Skip to main content
Erschienen in: Inflammopharmacology 5/2022

09.08.2022 | Original Article

Therapeutic effect of the sulforaphane derivative JY4 on ulcerative colitis through the NF-κB-p65 pathway

verfasst von: Xiu-Juan Zhao, Yi-Ran Zhang, Wen-Fei Bai, Tong-Yan Sun, Yu-Fen Yang, Tong-Xin Wang, Cui-Gai Bai

Erschienen in: Inflammopharmacology | Ausgabe 5/2022

Einloggen, um Zugang zu erhalten

Abstract

The efficacy of the sulforaphane derivative JY4 was evaluated in acute and chronic mouse models of ulcerative colitis induced by dextran sodium sulfate. Oral administration of JY4 led to significant improvements in symptoms, with recovery of body weight and colorectal length, together with reduced diarrhoea, bloody stools, ulceration of colonic tissue and infiltration of inflammatory cells. The oral bioavailability of JY4, determined by comparing oral dosing with injection into the tail vein, was 5.67%, which was comply with the idea in the intestinal function. Using a dual-luciferase reporter assay, immunofluorescence studies, western blot analysis and immunohistochemical staining, JY4 was shown to significant interfere with the NF-κB-p65 signaling pathway. By preventing the activation of NF-κB-p65, JY4 inhibited the overexpression of downstream inflammatory factors, thereby exerting an anti-inflammatory effect on the intestinal tract. This study thus provides a promising candidate drug, and a new concept for the treatment of ulcerative colitis.

Graphical Abstract

Literatur
Zurück zum Zitat Atreya I, Atreya R, Neurath MF (2008) NF-kappaB in inflammatory bowel disease. J Intern Med 263:591–596CrossRef Atreya I, Atreya R, Neurath MF (2008) NF-kappaB in inflammatory bowel disease. J Intern Med 263:591–596CrossRef
Zurück zum Zitat Bouma G, Strober W (2003) The immunological and genetic basis of inflammatory bowel disease. Nat Rev Immunol 3:521–533CrossRef Bouma G, Strober W (2003) The immunological and genetic basis of inflammatory bowel disease. Nat Rev Immunol 3:521–533CrossRef
Zurück zum Zitat Bayat Mokhtari R, Baluch N, Homayouni TS, Morgatskaya E, Kumar S, Kazemi P et al (2017) The role of Sulforaphane in cancer chemoprevention and health benefits: a mini-review. J Cell Commun Signal 12:91–101CrossRef Bayat Mokhtari R, Baluch N, Homayouni TS, Morgatskaya E, Kumar S, Kazemi P et al (2017) The role of Sulforaphane in cancer chemoprevention and health benefits: a mini-review. J Cell Commun Signal 12:91–101CrossRef
Zurück zum Zitat Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867CrossRef Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867CrossRef
Zurück zum Zitat Choi KM, Lee YS, Kim W, Kim SJ, Shin KO, Yu JY et al (2014) Sulforaphane attenuates obesity by inhibiting adipogenesis and activating the AMPK pathway in obese mice. J Nutr Biochem 25:201–207CrossRef Choi KM, Lee YS, Kim W, Kim SJ, Shin KO, Yu JY et al (2014) Sulforaphane attenuates obesity by inhibiting adipogenesis and activating the AMPK pathway in obese mice. J Nutr Biochem 25:201–207CrossRef
Zurück zum Zitat Checker R, Gambhir L, Thoh M, Sharma D, Sandur SK (2015) Sulforaphane, a naturally occurring isothiocyanate, exhibits anti-inflammatory effects by targeting GSK3β/Nrf-2 and NF-κB pathways in T cells. J Funct Foods 19:426–438CrossRef Checker R, Gambhir L, Thoh M, Sharma D, Sandur SK (2015) Sulforaphane, a naturally occurring isothiocyanate, exhibits anti-inflammatory effects by targeting GSK3β/Nrf-2 and NF-κB pathways in T cells. J Funct Foods 19:426–438CrossRef
Zurück zum Zitat Chi X, Zhang R, Shen N, Jin Y, Alina A, Yang S et al (2015) Sulforaphane reduces apoptosis and oncosis along with protecting liver injury-induced ischemic reperfusion by activating the Nrf2/ARE pathway. Hepatol Int 9:321–329CrossRef Chi X, Zhang R, Shen N, Jin Y, Alina A, Yang S et al (2015) Sulforaphane reduces apoptosis and oncosis along with protecting liver injury-induced ischemic reperfusion by activating the Nrf2/ARE pathway. Hepatol Int 9:321–329CrossRef
Zurück zum Zitat Dinkova-Kostova AT, Fahey JW, Kostov RV, Kensler TW (2017) KEAP1 and done? Targeting the NRF2 pathway with sulforaphane. Trends Food Sci Technol 3:257–269CrossRef Dinkova-Kostova AT, Fahey JW, Kostov RV, Kensler TW (2017) KEAP1 and done? Targeting the NRF2 pathway with sulforaphane. Trends Food Sci Technol 3:257–269CrossRef
Zurück zum Zitat Fuss IJ, Strober W (2008) The role of IL-13 and NK T cells in experimental and human ulcerative colitis. Mucosal Immunol 10:31–33CrossRef Fuss IJ, Strober W (2008) The role of IL-13 and NK T cells in experimental and human ulcerative colitis. Mucosal Immunol 10:31–33CrossRef
Zurück zum Zitat Guo L, Yang R, Wang Z, Guo Q, Gu Z (2014) Gl32ucoraphanin, sulforaphane and myrosinase activity in germinating broccoli sprouts as affected by growth temperature and plant organs. J Funct Foods 9:70–77CrossRef Guo L, Yang R, Wang Z, Guo Q, Gu Z (2014) Gl32ucoraphanin, sulforaphane and myrosinase activity in germinating broccoli sprouts as affected by growth temperature and plant organs. J Funct Foods 9:70–77CrossRef
Zurück zum Zitat Greaney AJ, Maier NK, Leppla SH, Moayeri M (2016) Sulforaphane inhibits multiple inflammasomes through an Nrf2-independent mechanism. J Leukocyte Biol 99:1–11CrossRef Greaney AJ, Maier NK, Leppla SH, Moayeri M (2016) Sulforaphane inhibits multiple inflammasomes through an Nrf2-independent mechanism. J Leukocyte Biol 99:1–11CrossRef
Zurück zum Zitat Hibi T, Inoue N, Ogata H, Naganuma M (2003) Introduction and overview: recent advances in the immunotherapy of inflammatory bowel disease. J Gastroenterol 38:36–42CrossRef Hibi T, Inoue N, Ogata H, Naganuma M (2003) Introduction and overview: recent advances in the immunotherapy of inflammatory bowel disease. J Gastroenterol 38:36–42CrossRef
Zurück zum Zitat Ingersoll SA, Ayyadurai S, Charania MA, Laroui H, Yan Y, Merlin D (2012) The role and pathophysiological relevance of membrane transporter PepT1 in intestinal inflammation and inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 302:484–492CrossRef Ingersoll SA, Ayyadurai S, Charania MA, Laroui H, Yan Y, Merlin D (2012) The role and pathophysiological relevance of membrane transporter PepT1 in intestinal inflammation and inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol 302:484–492CrossRef
Zurück zum Zitat Jiang Y, Li HY, Li XH, Lu J, Zhang Q, Bai CG et al (2018) Therapeutic effects of isothiocyanate prodrugs on rheumatoid arthritis. Bioorg Med Chem Lett 28:734–741 Jiang Y, Li HY, Li XH, Lu J, Zhang Q, Bai CG et al (2018) Therapeutic effects of isothiocyanate prodrugs on rheumatoid arthritis. Bioorg Med Chem Lett 28:734–741
Zurück zum Zitat Kaser A, Zeissig S, Blumberg RS (2010) Inflammatory bowel disease. Annu Rev Immunol 28:573–621CrossRef Kaser A, Zeissig S, Blumberg RS (2010) Inflammatory bowel disease. Annu Rev Immunol 28:573–621CrossRef
Zurück zum Zitat Kong L, Liu B, Zhang C, Wang B, Wang H, Song X et al (2016) The therapeutic potential of sulforaphane on light-induced photoreceptor degeneration through antiapoptosis and antioxidant protection. Neurochem Int 100:52–61CrossRef Kong L, Liu B, Zhang C, Wang B, Wang H, Song X et al (2016) The therapeutic potential of sulforaphane on light-induced photoreceptor degeneration through antiapoptosis and antioxidant protection. Neurochem Int 100:52–61CrossRef
Zurück zum Zitat Liang WD, Li JS, Li KS, Jin J, Yan J, Yang JF et al (2011) Association of IL-8 gene polymorphisms with inflammatory bowel disease in Chinese patients. Zhonghua Yi Xue Za Zhi 91:1825–1829PubMed Liang WD, Li JS, Li KS, Jin J, Yan J, Yang JF et al (2011) Association of IL-8 gene polymorphisms with inflammatory bowel disease in Chinese patients. Zhonghua Yi Xue Za Zhi 91:1825–1829PubMed
Zurück zum Zitat Lee JH, Moon MH, Jeong JK, Park YG, Lee YJ, Seol JW et al (2012) Sulforaphane induced adipolysis via hormone sensitive lipase activation, regulated by AMPK signaling pathway. Biochem Bioph Res Co 426:492–497CrossRef Lee JH, Moon MH, Jeong JK, Park YG, Lee YJ, Seol JW et al (2012) Sulforaphane induced adipolysis via hormone sensitive lipase activation, regulated by AMPK signaling pathway. Biochem Bioph Res Co 426:492–497CrossRef
Zurück zum Zitat Li B, Cui W, Liu J, Li R, Liu Q, Xie XH et al (2013) Sulforaphane ameliorates the development of experimental autoimmune encephalomyelitis by antagonizing oxidative stress and Th17-related inflammation in mice. Exp Neurol 250:239–249CrossRef Li B, Cui W, Liu J, Li R, Liu Q, Xie XH et al (2013) Sulforaphane ameliorates the development of experimental autoimmune encephalomyelitis by antagonizing oxidative stress and Th17-related inflammation in mice. Exp Neurol 250:239–249CrossRef
Zurück zum Zitat Lacruz-Guzman D, Torres-Moreno D, Pedrero F, Romero-Cara P, Garcia-Tercero I, Trujillo-Santos J et al (2013) Influence of polymorphisms and TNF and IL1beta serum concentration on the infliximab response in Crohn’s disease and ulcerative colitis. Eur J Clin Pharmacol 69:431–438CrossRef Lacruz-Guzman D, Torres-Moreno D, Pedrero F, Romero-Cara P, Garcia-Tercero I, Trujillo-Santos J et al (2013) Influence of polymorphisms and TNF and IL1beta serum concentration on the infliximab response in Crohn’s disease and ulcerative colitis. Eur J Clin Pharmacol 69:431–438CrossRef
Zurück zum Zitat Liu TC, Stappenbeck TS (2016) Enetics and pathogenesis of inflammatory bowel disease. Annu Rev Pathol Mech Dis 11:127–148CrossRef Liu TC, Stappenbeck TS (2016) Enetics and pathogenesis of inflammatory bowel disease. Annu Rev Pathol Mech Dis 11:127–148CrossRef
Zurück zum Zitat Nallasamy P, Si H, Babu PVA, Pan D, Fu Y, Brooke EA et al (2014) Sulforaphane reduces vascular inflammation in mice and prevents TNF-α-induced monocyte adhesion to primary endothelial cells through interfering with the NF-κB pathway. J Nutr Biochem 25:824–833CrossRef Nallasamy P, Si H, Babu PVA, Pan D, Fu Y, Brooke EA et al (2014) Sulforaphane reduces vascular inflammation in mice and prevents TNF-α-induced monocyte adhesion to primary endothelial cells through interfering with the NF-κB pathway. J Nutr Biochem 25:824–833CrossRef
Zurück zum Zitat Pan H, He M, Liu R, Brecha NC, Yu ACH, Pu M et al (2014) Sulforaphane protects rodent retinas against ischemia-reperfusion injury through the activation of the Nrf2/HO-1 antioxidant pathway. PLoS ONE 9:114186–114210CrossRef Pan H, He M, Liu R, Brecha NC, Yu ACH, Pu M et al (2014) Sulforaphane protects rodent retinas against ischemia-reperfusion injury through the activation of the Nrf2/HO-1 antioxidant pathway. PLoS ONE 9:114186–114210CrossRef
Zurück zum Zitat Qi T, Xu F, Yan X, Li S, Li H (2016) Sulforaphane exerts anti-inflammatory effects against lipopolysaccharide-induced acute lung injury in mice through the Nrf2/ARE pathway. Int J Mol Med 37:182–188CrossRef Qi T, Xu F, Yan X, Li S, Li H (2016) Sulforaphane exerts anti-inflammatory effects against lipopolysaccharide-induced acute lung injury in mice through the Nrf2/ARE pathway. Int J Mol Med 37:182–188CrossRef
Zurück zum Zitat Rogler G, Brand K, Vogl D, Page S, Hofmeister R, Andus T et al (1998) Nuclear factor kappaB is activated in macropHages and epithelial cells of inflamed intestinal mucosa. Gastroenterology 115:357–369CrossRef Rogler G, Brand K, Vogl D, Page S, Hofmeister R, Andus T et al (1998) Nuclear factor kappaB is activated in macropHages and epithelial cells of inflamed intestinal mucosa. Gastroenterology 115:357–369CrossRef
Zurück zum Zitat Reddy KP, Markowitz JE, Ruchelli ED, Baldassano RN, Brown KA (2007) Lamina propria and circulating interleukin-8 in newly and previously diagnosed pediatric inflammatory bowel disease patients. Dig Dis Sci 52:365–372CrossRef Reddy KP, Markowitz JE, Ruchelli ED, Baldassano RN, Brown KA (2007) Lamina propria and circulating interleukin-8 in newly and previously diagnosed pediatric inflammatory bowel disease patients. Dig Dis Sci 52:365–372CrossRef
Zurück zum Zitat Reddy SA, Shelar SB, Dang TM, Lee BNC, Yang H, Ong SM et al (2015) Sulforaphane and its methylcarbonyl analogs inhibit the LPS-stimulated inflammatory response in human monocytes through modulating cytokine production, suppressing chemotactic migration and phagocytosis in a NF-κB- and MAPK-dependent manner. Int Immunopharmacol 24:440–450CrossRef Reddy SA, Shelar SB, Dang TM, Lee BNC, Yang H, Ong SM et al (2015) Sulforaphane and its methylcarbonyl analogs inhibit the LPS-stimulated inflammatory response in human monocytes through modulating cytokine production, suppressing chemotactic migration and phagocytosis in a NF-κB- and MAPK-dependent manner. Int Immunopharmacol 24:440–450CrossRef
Zurück zum Zitat Rezende BM, Athayde RM, Gonçalves WA, Resende CB, de Tolêdo T, Bernardes P, Perez DA et al (2017) Inhibition of 5-lipoxygenase alleviates graft-versus-host disease. J Exp Med 214:3399–3415CrossRef Rezende BM, Athayde RM, Gonçalves WA, Resende CB, de Tolêdo T, Bernardes P, Perez DA et al (2017) Inhibition of 5-lipoxygenase alleviates graft-versus-host disease. J Exp Med 214:3399–3415CrossRef
Zurück zum Zitat Shehatou GS, Suddek GM (2016) Sulforaphane attenuates the development of atherosclerosis and improves endothelial dysfunction in hypercholesterolemic rabbits. Exp Biol Med 241:426–436CrossRef Shehatou GS, Suddek GM (2016) Sulforaphane attenuates the development of atherosclerosis and improves endothelial dysfunction in hypercholesterolemic rabbits. Exp Biol Med 241:426–436CrossRef
Zurück zum Zitat Triantafillidis JK, Merikas E, Georgopoulos F (2011) Current and emerging drugs for the treatment of inflammatory bowel disease. Drug Des Dev Ther 5:185–210CrossRef Triantafillidis JK, Merikas E, Georgopoulos F (2011) Current and emerging drugs for the treatment of inflammatory bowel disease. Drug Des Dev Ther 5:185–210CrossRef
Zurück zum Zitat Uhlik M, Good L, Xiao G, Harhaj EW, Zandi E, Karin M et al (1998) NF-κB-inducing Kinase and IκB kinase participate in human T-cell leukemia virus I tax-mediated NF-κB activation. J Biol Chem 273:21132–21136CrossRef Uhlik M, Good L, Xiao G, Harhaj EW, Zandi E, Karin M et al (1998) NF-κB-inducing Kinase and IκB kinase participate in human T-cell leukemia virus I tax-mediated NF-κB activation. J Biol Chem 273:21132–21136CrossRef
Zurück zum Zitat Weisshof R, Jurdi EI, Zmeter N, Rubin DT (2018) Emerging therapies for inflammatory bowel disease. Adv Ther 35:1746–1762CrossRef Weisshof R, Jurdi EI, Zmeter N, Rubin DT (2018) Emerging therapies for inflammatory bowel disease. Adv Ther 35:1746–1762CrossRef
Zurück zum Zitat Zubair A, Frieri M (2013) Role of nuclear factor-ĸB in breast and colorectal cancer. Curr Aller Asthma Rep 13:44–49CrossRef Zubair A, Frieri M (2013) Role of nuclear factor-ĸB in breast and colorectal cancer. Curr Aller Asthma Rep 13:44–49CrossRef
Zurück zum Zitat Zhang YZ, Li YY (2014) Inflammatory bowel disease: pathogenesis. World J Gastroenterol 20:91–99CrossRef Zhang YZ, Li YY (2014) Inflammatory bowel disease: pathogenesis. World J Gastroenterol 20:91–99CrossRef
Zurück zum Zitat Zhang JC, Yao W, Dong C, Yang C, Ren Q, Ma M et al (2017) Prophylactic effects of sulforaphane on depression-like behavior and dendritic changes in mice after inflammation. J Nutr Biochem 39:134–144CrossRef Zhang JC, Yao W, Dong C, Yang C, Ren Q, Ma M et al (2017) Prophylactic effects of sulforaphane on depression-like behavior and dendritic changes in mice after inflammation. J Nutr Biochem 39:134–144CrossRef
Metadaten
Titel
Therapeutic effect of the sulforaphane derivative JY4 on ulcerative colitis through the NF-κB-p65 pathway
verfasst von
Xiu-Juan Zhao
Yi-Ran Zhang
Wen-Fei Bai
Tong-Yan Sun
Yu-Fen Yang
Tong-Xin Wang
Cui-Gai Bai
Publikationsdatum
09.08.2022
Verlag
Springer International Publishing
Erschienen in
Inflammopharmacology / Ausgabe 5/2022
Print ISSN: 0925-4692
Elektronische ISSN: 1568-5608
DOI
https://doi.org/10.1007/s10787-022-01044-5

Weitere Artikel der Ausgabe 5/2022

Inflammopharmacology 5/2022 Zur Ausgabe