Morusin is a prenylated flavonoid isolated from the root bark of Morus alba. Many studies have shown the ability of flavonoids to act as anti-inflammatory agents. The aim of this study was to evaluate the effect of morusin on experimentally colitis induced by 2,4,6-trinitrobenzensulfonic acid in Wistar rats and to compare it with sulfasalazine, a drug conventionally used in the treatment of inflammatory bowel disease. Morusin was administered by gavage at doses of 12.5, 25, or 50 mg/kg/day for five days. The colonic tissue was evaluated macroscopically, histologically, and by performing immunodetection and zymographic analysis to determine the levels of antioxidant enzymes [superoxide dismutase (SOD) and catalase (CAT)], interleukin (IL)-1β, and transforming growth factor (TGF)-β1 and the activities of matrix metalloproteinases (MMP) 2 and 9. The tissue damage scores were significantly reduced with increasing dose of morusin, however efficacy was not demonstrated at the highest dose. At the dose of 12.5 mg/kg, morusin exerted therapeutic effectivity similar to that of sulfasalazine (50 mg/kg). This was associated with significant reduction of TGF-β1 levels and MMP2 and MMP9 activities, and slight reduction of IL-1β. Our results suggest that morusin possesses therapeutic potential for the treatment of chronic inflammatory diseases.

Department of Human Pharmacology and Toxicology Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences Brno Brno Czech Republic

Department of Molecular Biology and Pharmaceutical Biotechnology Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences Brno Brno Czech Republic

Department of Natural Drugs Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences Brno Brno Czech Republic

Department of Pathological Morphology and Parasitology Faculty of Veterinary Medicine University of Veterinary and Pharmaceutical Sciences Brno Brno Czech Republic

Department of Pharmaceutics Faculty of Pharmacy University of Veterinary and Pharmaceutical Sciences Brno Brno Czech Republic

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Hošek J, Šmejkal K. Flavonoids as anti-inflammatory agents In: Parnham MJ, editor. Compendium of Inflammatory Diseases. Basel: Birkhäuser Springer; 2016.

Kim HP, Son KH, Chang HW, Kang SS. Anti-inflammatory plant flavonoids and cellular action mechanisms. J Pharmacol Sci. 2004;96(3):229–245. doi: 10.1254/jphs.CRJ04003X PubMed DOI

Benavente-García O, Castillo J. Update on uses and properties of citrus flavonoids: New findings in anticancer, cardiovascular, and anti-inflammatory activity. J Agric Food Chem. 2008;56(15):6185–6205. doi: 10.1021/jf8006568 PubMed DOI

Terao J, Mukai R. Prenylation modulates the bioavailability and bioaccumulation of dietary flavonoids. Arch Biochem Biophys. 2014;559:12–16. doi: 10.1016/j.abb.2014.04.002 PubMed DOI

Zelova H, Hanakova Z, Cermakova Z, Smejkal K, Dall'Acqua S, Babula P, et al. Evaluation of Anti-Inflammatory Activity of Prenylated Substances Isolated from Morus alba and Morus nigra. J Nat Prod. 2014;77(6):1297–1303. doi: 10.1021/np401025f PubMed DOI

Lee HJ, Ryu J, Park SH, Woo ER, Kim AR, Lee SK, et al. Effects of Morus alba L. and natural products including morusin on in vivo secretion and in vitro production of airway MUC5AC mucin. Tuberc Respir Dis. 2014;77(2):65–72. doi: 10.4046/trd.2014.77.2.65 PubMed DOI PMC

Fukai T, Satoh K, Nomura T, Sakagami H. Antinephritis and radical scavenging activity of prenylflavonoids. Fitoterapia. 2003;74(7–8):720–724. PubMed

Gupta G, Chellappan DK, Dua K, Ashwathanarayana M. Pharmacological evaluation of the recuperative effect of morusin against aluminum trichloride (AlCl3)—induced memory impairment in rats. Centr Nerv Sys Agents Med Chem. 2016: Forthcoming. PubMed

Hošek J, Bartos M, Chudík S, Dall’Acqua S, Innocenti G, Kartal M, et al. Natural Compound Cudraflavone B Shows Promising Anti-inflammatory Properties in Vitro. J Nat Prod. 2011;74(4):614–619. doi: 10.1021/np100638h PubMed DOI

Hošek J, Toniolo A, Neuwirth O, Bolego C. Prenylated and Geranylated Flavonoids Increase Production of Reactive Oxygen Species in Mouse Macrophages but Inhibit the Inflammatory Response. J Nat Prod. 2013;76(9):1586–1591. doi: 10.1021/np400242e PubMed DOI

An R-B, Sohn D-H, Kim Y-C. Hepatoprotective Compounds of the Roots of Cudrania tricuspidata on Tacrine-Induced Cytotoxicity in Hep G2 Cells. Biol Pharm Bull. 2006;29(4):838–840. doi: 10.1248/bpb.29.838 PubMed DOI

Lee D-S, Ko W, Kim D-C, Kim Y-C, Jeong G-S. Cudarflavone B Provides Neuroprotection against Glutamate-Induced Mouse Hippocampal HT22 Cell Damage through the Nrf2 and PI3K/Akt Signaling Pathways. Molecules. 2014;19(8):10818 doi: 10.3390/molecules190810818 PubMed DOI PMC

Sun Q, Wang D, Li FF, Yao GD, Li X, Li LZ, et al. Cytotoxic prenylated flavones from the stem and root bark of Daphne giraldii. Bioorg Med Chem Lett. 2016;26(16):3968–3972. doi: 10.1016/j.bmcl.2016.07.002 PubMed DOI

Morris GP, Beck PL, Herridge MS, Depew WT, Szewczuk MR, Wallace JL. Hapten-induced model of chronic inflammation and ulceration in the rat colon. Gastroenterology. 1989;96:795–803. PubMed

Minaiyan M, Ghannadi A, Asadi M, Etemad M, Mahzouni P. Anti-inflammatory effect of Prunus armeniaca L. (Apricot) extracts ameliorates TNBS-induced ulcerative colitis in rats. Res Pharm Sci. 2014;9(4):225–231. PubMed PMC

Vochyanova Z, Bartosova L, Bujdakova V, Fictum P, Husnik R, Suchy P, et al. Diplacone and mimulone ameliorate dextran sulfate sodium-induced colitis in rats. Fitoterapia. 2015;101:201–207. doi: 10.1016/j.fitote.2015.01.012 PubMed DOI

Tao F, Qian C, Guo W, Luo Q, Xu Q, Sun Y. Inhibition of Th1/Th17 responses via suppression of STAT1 and STAT3 activation contributes to the amelioration of murine experimental colitis by a natural flavonoid glucoside icariin. Bioch Pharmacol. 2013;85(6):798–807. doi: 10.1016/j.bcp.2012.12.002 PubMed DOI

Kollar P, Bárta T, Hošek J, Souček K, Závalová VM, Artinian S, et al. Prenylated flavonoids from Morus alba L. cause inhibition of G1/S transition in THP-1 human leukemia cells and prevent the lipopolysaccharide-induced inflammatory response. Evid Based Complement Alternat Med. 2013;2013:350519 doi: 10.1155/2013/350519 PubMed DOI PMC

Ahn BO, Ko KH, Oh TY, Cho H, Kim WB, Lee KJ, et al. Efficacy of use of colonoscopy in dextran sulfate sodium induced ulcerative colitis in rats: the evaluation of the effects of antioxidant by colonoscopy. Int J Colorectal Dis. 2001;16(3):174–181. PubMed

Brückner M, Westphal S, Domschke W, Kucharzik T, Lügering A. Green tea polyphenol epigallocatechin-3-gallate shows therapeutic antioxidative effects in a murine model of colitis. J Crohns Colitis. 2012;6(2):226–235. doi: 10.1016/j.crohns.2011.08.012 PubMed DOI

Sakthivel KM, Guruvayoorappan C. Amentoflavone inhibits iNOS, COX-2 expression and modulates cytokine profile, NF-κB signal transduction pathways in rats with ulcerative colitis. Int Immunopharmacol. 2013;17(3):907–916. doi: 10.1016/j.intimp.2013.09.022 PubMed DOI

Yamaguchi H, Suzuki K, Nagata M, Kawase T, Sukumaran V, Thandavarayan RA, et al. Irsogladine maleate ameliorates inflammation and fibrosis in mice with chronic colitis induced by dextran sulfate sodium. Med Mol Morphol. 2012;45(3):140–151. doi: 10.1007/s00795-011-0550-7 PubMed DOI

Kisseleva T, Brenner DA. Fibrogenesis of Parenchymal Organs. Am Thor Soc. 2008;5(3):338–342. doi: 10.1513/pats.200711-168DR PubMed DOI PMC

Medina C, Santos-Martinez MJ, Santana A, Paz-Cabrera MC, Johnston MJ, Mourelle M, et al. Transforming growth factor-beta type 1 receptor (ALK5) and Smad proteins mediate TIMP-1 and collagen synthesis in experimental intestinal fibrosis. J Pathol. 2011;224(4):461–472. doi: 10.1002/path.2870 PubMed DOI

Loeuillard E, Bertrand J, Herranen A, Melchior C, Guerin C, Coeffier M, et al. 2,4,6-trinitrobenzene sulfonic acid-induced chronic colitis with fibrosis and modulation of TGF-beta1 signaling. World J Gastroenterol. 2014;20(48):18207–18215. doi: 10.3748/wjg.v20.i48.18207 PubMed DOI PMC

Latella G, Sferra R, Vetuschi A, Zanninelli G, D’Angelo A, Catitti V, et al. Prevention of colonic fibrosis by Boswellia and Scutellaria extracts in rats with colitis induced by 2,4,5-trinitrobenzene sulphonic acid. Eur J Clin Invest. 2008;38(6):410–420. doi: 10.1111/j.1365-2362.2008.01955.x PubMed DOI

Mao J-W, He X-M, Tang H-Y, Wang Y-D. Protective role of metalloproteinase inhibitor (AE-941) on ulcerative colitis in rats. World J Gastroenterol. 2012;47(18):7063–7069. PubMed PMC

von Lampe B, Barthel B, Coupland S, Riecken E, Rosewicz S. Differential expression of matrix metalloproteinases and their tissue inhibitors in colon mucosa of patients with inflammatory bowel disease. Gut. 2000;47(1):63–73. doi: 10.1136/gut.47.1.63 PubMed DOI PMC

Witaicenis A, Luchini AC, Hiruma-Lima CA, Felisbino SL, Garrido-Mesa N, Utrilla P, et al. Suppression of TNBS-induced colitis in rats by 4-methylesculetin, a natural coumarin: Comparison with prednisolone and sulphasalazine. Chem Biol Interact. 2012;195(1):76–85. doi: 10.1016/j.cbi.2011.11.004 PubMed DOI

Marshall DC, Lyman SK, McCauley S, Kovalenko M, Spangler R, Liu C, et al. Selective allosteric inhibition of MMP9 is efficacious in preclinical models of ulcerative colitis and colorectal cancer. PLoS ONE. 2015;10(5):e0127063 doi: 10.1371/journal.pone.0127063 PubMed DOI PMC