boengler K, Dodoni G, Rodriguez-Sinovas A, Cabestrero A, Ruiz-Meana M, Gres P et al. Connexin 43 in cardiomyocyte mitochondria and its increase by ischemic preconditioning. Cardiovasc Res. 2005;67:234-44.
- Denuc A, Nunez E, Calvo E, Loureiro M, Miro-Casas E, Guarás A et al. New protein–protein interactions of mitochondrial connexin 43 in mouse heart. J Cell Mol Med. 2016;20:794-803.
- Tu RH, Li QJ, Huang Z, He Y, Meng JJ, Zheng HL et al. Novel functional role of heat shock protein 90 in mitochondrial connexin 43-mediated hypoxic postconditioning. Cell Physiol Biochem. 2017;44:982-97.
- Roberts RJ, Hallee L, Lam CK. The potential of Hsp90 in targeting pathological pathways in cardiac diseases. J Pers Med. 2021;11:1373.
- Walter S, Buchner J. Molecular chaperones-cellular machines for protein folding. Angew Chem Int Ed. 2002;41:1098-113.
- Zhong GQ, Tu RH, Zeng ZY, Li Q jie, He Y, Li S et al. Novel functional role of heat shock protein 90 in protein kinase C-mediated ischemic postconditioning. J Surg Res. 2014;189:198-206.
- Yu J, Bao E, Yan J, Lei L. Expression and localization of Hsps in the heart and blood vessel of heat-stressed broilers. Cell Stress Chaperones. 2008;13:327-35.
- Hölscher M, Schäfer K, Krull S, Farhat K, Hesse A, Silter M et al. Unfavourable consequences of chronic cardiac HIF-1α stabilization. Cardiovasc Res. 2012;94:77-86.
- Mabjeesh NJ, Post DE, Willard MT, Kaur B, Van Meir EG, Simons JW et al. Geldanamycin induces degradation of hypoxia-inducible factor 1α protein via the proteosome pathway in prostate cancer cells. Cancer Res. 2002;62:2478-82.
- Semenza GL, Agani F, Iyer N, Kotch L, Laughner E, Leung S et al. Regulation of cardiovascular development and physiology by hypoxia-inducible factor 1α. Ann N Y Acad Sci. 1999;874:262-8.
- Fialho M da LS, Abd Jamil AH, Stannard GA, Heather LC. Hypoxia-inducible factor 1 signalling, metabolism and its therapeutic potential in cardiovascular disease. Biochim Biophys Acta BBA-Mol Basis Dis. 2019;1865:831-43.
- Hashmi S, Al-Salam S. Hypoxia-inducible factor-1 alpha in the heart: a double agent? Cardiol Rev. 2012;20:268-73.
- Dogan Z, Durmus S, Ergun DD, Gelisgen R, Uzun H. Ranolazine exhibits anti-inflammatory and antioxidant activities in H9c2 cardiomyocytes. Eur Rev Med Pharmacol Sci. 2023;27:2953-63.
Abstract
Purpose: The study aimed to evaluate the effect of thymoquinone on cardiac tissue in MTX-induced cardiac toxicity in rats with various parameters.
Materials and Methods: Group I (n:8) was administered intraperitoneal saline for 10 days. Intraperitoneal olive oil was applied to Group II (n:8) for 10 days. Group III (n:8) was administered a single dose of 20 mg/kg Methotrexate (MTX) (500 mg/20 ml) intraperitoneally on the 1st day of the experiment. Since Methotrexate was in liquid form, no solvent was used. Group IV (n:8) received 10 mg/kg Thymoquinone (THQ) intraperitoneally for 10 days. Group V (n:8) (MTX: (20 mg/kg single dose intraperitoneally on the 1st day); THQ: 10mg/kg i.p. administered for 10 days. At the end of the experimental period, the rats were sacrificed for analysis of heart tissue. The structure of heart tissue was evaluated by haematoxylin-eosin staining. Immunohistochemically, connexin-43, HSP90, and HIF-1α antibodies were stained. The results were analysed statistically.
Results: According to our results, thymoquinone has a positive effect on the expression of Cx43, one of the proteins providing transmission in the intercalary discs, HSP90, one of the chaperones in the cell, and HIF-1α expression against MTX toxicity and provides a significant improvement by showing a cardioprotective effect histopathologically.
Conclusion: THQ could be considered a crucial cardioprotective phytochemical against MTX cardiotoxicity.
Project Number
21/036
References
- Genestier L, Paillot R, Quemeneur L, Izeradjene K, Revillard JP. Mechanisms of action of methotrexate. Immunopharmacology. 2000;47:247-57.
- Perez-Verdia A, Angulo F, Hardwicke FL, Nugent KM. Acute cardiac toxicity associated with high-dose intravenous methotrexate therapy: case report and review of the literature. Pharmacother J Hum Pharmacol Drug Ther. 2005;25:1271-6.
- Al-Taher AY, Morsy MA, Rifaai RA, Zenhom NM, Abdel-Gaber SA. Paeonol attenuates methotrexate-induced cardiac toxicity in rats by inhibiting oxidative stress and suppressing TLR4-induced NF-κB inflammatory pathway. Mediators Inflamm. 2020;2020:8641026.
- Abdel-Daim MM, Khalifa HA, Abushouk AI, Dkhil MA, Al-Quraishy SA. Diosmin attenuates methotrexate-induced hepatic, renal, and cardiac injury: a biochemical and histopathological study in mice. Oxid Med Cell Longev. 2017;2017:3281670.
- Johnson RD, Camelliti P. Role of non-myocyte gap junctions and connexin hemichannels in cardiovascular health and disease: novel therapeutic targets? Int J Mol Sci. 2018;19:866.
- Severs NJ, Bruce AF, Dupont E, Rothery S. Remodelling of gap junctions and connexin expression in diseased myocardium. Cardiovasc Res. 2008;80:9-19.
- Ko YS, Yeh HI, Ko YL, Hsu YC, Chen CF, Wu S et al. Three-dimensional reconstruction of the rabbit atrioventricular conduction axis by combining histological, desmin, and connexin mapping data. Circulation. 2004;109:1172-9.
- Desplantez T. Cardiac Cx43, Cx40 and Cx45 co-assembling: Involvement of connexins epitopes in formation of hemichannels and Gap junction channels. BMC Cell Biol. 2017;18:1-13.
- Yu X, Mao M, Liu X, Shen T, Li T, Yu H et al. A cytosolic heat shock protein 90 and co-chaperone p23 complex activates RIPK3/MLKL during necroptosis of endothelial cells in acute respiratory distress syndrome. J Mol Med. 2020;98:569-83.
- Minet E, Mottet D, Michel G, Roland I, Raes M, Remacle J et al. Hypoxia-induced activation of HIF-1: role of HIF-1α-Hsp90 interaction. FEBS Lett. 1999;460:251-6.
- Isaacs JS, Jung YJ, Mimnaugh EG, Martinez A, Cuttitta F, Neckers LM. Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1α-degradative pathway. J Biol Chem. 2002;277:29936-44.
- Park SY, Jang WJ, Yi EY, Jang JY, Jung Y, Jeong JW et al. Melatonin suppresses tumor angiogenesis by inhibiting HIF-1α stabilization under hypoxia. J Pineal Res. 2010;48:178-84.
- Schmid T, Zhou J, Brüne B. HIF-1 and p53: communication of transcription factors under hypoxia. J Cell Mol Med. 2004;8:423-31.
- Yeo EJ, Chun YS, Park JW. New anticancer strategies targeting HIF-1. Biochem Pharmacol. 2004;68:1061-9.
- Alrashedi M. The protective role of thymoquinone against drugs toxicity : a review. 2018;24:1-11.
- Farooq J, Sultana R, Taj T, Asdaq SMB, Alsalman AJ, Mohaini MA et al. Insights into the protective effects of thymoquinone against toxicities induced by chemotherapeutic agents. Molecules. 2022;27:226.
- Sonmez MF, Cılenk KT, Karabulut D, Unalmıs S, Deligonul E, Ozturk I et al. Protective effects of propolis on methotrexate-induced testis injury in rat. Biomed Pharmacother. 2016;79: 44-51.
- Yildirim AB, Karabulut D, Dundar M, Ulusoy HB, Sonmez MF. Expression of Ghrelin and GHSR-1a in Long Term Diabetic Rat’s Kidney. Braz Arch Biol Technol. 2016;59:150312.
- Michela P, Velia V, Aldo P, Ada P. Role of connexin 43 in cardiovascular diseases. Eur J Pharmacol. 2015;768:71-6.
- Boengler K, Dodoni G, Rodriguez-Sinovas A, Cabestrero A, Ruiz-Meana M, Gres P et al. Connexin 43 in cardiomyocyte mitochondria and its increase by ischemic preconditioning. Cardiovasc Res. 2005;67:234-44.
- Denuc A, Nunez E, Calvo E, Loureiro M, Miro-Casas E, Guarás A et al. New protein–protein interactions of mitochondrial connexin 43 in mouse heart. J Cell Mol Med. 2016;20:794-803.
- Tu RH, Li QJ, Huang Z, He Y, Meng JJ, Zheng HL et al. Novel functional role of heat shock protein 90 in mitochondrial connexin 43-mediated hypoxic postconditioning. Cell Physiol Biochem. 2017;44:982-97.
- Roberts RJ, Hallee L, Lam CK. The potential of Hsp90 in targeting pathological pathways in cardiac diseases. J Pers Med. 2021;11:1373.
- Walter S, Buchner J. Molecular chaperones-cellular machines for protein folding. Angew Chem Int Ed. 2002;41:1098-113.
- Zhong GQ, Tu RH, Zeng ZY, Li Q jie, He Y, Li S et al. Novel functional role of heat shock protein 90 in protein kinase C-mediated ischemic postconditioning. J Surg Res. 2014;189:198-206.
- Yu J, Bao E, Yan J, Lei L. Expression and localization of Hsps in the heart and blood vessel of heat-stressed broilers. Cell Stress Chaperones. 2008;13:327-35.
- Hölscher M, Schäfer K, Krull S, Farhat K, Hesse A, Silter M et al. Unfavourable consequences of chronic cardiac HIF-1α stabilization. Cardiovasc Res. 2012;94:77-86.
- Mabjeesh NJ, Post DE, Willard MT, Kaur B, Van Meir EG, Simons JW et al. Geldanamycin induces degradation of hypoxia-inducible factor 1α protein via the proteosome pathway in prostate cancer cells. Cancer Res. 2002;62:2478-82.
- Semenza GL, Agani F, Iyer N, Kotch L, Laughner E, Leung S et al. Regulation of cardiovascular development and physiology by hypoxia-inducible factor 1α. Ann N Y Acad Sci. 1999;874:262-8.
- Fialho M da LS, Abd Jamil AH, Stannard GA, Heather LC. Hypoxia-inducible factor 1 signalling, metabolism and its therapeutic potential in cardiovascular disease. Biochim Biophys Acta BBA-Mol Basis Dis. 2019;1865:831-43.
- Hashmi S, Al-Salam S. Hypoxia-inducible factor-1 alpha in the heart: a double agent? Cardiol Rev. 2012;20:268-73.
- Dogan Z, Durmus S, Ergun DD, Gelisgen R, Uzun H. Ranolazine exhibits anti-inflammatory and antioxidant activities in H9c2 cardiomyocytes. Eur Rev Med Pharmacol Sci. 2023;27:2953-63.
Details
| Primary Language | English |
|---|---|
| Subjects | Oncologic Surgery, Histology and Embryology |
| Journal Section | Research |
| Authors | |
| Project Number | 21/036 |
| Early Pub Date | September 25, 2023 |
| Publication Date | September 30, 2023 |
| Acceptance Date | August 23, 2023 |
| Published in Issue | Year 2023 Volume: 48 Issue: 3 |
