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Sıçanlarda 5-Fluorourasil ile Oluşturulmuş Gastrointestinal Mukozitte Berberinin Terapötik Etkisi

Yıl 2024, Cilt: 46 Sayı: 1, 139 - 146, 16.01.2024
https://doi.org/10.20515/otd.1410189

Öz

Çalışmamızda, sıçanlara 5-florourasil uygulanması ile oluşturulan gastrointestinal mukoza hasarına karşı berberinin terapötik potansiyelinin araştırılması. Gereç ve Yöntem: Çalışmada 6-8 haftalık Wistar Albino erkek sıçanlar kontrol, 5FU, BER75, BER150 ve BER300 olarak 5 gruba ayrılmıştır (n=8/grup). 5FU, BER75, BER150 ve BER300 gruplarına 0-7. günler arasında gün aşırı 5-FU (60 mg/kg, ip) uygulanarak mukozit oluşturuldu. BER75, BER150 ve BER300 gruplarına sırasıyla 75, 150 ve 300 mg/kg/gün dozlarda berberin yine 0-7. günler arasında hergün po uygulandı. Deneyin başında ve sonunda hayvanların vücut ağırlıkları ölçüldü. Total antioksidan aktivite (TAS), total oksidan aktivite (TOS), TNF-α, IL-6 ve NF-κB düzeylerinin serumda tayinleri için ELISA yöntemi kullanıldı. Jejenum ve ileum doku kesitlerinde histopatolojik değerlendirme yapıldı. Bulgular: Deneyin sonunda hayvanların vücut ağırlıklarındaki yüzde değişimi (%VA) tedavi gruplarında kontrol grubuna göre anlamlı derecede daha düşüktü (her biri için p ˂0,001), ancak berberin tedavisi 5-FU’in oluşturduğu kilo kaybını düzeltmemiştir. Oksidatif stres indeks değerleri açısından gruplar arasında anlamlı fark bulunamadı (p >0,05). IL-6 düzeyi 5FU grubuna kıyasla BER75 grubunda hafif, BER150 ve BER300 gruplarında anlamlı derecede azaldı (sırasıyla, p>0,05; p=0,002 ve p=0,002). TNF-α düzeyi 5-FU grubuna kıyasla BER75, BER150 ve BER300 gruplarında azaldı (sırasıyla p> 0,05; p=0,003; p> 0,05). NF-κB düzeyi kontrol grubuna kıyasla 5FU grubunda bir miktar yüksek bulunmuştur (p> 0,05). BER75, BER150 ve BER300 gruplarında ise anlamlı derecede azaldı (sırasıyla p<0.05, p<0,001 ve p<0.05). Histopatolojik olarak 5-FU grubunda yoğun epitel hasarı, inflamatuvar hücre infiltrasyonu, kanama ve ödem odakları görüldü. Tedavi gruplarında ise berberinin doz bağımlı bir şekilde bu hasarı azalttığı tespit edildi. Sonuç: Berberinin doz bağımlı olarak sıçanlarda 5-florourasil ile oluşturulan gastrointestinal mukozitte potansiyel bir terapötik ajan olabileceği düşünülmektedir.

Etik Beyan

The study was performed in accordance with the guidelines for the care and use of laboratory animals approved by Eskişehir Osmangazi University Local Ethics Committee (Decision number: 2018-693/693-1).

Destekleyen Kurum

This study was supported by Eskisehir Osmangazi University Scientific Research Projects Commission within the scope of the project numbered 201911A106.

Proje Numarası

201911A106

Teşekkür

This manuscript was derived from the first author’s master thesis

Kaynakça

  • 1. AlQahtani SA, Harisa GI, Alomrani AH, Alanazi FK, Badran MM. Improved pharmacokinetic and biodistribution of 5-fluorouracil loaded biomimetic nanoerythrocytes decorated nanocarriers for liver cancer treatment. Colloids Surf B Biointerfaces. 2021;197:111380.
  • 2. Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003;3(5):330-8.
  • 3. Goirand F, Lemaitre F, Launay M, Tron C, Chatelut E, Boyer JC, et al. How can we best monitor 5-FU administration to maximize benefit to risk ratio? Expert Opin Drug Metab Toxicol. 2018;14(12):1303-13.
  • 4. Depetris I, Marino D, Bonzano A, Cagnazzo C, Filippi R, Aglietta M, et al. Fluoropyrimidine-induced cardiotoxicity. Crit Rev Oncol Hematol. 2018;124:1-10.
  • 5. Boileve A, Thomas L, Lillo-Le Louet A, Gaboriau L, Chouchana L, Ducreux M, et al. 5-Fluorouracil-induced hyperammonaemic encephalopathy: A French national survey. Eur J Cancer. 2020;129:32-40.
  • 6. Polk A, Vaage-Nilsen M, Vistisen K, Nielsen DL. Cardiotoxicity in cancer patients treated with 5-fluorouracil or capecitabine: a systematic review of incidence, manifestations and predisposing factors. Cancer Treat Rev. 2013;39(8):974-84.
  • 7. Atiq A, Shal B, Naveed M, Khan A, Ali J, Zeeshan S, et al. Diadzein ameliorates 5-fluorouracil-induced intestinal mucositis by suppressing oxidative stress and inflammatory mediators in rodents. Eur J Pharmacol. 2019;843:292-306.
  • 8. Gori S, Inno A, Belluomini L, Bocus P, Bisoffi Z, Russo A, et al. Gut microbiota and cancer: How gut microbiota modulates activity, efficacy and toxicity of antitumoral therapy. Crit Rev Oncol Hematol. 2019;143:139-47.
  • 9. de Morais EF, Batista Severo ML, Dantas Martins HD, Trevizani Martins MA, Martins MD, de Almeida Freitas R, et al. Effectiveness of phytotherapeutics in the prevention and treatment of 5-fluorouracil-induced oral mucositis in animal models: A systematic review. Arch Oral Biol. 2021;123:104998.
  • 10. Wang Y, Liu J, Huang Z, Li Y, Liang Y, Luo C, et al. Coptisine ameliorates DSS-induced ulcerative colitis via improving intestinal barrier dysfunction and suppressing inflammatory response. Eur J Pharmacol. 2021;896:173912.
  • 11. Li C, Ai G, Wang Y, Lu Q, Luo C, Tan L, et al. Oxyberberine, a novel gut microbiota-mediated metabolite of berberine, possesses superior anti-colitis effect: Impact on intestinal epithelial barrier, gut microbiota profile and TLR4-MyD88-NF-kappaB pathway. Pharmacol Res. 2020;152:104603.
  • 12. Chen H, Zhang F, Li R, Liu Y, Wang X, Zhang X, et al. Berberine regulates fecal metabolites to ameliorate 5-fluorouracil induced intestinal mucositis through modulating gut microbiota. Biomed Pharmacother. 2020;124:109829.
  • 13. Lu Y, Huang J, Zhang Y, Huang Z, Yan W, Zhou T, et al. Therapeutic Effects of Berberine Hydrochloride on Stress-Induced Diarrhea-Predominant Irritable Bowel Syndrome Rats by Inhibiting Neurotransmission in Colonic Smooth Muscle. Front Pharmacol. 2021;12:596686.
  • 14. Yigitaslan S. ÖA, Açıkgöz A., Balcı A.G., Toprak Ç., Göger F., Şahin E Therapeutic Potential of Morus Nigra on 5-Fluorouracil-İnduced Gastrointestinal Mucositis in Rats. Osmangazi Tıp Dergisi. 2020;42(4):363 - 72.
  • 15. Sakai H, Sagara A, Matsumoto K, Jo A, Hirosaki A, Takase K, et al. Neutrophil recruitment is critical for 5-fluorouracil-induced diarrhea and the decrease in aquaporins in the colon. Pharmacol Res. 2014;87:71-9.
  • 16. Cool JC, Dyer JL, Xian CJ, Butler RN, Geier MS, Howarth GS. Pre-treatment with insulin-like growth factor-I partially ameliorates 5-fluorouracil-induced intestinal mucositis in rats. Growth Horm IGF Res. 2005;15(1):72-82.
  • 17. Ali J, Khan AU, Shah FA, Ali H, Islam SU, Kim YS, et al. Mucoprotective effects of Saikosaponin-A in 5-fluorouracil-induced intestinal mucositis in mice model. Life Sci. 2019;239:116888.
  • 18. Torres DM, Tooley KL, Butler RN, Smith CL, Geier MS, Howarth GS. Lyprinol only partially improves indicators of small intestinal integrity in a rat model of 5-fluorouracil-induced mucositis. Cancer Biol Ther. 2008;7(2):295-302.
  • 19. Trindade LM, Martins VD, Rodrigues NM, Souza ELS, Martins FS, Costa GMF, et al. Oral administration of Simbioflora(R) (synbiotic) attenuates intestinal damage in a mouse model of 5-fluorouracil-induced mucositis. Benef Microbes. 2018;9(3):477-86.
  • 20. Yasuda M, Kato S, Yamanaka N, Iimori M, Matsumoto K, Utsumi D, et al. 5-HT(3) receptor antagonists ameliorate 5-fluorouracil-induced intestinal mucositis by suppression of apoptosis in murine intestinal crypt cells. Br J Pharmacol. 2013;168(6):1388-400.
  • 21. Kline CL, Schiccitano A, Zhu J, Beachler C, Sheikh H, Harvey HA, et al. Personalized dosing via pharmacokinetic monitoring of 5-fluorouracil might reduce toxicity in early- or late-stage colorectal cancer patients treated with infusional 5-fluorouracil-based chemotherapy regimens. Clin Colorectal Cancer. 2014;13(2):119-26.
  • 22. Liu CS, Zheng YR, Zhang YF, Long XY. Research progress on berberine with a special focus on its oral bioavailability. Fitoterapia. 2016;109:274-82.
  • 23. Smith CL, Geier MS, Yazbeck R, Torres DM, Butler RN, Howarth GS. Lactobacillus fermentum BR11 and fructo-oligosaccharide partially reduce jejunal inflammation in a model of intestinal mucositis in rats. Nutr Cancer. 2008;60(6):757-67.
  • 24. Mashtoub S, Tran CD, Howarth GS. Emu oil expedites small intestinal repair following 5-fluorouracil-induced mucositis in rats. Exp Biol Med (Maywood). 2013;238(11):1305-17.
  • 25. Liu JH, Hsieh CH, Liu CY, Chang CW, Chen YJ, Tsai TH. Anti-inflammatory effects of Radix Aucklandiae herbal preparation ameliorate intestinal mucositis induced by 5-fluorouracil in mice. J Ethnopharmacol. 2021;271:113912.
  • 26. Pandey MK, Sung B, Kunnumakkara AB, Sethi G, Chaturvedi MM, Aggarwal BB. Berberine modifies cysteine 179 of IkappaBalpha kinase, suppresses nuclear factor-kappaB-regulated antiapoptotic gene products, and potentiates apoptosis. Cancer Res. 2008;68(13):5370-9.
  • 27. Lima V, Brito GA, Cunha FQ, Reboucas CG, Falcao BA, Augusto RF, et al. Effects of the tumour necrosis factor-alpha inhibitors pentoxifylline and thalidomide in short-term experimental oral mucositis in hamsters. Eur J Oral Sci. 2005;113(3):210-7.
  • 28. Tung D, Cheung PH, Tudor G, Booth C, Saha S. In vivo effects of immunomodulators in a murine model of Fluorouracil-induced mucositis. Curr Ther Res Clin Exp. 2011;72(6):262-72.
  • 29. Huang L, Chiang Chiau JS, Cheng ML, Chan WT, Jiang CB, Chang SW, et al. SCID/NOD mice model for 5-FU induced intestinal mucositis: Safety and effects of probiotics as therapy. Pediatr Neonatol. 2019;60(3):252-60.
  • 30. de Barros PAV, Rabelo Andrade ME, de Vasconcelos Generoso S, Mendes Miranda SE, Dos Reis DC, Lacerda Leocadio PC, et al. Conjugated linoleic acid prevents damage caused by intestinal mucositis induced by 5-fluorouracil in an experimental model. Biomed Pharmacother. 2018;103:1567-76.
  • 31. Zhang L, Jin Y, Peng J, Chen W, Lisha L, Lin J. Qingjie Fuzheng Granule attenuates 5-fluorouracil-induced intestinal mucosal damage. Biomed Pharmacother. 2019;118:109223.

The Potential Effect of Berberine on 5-Fluorouracil Induced Gastrointestinal Mucositis in Rats

Yıl 2024, Cilt: 46 Sayı: 1, 139 - 146, 16.01.2024
https://doi.org/10.20515/otd.1410189

Öz

5-Fluorouracil (5-FU), an antineoplastic agent, causes intestinal mucositis (IM) that limits the drug efficacy. The aim of this study was to reveal the protective and/or therapeutic effects of berberine (BER), an isoquinoline quaternary alkaloid, on IM induced by 5-FU in rats. Forty Wistar albino male rats were randomly divided into five groups: Control, 5-FU, 5-FU+BER75 (75 mg/kg/day), 5-FU+BER150 (150 mg/kg/day) and 5-FU+BER300 (300 mg/kg/day). 5-FU was intraperitoneally (i.p) injected at a dose of 60 mg/kg on alternate days for 4 days, while other groups were orally received BER daily for 7 days. By the end of study, intracardiac blood samples were collected and intestinal tissues were removed for histological examination. TNF-α, IL-6 and NF-κB levels were measured in serum using commercial ELISA kits. Results showed that BER at increasing doses ameliorated body weight loss and histopathological damage. It was concluded that BER may be effective in the treatment and/or prophylaxis of the damage in the gastrointestinal system caused by 5-FU in a dose-dependent manner.

Etik Beyan

The study was performed in accordance with the guidelines for the care and use of laboratory animals approved by Eskişehir Osmangazi University Local Ethics Committee (Decision number: 2018-693/693-1).

Destekleyen Kurum

This study was supported by Eskisehir Osmangazi University Scientific Research Projects Commission within the scope of the project numbered 201911A106.

Proje Numarası

201911A106

Teşekkür

This manuscript was derived from the first author’s master thesis

Kaynakça

  • 1. AlQahtani SA, Harisa GI, Alomrani AH, Alanazi FK, Badran MM. Improved pharmacokinetic and biodistribution of 5-fluorouracil loaded biomimetic nanoerythrocytes decorated nanocarriers for liver cancer treatment. Colloids Surf B Biointerfaces. 2021;197:111380.
  • 2. Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003;3(5):330-8.
  • 3. Goirand F, Lemaitre F, Launay M, Tron C, Chatelut E, Boyer JC, et al. How can we best monitor 5-FU administration to maximize benefit to risk ratio? Expert Opin Drug Metab Toxicol. 2018;14(12):1303-13.
  • 4. Depetris I, Marino D, Bonzano A, Cagnazzo C, Filippi R, Aglietta M, et al. Fluoropyrimidine-induced cardiotoxicity. Crit Rev Oncol Hematol. 2018;124:1-10.
  • 5. Boileve A, Thomas L, Lillo-Le Louet A, Gaboriau L, Chouchana L, Ducreux M, et al. 5-Fluorouracil-induced hyperammonaemic encephalopathy: A French national survey. Eur J Cancer. 2020;129:32-40.
  • 6. Polk A, Vaage-Nilsen M, Vistisen K, Nielsen DL. Cardiotoxicity in cancer patients treated with 5-fluorouracil or capecitabine: a systematic review of incidence, manifestations and predisposing factors. Cancer Treat Rev. 2013;39(8):974-84.
  • 7. Atiq A, Shal B, Naveed M, Khan A, Ali J, Zeeshan S, et al. Diadzein ameliorates 5-fluorouracil-induced intestinal mucositis by suppressing oxidative stress and inflammatory mediators in rodents. Eur J Pharmacol. 2019;843:292-306.
  • 8. Gori S, Inno A, Belluomini L, Bocus P, Bisoffi Z, Russo A, et al. Gut microbiota and cancer: How gut microbiota modulates activity, efficacy and toxicity of antitumoral therapy. Crit Rev Oncol Hematol. 2019;143:139-47.
  • 9. de Morais EF, Batista Severo ML, Dantas Martins HD, Trevizani Martins MA, Martins MD, de Almeida Freitas R, et al. Effectiveness of phytotherapeutics in the prevention and treatment of 5-fluorouracil-induced oral mucositis in animal models: A systematic review. Arch Oral Biol. 2021;123:104998.
  • 10. Wang Y, Liu J, Huang Z, Li Y, Liang Y, Luo C, et al. Coptisine ameliorates DSS-induced ulcerative colitis via improving intestinal barrier dysfunction and suppressing inflammatory response. Eur J Pharmacol. 2021;896:173912.
  • 11. Li C, Ai G, Wang Y, Lu Q, Luo C, Tan L, et al. Oxyberberine, a novel gut microbiota-mediated metabolite of berberine, possesses superior anti-colitis effect: Impact on intestinal epithelial barrier, gut microbiota profile and TLR4-MyD88-NF-kappaB pathway. Pharmacol Res. 2020;152:104603.
  • 12. Chen H, Zhang F, Li R, Liu Y, Wang X, Zhang X, et al. Berberine regulates fecal metabolites to ameliorate 5-fluorouracil induced intestinal mucositis through modulating gut microbiota. Biomed Pharmacother. 2020;124:109829.
  • 13. Lu Y, Huang J, Zhang Y, Huang Z, Yan W, Zhou T, et al. Therapeutic Effects of Berberine Hydrochloride on Stress-Induced Diarrhea-Predominant Irritable Bowel Syndrome Rats by Inhibiting Neurotransmission in Colonic Smooth Muscle. Front Pharmacol. 2021;12:596686.
  • 14. Yigitaslan S. ÖA, Açıkgöz A., Balcı A.G., Toprak Ç., Göger F., Şahin E Therapeutic Potential of Morus Nigra on 5-Fluorouracil-İnduced Gastrointestinal Mucositis in Rats. Osmangazi Tıp Dergisi. 2020;42(4):363 - 72.
  • 15. Sakai H, Sagara A, Matsumoto K, Jo A, Hirosaki A, Takase K, et al. Neutrophil recruitment is critical for 5-fluorouracil-induced diarrhea and the decrease in aquaporins in the colon. Pharmacol Res. 2014;87:71-9.
  • 16. Cool JC, Dyer JL, Xian CJ, Butler RN, Geier MS, Howarth GS. Pre-treatment with insulin-like growth factor-I partially ameliorates 5-fluorouracil-induced intestinal mucositis in rats. Growth Horm IGF Res. 2005;15(1):72-82.
  • 17. Ali J, Khan AU, Shah FA, Ali H, Islam SU, Kim YS, et al. Mucoprotective effects of Saikosaponin-A in 5-fluorouracil-induced intestinal mucositis in mice model. Life Sci. 2019;239:116888.
  • 18. Torres DM, Tooley KL, Butler RN, Smith CL, Geier MS, Howarth GS. Lyprinol only partially improves indicators of small intestinal integrity in a rat model of 5-fluorouracil-induced mucositis. Cancer Biol Ther. 2008;7(2):295-302.
  • 19. Trindade LM, Martins VD, Rodrigues NM, Souza ELS, Martins FS, Costa GMF, et al. Oral administration of Simbioflora(R) (synbiotic) attenuates intestinal damage in a mouse model of 5-fluorouracil-induced mucositis. Benef Microbes. 2018;9(3):477-86.
  • 20. Yasuda M, Kato S, Yamanaka N, Iimori M, Matsumoto K, Utsumi D, et al. 5-HT(3) receptor antagonists ameliorate 5-fluorouracil-induced intestinal mucositis by suppression of apoptosis in murine intestinal crypt cells. Br J Pharmacol. 2013;168(6):1388-400.
  • 21. Kline CL, Schiccitano A, Zhu J, Beachler C, Sheikh H, Harvey HA, et al. Personalized dosing via pharmacokinetic monitoring of 5-fluorouracil might reduce toxicity in early- or late-stage colorectal cancer patients treated with infusional 5-fluorouracil-based chemotherapy regimens. Clin Colorectal Cancer. 2014;13(2):119-26.
  • 22. Liu CS, Zheng YR, Zhang YF, Long XY. Research progress on berberine with a special focus on its oral bioavailability. Fitoterapia. 2016;109:274-82.
  • 23. Smith CL, Geier MS, Yazbeck R, Torres DM, Butler RN, Howarth GS. Lactobacillus fermentum BR11 and fructo-oligosaccharide partially reduce jejunal inflammation in a model of intestinal mucositis in rats. Nutr Cancer. 2008;60(6):757-67.
  • 24. Mashtoub S, Tran CD, Howarth GS. Emu oil expedites small intestinal repair following 5-fluorouracil-induced mucositis in rats. Exp Biol Med (Maywood). 2013;238(11):1305-17.
  • 25. Liu JH, Hsieh CH, Liu CY, Chang CW, Chen YJ, Tsai TH. Anti-inflammatory effects of Radix Aucklandiae herbal preparation ameliorate intestinal mucositis induced by 5-fluorouracil in mice. J Ethnopharmacol. 2021;271:113912.
  • 26. Pandey MK, Sung B, Kunnumakkara AB, Sethi G, Chaturvedi MM, Aggarwal BB. Berberine modifies cysteine 179 of IkappaBalpha kinase, suppresses nuclear factor-kappaB-regulated antiapoptotic gene products, and potentiates apoptosis. Cancer Res. 2008;68(13):5370-9.
  • 27. Lima V, Brito GA, Cunha FQ, Reboucas CG, Falcao BA, Augusto RF, et al. Effects of the tumour necrosis factor-alpha inhibitors pentoxifylline and thalidomide in short-term experimental oral mucositis in hamsters. Eur J Oral Sci. 2005;113(3):210-7.
  • 28. Tung D, Cheung PH, Tudor G, Booth C, Saha S. In vivo effects of immunomodulators in a murine model of Fluorouracil-induced mucositis. Curr Ther Res Clin Exp. 2011;72(6):262-72.
  • 29. Huang L, Chiang Chiau JS, Cheng ML, Chan WT, Jiang CB, Chang SW, et al. SCID/NOD mice model for 5-FU induced intestinal mucositis: Safety and effects of probiotics as therapy. Pediatr Neonatol. 2019;60(3):252-60.
  • 30. de Barros PAV, Rabelo Andrade ME, de Vasconcelos Generoso S, Mendes Miranda SE, Dos Reis DC, Lacerda Leocadio PC, et al. Conjugated linoleic acid prevents damage caused by intestinal mucositis induced by 5-fluorouracil in an experimental model. Biomed Pharmacother. 2018;103:1567-76.
  • 31. Zhang L, Jin Y, Peng J, Chen W, Lisha L, Lin J. Qingjie Fuzheng Granule attenuates 5-fluorouracil-induced intestinal mucosal damage. Biomed Pharmacother. 2019;118:109223.
Toplam 31 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Tıbbi Farmakoloji
Bölüm ORİJİNAL MAKALELER / ORIGINAL ARTICLES
Yazarlar

Melike Kırcadere 0000-0003-1740-7416

Nuşin Harmancı 0000-0002-5777-2162

Ezgi Eroğlu 0000-0002-9878-3431

Çiğdem Çengelli Ünel 0000-0001-7680-0141

Erhan Şahin 0000-0003-2152-0542

Semra Yigitaslan 0000-0001-6722-2394

Proje Numarası 201911A106
Yayımlanma Tarihi 16 Ocak 2024
Gönderilme Tarihi 26 Aralık 2023
Kabul Tarihi 4 Ocak 2024
Yayımlandığı Sayı Yıl 2024 Cilt: 46 Sayı: 1

Kaynak Göster

Vancouver Kırcadere M, Harmancı N, Eroğlu E, Çengelli Ünel Ç, Şahin E, Yigitaslan S. The Potential Effect of Berberine on 5-Fluorouracil Induced Gastrointestinal Mucositis in Rats. Osmangazi Tıp Dergisi. 2024;46(1):139-46.


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