Intestinal fibrosis is a significant clinical challenge in inflammatory bowel diseases, but no effective anti-fibrotic therapy is currently available. Glucagon receptor (GCGR) and glucagon-like peptide 1 receptor (GLP1R) are both peptide hormone receptors involved in energy metabolism of epithelial cells. However, their role in intestinal fibrosis and the underlying mechanisms remain largely unexplored. Herein GCGR and GLP1R were found to be reduced in the stenotic ileum of patients with Crohn's disease as well as in the fibrotic colon of mice with chronic colitis. The downregulation of GCGR and GLP1R led to the accumulation of the metabolic byproduct lactate, resulting in histone H3K9 lactylation and exacerbated intestinal fibrosis through epithelial-to-mesenchymal transition (EMT). Dual activating GCGR and GLP1R by peptide 1907B reduced the H3K9 lactylation in epithelial cells and ameliorated intestinal fibrosis in vivo. We uncovered the role of GCGR/GLP1R in regulating EMT involved in intestinal fibrosis via histone lactylation. Simultaneously activating GCGR/GLP1R with the novel dual agonist peptide 1907B holds promise as a treatment strategy for alleviating intestinal fibrosis.

This study was aimed at exploring the mechanism underlying the effects of nitidine chloride against Talaromyces marnef-fei through network pharmacology analysis.We collected NC and TM action targets from various databases;constructed a protein-protein interaction(PPI)network by using common drug and disease targets;and performed KEGG pathway and GO enrichment analy-ses.In vitro cellular experiments were conducted to test the antibacterial ability of NC at various concentrations,qPCR was used to de-tect the mRNA expression of genes in the target pathway,and WB was used to examine the expression of proteins associated with tar-get signaling pathways in cells.We identified 153 target genes for NC and 2 095 target genes for TM,among which 23 targets over-lapped.By integrating the PPI network with KEGG enrichment analysis,we selected key target genes in the MAPK signaling pathway,such as FLT1,FLT3,CD38,and PRF1.The CFU results indicated that NC had favorable antibacterial capability.Moreover,qPCR demonstrated that NC downregulated the mRNA expression of FLT1,FLT3,and RPS6KA3,and upregulated the mRNA expression of MAP3K8.WB findings indicated that NC downregulated the expression of RSK2,VEGF,and FLT3 proteins,and upregulated the ex-pression of MAP3K8 protein.NC may exert its anti-TM effects by downregulating the expression of RSK2,VEGF,and FLT3 proteins,thereby inhibiting MAPK pathway activation.The potential targets and signaling pathways underlying NC's anti-TM action may pro-vide new insights to guide the clinical application of NC.

Objective:To assess the long-term risk of relapse in patients with Crohn's disease (CD) who discontinued infliximab (IFX) monoclonal antibody and to identify risk factors associated with relapse.Methods:A single-center retrospective observational study was conducted from February 2006 to October 2016. The study included CD patients who were treated with scheduled IFX infusions at the First Affiliated Hospital of Sun Yat-sen University and assessed in corticosteroid-free clinical remission at the time of withdrawal were included. The primary outcome was clinical relapse. We evaluated the risk of relapse using Kaplan-Meier method. Factors associated with time to relapse was identified using the multiple Cox proportional hazards regression analysis.Results:We included 97 eligible patients, and 75 (77.3%) experienced a relapse after a median follow-up time of 124 months. Among them, 45 patients (46.4%) relapsed within 3 years after IFX withdrawal. The 1-, 2-, 3-, 5-, and 10-year relapse-free survival were 79.4%, 59.8%, 52.6%, 42.0% and 22.6%, respectively. Risk factors for relapse included age ≤ 16 ( HR = 2.62, 95% CI: 1.30-5.31; P = 0.007) and failure to achieve biological remission (CRP > 3 mg/L, HR = 2.37, 95% CI: 1.29-4.36; P = 0.006) at drug withdrawal. Induction with biologics or systemic steroids were both effective (89%-100% relieved) in relapsers. Conclusions:Nearly half of CD patients relapsed within 3 years after discontinuation of IFX treatment. Early age of discontinuation and failure to achieve serum biological remission at the time of discontinuation are independent predictors of clinical relapse.

Objective:To assess the long-term risk of relapse in patients with Crohn's disease (CD) who discontinued infliximab (IFX) monoclonal antibody and to identify risk factors associated with relapse.Methods:A single-center retrospective observational study was conducted from February 2006 to October 2016. The study included CD patients who were treated with scheduled IFX infusions at the First Affiliated Hospital of Sun Yat-sen University and assessed in corticosteroid-free clinical remission at the time of withdrawal were included. The primary outcome was clinical relapse. We evaluated the risk of relapse using Kaplan-Meier method. Factors associated with time to relapse was identified using the multiple Cox proportional hazards regression analysis.Results:We included 97 eligible patients, and 75 (77.3%) experienced a relapse after a median follow-up time of 124 months. Among them, 45 patients (46.4%) relapsed within 3 years after IFX withdrawal. The 1-, 2-, 3-, 5-, and 10-year relapse-free survival were 79.4%, 59.8%, 52.6%, 42.0% and 22.6%, respectively. Risk factors for relapse included age ≤ 16 ( HR = 2.62, 95% CI: 1.30-5.31; P = 0.007) and failure to achieve biological remission (CRP > 3 mg/L, HR = 2.37, 95% CI: 1.29-4.36; P = 0.006) at drug withdrawal. Induction with biologics or systemic steroids were both effective (89%-100% relieved) in relapsers. Conclusions:Nearly half of CD patients relapsed within 3 years after discontinuation of IFX treatment. Early age of discontinuation and failure to achieve serum biological remission at the time of discontinuation are independent predictors of clinical relapse.

This study was aimed at exploring the mechanism underlying the effects of nitidine chloride against Talaromyces marnef-fei through network pharmacology analysis.We collected NC and TM action targets from various databases;constructed a protein-protein interaction(PPI)network by using common drug and disease targets;and performed KEGG pathway and GO enrichment analy-ses.In vitro cellular experiments were conducted to test the antibacterial ability of NC at various concentrations,qPCR was used to de-tect the mRNA expression of genes in the target pathway,and WB was used to examine the expression of proteins associated with tar-get signaling pathways in cells.We identified 153 target genes for NC and 2 095 target genes for TM,among which 23 targets over-lapped.By integrating the PPI network with KEGG enrichment analysis,we selected key target genes in the MAPK signaling pathway,such as FLT1,FLT3,CD38,and PRF1.The CFU results indicated that NC had favorable antibacterial capability.Moreover,qPCR demonstrated that NC downregulated the mRNA expression of FLT1,FLT3,and RPS6KA3,and upregulated the mRNA expression of MAP3K8.WB findings indicated that NC downregulated the expression of RSK2,VEGF,and FLT3 proteins,and upregulated the ex-pression of MAP3K8 protein.NC may exert its anti-TM effects by downregulating the expression of RSK2,VEGF,and FLT3 proteins,thereby inhibiting MAPK pathway activation.The potential targets and signaling pathways underlying NC's anti-TM action may pro-vide new insights to guide the clinical application of NC.

Objective　To explore the effect of Mp1p on host macrophages through transcriptomics combined with metabolomics. Methods Firstly, a THP-1 macrophage strain (THP-1-Mp1p+) stably expressing Mp1p was constructed using lentivirus. Secondly, using high-throughput RNA sequencing (RNA Seq) technology, the expression level of intracellular mRNA was detected in transcriptomics analysis to determine differentially expressed genes; In metabolomics analysis, metabolite identification was performed through database comparison, and pathway analysis was performed on differential metabolites to reveal potential mechanisms of action. Finally, the results of metabolomics and transcriptomics were combined for analysis, and differential metabolites and genes were analyzed to further elucidate the mechanism of action of Mp1p on macrophages. Results Transcriptome analysis showed that, compared with the negative control group, the THP-1-Mp1p+ group had a total of 1 180 differentially expressed genes (DEGs), with 345 upregulated genes and 835 downregulated genes. GO enrichment analysis of DEGs showed that there were 135 differentially expressed genes, including 105 in biological processes (BP), 28 in cellular components (CC), and 2 in molecular functions (MF). The KEGG analysis results showed that the effect of Mp1p on THP-1 macrophages was highly correlated with the TNF pathway. The metabolomic analysis found that both the blank control group and the THP-1-Mp1p+ macrophage group achieved good separation between QC samples in both positive and negative ion modes. The threshold for significant differential metabolites was set at: VIP≥1 and T-test P<0.05, resulting in the identification of 488 differential metabolites, with 230 in the positive ion mode and 258 in the negative ion mode. Pathway enrichment analysis of the identified metabolites pointed to significant enrichment in metabolic pathways. The combined analysis confirmed that the tumor necrosis factor signaling pathway, interleukin-17 signaling pathway, and NF-kappaB signaling pathway were important metabolic pathways involved. Conclusions The virulence factor Mp1p may affect host macrophages by modulating the tumor necrosis factor signaling pathway, interleukin-17 signaling pathway, and NF-kappaB signaling pathway. The findings contribute to a better understanding of the mechanisms of action of Mp1p and may offer potential directions for the selection of relevant diagnostic and therapeutic targets in the future.

Objective:To investigate the psychology status and quality of life in patients with inflammatory bowel disease(IBD) in China, and to analyze the influencing factors.Methods:From September 2021 to May 2022, 42 hospitals in 22 provinces(autonomous regions and municipalities directly under the central government) in China, the clinical data of 2 478 IBD patients were collected, which included age, gender, weight, first visit or not, disease activity, disease course, main clinical manifestations(diarrhea, abdominal pain, hematochezia, extraintestinal manifestations), complications, treatment medication(5-aminosalicylic acid, glucocorticoids, immunosuppressive agents, and biological agents), and whether to have surgery. Anxiety, depression, sleep quality and quality of life of IBD patients were evaluated by generalized anxiety disorder-7 items, patient health questionnaire-9 items, Pittsburgh sleep quality index and inflammatory bowel disease questionnaire, and the related influencing factors were analyzed. Univariate analysis and multiple linear regression analysis were used for statistical analysis.Results:The average age of 2 478 IBD patients was 37.96 years old, and male counted for 62.43%(1 547/2 478). There were 61.82%(1 532/2 478) of the IBD patients in the active stage of disease, mostly mild or moderate(588 and 734 cases). There were 60.61%(1 502/2 478) of the IBD patients with different degrees of anxiety, 58.35%(1 446/2 478) of the IBD patients with different degrees of depression, and 48.87%(1 211/2 478) of the IBD patients had different degrees of sleep problems. The results of multiple linear regression analysis indicated that female, higher level of disease activity and longer disease course were independent risk factors of anxiety, depression and sleep quality in the IBD patients(unstandardized regression coefficient(95% confidence interval) 1.08(0.65 to 1.50), 0.45(0.23 to 0.68), 0.19(0.02 to 0.36), 0.83(0.33 to 1.32), 0.62(0.36 to 0.88), 0.28(0.08 to 0.47), 0.47(0.16 to 0.77), 0.39(0.23 to 0.55), 0.14(0.02 to 0.26); P<0.001, <0.001, =0.025 , =0.001, <0.001, =0.005, =0.003, <0.001, =0.027). The usage of biological agents was an independent protective factor of anxiety(unstandardized regression coefficient(95% confidence interval) -0.67(-1.17 to -0.17), P=0.008), and older age was an independent risk factor of sleep quality(unstandardized regression coefficient(95% confidence interval) 0.35(0.09 to 0.61), P=0.008). Higher level of disease activity, symptoms of diarrhea, abdominal pain, presence of extraintestinal manifestations, usage of 5-aminosalicylic acid and glucocorticoid, and with surgical treatment were independent risk factors of quality of life(unstandardized regression coefficient(95% confidence interval) -11.00(-12.24 to -9.76), -2.90(-5.26 to -0.55), -3.93(-6.25 to -1.61), -5.79(-9.87 to -1.71), -4.78(-7.79 to -1.76), -7.71(-11.07 to -4.35), -4.37(-8.00 to -0.73); P<0.001, =0.016, =0.001, =0.005 , =0.002, <0.001, =0.019), while the usage of biological agents was an independent protective factor of quality of life (unstandardized regression coefficient(95% confidence interval) 4.72(1.97 to 7.48), P=0.001). Conclusion:IBD patients generally have different degrees of anxiety, depression and sleep problems, which affect the quality of life of patients. Gender, disease activity and disease course are the influencing factors of mental disorders in IBD patients.

With the wide application of immune checkpoint inhibitors in a variety of tumor diseases, various immune-related adverse effects have appeared. The immune-mediated colitis (IMC) is one of the main adverse effects. A case of IMC caused by programmed cell death protein-1 (PD-1) inhibitor at Department of Gastroenterology in the First Affiliated Hospital of Sun Yat-sen University is reported.

With the wide application of immune checkpoint inhibitors in a variety of tumor diseases, various immune-related adverse effects have appeared. The immune-mediated colitis (IMC) is one of the main adverse effects. A case of IMC caused by programmed cell death protein-1 (PD-1) inhibitor at Department of Gastroenterology in the First Affiliated Hospital of Sun Yat-sen University is reported.

Immune checkpoint inhibitors (ICI) have been widely used in the treatment of a variety of malignancies. ICI may induce immune-related adverse events (irAEs) . irAEs could affect multiple organs in the body, among which gastrointestinal adverse reactions are the most common ones, mainly involved the colon and small intestine, often accompanied by diarrhea symptoms, which is called immune checkpoint inhibitor-induced enterocolitis. This article mainly introduces the pathogenesis, risk factors, clinical manifestations and management of ICI-induced enterocolitis, in order to better identify ICI-related gastrointestinal adverse reactions and improve its effectiveness of treatment.