Isothiocyanate-enriched moringa seed extract alleviates ulcerative colitis symptoms in mice

Moringa (Moringa oleifera Lam.) seed extract (MSE) has anti-inflammatory and antioxidant activities. We investigated the effects of MSE enriched in moringa isothiocyanate-1 (MIC-1), its putative bioactive, on ulcerative colitis (UC) and its anti-inflammatory/antioxidant mechanism likely mediated through Nrf2-signaling pathway. Dextran sulfate sodium (DSS)-induced acute (n = 8/group; 3% DSS for 5 d) and chronic (n = 6/group; cyclic rotations of 2.5% DSS/water for 30 d) UC was induced in mice that were assigned to 4 experimental groups: healthy control (water/vehicle), disease control (DSS/vehicle), MSE treatment (DSS/MSE), or 5-aminosalicyic acid (5-ASA) treatment (positive control; DSS/5-ASA). Following UC induction, water (vehicle), 150 mg/kg MSE, or 50 mg/kg 5-ASA were orally administered for 1 or 2 wks. Disease activity index (DAI), spleen/colon sizes, and colonic histopathology were measured. From colon and/or fecal samples, pro-inflammatory biomarkers, tight-junction proteins, and Nrf2-mediated enzymes were analyzed at protein and/or gene expression levels. Compared to disease control, MSE decreased DAI scores, and showed an increase in colon lengths and decrease in colon weight/length ratios in both UC models. MSE also reduced colonic inflammation/damage and histopathological scores (modestly) in acute UC. MSE decreased colonic secretions of pro-inflammatory keratinocyte-derived cytokine (KC), tumor necrosis factor (TNF)-α, nitric oxide (NO), and myeloperoxidase (MPO) in acute and chronic UC; reduced fecal lipocalin-2 in acute UC; downregulated gene expression of pro-inflammatory interleukin (IL)-1, IL-6, TNF-α, and inducible nitric oxide synthase (iNOS) in acute UC; upregulated expression of claudin-1 and ZO-1 in acute and chronic UC; and upregulated GSTP1, an Nrf2-mediated phase II detoxifying enzyme, in chronic UC. MSE was effective in mitigating UC symptoms and reducing UC-induced colonic pathologies, likely by suppressing pro-inflammatory biomarkers and increasing tight-junction proteins. This effect is consistent with Nrf2-mediated anti-inflammatory/antioxidant signaling pathway documented for other isothiocyanates similar to MIC-1. Therefore, MSE, enriched with MIC-1, may be useful in prevention and treatment of UC.

[1]  Brittany L. Graf,et al.  Biochemical characterization and anti-inflammatory properties of an isothiocyanate-enriched moringa (Moringa oleifera) seed extract , 2017, PloS one.

[2]  Meng-Chen Lu,et al.  The Keap1–Nrf2–ARE Pathway As a Potential Preventive and Therapeutic Target: An Update , 2016, Medicinal research reviews.

[3]  Ta-Chiang Liu,et al.  Genetics and Pathogenesis of Inflammatory Bowel Disease. , 2016, Annual review of pathology.

[4]  S. Brand,et al.  Lipocalin-2 Is a Disease Activity Marker in Inflammatory Bowel Disease Regulated by IL-17A, IL-22, and TNF-&agr; and Modulated by IL23R Genotype Status , 2015, Inflammatory bowel diseases.

[5]  Qi Ying Lean,et al.  Fucoidan Extracts Ameliorate Acute Colitis , 2015, PloS one.

[6]  I. Raskin,et al.  Isothiocyanate-rich Moringa oleifera extract reduces weight gain, insulin resistance, and hepatic gluconeogenesis in mice. , 2015, Molecular nutrition & food research.

[7]  A. Spada,et al.  Cultivation, Genetic, Ethnopharmacology, Phytochemistry and Pharmacology of Moringa oleifera Leaves: An Overview , 2015, International journal of molecular sciences.

[8]  A. Kong,et al.  Dietary Glucosinolates Sulforaphane, Phenethyl Isothiocyanate, Indole-3-Carbinol/3,3′-Diindolylmethane: Antioxidative Stress/Inflammation, Nrf2, Epigenetics/Epigenomics and In Vivo Cancer Chemopreventive Efficacy , 2015, Current Pharmacology Reports.

[9]  I. Raskin,et al.  Direct and indirect antioxidant activity of polyphenol- and isothiocyanate-enriched fractions from Moringa oleifera. , 2015, Journal of agricultural and food chemistry.

[10]  A. Kong,et al.  Nrf2 Knockout Attenuates the Anti-Inflammatory Effects of Phenethyl Isothiocyanate and Curcumin , 2014, Chemical research in toxicology.

[11]  M. Baliga,et al.  Dietary Agents and Phytochemicals in the Prevention and Treatment of Experimental Ulcerative Colitis , 2014, Journal of traditional and complementary medicine.

[12]  I. Raskin,et al.  Stable, water extractable isothiocyanates from Moringa oleifera leaves attenuate inflammation in vitro. , 2014, Phytochemistry.

[13]  Markus F. Neurath,et al.  Cytokines in inflammatory bowel disease , 2014, Nature Reviews Immunology.

[14]  B. Chassaing,et al.  Dextran Sulfate Sodium (DSS)‐Induced Colitis in Mice , 2014, Current protocols in immunology.

[15]  P. Rosenstiel,et al.  DSS-induced acute colitis in C57BL/6 mice is mitigated by sulforaphane pre-treatment. , 2013, The Journal of nutritional biochemistry.

[16]  Gemma A. Figtree,et al.  Biological markers of oxidative stress: Applications to cardiovascular research and practice☆ , 2013, Redox biology.

[17]  B. Molnár,et al.  Changes of the cytokine profile in inflammatory bowel diseases. , 2012, World journal of gastroenterology.

[18]  A. Young,et al.  Fecal Lipocalin 2, a Sensitive and Broadly Dynamic Non-Invasive Biomarker for Intestinal Inflammation , 2012, PloS one.

[19]  M. Perše,et al.  Dextran Sodium Sulphate Colitis Mouse Model: Traps and Tricks , 2012, Journal of biomedicine & biotechnology.

[20]  Yutao Yan,et al.  Dextran Sodium Sulfate (DSS) Induces Colitis in Mice by Forming Nano-Lipocomplexes with Medium-Chain-Length Fatty Acids in the Colon , 2012, PloS one.

[21]  M. Mbikay.  Therapeutic Potential of Moringa oleifera Leaves in Chronic Hyperglycemia and Dyslipidemia: A Review , 2012, Front. Pharmacol..

[22]  W. Khan,et al.  Investigating intestinal inflammation in DSS-induced model of IBD. , 2012, Journal of visualized experiments : JoVE.

[23]  S. Boddupalli,et al.  Induction of Phase 2 Antioxidant Enzymes by Broccoli Sulforaphane: Perspectives in Maintaining the Antioxidant Activity of Vitamins A, C, and E , 2012, Front. Gene..

[24]  Z. Dvořák,et al.  Rifampicin Does not Significantly Affect the Expression of Small Heterodimer Partner in Primary Human Hepatocytes , 2011, Front. Pharmacol..

[25]  S. Sarna,et al.  Impaired integrity of DNA after recovery from inflammation causes persistent dysfunction of colonic smooth muscle. , 2011, Gastroenterology.

[26]  S. Melgar,et al.  Use of bioluminescence imaging to track neutrophil migration and its inhibition in experimental colitis , 2010, Clinical and experimental immunology.

[27]  J. Pezzuto,et al.  Potential anti-inflammatory phenolic glycosides from the medicinal plant Moringa oleifera fruits. , 2010, Bioorganic & medicinal chemistry.

[28]  S. Snapper,et al.  Cytokines and Chemokines in Mucosal Homeostasis , 2010 .

[29]  I. Raskin,et al.  Dietary phenethylisothiocyanate attenuates bowel inflammation in mice , 2010, BMC chemical biology.

[30]  M. D’Incalci,et al.  The isothiocyanate produced from glucomoringin inhibits NF-kB and reduces myeloma growth in nude mice in vivo. , 2010, Biochemical pharmacology.

[31]  A. Kong,et al.  Molecular Targets of Dietary Phenethyl Isothiocyanate and Sulforaphane for Cancer Chemoprevention , 2010, The AAPS Journal.

[32]  Julie S. Jurenka.  Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research. , 2009, Alternative medicine review : a journal of clinical therapeutic.

[33]  Paul Rutgeerts,et al.  Biological therapies for inflammatory bowel diseases. , 2009, Gastroenterology.

[34]  S. Furner,et al.  Breastfeeding and genetic factors in the etiology of inflammatory bowel disease in children. , 2009, World journal of gastroenterology.

[35]  A. Kong,et al.  Activation of Nrf2-antioxidant signaling attenuates NFkappaB-inflammatory response and elicits apoptosis. , 2008, Biochemical pharmacology.

[36]  J. Lewis,et al.  Passive Smoking and Inflammatory Bowel Disease: A Meta-Analysis , 2008, The American Journal of Gastroenterology.

[37]  T. Murata,et al.  Anti‐inflammatory effects of phytosteryl ferulates in colitis induced by dextran sulphate sodium in mice , 2008, British journal of pharmacology.

[38]  R. Häsler,et al.  From model cell line to in vivo gene expression: disease-related intestinal gene expression in IBD , 2008, Genes and Immunity.

[39]  S. Akira,et al.  Deletion of TLR5 results in spontaneous colitis in mice. , 2007, The Journal of clinical investigation.

[40]  Stefan Schreiber,et al.  Diagnostics of inflammatory bowel disease. , 2007, Gastroenterology.

[41]  I. Chaudry,et al.  KERATINOCYTE-DERIVED CHEMOKINE PLAYS A CRITICAL ROLE IN THE INDUCTION OF SYSTEMIC INFLAMMATION AND TISSUE DAMAGE AFTER TRAUMA-HEMORRHAGE , 2007, Shock.

[42]  W. Koltun,et al.  Loss of the tight junction protein ZO-1 in dextran sulfate sodium induced colitis. , 2007, The Journal of surgical research.

[43]  W. Sandborn,et al.  Inflammatory bowel disease: clinical aspects and established and evolving therapies , 2007, The Lancet.

[44]  J. Wallace,et al.  Enhanced activity of a hydrogen sulphide‐releasing derivative of mesalamine (ATB‐429) in a mouse model of colitis , 2007, British journal of pharmacology.

[45]  Stefan Wirtz,et al.  Chemically induced mouse models of intestinal inflammation , 2007, Nature Protocols.

[46]  Dean P Jones,et al.  Prohibitin protects against oxidative stress in intestinal epithelial cells , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[47]  A. Kong,et al.  Gene expression profiles induced by cancer chemopreventive isothiocyanate sulforaphane in the liver of C57BL/6J mice and C57BL/6J/Nrf2 (-/-) mice. , 2006, Cancer letters.

[48]  J. Fahey,et al.  Moringa oleifera: A Review of the Medical Evidence for Its Nutritional, Therapeutic, and Prophylactic Properties. Part 1. , 2005 .

[49]  B. Mannervik,et al.  Selective expression of detoxifying glutathione transferases in mouse colon: effect of experimental colitis and the presence of bacteria , 2004, Histochemistry and Cell Biology.

[50]  P. Kroon,et al.  Profiling glucosinolates and phenolics in vegetative and reproductive tissues of the multi-purpose trees Moringa oleifera L. (horseradish tree) and Moringa stenopetala L. , 2003, Journal of agricultural and food chemistry.

[51]  R. Colman,et al.  Experimental models of inflammatory bowel disease. , 2003, Archivum immunologiae et therapiae experimentalis.

[52]  D. Coppola,et al.  RDP58, a locally active TNF inhibitor, is effective in the dextran sulphate mouse model of chronic colitis , 2002, Inflammation Research.

[53]  Philipp Lirk,et al.  Inducible nitric oxide synthase--time for reappraisal. , 2002, Current drug targets. Inflammation and allergy.

[54]  Judy H. Cho,et al.  Clinical Aspects and Pathophysiology of Inflammatory Bowel Disease , 2002, Clinical Microbiology Reviews.

[55]  F. Autschbach,et al.  Inflammatory bowel disease is associated with changes of enterocytic junctions. , 2001, American journal of physiology. Gastrointestinal and liver physiology.

[56]  J. Rotter,et al.  Increased intestinal permeability in patients with Crohn's disease and their relatives. A possible etiologic factor. , 1986, Annals of internal medicine.