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.
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.
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.
Microsponge is a novel approach for targeting the drug to the colon for the management of colon ailments such as inflammatory bowel disease.
Patients with inflammatory bowel disease (IBD) have a high risk of developing colorectal neoplasia.
The corticotropin-releasing factor (CRF) family is involved in modulating gastrointestinal motility, sensitivity and inflammation. CRF signalling exerts an important role in inflammatory bowel disease (IBD), predominantly by activating CRF receptors. The aim of the present study was to investigate the function of CRF receptor 1 (CRF‑R1) in the development of mucosal inflammation induced by dextran sulphate sodium (DSS) and the underlying mechanism. Consecutive administration of CRF or CP154526 was used to activate or block the CRF‑R1 in DSS‑treated mice. Colonic inflammation was evaluated by determining the Disease Activity Index (DAI) and histology score. CRF‑R1 expression was proportional to the DAI, the histology score and the number of macrophages. Activation of CRF‑R1 aggravated mucosal inflammation by activating nuclear factor (NF)‑κB and subsequently increasing the expression levels of tumour necrosis factor (TNF)‑α and interleukin (IL)‑6. Inhibition of CRF‑R1 decreased the expression level of CRF‑R1, macrophage infiltration, NF‑κB activation, and TNF‑α and IL‑6 expression levels, ultimately alleviating the mucosal inflammation. Thus, CRF‑R1 expression was proportional to the severity of DSS‑induced colitis. Activation of CRF‑R1 increased the DAI and histological scores of the colons from DSS‑treated mice by promoting M1 macrophage polarization, demonstrated as increased NF‑κB activation, and TNF‑α and IL‑6 release. These results provide evidence of the pro‑inflammatory role of CRF‑R1 in a DSS‑induced ulcerative colitis (UC) model and a possible underlying mechanism, which may facilitate the elucidation of potential treatment approaches for UC.
Glyceollins, which are derived from daidzein in soybean in response to various stimuli or stresses, have been reported to activate antioxidant/detoxifying enzymes in a nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent manner, in addition to exerting anti-inflammatory effects in murine macrophages. As the Nrf2 signaling pathway is known to antagonize nuclear factor (NF)-κB signaling, glyceollins likely have the potential to prevent or treat inflammatory bowel disease. Thus, this study was conducted to examine whether glyceollins could inhibit dextran sulfate sodium (DSS)-induced colitis in a mouse model. Ulcerative colitis (UC) was induced in male BALB/c mice by administering drinking water with 4% DSS for 5 days. Glyceollins (4 or 10 mg/kg of body weight) were orally administered 48 h before and after DSS treatment. We found that glyceollins alleviated histological colon damage and inflammation induced by DSS treatment. More specifically, glyceollins reduced plasma levels of inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6, which were otherwise markedly increased by DSS treatment. Markers of tissue damage, including malondialdehyde and 8-hydroxy-2-guanosine, were significantly increased by DSS treatment; however, this effect was mitigated through concomitant treatment with glyceollins. Furthermore, nuclear accumulation of NF-κB p65 and the expression of inducible nitric oxide synthase were upregulated by glyceollins, consistent with the observed modulation of inflammatory markers. In conclusion, glyceollins have therapeutic potential for UC and merit further clinical study.
A 35-year-old nulliparous woman underwent uterine artery embolisation (UAE) for heavy menstrual bleeding and anaemia due to fibroids, refractive to medical and surgical treatment.Bilateral UAE was performed after cephazolin prophylaxis and analgesia. Postoperatively, pain and abdominal bloating were prominent. Symptoms were initially treated as postembolisation syndrome, and analgesia was escalated. By the third day, pain was worsening and the woman developed marked tachypnoea and tachycardia, with raised inflammatory markers and lactate. An abdominal X-ray and CT showed dilated colon. A colonoscopy demonstrated severe mucosal ulceration down to the muscular layer.A subtotal colectomy and end ileostomy formation was performed with intraoperative findings of toxic megacolon with near perforation. The cause of the toxic megacolon, in the absence of previous bowel pathology, was attributed to pseudomembranous colitis as a consequence of single dose prophylactic antibiotic.
The aim of this work was to investigate the efficient targeting and delivery of indometacin (IND), as a model anti-inflammatory drug to the colon for treatment of inflammatory bowel disease. We prepared fast disintegrating tablets (FDT) containing IND encapsulated within poly(glycerol-adipate-co-ɷ-pentadecalactone), PGA-co-PDL, microparticles and coated with Eudragit L100-55 at different ratios (1:1.5, 1:1, 1:0.5). Microparticles encapsulated with IND were prepared using an o/w single emulsion solvent evaporation technique and coated with Eudragit L-100-55 via spray drying. The produced coated microparticles (PGA-co-PDL-IND/Eudragit) were formulated into optimised FTD using a single station press. The loading, in vitro release, permeability and transport of IND from PGA-co-PDL-IND/Eudragit microparticles was studied in Caco-2 cell lines. IND was efficiently encapsulated (570.15±4.2μg/mg) within the PGA-co-PDL microparticles. In vitro release of PGA-co-PDL-IND/Eudragit microparticles (1:1.5) showed significantly (p<0.05, ANOVA/Tukey) lower release of IND 13.70±1.6 and 56.46±3.8% compared with 1:1 (89.61±2.5, 80.13±2.6%) and 1:0.5 (39.46±0.9 & 43.38±3.12) after 3 and 43h at pH 5.5 and 6.8, respectively. The permeability and transport studies indicated IND released from PGA-co-PDL-IND/Eudragit microparticles had a lower permeability coefficient of 13.95±0.68×10(-6)cm/s compared to free IND 23.06±3.56×10(-6)cm/s. These results indicate the possibility of targeting anti-inflammatory drugs to the colon using FDTs containing microparticles coated with Eudragit.