Concept: Toxic megacolon
Ulcerative colitis (UC) is a chronic relapsing-remitting form of inflammatory bowel disease (IBD) that increases the risk of colorectal cancer, the third most common malignancy in humans. Oxidative stress is a risk factor for the development of UC. The Keap1-Nrf2-ARE pathway is one of the most important defensive mechanisms against oxidative and/or electrophilic stresses. In this study, we identified CPUY192018 as a potent small-molecule inhibitor of the Keap1-Nrf2 PPI, investigated the cyto-protective effects of CPUY192018 on the NCM460 colonic cells and evaluated whether treatment with the inhibitor of the Keap1-Nrf2 PPI exerts protection on an established experimental model of UC induced by dextran sodium sulfate (DSS). Our study clearly demonstrated that CPUY192018 had a cytoprotective effect against DSS in both NCM460 cells and mouse colon via the activation of Nrf2 signaling. These results suggested that activation of Nrf2 by directly inhibiting the Keap1-Nrf2 PPI may be beneficial as a treatment for UC.
- Anti-inflammatory & anti-allergy agents in medicinal chemistry
- Published over 2 years ago
Although, a number of formulations have been developed for the treatment of IBD yet the developed formulations are having side effects such as high dose, lack of solubility and permeability problems at the site of action. Very few formulations have been developed for the IBD treatment in the form of nanoparticles. Nanoparticles have shown their potential in the recent findings in the treatment of IBD at cellular level. This research work aims to develop nanosuspension of newly introduced drug Rifaximin currently available in the form of tablet for the treatment of IBD. Rifaximin in the form of tablet is given in high dose concentration so to avoid the large dose and to increase the permeability action of drug a nanosuspension is prepared using a well known polymer Eudragit S 100 which is itself a colon targeted polymer and simultaneously improve the site specific delivery of the drug.
Varying recommendations regarding the detection and management of dysplasia can lead to uncertainty and may have impeded the uptake of strategies that could improve surveillance in patients with inflammatory bowel disease (IBD). As such, an educational event was held to assist in disseminating the recently published Surveillance for Colorectal Endoscopic Neoplasia Detection and Management in Inflammatory Bowel Disease Patients: International Consensus Recommendations (SCENIC).
Although NOD2 is the major inflammatory bowel disease susceptibility gene, its role in colorectal tumorigenesis is poorly defined. Here, we show that Nod2-deficient mice are highly susceptible to experimental colorectal tumorigenesis independent of gut microbial dysbiosis. Interestingly, the expression of inflammatory genes and the activation of inflammatory pathways, including NF-κB, ERK, and STAT3 are significantly higher in Nod2(-/-) mouse colons during colitis and colorectal tumorigenesis, but not at homeostasis. Consistent with higher inflammation, there is greater proliferation of epithelial cells in hyperplastic regions of Nod2(-/-) colons. In vitro studies demonstrate that, while NOD2 activates the NF-κB and MAPK pathways in response to MDP, it inhibits TLR-mediated activation of NF-κB and MAPK. Notably, NOD2-mediated downregulation of NF-κB and MAPK is associated with the induction of IRF4. Taken together, NOD2 plays a critical role in the suppression of inflammation and tumorigenesis in the colon via downregulation of the TLR signaling pathways.
Oxidative stress (OS) is considered as one of the etiologic factors involved in several signals and symptoms of inflammatory bowel diseases (IBD) that include diarrhea, toxic megacolon and abdominal pain. This systematic review discusses approaches, challenges and perspectives into the use of nontraditional antioxidant therapy on IBD, including natural and synthetic compounds in both human and animal models. One hundred and thirty four papers were identified, of which only four were evaluated in humans. Some of the challenges identified in this review can shed light on this fact: lack of standardization of OS biomarkers, absence of safety data and clinical trials for the chemicals and biological molecules, as well as the fact that most of the compounds were not repeatedly tested in several situations, including acute and chronic colitis. This review hopes to stimulate researchers to become more involved in this fruitful area, to warrant investigation of novel, alternative and efficacious antioxidant-based therapies.
Portulaca oleracea L. (P. oleracea) is an herb that is widely used in traditional medicine to treat various diseases. However, its effects on inflammatory diseases, such as inflammatory bowel disease (IBD), are not yet well characterized. Here, we investigated the impact of the ethyl acetate (EtOAc) and ethanol (EtOH) extracts of P. oleracea on lipopolysaccharide (LPS)-induced inflammatory responses and phosphorylation of ERK, JNK, and p38 expression in RAW264.7 macrophages. In addition, the inhibitory effects of these extracts and fractions on 3% dextran sulphate sodium (DSS)-induced ulcerative colitis were examined using an ICR mouse model. DSS-induced colitis, including body weight loss, reduced colon length, and histological colon injury, was significantly ameliorated in mice fed the P. oleracea extracts (200 and 500mg/kg). In particular, P. oleracea extracts also inhibited pro-inflammatory cytokine (TNF-α, IL-6, and 1L-1β) production in mice with DSS-induced colitis; the P. oleracea extracts displayed higher and/or similar inhibitory activity to sulfasalazine at high concentrations. Furthermore, the chemical structures of active compounds separated from the EtOAc extract of P. oleracea were elucidated using nuclear magnetic resonance (NMR) spectroscopy (see Figure in supplementary materials), resulting in the identification of three known compounds. Among these active compounds, cis-N-feruloyl-3'-methoxytyramine (2) exhibited the strongest effects on preventing DSS-induced IBD in animal models. Thus, extract of P. oleracea and their active compounds represents a new therapeutic approach for patients with inflammatory bowel diseases.
Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD) characterized by chronic inflammation of colon. It is commonly believed that the imbalance of immune system and overwhelming production of cytokines are involved in the pathogenesis of UC. Recent studies demonstrated that interleukin-35 (IL-35), a key player in the regulation of inflammation, has been identified as potential therapeutic target to treat UC. However, conventional intravenous administration is costly and inconvenient. The present study was designed to establish a novel IL-35 delivery system and investigate its therapeutic effects on dextran sulfate sodium (DSS)-induced experimental colitis in mice for the first time.
The purpose of this study was to assess outcome measures and cost-effectiveness of robotic colorectal resections in adult patients with inflammatory bowel disease. The Cochrane Library, PubMed/Medline and Embase databases were reviewed, using the text “robotic(s)” AND (“inflammatory bowel disease” OR “Crohn’s” OR “Ulcerative Colitis”). Two investigators screened abstracts for eligibility. All English language full-text articles were reviewed for specified outcomes. Data were presented in a summarised and aggregate form, since the lack of higher-level evidence studies precluded meta-analysis. Primary outcomes included mortality and postoperative complications. Secondary outcomes included readmission rate, length of stay, conversion rate, procedure time, estimated blood loss and functional outcome. The tertiary outcome was cost-effectiveness. Eight studies (3 case-matched observational studies, 4 case series and 1 case report) met the inclusion criteria. There was no reported mortality. Overall, complications occurred in 81 patients (54%) including 30 (20%) Clavien-Dindo III-IV complications. Mean length of stay was 8.6 days. Eleven cases (7.3%) were converted to open. The mean robotic operating time was 99 min out of a mean total operating time of 298.6 min. Thirty-two patients (24.7%) were readmitted. Functional outcomes were comparable among robotic, laparoscopic and open approaches. Case-matched observational studies comparing robotic to laparoscopic surgery revealed a significantly longer procedure time; however, conversion, complication, length of stay and readmission rates were similar. The case-matched observational study comparing robotic to open surgery also revealed a longer procedure time and a higher readmission rate; postoperative complication rates and length of stay were similar. No studies compared cost-effectiveness between robotic and traditional approaches. Although robotic resections for inflammatory bowel disease are technically feasible, outcomes must be interpreted with caution due to low-quality studies.
Gastrointestinal (GI) motility problems are common complications in critical care patients. GI problems contribute to an increased risk of morbidity and mortality. Toxic megacolon ™ is a type of acquired megacolon categorized as a medical emergency and includes severe inflammation affecting all layers of the colon wall. The high incidence of GI complications in critically ill patients requires the critical care nurse to provide close monitoring of patients at risk and an acute awareness of the causation, signs and symptoms, and treatment of various GI motility disorders, including gastroparesis, ileus, and TM.
The association between thiopurines and colorectal neoplasia risk remains controversial in inflammatory bowel disease (IBD) patients. We performed a systematic review and meta-analysis examining this association.