Dodder (Cuscuta sp.) Extract Ameliorates Liver Fibrosis in Bile Duct-Ligated Rats

Year 2022, , 31 - 40, 30.06.2022

Ömercan Albayrak , Dilek Özbeyli , Ali Şen , Ozge Cevik , Ömer Erdoğan , Feriha Ercan , Fatma Kanpalta Mustafaoğlu , Seren Ede , Göksel Şener

https://doi.org/10.26650/EurJBiol.2022.1097509

Abstract

Objective: The aim is to examine the possible protective effect of Cuscuta sp. extract against liver damage induced by biliary obstruction in rats. Materials and Methods: To induce biliary obstruction, the bile duct ligation (BDL) method was used. Sprague Dawley rats were allocated to 4 groups: Control (C), Cuscuta (CUS), bile duct ligation (BDL), and bile duct ligation + Cuscuta (BDL+CUS). Control and BDL rats were given physiological saline (SF), while CUS and BDL+CUS groups were administered 250 mg/ kg of Cuscuta extract by oral gavage. At the end of 28th day, the rats were decapitated, serum and tissue samples were collected, and aspartate aminotransferase (AST), alanine transaminase (ALT), and direct and total bilirubin (DB and TB) levels were determined in blood samples. In liver tissues, transforming growth factor-β (TGF-β), 8-hydroxyguanosine (8-OHdG), hydroxyproline, and sodium–potassium ATPase (Na+/K+-ATPase) levels were determined. Results: Serum samples of rats with cholestasis had high ALT, AST, DB, and TB levels, while TGF-β, 8-OHdG, and hydroxyproline concentrations were found to be significantly high in tissues. Hepatic Na+/K+-ATPase levels were decreased through biliary obstruction. Biochemical parameters were drastically reversed by Cuscuta care; also, this was supported histologically. Conclusion: Results showed that Cuscuta extract, through its antioxidant and anti-inflammatory properties, provided protection against oxidative injury by biliary obstruction. Also, these results confirm the traditional use of Cuscuta sp. as hepatoprotective.

Keywords

Liver damage, Dodder, Inflammation, Oxidative injury

References

• 1. Lai M, Afdhal NH. Liver Fibrosis Determination. Gastroenterol Clin North Am 2019; 48(2): 281-9.
• 2. Han JM, Kim HG, Choi MK, Lee JS, Park HJ, Wang JH, et al. Aqueous extract of Artemisia iwayomogi Kitamura attenuates cholestatic liver fibrosis in a rat model of bile duct ligation. Food Chem Toxicol 2012; 50(10): 3505-13.
• 3. Noll C, Raaf L, Planque C, Benard L, Secardin L, Petit E, et al. Protection and reversal of hepatic fibrosis by red wine polyphenols in hyperhomocysteinemic mice. J Nutr Biochem 2011; 22(9): 856-64.
• 4. Tsukada S, Parsons CJ, Rippe RA. Mechanisms of liver fibrosis. Clin Chim Acta 2006; 364(1-2): 33-60.
• 5. Xu R, Zhang Z, Wang FS. Liver fibrosis: Mechanisms of immune-mediated liver injury. Cell Mol Immunol 2012; 9(4): 296-301.
• 6. Dulundu E, Ozel Y, Topaloglu U, Toklu H, Ercan F, Gedik N, et al. Grape seed extract reduces oxidative stress and fibrosis in experimental biliary obstruction. J Gastroenterol Hepatol 2007; 22(6): 885-92.
• 7. Işeri SÖ, Şener G, Saglam B, Ercan F, Gedik N, Yeğen BÇ. Ghrelin alleviates biliary obstruction-induced chronic hepatic injury in rats. Regul Pept 2008; 146(1-3): 73-9.
• 8. Li S, Tan HY, Wang N, Zhang ZJ, Lao L, Wong CW, et al. The role of oxidative stress and antioxidants in liver diseases. Int J Mol Sci 2015; 16(11): 26087-124.
• 9. Sokol RJ, Devereaux M, Khandwala R, O’Brien K. Evidence for involvement of oxygen free radicals in bile acid toxicity to isolated rat hepatocytes. Hepatology 1993; 17(5): 869-81.
• 10. Videla LA, Rodrigo R, Orellana M, Fernandez V, Tapia G, Quiñones L, et al. Oxidative stress-related parameters in the liver of non-alcoholic fatty liver disease patients. Clin Sci 2004; 106(3): 261-8.
• 11. Koca-Caliskan U, Yilmaz I, Taslidere A, Yalcin FN, Aka C, Sekeroglu N. Cuscuta arvensis Beyr “dodder”: In Vivo Hepatoprotective Effects Against Acetaminophen-Induced Hepatotoxicity in Rats. J Med Food 2018; 21(6): 625-31.
• 12. Erecevit Sönmez P, Kirbağ S, İnci Ş. Antifungal and antibacterial effect of dodder (Cuscuta campestris) used for hepatitis treatment of mothers and newborn infants in Province Mardin in Turkey. Yuz Yil Univ J Agric Sci 2019; 29(4): 722-30.
• 13. Noureen S, Noreen S, Ghumman SA, Batool F, Bukhari SNA. The genus Cuscuta (Convolvolaceac): An updated review on indigenous uses, phytochemistry, and pharmacology. Iran J Basic Med Sci 2019; 22(11): 1225-52.
• 14. Şekeroğlu N, Koca U, Meraler SA. Geleneksel Bir Halk İlacı:Iksut. YYÜ TAR BİL DERG 2012; 22(1): 56-61.
• 15. Bulut G, Biçer M, Tuzlaci E. The folk medicinal plants of Yüksekova (Hakkari-Turkey). J Pharm Istanbul Univ 2016; 46(2): 115-24.
• 16. Sari AO, Üniversitesi E, Fakültesi F, Bölümü B, Anabilim B. Ege ve Güney Marmara Bölgelerinde Halk İlacı Olarak Kullanılan Bitkiler. Anadolu 2010; 20(2): 1-21.
• 17. Ahmad A, Tandon S, Xuan TD, Nooreen Z. A Review on Phytoconstituents and Biological activities of Cuscuta species. Biomed Pharmacother 2017; 92: 772-95.
• 18. Criado M, Flores O, Ortíz MC, Hidalgo F, Rodríguez-López AM, Eleno N, et al. Elevated glomerular and blood mononuclear lymphocyte nitric oxide production in rats with chronic bile duct ligation: Role of inducible nitric oxide synthase activation. Hepatology 1997; 26(2): 268-76.
• 19. Zou Y, Chang SKC, Gu Y, Qian SY. Antioxidant activity and phenolic compositions of lentil (Lens culinaris var. morton) extract and its fractions. J Agric Food Chem 2011; 59(6): 2268-76.
• 20. Phosrithong N, Nuchtavorn N. Antioxidant and anti-inflammatory activites of Clerodendrum leaf extracts collected in Thailand. Eur J Integr Med 2016; 8(3): 281-5.
• 21. Şen A, Yıldırım A, Bitis L, Doğan A. Antioxidant and anti-inflammatory activity of capitula, leaf and stem extracts of Tanacetum cilicicum (Boiss.) Grierson. Int J Second Metab 2019; 6(2): 211-22.
• 22. Gao X, Ohlander M, Jeppsson N, Björk L, Trajkovski V. Changes in antioxidant effects and their relationship to phytonutrients in fruits of sea buckthorn (Hippophae rhamnoides L.) during maturation. J Agric Food Chem 2000; 48(5): 1485-90.
• 23. Limdi JK, Hyde GM. Evaluation of abnormal liver function tests. Postgrad Med J 2003; 79: 307-12.
• 24. Strazzabosco M. Transport systems in cholangiocytes: Their role in bile formation and cholestasis. Yale J Biol Med 1997; 70(4): 427-34.
• 25. Hernandez-Gea V, Friedman SL. Pathogenesis of liver fibrosis. Annu Rev Pathol Mech Dis 2011; 6: 425-56.
• 26. Goldbecker A, Buchert R, Berding G, Bokemeyer M, Lichtinghagen R, Wilke F, et al. Blood-brain barrier permeability for ammonia in patients with different grades of liver fibrosis is not different from healthy controls. J Cereb Blood Flow Metab 2010; 30(7): 1384-93.
• 27. Khan A, Ayub M, Khan WM. Hyperammonemia Is Associated with Increasing Severity of Both Liver Cirrhosis and Hepatic Encephalopathy. Int J Hepatol 2016; 2016.
• 28. Zhangdi HJ, Su SB, Wang F, Liang ZY, Yan YD, Qin SY, et al. Crosstalk network among multiple inflammatory mediators in liver fibrosis. World J Gastroenterol 2019; 25(33): 4835-49.
• 29. Tahan G, Akin H, Aydogan F, Ramadan SS, Yapicier O, Tarcin O, et al. Melatonin ameliorates liver fibrosis induced by bile-duct ligation in rats. Can J Surg 2010; 53(5): 313-8.
• 30. Gedik N, Kabasakal L, Şehirli Ö, Ercan F, Sirvanci S, Keyer-Uysal M, et al. Long-term administration of aqueous garlic extract (AGE) alleviates liver fibrosis and oxidative damage induced by biliary obstruction in rats. Life Sci 2005; 76(22): 2593-606.
• 31. Singh U, Singh S, Kochhar A. Therapeutic potential of antidiabetic nutraceuticals. Phytopharmacology 2012; 2(1): 144-69.
• 32. Koca-Caliskan U, Yilmaz I, Taslidere A, Yalcin FN, Aka C, Sekeroglu N. Cuscuta arvensis Beyr “dodder”: In Vivo Hepatoprotective Effects Against Acetaminophen-Induced Hepatotoxicity in Rats. J Med Food 2018; 21(6): 625-31.
• 33. Ramaiah SK. A toxicologist guide to the diagnostic interpretation of hepatic biochemical parameters. Food Chem Toxicol 2007; 45(9): 1551-7.
• 34. Kobayashi A, Yokoyama H, Kataoka J, Ishida T, Kuno H, Sugai S, et al. Effects of spaced feeding on gene expression of hepatic transaminase and gluconeogenic enzymes in rats. J Toxicol Sci 2011; 36(3): 325-37.
• 35. Qian K, Zhong S, Xie K, Yu D, Yang R, Gong D-W. Hepatic ALT isoenzymes are elevated in gluconeogenic conditions including diabetes and suppressed by insulin at the protein level Kun. Diabetes Metab Res Rev 2015; 31(6): 562-71.
• 36. Horio Y, Tanaka T, Taketoshi M, Uno T, Wada H. Rat cytosolic aspartate aminotransferase: Regulation of its mRNA and contribution to gluconeogenesis. J Biochem 1988; 103(5): 805-8.
• 37. Jadaho SB, Yang RZ, Lin Q, Hu H, Anania FA, Shuldiner AR, et al. Murine Alanine Aminotransferase: cDNA Cloning, Functional Expression, and Differential Gene Regulation in Mouse Fatty Liver. Hepatology 2004; 39(5): 1297-302.
• 38. Tomkiewicz C, Muzeau F, Edgar AD, Barouki R, Aggerbeck M. Opposite regulation of the rat and human cytosolic aspartate aminotransferase genes by fibrates. Biochem Pharmacol 2004; 67(2): 213-25.
• 39. Yang RZ, Park S, Reagan WJ, Goldstein R, Zhong S, Lawton M, et al. Alanine aminotransferase isoenzymes: Molecular cloning and quantitative analysis of tissue expression in rats and serum elevation in liver toxicity. Hepatology 2009; 49(2): 598-607.
• 40. Raval N, Kalyane D, Maheshwari R, Tekade RK. Surface Modifications of Biomaterials and Their Implication on Biocompatibility. Biomaterials and Bionanotechnology. Elsevier Inc 2019; 639- 674.
• 41. Jo J, Yun JE, Lee H, Kimm H, Jee SH. Total, direct, and indirect serum bilirubin concentrations and metabolic syndrome among the Korean population. Endocrine 2011; 39(2): 182-9.
• 42. Lim JH, Kim TW, Song IB, Park SJ, Kim MS, Cho ES, et al. Protective effect of the roots extract of Platycodon grandiflorum on bile duct ligation-induced hepatic fibrosis in rats. Hum Exp Toxicol 2013; 32(11): 1197-205.
• 43. Şener G, Kabasakal L, Şehirli Ö, Ercan F, Gedik N. 2-Mercaptoethane sulfonate (MESNA) protects against biliary obstruction-induced oxidative damage in rats. Hepatol Res 2006; 35(2): 140-6.
• 44. Yada K, Ishibashi H, Mori H, Morine Y, Zhu C, Feng R, et al. The Kampo medicine “daikenchuto (TU-100)” prevents bacterial translocation and hepatic fibrosis in a rat model of biliary atresia. Surg 2016; 159(6): 1600-11.
• 45. Atalay S, Soylu B, Aykaç A, Oğünç AV, Çetinel Ş, Ozkan N, et al. Protective effects of St. John’s wort in the hepatic ischemia/ reperfusion injury in rats. Turkish J Surg 2018; 34(3): 198-204.
• 46. Muriel P. Interferon‐α preserves erythrocyte and hepatocyte atpase activities from liver damage induced by prolonged bile duct ligation in the rat. J Appl Toxicol 1995; 15(6): 449-53.
• 47. Muriel P, Suarez OR, Gonzalez P, Zuñiga L. Protective effect of S-adenosyl-l-methionine on liver damage induced by biliary obstruction in rats: a histological, ultrastructural and biochemical approach. J Hepatol 1994; 21(1): 95-102.
• 48. Shin S, Lee YJ, Kim EJ, Lee AS, Kang DG, Lee HS. Effect of Cuscuta chinensis on renal function in ischemia/reperfusion- induced acute renal failure rats. Am J Chin Med 2011; 39(5): 889-902.
• 49. Forman HJ, Zhang H. Targeting oxidative stress in disease: promise and limitations of antioxidant therapy. Nat Rev Drug Discov 2021; 20(9): 689-709.
• 50. Atmaca E, Aksoy A. Oksidatif DNA Hasarı ve Kromatografik Yöntemlerle Tespit Edilmesi. YYU Veteriner Fakultesi Dergisi 2009; 20(2): 79-83.
• 51. Li P, Ramm GA, Macdonald GA. Value of the 8-oxodG/dG ratio in chronic liver inflammation of patients with hepatocellular carcinoma. Redox Biol 2016; 8: 259-70. 52. Huang YT, Hsu YC, Chen CJ, Liu CT, Wei YH. Oxidative-stress-related changes in the livers of bile-duct-ligated rats. J Biomed Sci 2003; 10(2): 170-8.
• 53. Maeda K, Koda M, Matono T, Sugihara T, Yamamoto S, Ueki M, et al. Preventive effects of ME3738 on hepatic fibrosis induced by bile duct ligation in rats. Hepatol Res 2008; 38(7): 727-35.
• 54. Matono T, Koda M, Tokunaga S, Sugihara T, Ueki M, Murawaki Y. The effects of the selective mineralocorticoid receptor antagonist eplerenone on hepatic fibrosis induced by bile duct ligation in rat. Int J Mol Med 2010; 25: 875-82.
• 55. Aydin S, Aytac E, Uzun H, Altug T, Mansur B, Saygili S, et al. Effects of Ganoderma lucidum on obstructive jaundice-induced oxidative stress. Asian J Surg 2010; 33(4): 173-80.
• 56. Fabregat I, Moreno-Càceres J, Sánchez A, Dooley S, Dewidar B, Giannelli G, et al. TGF-β signalling and liver disease. FEBS J 2016; 283: 2219-32.
• 57. Asakawa T, Yagi M, Tanaka Y, Asagiri K, Kobayashi H, Egami H, et al. The herbal medicine Inchinko-to reduces hepatic fibrosis in cholestatic rats. Pediatr Surg Int 2012; 28(4): 379-84.
• 58. Du JX, Sun MY, Du GL, Li FH, Liu C, Mu YP, et al. Ingredients of Huangqi decoction slow biliary fibrosis progression by inhibiting the activation of the transforming growth factor-beta signaling pathway. BMC Complement Altern Med 2012; 12: 1-11.
• 59. Sharawy MH, Abdel-Rahman N, Megahed N, El-Awady MS. Paclitaxel alleviates liver fibrosis induced by bile duct ligation in rats: Role of TGF-β1, IL-10 and c-Myc. Life Sci 2018; 211: 245-51.
• 60. Mu M, Zuo S, Wu RM, Deng KS, Lu S, Zhu JJ, et al. Ferulic acid attenuates liver fibrosis and hepatic stellate cell activation via inhibition of TGF-β/Smad signaling pathway. Drug Des Devel Ther 2018; 12: 4107-15.
• 61. Wang R, Song F, Li S, Wu B, Gu Y, Yuan Y. Salvianolic acid A attenuates CCl4-induced liver fibrosis by regulating the PI3K/AKT/mTOR, Bcl-2/Bax and caspase-3/cleaved caspase-3 signaling pathways. Drug Des Devel Ther 2019; 13: 1889-900.
• 62. Lee TY, Chang HH, Chen JH, Hsueh ML, Kuo JJ. Herb medicine Yin- Chen-Hao-Tang ameliorates hepatic fibrosis in bile duct ligation rats. J Ethnopharmacol 2007; 109(2): 318-24.
• 63. Nan J-X, Park E-J, Kim Y-C, Ko G, Sohn DH. Scutellaria baicalensis inhibits liver fibrosis induced by bile duct ligation or carbon tetrachloride in rats. J Pharm Pharmacol 2010; 54(4): 555-63.
• 64. Tian X, Zhao C, Guo J, Xie S, Yin F, Huo X, et al. Carvedilol Attenuates the Progression of Hepatic Fibrosis Induced by Bile Duct Ligation. Biomed Res Int 2017; 2017. 65. Yadav RK, Nandy BC, Maity S, Sarkar S, Saha S. Phytochemistry, pharmacology, toxicology, and clinical trial of Ficus racemosa. Pharmacogn Rev 2015; 9(17): 73-80.