Effect of Cucumis melo var. agrestis Naudin on doxorubicin-induced cardiotoxicity in rats

Yıl 2024, Cilt: 49 Sayı: 2, 353 – 362, 30.06.2024

Emine Sarman

https://doi.org/10.17826/cumj.1429969

Öz

Amaç: Kemoterapötik bir antibiyotik olan doksorubisin (DOX), kanserli olmayan hücreleri de öldürerek toksisiteye neden olur. Cucumis melo var. agrestis Naudin (CM), Cucurbitaceae familyasına ait olan ve yüksek antioksidan içeriğe sahip bir bitkidir. Bu çalışmanın amacı, DOX kaynaklı kalp hasarına karşı farklı dozlarda uygulanan CM etkisini araştırmaktır.
Gereç ve Yöntem: 30 adet erkek rat, rastgele her grupta 6 hayvan olacak şekilde 5 gruba ayrıldı: 10 gün gavajla distile su verilen sıçanlara, deneyin 5. gününde intraperitoneal (i.p.) serum fizyolojik uygulaması yapılan kontrol grubu. Deneyin 5. Günü 15 mg/kg tek doz i.p. DOX uygulanan sıçanlardan oluşan DOX grubu. Deneyin 5. Günü 15 mg/kg tek doz i.p. DOX uygulanan sıçanlara 10 gün gavajla sırasıyla 100 mg/kg: (DOX+CM100), 250 mg/kg: (DOX+CM250), 500 mg/kg: (DOX+CM500) CM uygulanan gruplar. Son ilaç uygulamasından 24 saat sonra deney hayvanları anestezi altında sakrifiye edildi. Kalp dokusu histokimyasal ve immunohistokimyasal olarak incelendi.
Bulgular: Deney sonunda kalp dokusunun histopatolojik incelenmesinde; kontrol grubuyla karşılaştırıldığında DOX grubunda kas liflerinin dejenerasyonu, kas lifleri arasında vakuol benzeri yapılar, damarlarda konjesyon, kollateraller arasında ödem gibi bulgular görülmüştür. Bu bulgular tedavi grubu olan DOX+CM250 grubunda önemli derecede azalmıştır. DOX grubunda Caspase-3, HSP 70 ve NF-κB-p65 immunreaktivitelerinde bir artış görülürken (+++); DOX+CM250 grubunda ise bu bulgular önemli derecede azalmıştır (+).
Sonuç: DOX’un apoptotik süreci hızlandırdığı, enflamatuvar yanıtı tetikleyerek hücre içi stresi ve oksidatif stresi arttırdığı histokimyasal ve immunohistokimyasal olarak görülmüştür. 250 mg/kg dozunda uygulanan CM kardiyak yeniden yapılanmayı hızlandırmıştır.

Anahtar Kelimeler

Doxorubicin, Cardiotoxicity, Cucumis melo var. agrestis Naudin, Caspase-3, HSP 70, NF-κB-p65

Etik Beyan

Ethical approval for the research project or animal experiments has been obtained with Decision Number 112, dated 08.11.2023, from the Local Ethics Committee for Animal Experiments at Afyon Kocatepe University under the reference number 49533702.

Kaynakça

• Christidi E, Brunham LR. Regulated cell death pathways in doxorubicin-induced cardiotoxicity. Cell Death Dis. 2021;12:339.
• Mansouri E, Jangaran A, Ashtari A. Protective effect of pravastatin on doxorubicin-induced hepatotoxicity. Bratisl Lek List. 2017;118:273-7.
• Osataphan N, Phrommintikul A, Chattipakorn SC, Chattipakorn N. Effects of doxorubicin-induced cardiotoxicity on cardiac mitochondrial dynamics and mitochondrial function: Insights for future interventions. J Cell Mol Med. 2020;24:6534-57.
• Croteau R, Kutchan TM, Lewis NG. Natural products (Secondary metabolites). Biochem Mol Biol Plants. 2000;24:1250–319.
• Silva MA, Albuquerque TG, Alves RC, Oliveira M, Costa HS. Melon (Cucumis melo L.) by-products: Potential food ingredients for novel functional foods? Trends Food Sci Technol. 2020;98:181–9.
• Singh AK, Kumar S, Singh HK, Rai VP, Singh BD, Pandey S. Genetic diversity in Indian snapmelon (Cucumis melo var. momordica) accessions revealed by ISSR markers. Plant Omics. 2015;8:9–16.
• Shankar K, Singh S, Kumar D, Varshney S, Gupta A, Rajan S et al. Cucumis melo ssp. agrestis var. agrestis ameliorates high fat diet induced dyslipidemia in Syrian golden hamsters and inhibits adipogenesis in 3T3-L1 adipocytes. Pharmacogn Mag. 2015;11:501-10.
• Srivastava AK, Mukerjee A, Tripathi A. Antidiabetic and antihyperlipidemic activities of Cucumis melo var. momordica fruit extract on experimental animals. Futur J Pharm Sci. 2020;6:92.
• Fernandes NP, Lagishetty CV, Panda VS, Naik SR. An experimental evaluation of the antidiabetic and antilipidemic properties of a standardized Momordica charantia fruit extract. Complement Altern Med. 2007;7:29.
• Alagar Raja M, Sahithi G, Vasanthi R, David B, KNV Rao, Selvekumar D. Study of phytochemical and antioxidant activity of Cucumis melo var. agrestis fruit. J Pharmacogn Phytochem. 2015;4:303–6.
• Gopalasatheeskumar K, Kalaichelvan VK Antıoxıdant potentıal of different parts (leaves, stem, fruit, seed, flower and root) extracts of Cucumıs melo Var agrestıs. Int J Pharm Sci Res. 2021;12:465–9.
• Mallek-Ayadi S, Bahloul N, Kechaou N. Phytochemical profile, nutraceutical potential and functional properties of Cucumis melo L. seeds. J Sci Food Agric. 2019;99:1294-1301.
• Singh D, Singh M, Yadav E, Falls N, Komal U, Dangi DS et al. Amelioration of diethylnitrosamine (DEN)-induced hepatocellular carcinogenesis in animal models via knockdown oxidative stress and proinflammatory markers by Madhuca longifolia embedded silver nanoparticles. RSC Adv. 2018;8:6940-53.
• Yadav JP, Grishina M, Shahbaaz M, Mukerjee A, Singh S, Pathak P. Cucumis melo var. momordica as a potent antidiabetic, antioxidant and possible anticovid alternative: Investigation through experimental and computational methods. Phytomedicine. 2022;19: e202200200.
• Akbulut Ö. Hayvan deneylerinde örneklem büyüklüğünün kaynak eşitlik yöntemi ile belirlenmesi ve güç analizi. KSÜ Tıp Fakültesi Dergisi. 2023;18:117-25.
• Vidya R, Kalaivani K, Amudha P. Therapeutic potential of Cucumis melo (L.) fruit extract and its silver nanopartciles against DEN-induced hepatocellular cancer in rats. Appl Biochem Biotechnol. 2022;194:368-81.
• Sarman E, Gulle K, Ilhan I. Histochemical, immunohistochemical, and biochemical investigation of the effect of resveratrol on testicular damage caused by methotrexate (MTX). Reprod Sci. 2023;30:3315-24.
• Karakuyu NF, Savran M, Candan IA, Buyukbayram HI, Erzurumlu Y. Investigation of cardioprotective effect of lercanidipine on doxorubicin-induced cardiotoxicity. Naunyn Schmiedebergs Arch Pharmacol. 2023;396:3635-45.
• Tepebaşi MY, Aşci H, Coşan S, Sevük MA, Karakuyu NF, Özmen Ö. Irbesartan has a curative effect on lipopolysaccharide-induced cardiotoxicity by antioxidant and antiapoptotic pathways. Rev Port Cardiol. 2023;42:895-903.
• Georgakopoulos P, Kyriakidis M, Perpinia A, Karavidas A, Zimeras S, Mamalis N et al. The role of metoprolol and enalapril in the prevention of doxorubicin-induced cardiotoxicity in lymphoma patients. Anticancer Res. 2019;39:5703-7.
• Mitra S, Rauf A, Sutradhar H, Sadaf S, Hossain MJ, Soma MA et al. Potential candidates from marine and terrestrial resources targeting mitochondrial inhibition: Insights from the molecular approach. Comp Biochem Physiol C Toxicol Pharmacol. 2023;264:109509.
• 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;96:1065-74.
• Hagag AA, Badraia IM, El-Shehaby WA, Mabrouk MM. Protective role of black seed oil in doxorubicin-induced cardiac toxicity in children with acute lymphoblastic leukemia. J Oncol Pharm Pr. 2020;26:1397-1406.
• Al-Amir H, Janabi A, Hadi NR. Ameliorative effect of nebivolol in doxorubicin-induced cardiotoxicity. Med Life. 2023;16:1357-63.
• Nabati M, Janbabai G, Baghyari S, Esmaili K, Yazdani J. Cardioprotective effects of carvedilol in inhibiting doxorubicin-induced cardiotoxicity. J Cardiovasc Pharmacol. 2017;69:279-85.
• Erdogmus Ozgen Z, Erdinc M, Kelle I, Erdinc L, Nergiz Y. Protective effects of necrostatin-1 on doxorubicin-induced cardiotoxicity in rat heart. Hum Exp Toxicol. 2022;41:9603271211066066.
• Ibrahim SRM, Khedr AIM, Mohamed GA, Zayed MF, El-Kholy AAS, Al Haidari RA. Cucumol B, a new triterpene benzoate from Cucumis melo seeds with cytotoxic effect toward ovarian and human breast adenocarcinoma. J Asian Nat Prod Res. 2019;21:1112-18.
• Arora R, Kaur M, Gill NS. Antioxidant activity and pharmacological evaluation of Cucumis melo var. agrestis methanolic seed extract. Res J Phytochem. 2011;5:146–55.
• Bilgic S, Ozgocmen M, Ozer MK, Asci H. Misoprostol ameliorates doxorubicin induced cardiac damage by decreasing oxidative stress and apoptosis in rats. Biotech Histochem. 2020;95:514-21.
• Ai Y, Meng Y, Yan B, Zhou Q, Wang X. The biochemical pathways of apoptotic, necroptotic, pyroptotic, and ferroptotic cell death. Mol Cell. 2024;84:170-9.
• Jamshidi Z, Roohbakhsh A, Karimi G. An overview on the protective effects of ellagic acid against heavy metals, drugs, and chemicals. Food Sci Nutr. 2023;11:7469-84.
• El-Agamy DS, Abo-Haded HM, Elkablawy MA. Cardioprotective effects of sitagliptin against doxorubicin-induced cardiotoxicity in rats. Exp Biol Med. 2016;241:1577-87.
• Goda AE, Elenany AM, Elsisi AE. Novel in vivo potential of trifluoperazine to ameliorate doxorubicin-induced cardiotoxicity involves suppression of NF-κB and apoptosis. Life Sci. 2021;283:119849.
• Gutiérrez SH, Kuri MR, del Castillo ER. Cardiac role of the transcription factor NF-kappaB. Cardiovasc Hematol Disord Drug Targets. 2008;8:153-60.
• Timmers L, van Keulen JK, Hoefer IE, Meijs MF, van Middelaar B, den Ouden K et al. Targeted deletion of nuclear factor kappaB p50 enhances cardiac remodeling and dysfunction following myocardial infarction. Circ Res. 2009;104:699-706.
• Sklifasovskaya AP, Blagonravov M, Ryabinina A, Goryachev V, Syatkin S, Chibisov S et al. The role of heat shock proteins in the pathogenesis of heart failure. Int J Mol Med. 2023;52:106.
• Yun CW, Kim HJ, Lim JH, Lee SH. Heat Shock Proteins: Agents of cancer development and therapeutic targets in anti-cancer therapy. Cells. 2019;9:60.
• Haslbeck M, Vierling E. A first line of stress defense: Small heat shock proteins and their function in protein homeostasis. J Mol Biol. 2015;427:1537–48.
• Zerikiotis S, Angelidis C, Dhima I, Naka KK, Kasioumi P, Kalfakou V et al. The increased expression of the inducible Hsp70 (HSP70A1A) in serum of patients with heart failure and its protective effect against the cardiotoxic agent doxorubicin. Mol Cell Biochem. 2019;455:41-59.
• Altinok S, Sanchez-Hodge R, Stewart M, Smith K, Schisler JC. With or without you: Co-chaperones mediate health and disease by modifying chaperone function and protein triage. Cells. 2021;10:3121.
• Hui H, Zhai Y, Ao L, Cleveland JC, Liu H, Fullerton DA et al. Klotho suppresses the inflammatory responses and ameliorates cardiac dysfunction in aging endotoxemic mice. Oncotarget. 2017;8:15663-76.

Effect of Cucumis melo var. agrestis Naudin on doxorubicin-induced cardiotoxicity in rats

Yıl 2024, Cilt: 49 Sayı: 2, 353 – 362, 30.06.2024

Emine Sarman

https://doi.org/10.17826/cumj.1429969

Öz

Purpose: Doxorubicin (DOX), a chemotherapeutic antibiotic, induces toxicity by also targeting non-cancerous cells. Cucumis melo var. agrestis Naudin (CM), a plant belonging to the Cucurbitaceae family with high antioxidant content, is examined in this study for its potential impact on DOX-induced cardiac damage at different doses.
Materials and Methods: 30 male rats were randomly divided into 5 groups, with 6 animals in each group: Control group, which received distilled water by gavage for 10 days, and intraperitoneal (i.p.) normal saline application on the 5th day of the experiment. The DOX group consisted of rats receiving a single i.p. dose of 15 mg/kg DOX on the 5th day of the experiment. Rats receiving a single intraperitoneal dose of 15 mg/kg DOX on the 5th day of the experiment were subjected to gavage for 10 days with doses of 100 mg/kg (DOX+CM100), 250 mg/kg (DOX+CM250), and 500 mg/kg (DOX+CM500) of CM, respectively. 24 hours after the last drug administration, the experimental animals were sacrificed under anesthesia. Heart tissue was examined histochemically and immunohistochemically.
Results: At the end of the experiment, histopathological examination of the heart tissue; Compared to the control group, histolopathological findings such as degeneration of muscle fibers, vacuole-like structures between muscle fibers, congestion in vessels, and edema between collaterals were observed in the DOX group. These findings significantly decreased in the DOX+CM250 treatment group. While an increase in Caspase-3, HSP 70 and NF-κB-p65 immunoreactivities was observed in the DOX group (+++); In the DOX+CM250 group, these findings decreased significantly (+).
Conclusion: DOX accelerated the apoptotic process, increased intracellular and oxidative stress, and triggered an inflammatory response, as demonstrated histochemically and immunohistochemically. CM administered at a dose of 250 mg/kg expedited cardiac remodeling.

Anahtar Kelimeler

Doxorubicin, Cucumis melo var. agrestis Naudin, Caspase-3, HSP 70, NF-κB-p65

Kaynakça

• Christidi E, Brunham LR. Regulated cell death pathways in doxorubicin-induced cardiotoxicity. Cell Death Dis. 2021;12:339.
• Mansouri E, Jangaran A, Ashtari A. Protective effect of pravastatin on doxorubicin-induced hepatotoxicity. Bratisl Lek List. 2017;118:273-7.
• Osataphan N, Phrommintikul A, Chattipakorn SC, Chattipakorn N. Effects of doxorubicin-induced cardiotoxicity on cardiac mitochondrial dynamics and mitochondrial function: Insights for future interventions. J Cell Mol Med. 2020;24:6534-57.
• Croteau R, Kutchan TM, Lewis NG. Natural products (Secondary metabolites). Biochem Mol Biol Plants. 2000;24:1250–319.
• Silva MA, Albuquerque TG, Alves RC, Oliveira M, Costa HS. Melon (Cucumis melo L.) by-products: Potential food ingredients for novel functional foods? Trends Food Sci Technol. 2020;98:181–9.
• Singh AK, Kumar S, Singh HK, Rai VP, Singh BD, Pandey S. Genetic diversity in Indian snapmelon (Cucumis melo var. momordica) accessions revealed by ISSR markers. Plant Omics. 2015;8:9–16.
• Shankar K, Singh S, Kumar D, Varshney S, Gupta A, Rajan S et al. Cucumis melo ssp. agrestis var. agrestis ameliorates high fat diet induced dyslipidemia in Syrian golden hamsters and inhibits adipogenesis in 3T3-L1 adipocytes. Pharmacogn Mag. 2015;11:501-10.
• Srivastava AK, Mukerjee A, Tripathi A. Antidiabetic and antihyperlipidemic activities of Cucumis melo var. momordica fruit extract on experimental animals. Futur J Pharm Sci. 2020;6:92.
• Fernandes NP, Lagishetty CV, Panda VS, Naik SR. An experimental evaluation of the antidiabetic and antilipidemic properties of a standardized Momordica charantia fruit extract. Complement Altern Med. 2007;7:29.
• Alagar Raja M, Sahithi G, Vasanthi R, David B, KNV Rao, Selvekumar D. Study of phytochemical and antioxidant activity of Cucumis melo var. agrestis fruit. J Pharmacogn Phytochem. 2015;4:303–6.
• Gopalasatheeskumar K, Kalaichelvan VK Antıoxıdant potentıal of different parts (leaves, stem, fruit, seed, flower and root) extracts of Cucumıs melo Var agrestıs. Int J Pharm Sci Res. 2021;12:465–9.
• Mallek-Ayadi S, Bahloul N, Kechaou N. Phytochemical profile, nutraceutical potential and functional properties of Cucumis melo L. seeds. J Sci Food Agric. 2019;99:1294-1301.
• Singh D, Singh M, Yadav E, Falls N, Komal U, Dangi DS et al. Amelioration of diethylnitrosamine (DEN)-induced hepatocellular carcinogenesis in animal models via knockdown oxidative stress and proinflammatory markers by Madhuca longifolia embedded silver nanoparticles. RSC Adv. 2018;8:6940-53.
• Yadav JP, Grishina M, Shahbaaz M, Mukerjee A, Singh S, Pathak P. Cucumis melo var. momordica as a potent antidiabetic, antioxidant and possible anticovid alternative: Investigation through experimental and computational methods. Phytomedicine. 2022;19: e202200200.
• Akbulut Ö. Hayvan deneylerinde örneklem büyüklüğünün kaynak eşitlik yöntemi ile belirlenmesi ve güç analizi. KSÜ Tıp Fakültesi Dergisi. 2023;18:117-25.
• Vidya R, Kalaivani K, Amudha P. Therapeutic potential of Cucumis melo (L.) fruit extract and its silver nanopartciles against DEN-induced hepatocellular cancer in rats. Appl Biochem Biotechnol. 2022;194:368-81.
• Sarman E, Gulle K, Ilhan I. Histochemical, immunohistochemical, and biochemical investigation of the effect of resveratrol on testicular damage caused by methotrexate (MTX). Reprod Sci. 2023;30:3315-24.
• Karakuyu NF, Savran M, Candan IA, Buyukbayram HI, Erzurumlu Y. Investigation of cardioprotective effect of lercanidipine on doxorubicin-induced cardiotoxicity. Naunyn Schmiedebergs Arch Pharmacol. 2023;396:3635-45.
• Tepebaşi MY, Aşci H, Coşan S, Sevük MA, Karakuyu NF, Özmen Ö. Irbesartan has a curative effect on lipopolysaccharide-induced cardiotoxicity by antioxidant and antiapoptotic pathways. Rev Port Cardiol. 2023;42:895-903.
• Georgakopoulos P, Kyriakidis M, Perpinia A, Karavidas A, Zimeras S, Mamalis N et al. The role of metoprolol and enalapril in the prevention of doxorubicin-induced cardiotoxicity in lymphoma patients. Anticancer Res. 2019;39:5703-7.
• Mitra S, Rauf A, Sutradhar H, Sadaf S, Hossain MJ, Soma MA et al. Potential candidates from marine and terrestrial resources targeting mitochondrial inhibition: Insights from the molecular approach. Comp Biochem Physiol C Toxicol Pharmacol. 2023;264:109509.
• 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;96:1065-74.
• Hagag AA, Badraia IM, El-Shehaby WA, Mabrouk MM. Protective role of black seed oil in doxorubicin-induced cardiac toxicity in children with acute lymphoblastic leukemia. J Oncol Pharm Pr. 2020;26:1397-1406.
• Al-Amir H, Janabi A, Hadi NR. Ameliorative effect of nebivolol in doxorubicin-induced cardiotoxicity. Med Life. 2023;16:1357-63.
• Nabati M, Janbabai G, Baghyari S, Esmaili K, Yazdani J. Cardioprotective effects of carvedilol in inhibiting doxorubicin-induced cardiotoxicity. J Cardiovasc Pharmacol. 2017;69:279-85.
• Erdogmus Ozgen Z, Erdinc M, Kelle I, Erdinc L, Nergiz Y. Protective effects of necrostatin-1 on doxorubicin-induced cardiotoxicity in rat heart. Hum Exp Toxicol. 2022;41:9603271211066066.
• Ibrahim SRM, Khedr AIM, Mohamed GA, Zayed MF, El-Kholy AAS, Al Haidari RA. Cucumol B, a new triterpene benzoate from Cucumis melo seeds with cytotoxic effect toward ovarian and human breast adenocarcinoma. J Asian Nat Prod Res. 2019;21:1112-18.
• Arora R, Kaur M, Gill NS. Antioxidant activity and pharmacological evaluation of Cucumis melo var. agrestis methanolic seed extract. Res J Phytochem. 2011;5:146–55.
• Bilgic S, Ozgocmen M, Ozer MK, Asci H. Misoprostol ameliorates doxorubicin induced cardiac damage by decreasing oxidative stress and apoptosis in rats. Biotech Histochem. 2020;95:514-21.
• Ai Y, Meng Y, Yan B, Zhou Q, Wang X. The biochemical pathways of apoptotic, necroptotic, pyroptotic, and ferroptotic cell death. Mol Cell. 2024;84:170-9.
• Jamshidi Z, Roohbakhsh A, Karimi G. An overview on the protective effects of ellagic acid against heavy metals, drugs, and chemicals. Food Sci Nutr. 2023;11:7469-84.
• El-Agamy DS, Abo-Haded HM, Elkablawy MA. Cardioprotective effects of sitagliptin against doxorubicin-induced cardiotoxicity in rats. Exp Biol Med. 2016;241:1577-87.
• Goda AE, Elenany AM, Elsisi AE. Novel in vivo potential of trifluoperazine to ameliorate doxorubicin-induced cardiotoxicity involves suppression of NF-κB and apoptosis. Life Sci. 2021;283:119849.
• Gutiérrez SH, Kuri MR, del Castillo ER. Cardiac role of the transcription factor NF-kappaB. Cardiovasc Hematol Disord Drug Targets. 2008;8:153-60.
• Timmers L, van Keulen JK, Hoefer IE, Meijs MF, van Middelaar B, den Ouden K et al. Targeted deletion of nuclear factor kappaB p50 enhances cardiac remodeling and dysfunction following myocardial infarction. Circ Res. 2009;104:699-706.
• Sklifasovskaya AP, Blagonravov M, Ryabinina A, Goryachev V, Syatkin S, Chibisov S et al. The role of heat shock proteins in the pathogenesis of heart failure. Int J Mol Med. 2023;52:106.
• Yun CW, Kim HJ, Lim JH, Lee SH. Heat Shock Proteins: Agents of cancer development and therapeutic targets in anti-cancer therapy. Cells. 2019;9:60.
• Haslbeck M, Vierling E. A first line of stress defense: Small heat shock proteins and their function in protein homeostasis. J Mol Biol. 2015;427:1537–48.
• Zerikiotis S, Angelidis C, Dhima I, Naka KK, Kasioumi P, Kalfakou V et al. The increased expression of the inducible Hsp70 (HSP70A1A) in serum of patients with heart failure and its protective effect against the cardiotoxic agent doxorubicin. Mol Cell Biochem. 2019;455:41-59.
• Altinok S, Sanchez-Hodge R, Stewart M, Smith K, Schisler JC. With or without you: Co-chaperones mediate health and disease by modifying chaperone function and protein triage. Cells. 2021;10:3121.
• Hui H, Zhai Y, Ao L, Cleveland JC, Liu H, Fullerton DA et al. Klotho suppresses the inflammatory responses and ameliorates cardiac dysfunction in aging endotoxemic mice. Oncotarget. 2017;8:15663-76.

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