RRC ID 67498
Author Lohning A, Kidachi Y, Kamiie K, Sasaki K, Ryoyama K, Yamaguchi H.
Title 6-(methylsulfinyl)hexyl isothiocyanate (6-MITC) from Wasabia japonica alleviates inflammatory bowel disease (IBD) by potential inhibition of glycogen synthase kinase 3 beta (GSK-3β).
Journal Eur J Med Chem
Abstract Inflammatory bowel disease (IBD) describes a set of disorders involving alterations to gastrointestinal physiology and mucosal immunity. Unravelling its complex pathophysiology is important since many IBD patients are refractory to or suffer adverse side effects from current treatments. Isothiocyanates (ITCs), such as 6-(methylsulfinyl)hexyl ITC (6-MITC) in Wasabia japonica, have potential anti-inflammatory activity. We aimed to elucidate the pathways through which 6-MITC alleviates inflammation by examining its role in the nuclear factor-kappa B (NF-κB) pathway through inhibition of glycogen synthase kinase 3 beta (GSK-3β) using a chemically induced murine model of IBD, cell-based and in silico techniques. The effects of 6-MITC and two NF-κB inhibitors, sulfasalazine (SS), pyrrolidine dithiolcarbamate (PDTC) were investigated on a dextran sulfate sodium (DSS)-induced murine mouse model of acute and chronic colitis using macroscopic measurements and pro-inflammatory markers. The effect of 6-MITC on NF-κB induction was assessed using a murine macrophage cell line. Complexes of GSK-3β-6-MITC and GSK-3β-ATP were generated in silico to elucidate the mechanism of 6-MITC's direct inhibition of GSK-3β. Changes in pro-inflammatory markers, inducible nitric oxide synthase (iNOS) (increased) and interleukin-6 (IL-6) (decreased) demonstrated that iNOS regulation occurred at the translational level. Intraperitoneal (ip) injection of 6-MITC to the colitis-induced mice ameliorated weight loss whereas oral administration had negligible effect. Fecal blood and colon weight/length ratio parameters improved on treatment with 6-MITC and the other NF-κB inhibitors. Levels of NF-κB decreased upon addition of 6-MITC in vitro while structural studies showed 6-MITC acts competitively to inhibit GSK-3β at the ATP binding site. In this study we demonstrated that 6-MITC inhibits NF-κB signaling via GSK-3β inhibition ameliorating fecal blood, colonic alterations and DSS-induced weight loss indirectly indicating reduced intestinal stress. Taken together these results suggest a role for 6-MITC in the treatment of IBD acting to alleviate inflammation through the GSK-3β/NF-κB pathway. Furthermore, the GSK-3β-6-MITC model can be utilized as a basis for development of novel therapeutics targeting GSK-3β for use in other disorders including cancer.
Volume 216
Pages 113250
Published 2021-4-15
DOI 10.1016/j.ejmech.2021.113250
PII S0223-5234(21)00099-4
PMID 33691258
MeSH Animals Anti-Inflammatory Agents / chemistry* Anti-Inflammatory Agents / metabolism Anti-Inflammatory Agents / pharmacology Anti-Inflammatory Agents / therapeutic use Cell Line Dextran Sulfate / toxicity Down-Regulation / drug effects Female Glycogen Synthase Kinase 3 beta / antagonists & inhibitors* Glycogen Synthase Kinase 3 beta / metabolism Humans Inflammatory Bowel Diseases / chemically induced Inflammatory Bowel Diseases / drug therapy Inflammatory Bowel Diseases / pathology Interleukin-6 / metabolism Isothiocyanates / chemistry* Isothiocyanates / metabolism Isothiocyanates / pharmacology Isothiocyanates / therapeutic use Lipopolysaccharides / pharmacology Macrophages / cytology Macrophages / drug effects Macrophages / metabolism Mice Mice, Inbred BALB C NF-kappa B / antagonists & inhibitors NF-kappa B / metabolism Nitric Oxide Synthase Type II / metabolism Signal Transduction / drug effects Up-Regulation / drug effects Wasabia / chemistry* Wasabia / metabolism
IF 5.573
Human and Animal Cells J774.1(RCB0434)