Protection from inflammatory bowel disease and colitis-associated carcinogenesis with 4-vinyl-2,6-dimethoxyphenol (canolol) involves suppression of oxidative stress and inflammatory cytokines

BackgroundPatients with inflammatory bowel disease (IBD) have increased risk of developing colorectal cancer (CRC), depending on the duration and severity of the disease. The evolutionary process in IBD is driven by chronic inflammation leading to epithelial-to-mesenchymal transition (EMT) events in colonic fibrotic areas. EMT plays a determinant role in tumor formation and progression, through the acquisition of ‘stemness’ properties and the generation of neoplastic cells. The aim of this study is to monitor EMT/cancer initiating tracts in IBD in association with the deep characterization of inflammation in order to assess the mechanisms of IBD severity and progression towards malignancy.Methods10 pediatric and 20 adult IBD patients, admitted at Sidra Medicine (SM) and Hamad Medical Corporation (HMC) respectively, have been enrolled in this study, from whom gut tissue biopsies (from both left and right side) were collected. Retrospectively collected tissues (N=10) from patients with malignancy and history of IBD were included in the study. DNA and RNA were extracted from fresh small size (2–4 mm in diameter) gut tissues using the BioMasher II (Kimble) and All Prep DNA/RNA kits (Qiagen). MicroRNA (miRNA; N=700) and gene expression (N=800) profiling have been performed (cCounter platform; Nanostring) as well as the methylation profiling microarray (Infinium Methylation Epic Bead Chip kit, Illumina) to interrogate up to 850,000 methylation sites across the genome.ResultsDifferential miRNA profile (N=27 miRNA; p<0.05) was found by the comparison of tissues from pediatric and adult patients. These miRNAs regulate: i. oxidative stress damage (e.g., miR 99b), ii. hypoxia induced autophagy; iii. genes associated with the susceptibility to IBD (ATG16L1, NOD2, IRGM), iv. immune responses, such as TH17 T cell subset (miR 29). N=6 miRNAs (miR135b, 10a196b, 125b, let7c, 375) linked with the regulation of Wnt/b-catenin, EM-transaction, autophagy, oxidative stress and play role also in cell proliferation and mobilization and colorectal cancer development were differentially expressed (p<0.05) in tissues from left and right sides of gut. Gene expression signature, including genes associated with inflammation, stemness and fibrosis, has also been performed for the IBD tissues mentioned above. Methylation sites at single nucleotide resolution have been analyzed.ConclusionsAlthough the results warrant further investigation, differential genomic profiling suggestive of altered pathways involved in oxidative stress, EMT, and of the possible stemness signature was found. The integration of data from multiple platforms will provide insights of the overall molecular determinants in IBD patients along with the evolution of the disease.Ethics ApprovalThis study was approved by Sidra Medicine and Hamad Medical Corporation Ethics Boards; approval number 180402817 and MRC-02-18-096, respectively.

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Pathomechanisms of Oxidative Stress in Inflammatory Bowel Disease and Potential Antioxidant Therapies

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/4535194 ◽

2017 ◽

Vol 2017 ◽

pp. 1-18 ◽

Cited By ~ 96

Author(s):

Tian Tian ◽

Ziling Wang ◽

Jinhua Zhang

Keyword(s):

Oxidative Stress ◽

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Defense Mechanisms ◽

Gastrointestinal Disease ◽

Mucosal Immune Response ◽

Stress Signaling ◽

Substantial Progress ◽

Inflammatory Bowel ◽

Underlying Mechanisms

Inflammatory bowel disease (IBD) is a chronic gastrointestinal disease whose incidence has risen worldwide in recent years. Accumulating evidence shows that oxidative stress plays an essential role in the pathogenesis and progression of IBD. This review highlights the generation of reactive oxygen species (ROS) and antioxidant defense mechanisms in the gastrointestinal (GI) tract, the involvement of oxidative stress signaling in the initiation and progression of IBD and its relationships with genetic susceptibility and the mucosal immune response. In addition, potential therapeutic strategies for IBD that target oxidative stress signaling are reviewed and discussed. Though substantial progress has been made in understanding the role of oxidative stress in IBD in humans and experimental animals, the underlying mechanisms are still not well defined. Thus, further studies are needed to validate how oxidative stress signaling is involved in and contributes to the development of IBD.

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Evaluation of Effect CAT -262C/T, SOD + 35A/C, GPx1 Pro197Leu Polymorphisms in Patients with IBD in the Polish Population

Polish Journal of Surgery ◽

10.1515/pjs-2016-0071 ◽

2016 ◽

Vol 88 (6) ◽

Cited By ~ 4

Author(s):

Jerzy Mrowicki ◽

Małgorzata Mrowicka ◽

Ireneusz Majsterek ◽

Michał Mik ◽

Adam Dziki ◽

...

Keyword(s):

Oxidative Stress ◽

Ulcerative Colitis ◽

Inflammatory Bowel Disease ◽

Antioxidant Enzymes ◽

Bowel Disease ◽

Protective Effects ◽

Polish Population ◽

Nucleotide Polymorphisms ◽

Inflammatory Bowel ◽

Genotype C

AbstractInflammatory bowel disease (IBD) are a heterogeneous group of disorders in the course dominated by chronic, recurrent gastrointestinal inflammation. It is believed that the activation of IBD occurs in patients with a genetic predisposition to their development. Chronic inflammation develops as a result of an excessive reaction of the immune system principally under the influence of environmental risk factors. Among them, it has been shown that the mechanism of oxidative stress is associated with the pathophysiology of inflammatory bowel disease, responsible for the commencement and progress of these diseases.was the relationship between single nucleotide polymorphisms (SNPs) of individual antioxidant enzymes, and the prevalence of inflammatory bowel disease that may be associated with increased levels of oxidative stress.A total of 111 IBD patients, including 65 patients with ulcerative colitis (UC) and 46 with Crohn’s disease (CD) and 125 healthy controls recruited from the Polish population, were genotyped forThe performed analysis of genetic polymorphisms of antioxidant enzymes showed that polymorphic variant of the CAT -262 C / T may have protective effects in patients with ulcerative colitis in the range of genotype C / T; OR = 0.49 (0.25-0.99), p = 0.044. Trend protective, but statistically unrelated, it was also observed for genotype T / T and T allele of the same polymorphism and genotypes and allelesIt has been shown that the polymorphism of antioxidant enzymes

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Oxidative Stress and Redox-Modulating Therapeutics in Inflammatory Bowel Disease

Trends in Molecular Medicine ◽

10.1016/j.molmed.2020.06.006 ◽

2020 ◽

Vol 26 (11) ◽

pp. 1034-1046 ◽

Cited By ~ 4

Author(s):

Arno R. Bourgonje ◽

Martin Feelisch ◽

Klaas Nico Faber ◽

Andreas Pasch ◽

Gerard Dijkstra ◽

...

Keyword(s):

Oxidative Stress ◽

Inflammatory Bowel Disease ◽

Bowel Disease ◽

Inflammatory Bowel

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Increase in Epithelial Permeability and Cell Metabolism by High Mobility Group Box 1, Inflammatory Cytokines and TPEN in Caco-2 Cells as a Novel Model of Inflammatory Bowel Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21228434 ◽

2020 ◽

Vol 21 (22) ◽

pp. 8434

Author(s):

Maki Miyakawa ◽

Takumi Konno ◽

Takayuki Kohno ◽

Shin Kikuchi ◽

Hiroki Tanaka ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Growth Factor ◽

Inflammatory Cytokines ◽

Zinc Deficiency ◽

Bowel Disease ◽

Kinase Inhibitor ◽

Cell Metabolism ◽

High Mobility ◽

Epithelial Barrier ◽

Inflammatory Bowel

High mobility group box 1 protein (HMGB1) is involved in the pathogenesis of inflammatory bowel disease (IBD). Patients with IBD develop zinc deficiency. However, the detailed roles of HMGB1 and zinc deficiency in the intestinal epithelial barrier and cellular metabolism of IBD remain unknown. In the present study, Caco-2 cells in 2D culture and 2.5D Matrigel culture were pretreated with transforming growth factor-β (TGF-β) type 1 receptor kinase inhibitor EW-7197, epidermal growth factor receptor (EGFR) kinase inhibitor AG-1478 and a TNFα antibody before treatment with HMGB1 and inflammatory cytokines (TNFα and IFNγ). EW-7197, AG-1478 and the TNFα antibody prevented hyperpermeability induced by HMGB1 and inflammatory cytokines in 2.5D culture. HMGB1 affected cilia formation in 2.5D culture. EW-7197, AG-1478 and the TNFα antibody prevented the increase in cell metabolism induced by HMGB1 and inflammatory cytokines in 2D culture. Furthermore, ZnSO4 prevented the hyperpermeability induced by zinc chelator TPEN in 2.5D culture. ZnSO4 and TPEN induced cellular metabolism in 2D culture. The disruption of the epithelial barrier induced by HMGB1 and inflammatory cytokines contributed to TGF-β/EGF signaling in Caco-2 cells. The TNFα antibody and ZnSO4 as well as EW-7197 and AG-1478 may have potential for use in therapy for IBD.

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Beneficial Effect of Phosphodiesterase-5 Inhibitor in Experimental Inflammatory Bowel Disease; Molecular Evidence for Involvement of Oxidative Stress

Toxicology Mechanisms and Methods ◽

10.1080/15376510601003769 ◽

2007 ◽

Vol 17 (5) ◽

pp. 281-288 ◽

Cited By ~ 29

Author(s):

Pooneh Khoshakhlagh ◽

Mina Bahrololoumi-Shapourabadi ◽

Azadeh Mohammadirad ◽

Leila Ashtaral-Nakhai ◽

Bagher Minaie ◽

...

Keyword(s):

Oxidative Stress ◽

Inflammatory Bowel Disease ◽

Beneficial Effect ◽

Bowel Disease ◽

Molecular Evidence ◽

Phosphodiesterase 5 Inhibitor ◽

Experimental Inflammatory Bowel Disease ◽

Inflammatory Bowel ◽

Phosphodiesterase 5

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IL-35 recombinant protein reverses inflammatory bowel disease and psoriasis through regulation of inflammatory cytokines and immune cells

Journal of Cellular and Molecular Medicine ◽

10.1111/jcmm.13428 ◽

2017 ◽

Cited By ~ 11

Author(s):

Yuan Wang ◽

Ying Mao ◽

Junfeng Zhang ◽

Gang Shi ◽

Lin Cheng ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Recombinant Protein ◽

Inflammatory Cytokines ◽

Immune Cells ◽

Bowel Disease ◽

Inflammatory Bowel

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Recent Advances: The Imbalance of Cytokines in the Pathogenesis of Inflammatory Bowel Disease

Mediators of Inflammation ◽

10.1155/2017/4810258 ◽

2017 ◽

Vol 2017 ◽

pp. 1-8 ◽

Cited By ~ 42

Author(s):

Qingdong Guan ◽

Jiguo Zhang

Keyword(s):

Ulcerative Colitis ◽

Inflammatory Bowel Disease ◽

Inflammatory Cytokines ◽

Bowel Disease ◽

Intestinal Inflammation ◽

Beneficial Effects ◽

Recent Advances ◽

Inflammatory Bowel ◽

Inflammation Targeting ◽

Anti Inflammatory

Cytokines play an important role in the immunopathogenesis of inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, where they drive and regulate multiple aspects of intestinal inflammation. The imbalance between proinflammatory and anti-inflammatory cytokines that occurs in IBD results in disease progression and tissue damage and limits the resolution of inflammation. Targeting cytokines have been novel strategies in the treatment of IBD. Recent studies show the beneficial effects of anticytokine treatments to IBD patients, and multiple novel cytokines are found to be involved in the pathogenesis of IBD. In this review, we will discuss the recent advances of novel biologics in clinics and clinical trials, and novel proinflammatory and anti-inflammatory cytokines found in IBD with focusing on IL-12 family and IL-1 family members as well as their relevance to the potential therapy of IBD.

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