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Oxidative stress in ulcerative colitis: An old concept but a new concern
Abstract and Figures
Abstract Ulcerative colitis is an idiopathic, chronic and relapsing inflammatory bowel disease, which elicits the risk of colorectal cancer, the third most common malignancy in humans. It has been known for a long time that oxidative stress is a major pathogenic factor in the inflamed tissue that can pave the way towards DNA damage and carcinogenesis. However, the DNA damage produced due to oxidative stress in the inflamed tissue is not limited to the local site but extends globally, thereby augmenting the risk of global carcinogenesis. Targeting oxidative stress may provide an exciting avenue to combat inflammation-associated local as well as global DNA damage and the subsequent carcinogenesis. The present review portrays the role of oxidative stress in the pathogenesis of ulcerative colitis and the associated local as well as global DNA damage, which may lead to carcinogenesis.
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... UC is a recurrent, inflammatory disease of the rectum and colon. The precise etiology remains unknown; however, excessive oxidative stress within the colon is believed to be one of the most notable factors involved with the development of UC (Jena et al. 2012;Du et al. 2023). Although drugs currently available for use in the treatment of UC, such as 5-aminosalicylic acids, steroids, immunomodulators, and biologic agents, show some efficacy, they are also associated with substantial adverse side effects. ...
Ulcerative colitis (UC) is a chronic idiopathic inflammatory bowel disease with a relapsing–remitting course. Although its etiology remains unknown, excessive oxidative stress in colon is a major intermediate factor that can promote the progression of UC. In the present study, we investigated the effect and the underlying mechanisms of 4-Octyl itaconate (OI) on dextran sulfate sodium (DSS)-induced UC in mice. Our work identified that OI alleviated the colitis by reducing the oxidative stress and the apoptosis in colon tissue, then increasing the tight junction proteins expression and in turn enhancing the intestinal barrier function, thereby creating less severe inflammatory responses. Moreover, our results demonstrated that OI reduced the Kelch-like ECH-associated protein 1 (KEAP1) expression and subsequent upregulated nuclear factor E2-related factor (NRF2) expression and its nuclear translocation which in turn induced the expression of glutathione S-transferase (GST) and NAD(P)H: quinone oxidoreductase 1 (NQO1). In addition, ML385, a NRF2 antagonist, can inhibit the protective effects of OI on UC, indicating that the role of OI in this colitis model could be dependent on the activation of KEAP1-NRF2 pathway. Notably, OI co-administration significantly enhanced the therapeutic effects of mesalazine or 1400W on UC. Collectively, itaconate may have a great potential for use in the treatment of IBD.
... It is known that patients with UC have a higher risk of developing colorectal cancer. DNA damage induced by the oxidative stress involved in UC has been thought to be one of the major causes of carcinogenesis, because chronic inflammation generates oxidative stress-induced damage to DNA resulting in the activation of tumor-promoting genes and/or inactivation of tumor suppressor genes [33][34][35]. We are investigating the ORAIP-mediated apoptotic signaling pathway, including cell-surface receptors for ORAIP (that is, ORAIP-receptor; unpublished data) and downstream signaling cascades such as the Jak/STAT pathway, MEK/ERK pathway, and so on. ...
Oxidative stress is implicated in the pathogenesis of various acute disorders including ischemia/reperfusion injury, ultraviolet/radiation burn, as well as chronic disorders such as dyslipidemia, atherosclerosis, diabetes mellitus, chronic renal disease, and inflammatory bowel disease (IBD). However, the precise mechanism involved remains to be clarified. We formerly identified a novel apoptosis-inducing humoral protein, in a hypoxia/reoxygenation-conditioned medium of cardiac myocytes, which proved to be 69th tyrosine-sulfated eukaryotic translation initiation factor 5A (eIF5A). We named this novel tyrosine-sulfated secreted form of eIF5A Oxidative Stress-Responsive Apoptosis-Inducing Protein (ORAIP). To investigate the role of ORAIP in a dextran sulfate sodium (DSS)-induced murine model of ulcerative colitis (UC), we analyzed the effects of in vivo treatment with anti-ORAIP neutralizing monoclonal antibody (mAb) on the DSS-induced disease exacerbation. The body weight in anti-ORAIP mAb-treated group was significantly heavier than that in a mouse IgG-treated control group on day 8 of DSS-treatment ((85.21 ± 1.03%) vs. (77.38 ± 2.07%); (mean ± SE0, n = 5 each, p < 0.01, t-test). In vivo anti-ORAIP mAb-treatment also significantly suppressed the shortening of colon length as well as Disease Activity Index (DAI) score ((5.00 ± 0.44) vs. (8.20 ± 0.37); (mean ± SE), n = 5 each, p < 0.001, t-test) by suppressing inflammation of the rectal tissue and apoptosis of intestinal mucosal cells. These data reveal the pivotal role of ORAIP in DSS-induced oxidative stress involved in an animal model of UC.
... In contrast, antioxidant enzymes such as superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione reductase, and low-molecular-weight antioxidant molecules such as reduced glutathione (GSH) are present in the epithelium of the colon [8]. These antioxidant/reductant systems of the colonic mucosa are essential for the maintenance of intracellular reducing status and the protection of cells from oxidative stress and exposure to electrophiles such as drugs and phytochemicals [9,10]. ...
We recently reported that transient receptor potential canonical (TRPC) 6 channel activity contributes to intracellular Zn2+ homeostasis in the heart. Zn2+ has also been implicated in the regulation of intestinal redox and microbial homeostasis. This study aims to investigate the role of TRPC6-mediated Zn2+ influx in the stress resistance of the intestine. The expression profile of TRPC1-C7 mRNAs in the actively inflamed mucosa from inflammatory bowel disease (IBD) patients was analyzed using the GEO database. Systemic TRPC3 knockout (KO) and TRPC6 KO mice were treated with dextran sulfate sodium (DSS) to induce colitis. The Zn2+ concentration and the mRNA expression levels of oxidative/inflammatory markers in colon tissues were quantitatively analyzed, and gut microbiota profiles were compared. TRPC6 mRNA expression level was increased in IBD patients and DSS-treated mouse colon tissues. DSS-treated TRPC6 KO mice, but not TRPC3 KO mice, showed severe weight loss and increased disease activity index compared with DSS-treated WT mice. The mRNA abundances of antioxidant proteins were basically increased in the TRPC6 KO colon, with changes in gut microbiota profiles. Treatment with TRPC6 activator prevented the DSS-induced colitis progression accompanied by increasing Zn2+ concentration. We suggest that TRPC6-mediated Zn2+ influx activity plays a key role in stress resistance against IBD, providing a new strategy for treating colitis.
The incidence of ulcerative colitis (UC) is increasing worldwide and therapeutic drugs for UC are limited. Improvement of microbiome composition with the use of probiotics has the potential to increase the therapeutic index of UC drugs. Several lines of evidence suggested that Bifidobacterium significantly improve colitis by restoring the altered gut microbiota in DSS-treated mice, however the adjuvant effect of Bifidobacterium with UC drugs remains unknown. In this study, we tested the adjuvant potential of probiotic selenium-enriched Bifidobacterium Longum DD98 (SeDD98) on Mesalazine and Cyclosporin A (CsA) two medications used in the treatment of UC. We found that SeDD98 significantly improved the efficacy of Mesalazine and CsA in UC. The combination of SeDD98 and CsA showed the strongest efficacy in decreasing colitis histological scores, inflammation, and oxidative stress. Next we demonstrated that the combination of SeDD98 and CsA shifted the gut microbiota composition and increased with higher alpha diversity as well as beneficial bacteria such as Ruminococcaceae_UCG-014 and Lachnospiraceae_NK4A136. In parallel, we assessed if the adjuvant of SeDD98 with CsA had an impact on CsA-induced kidney injury which represents one of the major side effects. We found that SeDD98 significantly improved CsA nephrotoxicity in UC mice. We then validated this observation using chronic kidney disease (CKD) mice induced by CsA administration. These results demonstrated that SeDD98 in combination with CsA was associated with increased efficacy and reduced nephrotoxicity altogether, providing the scientific basis for the adjuvant therapy of probiotics in UC.
Background
There is limited evidence on the associations of dietary factors and patterns with risk of later‐onset ulcerative colitis (UC) in Chinese adults.
Aims
To investigate the associations of dietary factors and patterns with risk of later‐onset UC in Chinese.
Methods
The prospective China Kadoorie Biobank cohort study recruited 512,726 participants aged 30–79. Dietary habits were assessed using food frequency questionnaires. Dietary patterns were derived by factor analysis with a principal component method. Cox regression analysis was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).
Results
During a median follow‐up of 12.1 years, 312 cases of newly diagnosed UC were documented (median age of diagnosis 60.1 years). Egg consumption was associated with higher risk of UC (HR for daily vs. never or rarely: 2.29 [95% CI: 1.26–4.16]), while spicy food consumption was inversely associated with risk of UC (HR: 0.63 [0.45–0.88]). The traditional northern dietary pattern, characterised by high intake of wheat and low intake of rice, was associated with higher risk of UC (HR for highest vs. lowest quartile of score: 2.79 [1.93–4.05]). The modern dietary pattern, characterised by high intake of animal‐origin foods and fruits, was associated with higher risk of UC (HR: 2.48 [1.63–3.78]). Population attributable fraction was 13.04% (7.71%–19.11%) for daily/almost daily consumption of eggs and 9.87% (1.94%–18.22%) for never/rarely consumption of spicy food.
Conclusions
The findings highlight the importance of evaluating dietary factors and patterns in the primary prevention of later‐onset UC in Chinese adults.
Ulcerative colitis is an inflammatory bowel disease characterized by inflammation and increased oxidative stress in the colon tissue. Sodium phenylbutyrate (PBA) and suramin are histone deacetylase inhibitors that alter gene expression keeping histones in the acetylated form. Our aim in this study was to determine the effects of PBA and suramin on colon tissue in an acute colitis model in mice and to clarify the mechanisms of their action. Ulcerative colitis was induced by 3% dextran sulfate sodium (DSS). After PBA and suramin injection, disease activity index (DAI) and colitis scoring were used to verify colitis damage. Alterations in proliferation, antioxidant enzyme activities and oxidative stress were shown by Ki-67 immunohistochemistry and spectrophotometry respectively. Active caspase-3 and COX-2 as well as cytokine levels and H3K9me3 histone modification were designated by Western blotting. The gene expression of STAT1, STAT3 and SIRT were analyzed by real-time PCR. DSS treatment increased DAI, MDA, MPO, TNF-α, IL-1β, IL-6, caspase-3 and COX-2 levels, and decreased Ki-67, IL-10, GSH levels and antioxidant enzyme activities in the colon tissue. Injection of PBA or suramin into DSS-treated animals significantly prevented colitis damage by improving the manifestations. Also, both of them induced significant changes in STAT and SIRT gene expressions and histone modifications compared to the DSS colitis group. Our study demonstrated that PBA and suramin have anti-apoptotic, anti-inflammatory, antioxidant and protective effects in DSS-induced ulcerative colitis. Considering these results, PBA and suramin can be potential agents to be used therapeutically in inflammatory bowel diseases.
Background and aims:
Controversy surrounds the risk of colorectal cancer (CRC) in ulcerative colitis (UC). Many studies have investigated this risk and reported widely varying rates.
Methods:
A literature search using Medline with the explosion of references identified 194 studies. Of these, 116 met our inclusion criteria from which the number of patients and cancers detected could be extracted. Overall pooled estimates, with 95% confidence intervals (CI), of cancer prevalence and incidence were obtained using a random effects model on either the log odds or log incidence scale, as appropriate.
Results:
The overall prevalence of CRC in any UC patient, based on 116 studies, was estimated to be 3.7% (95% CI 3.2-4.2%). Of the 116 studies, 41 reported colitis duration. From these the overall incidence rate was 3/1000 person years duration (pyd), (95% CI 2/1000 to 4/1000). The overall incidence rate for any child was 6/1000 pyd (95% CI 3/1000 to 13/1000). Of the 41 studies, 19 reported results stratified into 10 year intervals of disease duration. For the first 10 years the incidence rate was 2/1000 pyd (95% CI 1/1000 to 2/1000), for the second decade the incidence rate was estimated to be 7/1000 pyd (95% CI 4/1000 to 12/1000), and in the third decade the incidence rate was 12/1000 pyd (95% CI 7/1000 to 19/1000). These incidence rates corresponded to cumulative probabilities of 2% by 10 years, 8% by 20 years, and 18% by 30 years. The worldwide cancer incidence rates varied geographically, being 5/1000 pyd in the USA, 4/1000 pyd in the UK, and 2/1000 pyd in Scandinavia and other countries. Over time the cancer risk has increased since 1955 but this finding was not significant (p=0.8).
Conclusions:
Using new meta-analysis techniques we determined the risk of CRC in UC by decade of disease and defined the risk in pancolitics and children. We found a non-significant increase in risk over time and estimated how risk varies with geography.
Transcription factors of the nuclear factor kappaB (NF-kappaB) family play an important role in the regulation of genes involved in inflammation. In inflammatory bowel diseases, proinflammatory cytokines known to be regulated by NF-kappaB are involved. The aim of this study was to investigate the role of NF-kappaB activation during mucosal inflammation in situ.
A monoclonal antibody, alpha-p65mAb, was applied for immunofluorescence and immunohistochemical analysis that recognizes activated NF-kappaB. Electrophoretic mobility shift assay was used to directly demonstrate the presence of active DNA-binding NF-kappaB.
Using the alpha-p65mAb antibody, activated NF-kappaB could be found in biopsy specimens from inflamed mucosa but was almost absent in uninflamed mucosa. The number of cells showing NF-kappaB activation correlated with the degree of mucosal inflammation but was not significantly different between inflamed mucosa from patients with Crohn's disease, ulcerative colitis, and nonspecific colitis or diverticulitis. NF-kappaB activation was localized in macrophages and in epithelial cells as identified by double-labeling techniques. Electrophoretic mobility shift assay with isolated lamina propria mononuclear cells and epithelial cells confirmed these results.
This study shows for the first time the activation of NF-kappaB during human mucosal inflammation in situ. In addition to macrophages, epithelial cells contained activated NF-kappaB, indicating an involvement in the inflammatory process.
Gene expression is modulated by both physiological signals (hormones, cytokines, etc.) and environmental stimuli (physical parameters, xenobiotics, etc.). Oxidative stress appears to be a key pleiotropic modulator which may be involved in either pathway. Indeed, reactive oxygen species (ROS) have been described as second messengers for several growth factors and cytokines, but have also been shown to rise following cellular insults such as xenobiotic metabolism or enzymic deficiency. Extensive studies on the induction of stress-response genes by oxidative stress have been reported. In contrast, owing to the historical focus on gene induction, less attention has been paid to gene repression by ROS. However, a growing number of studies have shown that moderate (i.e. non-cytotoxic) oxidative stress specifically down-regulates the expression of various genes. In this review, we describe the alteration of several physiological functions resulting from oxidative-stress-mediated inhibition of gene transcription. We will then focus on the repressive oxidative modulation of various transcription factors elicited by ROS.
The inflammatory bowel diseases (IBD; Crohn’s disease, ulcerative colitis) are a collection of chronic idiopathic inflammatory disorders of the intestine and/or colon. Although the pathophysiology of IBD is not known with certainty, a growing body of experimental and clinical data suggests that chronic gut inflammation may result from a dysregulated immune response to normal bacterial antigens. This uncontrolled immune system activation results in the sustained overproduction of reactive metabolites of oxygen and nitrogen. It is thought that some of the intestinal and/or colonic injury and dysfunction observed in IBD is due to elaboration of these reactive species. This review summarizes the current state-of-knowledge of the role of reactive oxygen species and nitric oxide in the pathophysiology of IBD.
Few studies have been conducted focusing on a potential role of reactive oxygen species in tumor cell metabolism. Here we studied human colorectal adenocarcinomas and adenomas to determine whether oxidative stress is imposed on cancer cells in vivo and used specific antibodies against 8-hydroxy-2-deoxyguanosine (8-OHdG), 4-hydroxy-2-nonenal (HNE)-modified proteins, and 3-nitro-L-tyrosine (3-NT) to determine whether there is an association between oxidative stress and cellular proliferation. Higher levels of oxidative modifications in DNA and proteins were observed in carcinoma cells, but not in adenoma cells, than in the corresponding nontumorous epithelial cells by immunohistochemistry as well as high-performance liquid chromatography (HPLC)-based 8-OHdG determination. The fraction of proliferating cell nuclear antigen-positive cells was proportionally associated in adenocarcinomas with the staining intensities of 8-OHdG and 3-NT. Furthermore, Western blot analysis of the proteins extracted from carcinoma cells revealed several specific proteins modified by HNE or peroxynitrite. Thus we concluded that colorectal carcinoma, but not adenoma cells, are exposed to more oxidative stress than their corresponding nontumorous epithelial cells, regardless of clinical stage and histology, and further that the oxidative stress in carcinoma cells might stimulate cellular proliferation.
Chronic intestinal inflammation induced by 2,4,6,-trinitrobenzene sulfonic acid (TNBS) is characterized by a transmural granulomatous colitis that mimics some characteristics of human Crohn's disease. Here, we show that the transcription factor NF-kappa B p65 was strongly activated in TNBS-induced colitis and in colitis of interleukin-10-deficient mice. Local administration of p65 antisense phosphorothioate oligonucleotides abrogated clinical and histological signs of colitis and was more effective in treating TNBS-induced colitis than single or daily administration of glucocorticoids. The data provide direct evidence for the central importance of p65 in chronic intestinal inflammation and suggest a potential therapeutic utility of p65 antisense oligonucleotides as a novel molecular approach for the treatment of patients with Crohn's disease.
In addition to their damaging effects, reactive oxygen intermediates exert a regulatory role on gene expression and cell apoptosis. In this study, we evaluated the effects of oxidative stress on human dendritic cells (DC), a cell type which is critical for the initiation of the immune response. For this purpose, we tested the effects of H2O2 on DC derived from adherent peripheral blood mononuclear cells cultured in the presence of granulocyte-macrophage colony-stimulating factor and IL-4. Despite a moderate increase of DC apoptosis in the presence of H2O2, we observed that H2O2 stimulated the production of IL-8 and TFN-α by DC in a dose-dependent manner. The induction of cytokine synthesis was found to depend on the oxidative properties of H2O2 as it was inhibited by the addition of catalase, and to require de novo protein synthesis as it was not observed in the presence of cycloheximide. These data suggest that DC could contribute to innate immunity through an enhanced production of inflammatory cytokines in response to oxidative stress.
: There is a growing body of experimental and clinical evidence to suggest that reactive oxygen metabolites (eg, superoxide, hydrogen peroxide, hydroxyl radical, and halogenated oxidants) may play an important role in the pathogenesis of inflammatory bowel disease (eg, Crohn's disease and ulcerative colitis). Recent studies have demonstrated enhanced production of reactive oxygen species in the chronically inflamed colon. The most likely sources of these oxidants are the phagocytic leukocytes (eg, neutrophils, monocytes, and macrophages), which are known to accumulate within the colonic interstitium during times of active inflammation. Many of these leukocyte-derived oxidants have been shown to mediate cytotoxicity, degrade the extracellular matrix, enhance electrolyte (and water) secretion, alter smooth muscle function, and promote mutagenesis. In addition, the anti-inflammatory effects of 5-aminosalicylic acid, a drug with potent antioxidant activity suggests that oxidants and free radicals may be important mediators of the pathophysiology observed in inflammatory bowel disease. Although there is a large volume of circumstantial evidence that implicates oxy radicals in chronic gut inflammation, there is a relative paucity of published reports that have attempted to directly assess the role of free radicals in models of chronic gut inflammation in vivo. This scarcity of information appears to be due to the lack of long-lived antioxidants with well-characterized mechanisms of action and specific inhibitors of phagocyte-associated reactive oxygen generators. The development of new generation, long-lived antioxidants and specific inhibitors should prove useful in defining a role for reactive oxygen metabolites in inflammatory bowel disease.
Current Opinion in Gastroenterology 1993, 9:971-980
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