Oxidative Stress In Inflammatory Bowel Disease Research Articles

The NRF2/Keap1 pathway as a therapeutic target in inflammatory bowel disease.

Oxidative stress (OS) is an important pathophysiological mechanism in inflammatory bowel disease (IBD). However, clinical trials investigating compounds directly targeting OS in IBD yielded mixed results. The NRF2 (nuclear factor erythroid 2-related factor 2)/Keap1 (Kelch-like ECH-associated protein 1) pathway orchestrates cellular responses to OS, and dysregulation of this pathway has been implicated in IBD. Activation of the NRF2/Keap1 pathway may enhance antioxidant responses. Although this approach could help to attenuate OS and potentially improve clinical outcomes, an overview of human evidence for modulating the NRF2/Keap1 axis and more recent developments in IBD is lacking. This review explores the NRF2/Keap1 pathway as potential therapeutic target in IBD and presents compounds activating this pathway for future clinical applications.

Development of melatonin loaded pectin nanoparticles for the treatment of inflammatory bowel disease: In vitro and in vivo studies

Inflammatory bowel disease (IBD) is a general term including long-term inflammatory disorders of all or some parts of the digestive system. Nanoparticles (NPs) can accumulate in the inflamed zone independently of the polymers’ mucoadhesive character.The aim of this study was to prepare and investigate the melatonin loaded pectin-based nanoparticles for Inflammatory Bowel Disease (IBD). Melatonin (MEL) was loaded into nanoparticle system with a modified ionotropic-gelation method. In vitro characterization studies of the nanoparticles were carried out.The effectiveness of the oral and intracolonically administered nanoparticles were investigated in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis rats. The indicators of oxidative stress and inflammation in the colonic tissue like nitric oxide, malondialdehyde, glutathione, tumor necrosis factor-alpha, Interleukin (IL)-10, and IL-17 levels were investigated. In addition, the histological evaluation was performed.The mean diameter, zeta potential and polydispersity index values of the obtained nanoparticles were 75.3 ± 3.3 nm, 24.24 ± 1.03 mV and 0.109 ± 0.067, respectively. The in vitro drug release studies showed that 84.0 ± 0.7% of the drug was released from the nanoparticles for 8 h. MEL-loaded pectin nanoparticles ameliorated the TNBS-induced colitis. Treatment of the melatonin decreased the damage score by 73.2% in oral and by 67.1% in intracolonic route, respectively. A meaningful decrease was observed in colonic fibrosis, oxidative stress, and inflammatory parameters of the colon accompanying histologic injury. The results of the experiments and histological data showed that MEL-loaded calcium pectinate nanoparticle may be a promising alternative in colonic tissue damage which develops due to oxidative stress in IBD.

EFFECT OF DSS ADMINISTRATION AND SULFASALAZINE TREATMENT ON BODY WEIGHT AND OXIDATIVE STRESS IN EXPERIMENTAL ULCERATIVE COLITIS IN MICE

Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD), characterized by chronic inflammation of the gastrointestinal tract. In general, IBD is more common in Western than in Eastern places, and in industrialized than in developing countries. However, the incidence of IBD has been rising recently in Eastern countries including Egypt. Symptoms of IBD include loss of appetite, tenesmus, abdominal cramps, diarrhea, and bloody stools. Available treatment options of IBD include drugs, surgery, or a combination of both. One of the most commonly used drugs for IBD management is an aminosalicylate called sulfasalazine. Several factors and symptoms of UC finally contribute to weight loss; thus, most of UC patients suffer from significant weight loss. The pathophysiology of IBD is complicated and involves several factors including immune, genetic, and environmental factors. Recently, a huge amount of research has concentrated on the role of oxidative stress in IBD, and several studies have proven that IBD patients suffer from excessive amounts of reactive oxygen species, while they have lower than normal amounts of antioxidant defenses. This leads to elevated amounts of oxidative stress-end products like malondialdehyde (MDA). In this study, we investigated body weight loss, histopathological alterations, and MDA levels in a mouse model of dextran sulfate sodium- induced UC, and the therapeutic effect of sulfasalazine. Our results showed that induction of colitis causes significant body weight loss and induces oxidative stress, and that treatment with sulfasalazine could restore normal mice body weights and combat the colitis-induced oxidative stress.

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

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.

Inflammatory Bowel Disease: Mechanisms, Redox Considerations, and Therapeutic Targets

Oxidative stress is thought to play a key role in the development of intestinal damage in inflammatory bowel disease (IBD), because of its primary involvement in intestinal cells' aberrant immune and inflammatory responses to dietary antigens and to the commensal bacteria. During the active disease phase, activated leukocytes generate not only a wide spectrum of pro-inflammatory cytokines, but also excess oxidative reactions, which markedly alter the redox equilibrium within the gut mucosa, and maintain inflammation by inducing redox-sensitive signaling pathways and transcription factors. Moreover, several inflammatory molecules generate further oxidation products, leading to a self-sustaining and auto-amplifying vicious circle, which eventually impairs the gut barrier. The current treatment of IBD consists of long-term conventional anti-inflammatory therapy and often leads to drug refractoriness or intolerance, limiting patients' quality of life. Immune modulators or anti-tumor necrosis factor α antibodies have recently been used, but all carry the risk of significant side effects and a poor treatment response. Recent developments in molecular medicine point to the possibility of treating the oxidative stress associated with IBD, by designing a proper supplementation of specific lipids to induce local production of anti-inflammatory derivatives, as well as by developing biological therapies that target selective molecules (i.e., nuclear factor-κB, NADPH oxidase, prohibitins, or inflammasomes) involved in redox signaling. The clinical significance of oxidative stress in IBD is now becoming clear, and may soon lead to important new therapeutic options to lessen intestinal damage in this disease.

Molecular fingerprints of neutrophil-dependent oxidative stress in inflammatory bowel disease

Neutrophil accumulation within epithelial crypts and in the intestinal mucosa directly correlates with clinical disease activity and epithelial injury in inflammatory bowel disease (IBD). Current advances have defined the mechanisms by which neutrophils are activated or migrate across endothelial and mucosal epithelial cells. A better understanding of this process will likely provide new insights into novel treatment strategies for IBD. Especially, activated neutrophils produce reactive oxygen and nitrogen species and myeloperoxidase within intestinal mucosa, which induce oxidative stress. Posttranslational modification of proteins generated by these reactive species serves as a "molecular fingerprint" of protein modification by lipid peroxidation-, nitric oxide-, and myeloperoxidase-derived oxidants. Measurement of these modified proteins may serve both as a quantitative index of oxidative stress and an important new biological marker of clinical relevance to IBD. We have succeeded in the clinical development of a novel granulocyte adsorptive apheresis therapy for IBD. In this review, we discuss current advances in defining the role of neutrophil-dependent oxidative stress in IBD.

Oxidative Stress and Pathogenesis of Inflammatory Bowel Disease: An Epiphenomenon or the Cause?

Crohn's disease (CD) and ulcerative colitis (UC), known as inflammatory bowel disease (IBD), are fairly common chronic inflammatory conditions of the gastrointestinal tract. Although the exact etiology of IBD remains uncertain, dysfunctional immunoregulation of the gut is believed to be the main culprit. Amongst the immunoregulatory factors, reactive oxygen species are produced in abnormally high levels in IBD. Their destructive effects may contribute to the initiation and/or propagation of the disease. We provided an extensive overview on the evidences from animal and human literature linking oxidative stress to IBD and its activity. Moreover, the effects of antioxidant therapy on IBD patients in randomized, controlled trials were reviewed and the need for further studies elaborated. We also summarized the evidence in support for causality of oxidative stress in IBD.