Therapeutic Potential of Morin in Ovalbumin-induced Allergic Asthma Via Modulation of SUMF2/IL-13 and BLT2/NF-kB Signaling Pathway

Author(s): Amit D. Kandhare, Zihao Liu, Anwesha A. Mukherjee, Subhash L. Bodhankar*.

Journal Name: Current Molecular Pharmacology

Volume 12 , Issue 2 , 2019

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Abstract:

Background: Allergic asthma is a chronic immune-inflammatory disorder, characterized by airway inflammation and airway hyperresponsiveness (AHR). Morin is a natural flavonoid reported to exhibit inhibitory action against IgE-mediated allergic response.

Aim: To determine the efficacy of murine model of ovalbumin (OVA)-induced AHR inhibition by morin and decipher the molecular mechanism involved.

Materials and Methods: Sprague-Dawley rats were sensitized and challenged with OVA to induce AHR. Rats received treatment with morin (10, 30 and 100 mg/kg, p.o.) for the next 28 days.

Results: Morin (30 and 100 mg/kg) significantly and dose-dependently attenuated (p < 0.01 and p < 0.001) OVA-induced alterations in pulse oxy and lung function test, increased bronchoalveolar lavage fluid cell counts, elevated total protein and albumin levels in serum, BALF, and lungs, increased serum total and OVA-specific IgE levels and, elevated oxidative stress levels in the lung. RT-PCR analysis revealed that morin treatment (30 and 100 mg/kg) significantly (p < 0.001) up-regulated SUMF2 mRNA expression in lungs whereas mRNA expressions of BLT2, NF-κB, and Th2-cytokine (TNF-α, IL-1β, IL-4, IL-6, and IL-13) were down-regulated significantly and dose-dependently (p < 0.01 and p < 0.001). Also, histologic and ultrastructural studies showed that morin significantly inhibited (p < 0.001) OVAinduced perivascular and peribranchial inflammatory infiltration and interstitial fibrosis.

Conclusion: Morin exhibited inhibitory effect against OVA-induced allergic asthma by activation of SUMF2 which impeded IL-13 expression and in turn attenuated Th2-cytokines, BLT2, NF-κB, and IgE levels to ameliorate AHR. Thus, our findings suggested that morin could be considered as a potential alternative therapeutic agent for the management of allergic asthma.

Keywords: Airway hyperresponsiveness, asthma, leukotriene B4 receptor 2, Morin, NF-kB, sulfate-modifying factor 2, Th2 cytokines.

[1]
Bousquet, J.; Clark, T.J.; Hurd, S.; Khaltaev, N.; Lenfant, C.; O’Byrne, P.; Sheffer, A. GINA guidelines on asthma and beyond. Allergy, 2007, 62(2), 102-112.
[2]
Braman, S.S. The global burden of asthma. Chest, 2006, 130(1)(Suppl.), 4S-12S.
[3]
Busse, W.W.; Lemanske, R.F., Jr Asthma. N. Engl. J. Med., 2001, 344(5), 350-362.
[4]
Bloemen, K.; Verstraelen, S.; Van Den Heuvel, R.; Witters, H.; Nelissen, I.; Schoeters, G. The allergic cascade: review of the most important molecules in the asthmatic lung. Immunol. Lett., 2007, 113(1), 6-18.
[5]
Kon, O.M.; Kay, A.B. T cells and chronic asthma. Int. Arch. Allergy Immunol., 1999, 118(2-4), 133-135.
[6]
Russo, M.; Nahori, M.A.; Lefort, J.; Gomes, E.; de Castro Keller, A.; Rodriguez, D.; Ribeiro, O.G.; Adriouch, S.; Gallois, V.; de Faria, A.M.; Vargaftig, B.B. Suppression of asthma-like responses in different mouse strains by oral tolerance. Am. J. Respir. Cell Mol. Biol., 2001, 24(5), 518-526.
[7]
Strid, J.; Thomson, M.; Hourihane, J.; Kimber, I.; Strobel, S. A novel model of sensitization and oral tolerance to peanut protein. Immunology, 2004, 113(3), 293-303.
[8]
Bradding, P.; Roberts, J.A.; Britten, K.M.; Montefort, S.; Djukanovic, R.; Mueller, R.; Heusser, C.H.; Howarth, P.H.; Holgate, S.T. Interleukin-4, -5, and -6 and tumor necrosis factor-alpha in normal and asthmatic airways: evidence for the human mast cell as a source of these cytokines. Am. J. Respir. Cell Mol. Biol., 1994, 10(5), 471-480.
[9]
Galli, S.J.; Grimbaldeston, M.; Tsai, M. Immunomodulatory mast cells: negative, as well as positive, regulators of immunity. Nat. Rev. Immunol., 2008, 8(6), 478-486.
[10]
Ma, Y.; Ge, A.; Zhu, W.; Liu, Y.N.; Ji, N.F.; Zha, W.J.; Zhang, J.X.; Zeng, X.N.; Huang, M. Morin attenuates ovalbumin-induced airway inflammation by modulating oxidative stress-responsive MAPK signaling. Oxid. Med. Cell. Longev., 2016, 2016, 5843672.
[11]
Sahiner, U.M.; Birben, E.; Erzurum, S.; Sackesen, C.; Kalayci, O. Oxidative stress in asthma. World Allergy Organ. J., 2011, 4(10), 151-158.
[12]
Hogan, S.P.; Rosenberg, H.F.; Moqbel, R.; Phipps, S.; Foster, P.S.; Lacy, P.; Kay, A.B.; Rothenberg, M.E. Eosinophils: biological properties and role in health and disease. Clin. Exp. Allergy, 2008, 38(5), 709-750.
[13]
Fang, C.; Li, X.; Liang, H.; Xue, L.; Liu, L.; Yang, C.; Gao, G.; Jiang, X. Downregulation of SUMF2 gene in ovalbumin-induced rat model of allergic inflammation. Int. J. Clin. Exp. Pathol., 2015, 8(10), 12053-12063.
[14]
Yamashita, N.; Tashimo, H.; Ishida, H.; Matsuo, Y.; Tamauchi, H.; Terashima, M.; Yoshiwara, I.; Habu, S.; Ohta, K. Involvement of GATA-3-dependent Th2 lymphocyte activation in airway hyperresponsiveness. Am. J. Physiol. Lung Cell. Mol. Physiol., 2006, 290(6), L1045-L1051.
[15]
Corren, J. Role of interleukin-13 in asthma. Curr. Allergy Asthma Rep., 2013, 13(5), 415-420.
[16]
Liang, H.; Li, Z.; Xue, L.; Jiang, X.; Liu, F. SUMF2 interacts with interleukin-13 and inhibits interleukin-13 secretion in bronchial smooth muscle cells. J. Cell. Biochem., 2009, 108(5), 1076-1083.
[17]
Longui, C.A. Glucocorticoid therapy: minimizing side effects. J. Pediatr., 2007, 83(5)(Suppl.), S163-S177.
[18]
Sato, M.N.; Oliveira, C.R.; Futata, E.A.; Victor, J.R.; Maciel, M.; Fusaro, A.E.; Carvalho, A.F.; Duarte, A.J. Oral tolerance induction to Dermatophagoides pteronyssinus and Blomia tropicalis in sensitized mice: Occurrence of natural autoantibodies to immunoglobulin E. Clin. Exp. Allergy, 2002, 32(11), 1667-1674.
[19]
Wiedermann, U.; Jahn-Schmid, B.; Bohle, B.; Repa, A.; Renz, H.; Kraft, D.; Ebner, C. Suppression of antigen-specific T- and B-cell responses by intranasal or oral administration of recombinant bet v 1, the major birch pollen allergen, in a murine model of type I allergy. J. Allergy Clin. Immunol., 1999, 103(6), 1202-1210.
[20]
Mukherjee, A.A.; Kandhare, A.D.; Rojatkar, S.R.; Bodhankar, S.L. Ameliorative effects of Artemisia pallens in a murine model of ovalbumin-induced allergic asthma via modulation of biochemical perturbations. Biomed. Pharmacother., 2017, 94, 880-889.
[21]
Kandhare, A.D.; Raygude, K.S.; Ghosh, P.; Gosavi, T.P.; Bodhankar, S.L. Patentability of animal models: India and the globe. Int. J. Pharm. Biol. Arch., 2011, 2(4), 1024-1032.
[22]
Ernst, E. Complementary therapies for asthma: what patients use. J. Asthma, 1998, 35(8), 667-671.
[23]
Urata, Y.; Yoshida, S.; Irie, Y.; Tanigawa, T.; Amayasu, H.; Nakabayashi, M.; Akahori, K. Treatment of asthma patients with herbal medicine TJ-96: a randomized controlled trial. Respir. Med., 2002, 96(6), 469-474.
[24]
Gupta, S.C.; Phromnoi, K.; Aggarwal, B.B. Morin inhibits STAT3 tyrosine 705 phosphorylation in tumor cells through activation of protein tyrosine phosphatase SHP1. Biochem. Pharmacol., 2013, 85(7), 898-912.
[25]
Wei, Z.; He, X.; Kou, J.; Wang, J.; Chen, L.; Yao, M.; Zhou, E.; Fu, Y.; Guo, C.; Yang, Z. Renoprotective mechanisms of morin in cisplatin-induced kidney injury. Int. Immunopharmacol., 2015, 28(1), 500-506.
[26]
Kim, J.W.; Lee, J.H.; Hwang, B.Y.; Mun, S.H.; Ko, N.Y.; Kim, D.K.; Kim, B.; Kim, H.S.; Kim, Y.M.; Choi, W.S. Morin inhibits Fyn kinase in mast cells and IgE-mediated type I hypersensitivity response in vivo. Biochem. Pharmacol., 2009, 77(9), 1506-1512.
[27]
Prahalathan, P.; Kumar, S.; Raja, B. Morin attenuates blood pressure and oxidative stress in deoxycorticosterone acetate-salt hypertensive rats: a biochemical and histopathological evaluation. Metabolism, 2012, 61(8), 1087-1099.
[28]
Franova, S.; Kazimierova, I.; Pappova, L.; Joskova, M.; Plank, L.; Sutovska, M. Bronchodilatory, antitussive and anti-inflammatory effect of morin in the setting of experimentally induced allergic asthma. J. Pharm. Pharmacol., 2016, 68(8), 1064-1072.
[29]
Kandhare, A.D.; Bodhankar, S.L.; Singh, V.; Mohan, V.; Thakurdesai, P.A. Anti-asthmatic effects of type-A procyanidine polyphenols from cinnamon bark in ovalbumin-induced airway hyperresponsiveness in laboratory animals. Biomed. Aging Pathol., 2013, 3(1), 23-30.
[30]
Conrad, M.L.; Yildirim, A.O.; Sonar, S.S.; Kilic, A.; Sudowe, S.; Lunow, M.; Teich, R.; Renz, H.; Garn, H. Comparison of adjuvant and adjuvant-free murine experimental asthma models. Clin. Exp. Allergy, 2009, 39(8), 1246-1254.
[31]
Shin, I.S.; Jeon, W.Y.; Shin, H.K.; Lee, M.Y. Effects of montelukast on subepithelial/peribronchial fibrosis in a murine model of ovalbumin induced chronic asthma. Int. Immunopharmacol., 2013, 17(3), 867-873.
[32]
Subash, S.; Subramanian, P. Morin a flavonoid exerts antioxidant potential in chronic hyperammonemic rats: a biochemical and histopathological study. Mol. Cell. Biochem., 2009, 327(1-2), 153-161.
[33]
Bhilare, N.V.; Dhaneshwar, S.S.; Sinha, A.J.; Kandhare, A.D.; Bodhankar, S.L. Novel thioester prodrug of N-acetylcysteine for odor masking and bioavailability enhancement. Curr. Drug Deliv., 2016, 13(4), 611-620.
[34]
Kandhare, A.D.; Bodhankar, S.L.; Mohan, V.; Thakurdesai, P.A. Effect of glycosides based standardized fenugreek seed extract in bleomycin-induced pulmonary fibrosis in rats: Decisive role of Bax, Nrf2, NF-κB, Muc5ac, TNF-α and IL-1β. Chem. Biol. Interact., 2015, 237, 151-165.
[35]
Visnagri, A.; Kandhare, A.D.; Ghosh, P.; Bodhankar, S.L. Endothelin receptor blocker bosentan inhibits hypertensive cardiac fibrosis in pressure overload-induced cardiac hypertrophy in rats. Cardiovasc. Endocrinol., 2013, 2(4), 85-97.
[36]
Badole, S.L.; Chaudhari, S.M.; Jangam, G.B.; Kandhare, A.D.; Bodhankar, S.L. Cardioprotective activity of pongamia pinnata in streptozotocin-nicotinamide induced diabetic rats. BioMed Res. Int., 2015, 2015, 403291.
[37]
Kandhare, A.D.; Raygude, K.S.; Kumar, V.S.; Rajmane, A.R.; Visnagri, A.; Ghule, A.E.; Ghosh, P.; Badole, S.L.; Bodhankar, S.L. Ameliorative effects quercetin against impaired motor nerve function, inflammatory mediators and apoptosis in neonatal streptozotocin-induced diabetic neuropathy in rats. Biomed. Aging Pathol., 2012, 2(4), 173-186.
[38]
Visnagri, A.; Adil, M.; Kandhare, A.D.; Bodhankar, S.L. Effect of naringin on hemodynamic changes and left ventricular function in renal artery occluded renovascular hypertension in rats. J. Pharm. Bioallied Sci., 2015, 7(2), 121-127.
[39]
Raygude, K.S.; Kandhare, A.D.; Ghosh, P.; Ghule, A.E.; Bodhankar, S.L. Evaluation of ameliorative effect of quercetin in experimental model of alcoholic neuropathy in rats. Inflammopharmacol., 2012, 20(6), 331-341.
[40]
Kandhare, A.D.; Shivakumar, V.; Rajmane, A.; Ghosh, P.; Bodhankar, S.L. Evaluation of the neuroprotective effect of chrysin via modulation of endogenous biomarkers in a rat model of spinal cord injury. J. Nat. Med., 2014, 68(3), 586-603.
[41]
Adil, M.; Kandhare, A.D.; Ghosh, P.; Venkata, S.; Raygude, K.S.; Bodhankar, S.L. Ameliorative effect of naringin in acetaminophen-induced hepatic and renal toxicity in laboratory rats: role of FXR and KIM-1. Ren. Fail., 2016, 38(6), 1007-1020.
[42]
Visnagri, A.; Kandhare, A.D.; Chakravarty, S.; Ghosh, P.; Bodhankar, S.L. Hesperidin, a flavanoglycone attenuates experimental diabetic neuropathy via modulation of cellular and biochemical marker to improve nerve functions. Pharm. Biol., 2014, 52(7), 814-828.
[43]
Brattstrom, A.; Schapowal, A.; Kamal, M.A.; Maillet, I.; Ryffel, B.; Moser, R. The plant extract Isatis tinctoria L. extract (ITE) inhibits allergen-induced airway inflammation and hyperreactivity in mice. Phytomedicine, 2010, 17(8-9), 551-556.
[44]
King, T.E., Jr; Tooze, J.A.; Schwarz, M.I.; Brown, K.R.; Cherniack, R.M. Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model. Am. J. Respir. Crit. Care Med., 2001, 164(7), 1171-1181.
[45]
Ngoc, P.L.; Gold, D.R.; Tzianabos, A.O.; Weiss, S.T.; Celedon, J.C. Cytokines, allergy, and asthma. Curr. Opin. Allergy Clin. Immunol., 2005, 5(2), 161-166.
[46]
Ferguson, S.; Teodorescu, M.C.; Gangnon, R.E.; Peterson, A.G.; Consens, F.B.; Chervin, R.D.; Teodorescu, M. Factors associated with systemic hypertension in asthma. Lung., 2014, 192(5), 675-683.
[47]
van der Hooft, C.S.; Heeringa, J.; Brusselle, G.G.; Hofman, A.; Witteman, J.C.; Kingma, J.H.; Sturkenboom, M.C.; Stricker, B.H. Corticosteroids and the risk of atrial fibrillation. Arch. Intern. Med., 2006, 166(9), 1016-1020.
[48]
Halwani, R.; Vazquez-Tello, A.; Sumi, Y.; Pureza, M.A.; Bahammam, A.; Al-Jahdali, H.; Soussi-Gounni, A.; Mahboub, B.; Al-Muhsen, S.; Hamid, Q. Eosinophils induce airway smooth muscle cell proliferation. J. Clin. Immunol., 2013, 33(3), 595-604.
[49]
Monteseirin, J. Neutrophils and asthma. J. Investig. Allergol. Clin. Immunol., 2009, 19(5), 340-354.
[50]
Hendeles, L.; Sorkness, C.A. Anti-immunoglobulin E therapy with omalizumab for asthma. Ann. Pharmacother., 2007, 41(9), 1397-1410.
[51]
Emson, C.L.; Bell, S.E.; Jones, A.; Wisden, W.; McKenzie, A.N. Interleukin (IL)-4-independent induction of immunoglobulin (Ig)E, and perturbation of T cell development in transgenic mice expressing IL-13. J. Exp. Med., 1998, 188(2), 399-404.
[52]
Keatings, V.M.; O’Connor, B.J.; Wright, L.G.; Huston, D.P.; Corrigan, C.J.; Barnes, P.J. Late response to allergen is associated with increased concentrations of tumor necrosis factor-alpha and IL-5 in induced sputum. J. Allergy Clin. Immunol., 1997, 99(5), 693-698.
[53]
Choy, E.H.; Panayi, G.S. Cytokine pathways and joint inflammation in rheumatoid arthritis. N. Engl. J. Med., 2001, 344(12), 907-916.
[54]
Brightling, C.E.; Symon, F.A.; Birring, S.S.; Bradding, P.; Pavord, I.D.; Wardlaw, A.J. TH2 cytokine expression in bronchoalveolar lavage fluid T lymphocytes and bronchial submucosa is a feature of asthma and eosinophilic bronchitis. J. Allergy Clin. Immunol., 2002, 110(6), 899-905.
[55]
Montuschi, P.; Barnes, P.J. Exhaled leukotrienes and prostaglandins in asthma. J. Allergy Clin. Immunol., 2002, 109(4), 615-620.
[56]
Cho, K.J.; Seo, J.M.; Shin, Y.; Yoo, M.H.; Park, C.S.; Lee, S.H.; Chang, Y.S.; Cho, S.H.; Kim, J.H. Blockade of airway inflammation and hyperresponsiveness by inhibition of BLT2, a low-affinity leukotriene B4 receptor. Am. J. Respir. Cell Mol. Biol., 2010, 42(3), 294-303.
[57]
Gaudreault, E.; Thompson, C.; Stankova, J.; Rola-Pleszczynski, M. Involvement of BLT1 endocytosis and Yes kinase activation in leukotriene B4-induced neutrophil degranulation. J. Immunol., 2005, 174(6), 3617-3625.
[58]
Higham, A.; Cadden, P.; Southworth, T.; Rossall, M.; Kolsum, U.; Lea, S.; Knowles, R.; Singh, D. Leukotriene B4 levels in sputum from asthma patients. ERJ Open Res., 2016, 2(4), 00088-02015.
[59]
Siebenlist, U.; Brown, K.; Claudio, E. Control of lymphocyte development by nuclear factor-kappaB. Nat. Rev. Immunol., 2005, 5(6), 435-445.
[60]
Galvez, J.; Coelho, G.; Crespo, M.E.; Cruz, T.; Rodriguez-Cabezas, M.E.; Concha, A.; Gonzalez, M.; Zarzuelo, A. Intestinal anti-inflammatory activity of morin on chronic experimental colitis in the rat. Aliment. Pharmacol. Ther., 2001, 15(12), 2027-2039.
[61]
Zhang, W.Y.; Liang, H.Y.; Yang, C.; Xue, L.; Jiang, X.F. Sos recruitment system for the analysis of the interaction between sulfatase-modifying factor 2 subtypes and interleukin-13. Genet. Mol. Res., 2013, 12(4), 5664-5672.
[62]
Ordonez, C.L.; Khashayar, R.; Wong, H.H.; Ferrando, R.; Wu, R.; Hyde, D.M.; Hotchkiss, J.A.; Zhang, Y.; Novikov, A.; Dolganov, G.; Fahy, J.V. Mild and moderate asthma is associated with airway goblet cell hyperplasia and abnormalities in mucin gene expression. Am. J. Respir. Crit. Care Med., 2001, 163(2), 517-523.
[63]
Henderson, W.R., Jr; Tang, L.O.; Chu, S.J.; Tsao, S.M.; Chiang, G.K.; Jones, F.; Jonas, M.; Pae, C.; Wang, H.; Chi, E.Y. A role for cysteinyl leukotrienes in airway remodeling in a mouse asthma model. Am. J. Respir. Crit. Care Med., 2002, 165(1), 108-116.
[64]
Yoshisue, H.; Kirkham-Brown, J.; Healy, E.; Holgate, S.T.; Sampson, A.P.; Davies, D.E. Cysteinyl leukotrienes synergize with growth factors to induce proliferation of human bronchial fibroblasts. J. Allergy Clin. Immunol., 2007, 119(1), 132-140.
[65]
Medford, A.R.L. Effects of leukotriene receptor antagonists on vascular endothelial growth factor levels in asthma. CHEST J., 2005, 127(4), 1460.
[66]
Takeda, K.; Shiraishi, Y.; Matsubara, S.; Miyahara, N.; Matsuda, H.; Okamoto, M.; Joetham, A.; Gelfand, E.W. Effects of combination therapy with montelukast and carbocysteine in allergen-induced airway hyperresponsiveness and airway inflammation. Br. J. Pharmacol., 2010, 160(6), 1399-1407.
[67]
Zubairi, A.B.; Salahuddin, N.; Khawaja, A.; Awan, S.; Shah, A.A.; Haque, A.S.; Husain, S.J.; Rao, N.; Khan, J.A. A randomized, double-blind, placebo-controlled trial of oral montelukast in acute asthma exacerbation. BMC Pulm. Med., 2013, 13, 20.
[68]
Knorr, B.; Franchi, L.M.; Bisgaard, H.; Vermeulen, J.H.; LeSouef, P.; Santanello, N.; Michele, T.M.; Reiss, T.F.; Nguyen, H.H.; Bratton, D.L. Montelukast, a leukotriene receptor antagonist, for the treatment of persistent asthma in children aged 2 to 5 years. Pediatrics, 2001, 108(3), E48.
[69]
van Adelsberg, J.; Moy, J.; Wei, L.X.; Tozzi, C.A.; Knorr, B.; Reiss, T.F. Safety, tolerability, and exploratory efficacy of montelukast in 6- to 24-month-old patients with asthma. Curr. Med. Res. Opin., 2005, 21(6), 971-979.
[70]
Currie, G.P.; McLaughlin, K. The expanding role of leukotriene receptor antagonists in chronic asthma. Ann. Allergy Asthma Immunol.,2006, 97(6), 731-741, quiz 741-732, 793.


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VOLUME: 12
ISSUE: 2
Year: 2019
Page: [122 - 138]
Pages: 17
DOI: 10.2174/1874467212666190102105052
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