The Size Differences of Breast Cancer and Benign Tumors Measured by Two-Dimensional Ultrasound and Contrast-Enhanced Ultrasound.

OBJECTIVES: Ultrasound (US) imaging has been observed to underestimate tumor size in clinical practice. This study aims to compare the size measurements of breast cancer and benign tumors using two-dimensional ultrasound (2DUS) and contrast-enhanced ultrasound (CEUS). METHODS: The study included 42 clinically confirmed breast cancer and 47 benign breast tumors. Two experienced physicians independently measured the maximal longitudinal and transverse diameters of the masses in 2DUS and CEUS. All analyses were performed in R (4.2.2) and GraphPad Prism 6. RESULTS: The maximal longitudinal and transverse diameters of breast cancer measured by CEUS were 26.61 ± 0.21% and 26.24 ± 0.19% larger compared with 2DUS, and benign breast tumors had an 11.74 ± 0.21% and 11.06 ± 0.14% increase in size compared with 2DUS. The area under the curve (AUC) of the receiver operating characteristic curve (ROC) for the difference between 2DUS and CEUS was 0.870 for longitudinal diameters (95% CI: 0.795-0.945, sensitivity 0.842, specificity 0.783, threshold value 0.215), and 0.863 for transverse diameters (95% CI: 0.785-0.942, sensitivity 0.667, specificity 0.936, threshold value 0.203). CONCLUSIONS: The size measurements of both breast cancer and benign tumors were larger in CEUS compared with 2DUS, with CEUS measurements of breast cancer being more pronounced than those of benign breast tumors. These findings suggest that CEUS may provide a more precise assessment of tumor size, which is crucial for determining optimal treatment strategies and improving patient outcomes in breast cancer management.

A case of achalasia associated with early esophageal cancer.

A 65-year-old man was admitted to our hospital complaining of reflux for more than 20 years. After endoscopy and barium-swallow examination, he was diagnosed with achalasia as well as a squamous cell carcinoma. Therefore, peroral endoscopic myotomy (POEM) combined with endoscopic submucosal dissection (ESD) was performed simultaneously. During the procedure, a mucosal erosion with a clear boundary was shown in the middle segment of the esophagus. ESD was first performed and the lesion was removed en-bloc. Subsequent POEM therapy was performed after marking the left esophageal wall 10cm above the cardia. After submucosal injection, the submucosal plane was created through a length 2cm longitudinal incision, then the muscle was cut a length of 10 cm into the esophagus and 2 cm below the cardia, and finally the incision was closed by clips. Pathological examination revealed high-grade intraepithelial neoplasia of squamous epithelium (carcinoma in situ) with a negative margin. The patient was recovered without complication four days after the procedure. The endoscopy showed perfect healing of the esophageal lesions during two-months follow-up , and the reflux symptom was resolved.

Efficacy and safety of vedolizumab in the treatment of patients with inflammatory bowel disease: A systematic review and meta­analysis of randomized controlled trials.

Few studies have thoroughly assessed the efficacy and safety of vedolizumab (VDZ) in the treatment of inflammatory bowel disease (IBD). Therefore, this systematic review and meta-analysis was performed to further evaluate this association. PubMed, Embase, and the Cochrane databases were searched until April 2022. Randomized controlled trials (RCTs) evaluating the efficacy and safety of VDZ in the treatment of IBD were included. The risk ratio (RR) and 95% confidence intervals (CI) were estimated for each outcome using a random effects model. A total of 12 RCTs, including 4,865 patients, met the inclusion criteria. In the induction phase, VDZ was more effective than placebo for patients with ulcerative colitis and Crohn's disease (CD) in clinical remission (RR=2.09; 95% CI=1.66-2.62) and clinical response (RR=1.54; 95% CI=1.34-1.78). In the maintenance therapy group, VDZ reached higher clinical remission (RR=1.98; 95% CI=1.58-2.49) and clinical response (RR=1.78; 95% CI=1.40-2.26) rates compared with the placebo group. VDZ particularly improved clinical remission (RR=2.07; 95% CI=1.48-2.89) and clinical response (RR=1.84; 95% CI=1.54-2.21) in patients with TNF antagonist failure. In terms of corticosteroid-free remission, VDZ was also more effective than placebo in patients with IBD (RR=1.98; 95% CI=1.51-2.59). In Crohn's patients, VDZ was more effective than placebo in terms of mucosal healing (RR=1.78; 95% CI=1.27-2.51). With respect to adverse events, VDZ significantly reduced the risk of IBD exacerbation compared with the placebo (RR=0.60; 95% CI=0.39-0.93; P=0.023). However, when compared with the placebo, VDZ increased the risk of nasopharyngitis in patients with CD (RR=1.77; 95% CI=1.01-3.10; P=0.045). No significant differences in other adverse events were observed. Although there might be underlying risk, such as selection bias, in the present study it can be safely concluded that VDZ is a safe and effective biological agent for IBD, particularly for patients with TNF antagonist failure.

Nursing Cooperation Pattern for Patients With Advanced Pancreatic Cancer and Abdominal Pain Undergoing Endoscopic Ultrasound-guided Celiac Plexus Neurolysis.

Context: Patients with pancreatic cancer (PC) at a late stage often suffer from severe abdominal pain due to the invasion of celiac plexus, and the analgesics they receive often have intolerable side effects. Endoscopic, ultrasound-guided, celiac plexus neurolysis (EUS-guided CPN) can have a good therapeutic effect. Objective: The study intended to evaluate the ability of two nursing cooperation patterns to reduce patients' pain, decrease operation times, increase operational efficiency, and increase nurses' satisfaction, for patients with advanced PC and abdominal pain who received EUS-guided CPN. Design: The research team designed a retrospective controlled study. Setting: The study took place at the Shenzhen People's Hospital of the Second Clinical Medical College of Jinan University in Shenzhen, China, and at the Changhai Hospital of the Second Military Medical University in Shanghai, China. Participants: Participants were 40 patients with advanced PC who received EUS-guided CPN at one of the two hospitals between January 2019 and January 2020. Intervention: Twenty participants at Changhai Hospital received the traditional nursing cooperation pattern and became the control group, and 20 participants at the Shenzhen People's Hospital received the new nursing cooperation pattern and became the intervention group. Outcome Measures: The study measured clinical data, nursing measures, diagnostic significance, and key points for the two patterns as well as compared the effects of the new nursing cooperation method to that of traditional nursing. If the measurement data met the requirements for normality, the team used the two independent sample t-test for the intergroup comparisons. If normality wasn't satisfied, the team used medians and interquartile ranges (IQRs) for expression and the rank sum test for the intergroup comparisons. Counting data were expressed using the constituent ratio, and team used the chi-square test for comparisons between groups. P < .05 was considered to be statistically significant. Results: The operations were successful, and no complications occurred. No significant difference existed in the pain scores between the control group and the intervention group (P > .05), while a significant difference occurred in the nurses' operation times and satisfaction. Not only were the scores for operation times for the control group (97) and the intervention group (59) significantly different, but also the nurses' satisfaction was significantly higher for the intervention group postintervention, at 83.35 ± 5.25, than for the control group, at 62.25 ± 8.18 (P < .001). Such a new nursing cooperation method could assist in patient's rehabilitation and increase nurses' satisfaction. Conclusions: The new nursing cooperation method for patients with advanced PC and abdominal pain undergoing EUS-guided CPN can reduce operation time and improve nurses' satisfaction.

Preparation of small bowel capsule endoscopy (SBCE) with simethicone: A meta-analysis.

BACKGROUND: It is disputed about optimal bowel preparation for small bowel capsule endoscopy (SBCE). This meta-analysis aimed to investigate the role of simethicone in intestinal preparation for SBCE. METHODS: We searched four databases (PubMed, web of science, Embase, and Scopus databases) for relevant studies. Studies evaluating the effect of simethicone as an adjunct to SBCE bowel preparation were included. The random-effects model was applied to calculate the risk estimates. Primary outcomes include the degree of gas bubbles and small bowel visualization quality (SBVQ). Secondary outcomes include diagnostic yield (DY), gastric transit time (GTT), small bowel transit time (SBTT), and completion rate (CR). RESULTS: A total of 10 studies were included (8 RCTs, 1 prospective, and 1 retrospective study). Compared with the control group, the simethicone group showed significant improvements in the degree of gas bubbling (RR = 2.05, 95%CI:1.56-2.71, P < 0.001, I2 = 62%) and SBVQ (RR = 1.41, 95%CI: 1.20-1.65, P < 0.001, I2 = 16%). Subgroup analysis showed that the SBVQ of simethicone group was better than fasting (RR = 2.62, 95% CI:1.49-4.59, P < 0.001, I2 = 0%), mannitol (RR = 1.35, 95% CI: 1.14-1.59, P < 0.001, I2 = 0%) and PEG group (RR = 1.32, 95%CI:1.06-1.65, P = 0.01, I2 = 0%). No significant associations were found for DY, GTT, SBTT, and CR. CONCLUSIONS: Simethicone for bowel preparation is useful to improve visualization and reduce the gas bubbling of SBCE.

Vitamin D intake as well as circulating 25-hydroxyvitamin D level and risk for the incidence and recurrence of colorectal cancer precursors: A meta-analysis.

Objective: Vitamin D consumption and circulating 25(OH)D level are associated with decreased risk of colorectal cancer (CRC) and colorectal adenoma (CRA), but few studies have assessed their relationship with the incidence and recurrence of CRC precursors. Therefore, we performed this meta-analysis to further evaluate the association. Methods: We searched PubMed, Web of Science, Scopus and Embase databases in English until August 2021. Studies evaluating the association of vitamin D intake and circulating 25(OH)D level with risk of CRC precursors were included. A random-effects model was used to pool the risk estimates. Results: A total of 48 studies were selected for inclusion. The CRC precursors incidence was negatively correlated with total vitamin D intake (RR = 0.84 95%CI: 0.80-0.88) and circulating 25(OH)D level (RR = 0.79 95%CI: 0.67-0.92). However, vitamin D intake and circulating 25(OH)D level did not show significant effects on the risk of CRC precursors recurrence. For dose-response analysis, evidence of a linear association was found between CRC precursors incidence and circulating 25(OH)D level, and the risk decreased by 14% per 10 ng/ml increment of circulating 25(OH)D level (RR = 0.86 95% CI: 0.75-0.99). Conclusion: Vitamin D intake and circulating 25(OH)D level can play an effective role in reducing the risk of incidence of CRC precursors. However, they have not prevented the recurrence of CRC precursors.

A Freshwater Fish-Based Diet Alleviates Liver Steatosis by Modulating Gut Microbiota and Metabolites: A Clinical Randomized Controlled Trial in Chinese Participants With Nonalcoholic Fatty Liver Disease.

INTRODUCTION: We aimed to assess the effects of 2 isoenergetic intervention diets (a freshwater fish-based diet [F group] or freshwater fish-based and red meat-based diets alternately [F/M group]) on liver steatosis and their relationship with intestinal flora in patients with nonalcoholic fatty liver disease (NAFLD). METHODS: In this open-label, 84-day randomized controlled trial, 34 NAFLD patients with hepatic steatosis ≥10% were randomly assigned to the F group or F/M group in a 1:1 ratio using a computer-generated random number allocation by a researcher not involved in the study. Liver fat content and gut microbiota and its metabolites were measured. RESULTS: At the end of intervention, the absolute reduction of hepatic steatosis was significantly greater in the F group than in the F/M group (-4.89% vs -1.83%, P = 0.032). Of the 16 secondary clinical outcomes, the improvement in 7 in the F group was greater compared with the F/M group, including alanine aminotransferase and gamma-glutamyl transferase. Furthermore, dietary freshwater fish and red meat consumption alternately did not exacerbate NAFLD. Moreover, changes in the enrichment of Faecalibacterium, short-chain fatty acids, and unconjugated bile acids and the depletion of Prevotella 9 and conjugated bile acids in the F group were significantly greater compared with the F/M group. DISCUSSION: Higher intake of freshwater fish may be beneficial to NAFLD by regulating gut microbiota and its metabolites, whereas intake of a similar total of animal protein and fat from the alternating freshwater fish and red meat may not be harmful for NAFLD in the dietary management of patients with NAFLD.

Comparison of Two Different Accesses Single Orifice Percutaneous Endoscopic Surgery in Diagnosis of Ascites of Unknown Origin: A Retrospective Study.

Background: Ascites is a common clinical finding caused by many different diseases, so we developed a technique termed single orifice percutaneous endoscopic surgery (SOPES) which can access peritoneal cavity through the contralateral McBurney's point or umbilicus to seek the underlying causes. In this study, we describe the initial clinical experience of SOPES and compare the application of two accesses. Methods: This is a retrospective study performed between 2007 and 2018. Patients with ascites of unknown origin who underwent these two kinds of SOPES were included. Main outcomes were measured by diagnostic accuracy, complication rate, procedure time, time till stitches removal, length of hospital stay, and hospital cost. Results: 148 patients successfully undergone SOPES via the contralateral McBurney's point (IM group, n = 70) or the umbilicus (UM group, n = 78). 63 patients in the IM group and 71 patients in the UM group reached clear diagnosis (90.0% vs. 91.0%, p = 0.831). The overall complication rate was 5.4%, while the UM group was higher than the IM group (10.3% vs. 0%, p = 0.017). All complications were resolved after medical treatment, and no mortality resulted from this procedure. The procedure time and the time until stitches removal in the UM group were longer than that in the IM group. There were no significant differences in length of hospital stay and hospital cost between the two groups. Conclusions: SOPES, which combines the strength of minimally invasive single orifice incision and flexible angles of examination and instrumentation, is a newly developed flexible endoscopic surgical modality that provides new important clinical valuable in evaluation of ascites of unknown origin. Moreover, SOPES via the contralateral McBurney's point was safer than the umbilicus approach.

Interleukin-28A maintains the intestinal epithelial barrier function through regulation of claudin-1.

BACKGROUND: Interleukin-28A (IL-28A or interferon-λ2) is reported to maintain intestinal mucosal homeostasis. However, the effects and mechanisms of IL-28A on intestinal ischemia reperfusion (I/R) have not yet been studied. METHODS: Adult C57BL/6 mice were randomly divided into three groups: sham, I/R, and I/R+IL-28A (n=5 in each group). The I/R+IL-28A group mice were injected with recombinant mouse IL-28A 12 hours before the operation. Mice were sacrificed 6 hours after reperfusion. The mucosal permeability was investigated, and histology analyses were performed. Additionally, a hypoxic Caco-2 cell culture model was established. Fludarabine was used to inhibit phosphorylated signal transducer and activator of transcription 1 (pSTAT1). The expression of IL-28A, tight junctions (TJs), and pSTAT1 was assessed by western blot, immunohistochemical (IHC) staining, or immunofluorescence staining. Epithelial permeability was measured by transepithelial electrical resistance (TER). RESULTS: The expression of IL-28A was decreased in intestinal lamina propria in the I/R group compared with the control group. Administration of IL-28A significantly alleviated the I/R-induced increase in intestinal permeability and tissue damage. Treatment with IL-28A significantly attenuated intestinal I/R-induced disruption of TJ proteins, including zonula occludens-1 (ZO-1), occludin, and claudin-1. In vitro, IL-28A treatment reversed the decrease in TER of Caco-2 monolayers exposed to hypoxic environments. IL-28A led to the activation of STAT1 and the upregulation of claudin-1 expression both in vivo and in vitro. Also, inhibiting phosphorylation of STAT1 reversed the effects of IL-28A on the expression and distribution of claudin-1 in Caco-2 cells. CONCLUSIONS: Intestinal epithelial barrier dysfunction caused by intestinal I/R is ameliorated by IL-28A via the regulation of claudin-1.

Identification of Fibroblast Activation Protein as an Osteogenic Suppressor and Anti-osteoporosis Drug Target.

Osteogenic suppressors such as Sclerostin not only regulate skeletal development and regeneration but also serve as anti-osteoporosis drug targets. However, very few druggable suppressors have been identified due to limited understanding of the molecular mechanisms governing osteogenesis. Here, we show that fibroblast activation protein (Fap), a serine protease inhibited by the bone growth factor Osteolectin, is an osteogenic suppressor. Genetic deletion of Fap significantly ameliorates limb trabecular bone loss during aging. Pharmacological inhibition of Fap significantly promotes bone formation and inhibits bone resorption in wild-type mice by differentially regulating canonical Wnt and nuclear factor κB (NF-κB) pathways. Pharmacological inhibition of Fap promotes osteoblast differentiation, inhibits osteoclast differentiation, and significantly attenuates osteoporosis in ovariectomized mice. Epistasis analyses in zebrafish show that Osteolectin functions as an endogenous inhibitor of Fap to promote vertebrae mineralization. Taken together, we identify Fap as an important osteogenic suppressor and a potential drug target to treat osteoporosis.

Possible role of microRNA miRNA-IL-25 interaction in mice with ulcerative colitis.

BACKGROUND: The regulatory network of ulcerative colitis (UC)-associated miRNAs is not fully understood. In this study, we aim to investigate the global profile and regulatory network of UC associated miRNAs in the context of dextran sulfate sodium (DSS). METHODS: UC was induced in C57BL mice using DSS. Differentially expressed miRNAs were screened by RNA sequencing and subjected to the Kyoto Encyclopedia of Genes and Genomes Pathway enrichment analysis. RT-qPCR was used to verify the differential expression of miRNAs and candidate target mRNA. Luciferase reporter vector bearing a miRNA binding site was constructed to verify the binding site of the miRNA on mRNA. RESULTS: A total of 95 miRNAs (31 were up-regulated and 64 were down regulated) differentially expressed in the colonic tissues of the UC mice. Among the differentially expressed miRNAs, IL-25 pathway genes were enriched. Subsequent RT-qPCR confirmed a decreased expression of IL-25 and a significant up regulation of IL-25 target miRNAs including mmu-miR-135b-5p, mmu-miR-7239-5p and mmu-miR-691 in UC mice. CONCLUSION: Using the luciferase assay, we verified the biding sites of mmu-miR-135b-5p and mmu-miR-691 to the IL-25 3'UTR. In conclusion, mmu-miR-135b-5p:IL-25 and mmu-miR-691:IL-25 interactions are important pathways that may exert a protective role in UC.

SCFAs induce autophagy in intestinal epithelial cells and relieve colitis by stabilizing HIF-1α.

Hypoxia-inducible factor-1α (HIF-1α) is a critical regulator of barrier integrity during colonic mucosal injury. Previous works have shown that the absence of autophagy is implicated in the development of inflammatory bowel disease (IBD). Additionally, changes in bacterial profiles in the gut are intimately associated with IBD. Although HIF-1α, autophagy, microbiota, and their metabolites are all involved in the pathogenesis of IBD, their roles are not known. In this study, we investigated the relationship between HIF-1α and autophagy in healthy and inflammatory states using transgenic mice, colitis models, and cell culture models. We confirmed that the absence of intestinal epithelial HIF-1α changed the composition of the intestinal microbes and increased the susceptibility of mice to dextran sodium sulfate (DSS)-induced colitis. In addition, autophagy levels in the intestinal epithelial cells (IECs) were significantly reduced in IEC-specific HIF-1α-deficient (HIF-1α∆IEC) mice. Moreover, in the cell culture models, butyrate treatment significantly increased autophagy in HT29 cells under normal conditions, whereas butyrate had little effect on autophagy after HIF-1α ablation. Furthermore, in the DSS-induced colitis model, butyrate administration relieved the colonic injury and suppressed inflammation in Cre-/HIF-1α- (HIF-1αloxP/loxP) mice. However, the butyrate-mediated protection against colonic injury was considerably diminished in the HIF-1α∆IEC mice. These results show that HIF-1α, autophagy, and intestinal microbes are essential for the maintenance of intestinal homeostasis. Butyrate can alleviate DSS-induced colitis by regulating autophagy via HIF-1α. These insights may have important implications for the development of therapeutic strategies for IBD. KEY MESSAGES: • The absence of intestinal epithelial HIF-1α leads to downregulation of autophagy in mice. • The absence of intestinal epithelial HIF-1α exacerbates DSS-induced colitis. • Short-chain fatty acids (SCFAs) can alleviate DSS-induced colitis by regulating autophagy via HIF-1α.

Berberine prevents stress-induced gut inflammation and visceral hypersensitivity and reduces intestinal motility in rats.

BACKGROUND: Irritable bowel syndrome (IBS) is a common chronic non-organic disease of the digestive system. Berberine (BBR) has been used to treat patients with IBS, but the underlying therapeutic mechanism is little understood. We believe that BBR achieves its therapeutic effect on IBS by preventing stress intestinal inflammation and visceral hypersensitivity and reducing bowel motility. AIM: To test the hypothesis that BBR achieves its therapeutic effect on IBS by preventing subclinical inflammation of the intestinal mucosa and reducing visceral hypersensitivity and intestinal motility. METHODS: IBS was induced in rats via water avoidance stress (WAS). qRT-PCR and histological analyses were used to evaluate the levels of cytokines and mucosal inflammation, respectively. Modified ELISA and qRT-PCR were used to evaluate the nuclear factor kappa-B (NF-κB) signal transduction pathway. Colorectal distention test, gastrointestinal transit measurement, Western blot, and qRT-PCR were used to analyze visceral sensitivity, intestinal motility, the expression of C-kit (marker of Cajal mesenchymal cells), and the expression of brain derived neurotrophic factor (BDNF) and its receptor TrkB. RESULTS: WAS led to mucosal inflammation, visceral hyperalgesia, and high intestinal motility. Oral administration of BBR inhibited the NF-κB signal transduction pathway, reduced the expression of pro-inflammatory cytokines [interleukin (IL)-1ß, IL-6, interferon-γ, and tumor necrosis factor-α], promoted the expression of anti-inflammatory cytokines (IL-10 and transforming growth factor-ß), and improved the terminal ileum tissue inflammation. BBR inhibited the expression of BDNF, TrkB, and C-kit in IBS rats, leading to the reduction of intestinal motility and visceral hypersensitivity. The therapeutic effect of BBR at a high dose (100 mg/kg) was superior to than that of the low-dose (25 mg/kg) group. CONCLUSION: BBR reduces intestinal mucosal inflammation by inhibiting the intestinal NF-κB signal pathway in the IBS rats. BBR reduces the expression of BDNF, its receptor TrkB, and C-kit. BBR also reduces intestinal motility and visceral sensitivity to achieve its therapeutic effect on IBS.

AhR activation protects intestinal epithelial barrier function through regulation of Par-6.

The Par complex (Par-6/Par-3/aPKC) plays a key role in the maintenance of the intestinal barrier function through the regulation of epithelial junction formation. The aryl hydrocarbon receptor (AhR) has been shown to be an important regulator for intestinal homeostasis. In this study, we investigated the role of the AhR activation on the regulation of Par complex. AhR activation by 6-formylindolo (3,2-b) carbazole (FICZ) represses the abnormal expression of the Par complex in a mouse model of dextran sulphate sodium (DSS)-induced colitis. In T84 cells, overexpression of Par-6 causes intestinal barrier dysfunction. Lipopolysaccharide (LPS)-induced intestinal epithelial barrier dysfunction and increase in Par-6 expression was prevented by AhR activation. However, FICZ did not alter the expression of Par-3 or aPKC. Furthermore, AhR activation alleviated LPS-induced increase of Par-6 through repressing the expression of activating protein-2γ (Ap-2γ). These results reveal the protective effects of AhR activation on LPS induced disruption of intestinal epithelial barrier function through suppressing the expression of Par-6 expression. Our findings provide novel insights into the protective role of AhR in intestinal barrier function.

Aryl Hydrocarbon Receptor Activation Modulates Intestinal Epithelial Barrier Function by Maintaining Tight Junction Integrity.

Activation of Aryl hydrocarbon receptor (AhR) is involved in the control of intestinal mucosal homeostasis. Intestinal barrier dysfunction contributes to the development of many intestinal diseases, such as inflammatory bowel disease (IBD). In this study, we investigated the mechanisms of AhR activation in the maintenance of intestinal barrier function. Adult C57BL/6 mice were treated with dextran sulphate sodium (DSS) for 7 days, with or without 6-Formylindolo(3,2-b)carbazole (FICZ), a ligand of AhR. We found that AhR activation by FICZ attenuated the decreased TJ protein expression in the colonic mucosa of the DSS-induced mice. Further, the increase of both MLC phosphorylation and MLCK expression in the mice with DSS-induced colitis was also significantly inhibited by FICZ induced AhR activation. For in vitro experiments, Caco-2 cells were treated with tumour necrosis factor alpha (TNF-α)/interferon gamma (IFN-γ) for 48 h, with or without FICZ. AhR activation prevented TNF-α/IFN-γ-induced decrease in TER and morphological disruption of the TJs in Caco-2 monolayers. It also inhibited TNF-α/IFN-γ-induced increase in MLCK expression and MLC phosphorylation by suppression of NF-κB p65 signaling pathway. Thus, AhR-activating factors might have potential as therapeutic agents for the treatment of patients with IBD.

Aryl hydrocarbon receptor inhibits inflammation in DSS­induced colitis via the MK2/p­MK2/TTP pathway.

The pathogenesis of inflammatory bowel disease (IBD) is believed to be associated with the abnormal expression of inflammatory factors. The aryl hydrocarbon receptor (AhR) is a ligand­dependent transcription factor, which can suppress the inflammatory response and attenuate experimental colitis. However, the detailed mechanism underlying the effects of AhR remains unclear. The present study investigated the role of AhR in the pathogenesis of IBD. Colitis was induced in mice by administration of 3% dextran sulphate sodium (DSS) for 7 days. The mice were also administered injections of the AhR agonist, 6­formylindolo(3,2­b)carbazole (FICZ), starting 2 days after the first administration of DSS. Furthermore, LoVo cells were treated with lipopolysaccharide (LPS) in the presence or absence of FICZ for 8 h. The protein expression levels of AhR, cytochrome P450 1A1 (CYP1A1) and tristetraprolin (TTP) were assessed by western blotting and immunofluorescence, whereas mRNA expression levels were assessed by reverse transcription­quantitative polymerase chain reaction. The results indicated that injection of mice with FICZ significantly attenuated DSS­induced colitis; in addition, the expression levels of inflammatory cytokines were markedly downregulated. Conversely, the expression levels of AhR and TTP were upregulated. In addition, mice in the AhR­knockout + DSS group exhibited elevated inflammatory cytokine production and developed more severe colitis. In LoVo cells, incubation with FICZ decreased the expression levels of inflammatory cytokines, whereas AhR and TTP expression was increased. In addition, the levels of phosphorylated­mitogen­activated protein kinase­activated protein kinase 2 (p­MK2) were decreased. These results suggested that AhR deficiency resulted in increased susceptibility to colitis, whereas activation of AhR by FICZ could ameliorate DSS­induced colitis via the MK2/p­MK2/TTP pathway.

Aryl hydrocarbon receptor activation maintained the intestinal epithelial barrier function through Notch1 dependent signaling pathway.

Intestinal ischemia/reperfusion (I/R) induces disruption of the intestinal barrier function. Aryl hydrocarbon receptor (AhR) has a vital role in maintaining the intestinal barrier function. However, the precise mechanism by which AhR maintains intestinal barrier function remains unclear. Notch1 signaling is downstream of AhR, and has also been reported to have a role in the development of tight junctions (TJs) and maintenance of intestinal homeostasis. Therefore, we hypothesized that AhR activation may attenuate the intestinal barrier dysfunction through increased activation of Notch1 signaling. Adult C57BL/6J mice were divided into three groups: Sham, I/R and I/R + 6-formylindolo(3,2-b)carbazole (Ficz) groups. Mice were sacrificed after I/R for 6 h and the intestine was harvested for histological examination, mRNA and protein content analysis, and mucosal permeability investigation. Additionally, a hypoxic Caco­2 cell culture model was used to evaluate the role of AhR­Notch1 signaling in the development of TJs and epithelial permeability in vitro. The AhR­Notch1 signaling components and TJ proteins were assessed by reverse transcription­quantitative polymerase chain reaction, western blotting, immunohistochemistry or immunofluorescence staining. Epithelial permeability was detected by transepithelium electrical resistance. The data demonstrated that Ficz significantly attenuated the intestinal tissue damage and the disrupted distribution of TJs, increased the expression of TJ proteins, reversed the decrease in TER and upregulated epithelial Notch1 signaling following intestinal I/R in vivo and hypoxia in vitro. Furthermore, inhibition of Notch1 signaling by N­[N­(3,5­difluorophenacetyl)­L­alanyl]­S­phenylglycine t­butyl ester (inhibitor of Notch signaling) counteracted the effects of Ficz on the development of TJs in hypoxic Caco­2 cells. In conclusion, AhR activation ameliorated epithelial barrier dysfunction following intestinal I/R and hypoxia through upregulation of Notch1 signaling, which suggests that AhR may be a potential pharmaceutical agent to combat this condition.

Aryl hydrocarbon receptor activation modulates CD8αα+TCRαß+ IELs and suppression of colitis manifestations in mice.

BACKGROUND: This research is dedicated to investigating the effects and potential mechanism of action of the aryl hydrocarbon receptor on the intestinal mucosal immune system in dextran sulfate sodium (DSS)-induced colitis. METHODS: Colitis was induced by the administration of 3% DSS to wild-type C57BL/6J mice for 7days. 6-formylindolo(3, 2-b)carbazole (FICZ), an endogenous agonist of the aryl hydrocarbon receptor (AhR), was given intraperitoneally on a daily basis beginning 2days after the start of DSS administration. The mice were weighed and assessed, and colon tissues were measured. Intraepithelial lymphocytes (IELs) were isolated from the colon and examined by flow cytometry and quantitative real-time PCR. RESULTS: FICZ ameliorated DSS-induced colitis, resulting in a reduced disease activity index and improvement in the histology and length of the colon. Colitis reduced the percentage and number of CD8αα+TCRαß+ IELs. FICZ prevented the reduction in the numbers of CD8αα+TCRαß+ IELs by upregulating the expression of the IL-15 receptor and the aryl hydrocarbon receptor (AhR), and attenuating the apoptotic rate of CD8αα+TCRαß+ IELs. Finally, IL-10 was increased and IFN-γ was decreased in CD8αα+TCRαß+ IELs by FICZ administration in DSS-induced colitis. CONCLUSIONS: The results suggest that AhR activation ameliorated DSS-induced acute colitis, in a manner that is associated with the local expansion and functions of CD8αα+TCRαß+ IELs in acute colitis. The findings indicate that AhR-related ligands might be targeted as novel drug targets for IBD.