Protective Effects of Aronia melanocarpa Extract against Cyclophosphamide-Induced Delayed Toxicity on the Bladder

Abstract

Aim: Aronia melanocarpa is a red-purple medicinal fruit known for its therapeutic properties in the urinary system by anti-inflammatory effects with high antioxidant content. The aim of the study is to show the supportive effect of Aronia melanocarpa extract delayed toxicity on the bladder induced by cyclophosphamide (CYC) that an antineoplastic agent. Material and Methods: In the study three groups were constituted control (n=7), CYC(urotoxicity group, n=7) and CYC+ARONIA(treatment group, n=7). 100 mg/kg CYC intraperitoneally were given to CYC and CYC+ARONIA groups and waited for 4 weeks to be created delayed toxicity. At the end of the 4 weeks, 200 mg/kg Aronia melanocarpa was administered 15 times by oral gavage every other different day to CYC+ARONIA group (1 month in total). Sacrification was performed and after serum and urine samples were taken, the bladder was released from the sphincter region with curved-tipped forceps. Bladder tissues were investigated histologically. P38 mitogen activated preotein kinase (P38 MAPK), total antioxidant (TAS) and oxidant (TOS) status were evaluated in serum and urine samples. Results: In histology, histological damage in the bladder continued in the CYC group, while Aronia melanocarpa treatment caused healing in the bladder tissue in the CYC+ARONIA group. No difference was found between the groups in terms of P38 MAPK, TAS and TOS in serum and urine samples. Conclusion: According to the experimental results, the fact that Aronia melanocarpa extract improves the histological damage caused by CYC in the delayed period, and the serum and urine findings were the same as the controls, brought up the therapeutic effect of Aronia melanocarpa in urotoxicity.

Keywords

• cyclophosphamide
• Aronia melanocarpa
• P38 MAPK
• TAS-TOS

Siklofosfamidin Gecikmiş Toksisitesine Karşı Aronia melanocarpa Ekstraktının Mesane Üzerine Koruyucu Etkileri

Abstract

Amaç: Aronia melanocarpa yüksek antioksidan içeriğiyle antiinflamatuar etkiler göstererek üriner sistemde tedavi edici özellikleri bilinen kırmızı-mor renkli tıbbi bir meyvedir. Çalışmanın amacı antineoplastik bir ajan olan siklofosfamidin (CYC) mesanede oluşturduğu gecikmiş toksisitede Aronia melanocarpa ekstraktının destekleyici etkisini göstermektir. Gereç ve Yöntemler: Çalışmada kontrol (n=7), CYC (ürotoksisite grubu, n=7) ve CYC+ARONIA (tedavi grubu, n=7) olacak şekilde üç grup oluşturuldu. CYC ve CYC+ARONIA gruplarına 100 mg/kg CYC intraperitoneal olarak 1 doz verildikten sonra gecikmiş toksisite oluşması için 4 hafta beklenildi. 4 haftanın sonunda Aronia melanocarpa ekstratı oral gavaj ile gün aşırı toplamda 1 ay olacak şekilde 15 kez 200 mg/kg dozunda CYC+ARONIA grubuna verildi. Sakrifikasyonda serum ve idrar örnekleri alındıktan sonra mesane dokusu sfinkter bölgesinden eğimli uçlu forsepsle serbestleştirilerek alındı. Mesane dokusu histolojik olarak değerlendirildi. Enflamatuvar belirteç olan P38 MAP Kinaz, toplam antioksidan (TAS) ve oksidan (TOS) durumu serum ve idrarda değerlendirildi. Bulgular: Histolojide CYC grubunda mesanedeki histolojik hasar devam ederken, CYC+ARONIA grubunda Aronia melanocarpa tedavisi mesane dokusunda iyileşmeye sebep oldu. Serum ve idrar örneklerinde P38 MAPK, TAS ve TOS açısından gruplar arasında fark bulunmadı. Sonuç: Deneysel sonuçlara göre Aronia melanocarpa ekstraktının CYC'nin neden olduğu histolojik hasarı geç dönemde iyileştirmesi, serum ve idrar bulgularının kontrollerle aynı olması Aronia melanocarpa'nın ürotoksisitede terapötik etkisini gündeme getirmiştir.

Keywords

• Aronia melanocarpa
• P38 MAPK
• TAS-TOS
• siklofosfamid

References

1. Ogino MH, Tadi P. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022. [Updated 2022 Jul 4]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK553087/
2. Kim SH, Lee IC, Baek HS, Shin IS, Moon C, Bae CS et al. Mechanism for the protective effect of diallyl disulfide against cyclophosphamide acute urotoxicity in rats. Food Chem Toxicol. 2014; 64:110-8.
3. Levine LA, Richie JP. Urological complications of cyclophosphamide. J Urol. 1989; 141(5): 1063-9.
4. Anton E. Differential sensitivity of DBA/2 and C57BL/6 mice to cyclophosphamide. J Appl Toxicol. 1993; 13(6): 423-7.
5. Arafa HM. Uroprotective effects of curcumin in cyclophosphamide‐induced haemorrhagic cystitis paradigm. Basic Clin Pharm Toxicol. 2009; 104(5): 393-9.
6. Ozcan A, Korkmaz A, Oter S, Coskun O. Contribution of flavonoid antioxidants to the preventive effect of mesna in cyclophosphamide-induced cystitis in rats. Arch Toxicol. 2005; 79(8): 461-5.
7. Ayhanci A, Tanriverdi DT, Sahinturk V, Cengiz M, Appak-Baskoy S, Sahin IK. Protective effects of boron on cyclophosphamide-induced bladder damage and oxidative stress in rats. Biol Trace Elem Res. 2020; 197(1): 184-91.
8. Mohammad MK, Avila D, Zhang J, Barve S, Arteel G, McClain C, et al. Acrolein cytotoxicity in hepatocytes involves endoplasmic reticulum stress, mitochondrial dysfunction and and oxidative stress. Toxicol Appl Pharm. 2012; 265(1): 73-82.

9. Haldar S, Dru C, Bhowmick NA. Mechanisms of hemorrhagic cystitis. Am J Clin Exp Urol. 2014; 2(3): 199-208.
10. Keles I, Bozkurt MF, Cemek M, Karalar M, Hazini A, Alpdagtas S, et al. Prevention of cyclophosphamide-induced hemorrhagic cystitis by resveratrol: a comparative experimental study with mesna. Int Urol Nephrol. 2014; 46(12): 2301-10.
11. Zhang X, He H, Lu G, Xu T, Qin L, Wang X, et al. Specific inhibition of ICAM-1 effectively reduces bladder inflammation in a rat model of severe non-bacterial cystitis. Sci Rep. 2016; 6: 35672.
12. Bhatia K, Ahmad F, Rashid H, Raisuddin S. Protective effect of S-allylcysteine against cyclophosphamide-induced bladder hemorrhagic cystitis in mice. Food Chem Toxicol. 2008; 46(11): 3368-74.
13. Bhagwat S, Haytowitz DB, Wassa-Kintu SI, Holden JM. USDA develops a database for flavonoids to assess dietary intakes. 36th Annual National Nutrient Databank Proceedings. Procedia Food Sci. 2013; 2: 81-6.
14. Masella R, Santangelo C, D'Archivio M, Li Volti G, Giovannini C, Galvano F. Protocatechuic acid and human disease prevention: biological activities and molecular mechanisms. Curr Med Chem. 2012; 19: 2901-17.
15. Cahyana Y, Gordon MH, Gibson TM. Urinary excretion of anthocyanins following consumption of strawberry and red grape juice. Int J Vitam Nutr Res. 2019; 89(1-2): 29-36.
16. Noce A, Di Daniele F, Campo M, Di Lauro M, Pietroboni Zaitseva A, Di Daniele N,et al. Effect of hydrolysable tannins and anthocyanins on recurrent urinary tract infections in nephropathic patients: preliminary data. Nutrients. 2021; 13(2): 591.
17. Higgins JA, Zainol M, Brown K, Jones GD. Anthocyans as tertiary chemopreventive agents in bladder cancer: anti-oxidant mechanisms and interaction with mitomycin C. Mutagenesis. 2014; 29(4): 227-35.
18. Gao N, Wang Y, Jiao X, Chou S, Li E, Li B. Preparative purification of polyphenols from Aronia melanocarpa (chokeberry) with cellular antioxidant and antiproliferative activity. Molecules. 2018; 23(1): 139.
19. Kokotkiewicz A, Jaremicz Z, Luczkiewicz M. Aronia plants: a review of traditional use, biological activities, and perspectives for modern medicine. J Med Food. 2010; 13: 255-69.
20. Kedzierska M, Olas B, Wachowicz B, Glowacki R, Bald E, Czernek U, et al. Effects of the commercial extract of aronia on oxidative stress in blood platelets isolated from breast cancer patients after the surgery and various phases of the chemotherapy. Fitoterapia. 2012; 83(2): 310-7.
21. Milosavljevic I, Jakovljevic V, Petrovic D, Draginic N, Jeremic J, Mitrovic M, et al. Standardized Aronia melanocarpa extract regulates redox status in patients receiving hemodialysis with anemia. Mol Cell Biochem. 2021; 476(11): 4167-75.
22. Valcheva-Kuzmanova SV, Beronova AB, Momekov GT. Protective effect of Aronia melanocarpa fruit juice in a model of cisplatin-induced cytotoxicity in vitro. Folia Med (Plovdiv). 2013; 55(3-4): 76-9.
23. Bushmeleva K, Vyshtakalyuk A, Terenzhev D, Belov T, Nikitin E, Zobov V. Effect of flavonols of Aronia melanocarpa fruits on morphofunctional state of immunocompetent organs of rats under cyclophosphamide-induced immunosuppression. Biomolecules. 2024; 14(5): 578.
24. Bushmeleva K, Vyshtakalyuk A, Terenzhev D, Belov T, Nikitin E, Zobov V. Aronia melanocarpa flavonol extract-antiradical and immunomodulating activities analysis. Plants (Basel). 2023; 12(16): 2976.
25. Kędzierska M, Malinowska J, Kontek B, Kołodziejczyk-Czepas J, Czernek U, Potemski P, et al. Chemotherapy modulates the biological activity of breast cancer patients plasma: the protective properties of black chokeberry extract. Food Chem Toxicol. 2013; 53: 126-32.
26. Bahceci SA, Kuruş M, Şimşek F, Keselik E, Kara S. Histopathological investigation of the effects of Aronia melanocarpa on the ovarian tissue of polycystic over syndrome in rats. Diniz Ünlü AG, Dirim Mete B, Anıl M, Varol U, Güvendi G, Çoban İ, Kılıç HT. 2nd Internetional Medical Congress of Izmir Democracy University, 2020; Izmir. Fulltext&Abstract Book; 2020. 244.
27. Erel OA. Novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin Biochem. 2004; 37(4): 277-85.
28. Erel OA. New automated colorimetric method for measuring total oxidant status. Clin Biochem. 2005; 38(12): 1103-11.
29. Yumru M, Savas HA, Kalenderoglu A, Bulut M, Celik H, Erel O. Oxidative imbalance in bipolar disorder subtypes: a comparative study. Prog Neuropsychopharmacol Biol Psychiatry. 2009; 33(6): 1070-4.
30. Kosecik M, Erel O, Sevinc E, Selek S. Increased oxidative stress in children exposed to passive smoking. Int J Cardiol. 2005; 100(1): 61-4.
31. Harma M, Harma M, Erel O. Increased oxidative stress in patients with hydatidiform mole. Swiss Med Wkly. 2003; 1;133(41-42): 563-6.
32. Dursun AD, Saricam E, Sariyildiz GT, Iscanli MD, Cantekin ÖF. The evaluation of oxidative stress in the young adults with COVID-19 mRNA vaccines induced acute pericarditis- myopericarditis. Int J Gen Med. 2022; 15: 161-7.
33. Lwin OM, Giribabu N, Kilari EK, Salleh N. Topical administration of mangiferin promotes healing of the wound of streptozotocin-nicotinamide-induced type-2 diabetic male rats. J Dermatolog Treat. 2020; 32(8): 1039-48.
34. Akiyama Y, Yao JR, Kreder KJ, O'Donnell MA, Lutgendorf SK, Lyu D, et al. Autoimmunity to urothelial antigen causes bladder inflammation, pelvic pain, and voiding dysfunction: a novel animal model for hunner-type interstitial cystitis. Am J Physiol Renal Physiol. 2021; 320: 174-82.
35. Linder BJ, Nelson JC, Gounder MM. UpToDate [Internet]. (accessed on 27 October 2021). Available online:https://www.uptodate.com/contents/chemotherapy-and-radiation-related-hemorrhagic-cystitis-in-cancerpatients?search=chemotherapy-and-radiation-related-hemorrhagic-cystitis-in-cancer-patientsrecommendationsforCPXHC& source=search_result&selectedTitle=1~{}
36. Miller MA, Zachary JF. Mechanisms and morphology of cellular injury, adaptation, and death. Pathol Basis Veterinary Disease. 2017; 2-43.e19.
37. Anton E. Delayed toxicity of cyclophosphamide on the bladder of DBA/2 and C57BL/6 female mouse. Int J Exp Pathol. 2002; 83(1): 47-53.
38. Lyon D, Howard EB, Montgomerie JZ. Increased severity of urinary tract infection and bacteremia in mice with urinary bladder injury induced by cyclophosphamide. Infect Immun. 1982; 38(2): 558-62.
39. Banerjee S, Biehl A, Ghaderi-Yeganeh M, Manna Z, Hasni S. Low incidence of opportunistic infections in lupus patients treated with cyclophosphamide and steroids in a tertiary care setting. Med Res Arch. 2017; 5(3): 10.
40. Sugumar E, Kanakasabapathy I, Abraham P. Normal plasma creatinine level despite histological evidence of damage and increased oxidative stress in the kidneys of cyclophosphamide treated rats. Clin Chim Acta. 2007; 376: 244-5.
41. Sherif IO. Uroprotective mechanism of quercetin against cyclophosphamide-induced urotoxicity: Effect on oxidative stress and inflammatory markers. J Cell Biochem. 2018; 119(9): 7441-8.
42. Barut EN, Engin S, Barut B, Kaya C, Kerimoglu G, Ozel A, et al. Uroprotective effect of ambroxol in cyclophosphamide-induced cystitis in mice. Int Urol Nephrol. 2019; 51(5): 803-10.
43. Li L, Li J, Xu H, Zhu F, Li Z, Lu H, et al. The Protective effect of anthocyanins extracted from Aronia melanocarpa berry in renal ischemia-reperfusion injury in mice. Mediators Inflamm. 2021; 22: 7372893.
44. Kowalczyk E, Kopff A, Fijałkowski P, Kopff M, Niedworok J, Błaszczyk J, et al. Effect of anthocyanins on selected biochemical parameters in rats exposed to cadmium. Acta Biochim Pol. 2003; 50(2): 543-8.
45. Song EK, Park H, Kim HS. Additive effect of walnut and chokeberry on regulation of antioxidant enzyme gene expression and attenuation of lipid peroxidation in d-galactose-induced aging-mouse model. Nutr Res. 2019; 70: 60-9.
46. Handeland M, Grude N, Torp T, Slimestad R. Black chokeberry juice (Aronia melanocarpa) reduces incidences of urinary tract infection among nursing home residents in the long term-a pilot study. Nutr Res. 2014; 34(6): 518-25.
47. García-Flores LA, Medina S, Cejuela-Anta R, Martínez-Sanz JM, Abellán Á, Genieser HG, et al. DNA catabolites in triathletes: effects of supplementation with an aronia-citrus juice (polyphenols-rich juice). Food Funct. 2016; 7(4): 2084-93.
48. Sinanoglu O, Ener AN, Ekici S, Midi A, Aksungar FB. The protective effects of spirulina in cyclophosphamide induced nephrotoxicity and urotoxicity in rats. Urology 2012; 80(6): 1392.e1-6.
49. Augé C, Gamé X, Vergnolle N, Lluel P, Chabot S. Characterization and validation of a chronic model of cyclophosphamide-induced interstitial cystitis/bladder pain syndrome in rats. Front Pharmacol. 2020; 11: 1305.
50. Dobrek L, Nalik-Iwaniak K, Fic K, Arent Z. The effect of acetylcysteine on renal function in experimental models of cyclophosphamide-and ifosfamide-induced cystitis. Curr Urol. 2020; 14(3): 150-62.