Objective:This study aimed to investigate the role of heat shock protein family A member 5 (HSPA5) in ferroptosis at its regulatory mechanisms in ulcerative colitis (UC), using both a dextran sulfate sodium (DSS)-induced mouse model of acute colitis and in vitro cell experiments.Methods:Differentially expressed genes in UC were identified using the GSE87466 dataset from the Gene Expression Omnibus, cross-referenced with the ferroptosis-related gene database FerrDB (version 2). A protein-protein interaction (PPI) network was constructed, identifying HSPA5 as a core hub gene. To validate its role in vivo, acute colitis was induced in C57BL/6 mice using DSS, followed by treatment with the ferroptosis inhibitor Ferrostatin-1 (Fer-1). Lipid peroxidation and ferroptosis levels were assessed by measuring malondialdehyde (MDA) and iron content in colon tissues. The expression of ferroptosis-related proteins, including prostaglandin-endoperoxide synthase 2 (PTGS2), glutathione peroxidase 4 (GPX4), ferritin light chain (FTL), activating transcription factor 4 (ATF4), and HSPA5, in addition to tight junction proteins ZO-1 and Occludin, were evaluated using immunohistochemistry and Western blotting. In vitro, an inflammatory model was established using lipopolysaccharide (LPS)-stimulated Caco-2 cells. Lentiviral knockdown of HSPA5 was performed to assess its regulatory effects on ferroptosis by assessing MDA levels, GPX4 activity, and the expression of related proteins. Statistical analyses were conducted with SPSS (version 29.1), with t-tests or one-way ANOVA for normally distributed data and the Mann-Whitney U test for ordinal data. Statistical significance was set at P<0.05. Results:Based on the PPI analysis and previous research, HSPA5 emerged as a key gene linking UC and ferroptosis. In DSS-treated mice, colonic injury was accompanied by elevated MDA levels ( t=5.72, P<0.001) and iron accumulation ( t=6.32, P<0.001). DSS also increased the expression of PTGS2 and proteins in the ATF4-HSPA5 pathway, while reducing the levels of GPX4, FTL, ZO-1, and Occludin. These findings could be partially reversed by Fer-1 (MDA: t=2.92, P<0.05; iron: t=5.84, P<0.001). In Caco-2 cells, LPS treatment elevated the expression of PTGS2, ATF4, and HSPA5, and elevated the MDA content ( t=9.63, P<0.001), while reducing the expression of FTL, GPX4, ZO-1, and Occludin, as well as GPX4 enzyme activity ( t=-11.20, P<0.001). Knockdown of HSPA5 further exacerbated these changes, significantly increasing MDA levels ( t=4.15, P<0.01), decreasing GPX4 activity ( t=-9.81, P<0.001), and altering ferroptosis-related protein expression. Conclusion:HSPA5 appears to protect against intestinal damage in UC by enhancing GPX4 expression and activity, thereby reducing ferroptosis and preserving epithelial barrier integrity through the maintenance of tight junction proteins.

Objective:This study aimed to investigate the role of heat shock protein family A member 5 (HSPA5) in ferroptosis at its regulatory mechanisms in ulcerative colitis (UC), using both a dextran sulfate sodium (DSS)-induced mouse model of acute colitis and in vitro cell experiments.Methods:Differentially expressed genes in UC were identified using the GSE87466 dataset from the Gene Expression Omnibus, cross-referenced with the ferroptosis-related gene database FerrDB (version 2). A protein-protein interaction (PPI) network was constructed, identifying HSPA5 as a core hub gene. To validate its role in vivo, acute colitis was induced in C57BL/6 mice using DSS, followed by treatment with the ferroptosis inhibitor Ferrostatin-1 (Fer-1). Lipid peroxidation and ferroptosis levels were assessed by measuring malondialdehyde (MDA) and iron content in colon tissues. The expression of ferroptosis-related proteins, including prostaglandin-endoperoxide synthase 2 (PTGS2), glutathione peroxidase 4 (GPX4), ferritin light chain (FTL), activating transcription factor 4 (ATF4), and HSPA5, in addition to tight junction proteins ZO-1 and Occludin, were evaluated using immunohistochemistry and Western blotting. In vitro, an inflammatory model was established using lipopolysaccharide (LPS)-stimulated Caco-2 cells. Lentiviral knockdown of HSPA5 was performed to assess its regulatory effects on ferroptosis by assessing MDA levels, GPX4 activity, and the expression of related proteins. Statistical analyses were conducted with SPSS (version 29.1), with t-tests or one-way ANOVA for normally distributed data and the Mann-Whitney U test for ordinal data. Statistical significance was set at P<0.05. Results:Based on the PPI analysis and previous research, HSPA5 emerged as a key gene linking UC and ferroptosis. In DSS-treated mice, colonic injury was accompanied by elevated MDA levels ( t=5.72, P<0.001) and iron accumulation ( t=6.32, P<0.001). DSS also increased the expression of PTGS2 and proteins in the ATF4-HSPA5 pathway, while reducing the levels of GPX4, FTL, ZO-1, and Occludin. These findings could be partially reversed by Fer-1 (MDA: t=2.92, P<0.05; iron: t=5.84, P<0.001). In Caco-2 cells, LPS treatment elevated the expression of PTGS2, ATF4, and HSPA5, and elevated the MDA content ( t=9.63, P<0.001), while reducing the expression of FTL, GPX4, ZO-1, and Occludin, as well as GPX4 enzyme activity ( t=-11.20, P<0.001). Knockdown of HSPA5 further exacerbated these changes, significantly increasing MDA levels ( t=4.15, P<0.01), decreasing GPX4 activity ( t=-9.81, P<0.001), and altering ferroptosis-related protein expression. Conclusion:HSPA5 appears to protect against intestinal damage in UC by enhancing GPX4 expression and activity, thereby reducing ferroptosis and preserving epithelial barrier integrity through the maintenance of tight junction proteins.

Inflammatory Bowel Diseases(IBD)is a class of genetically related diseases caused by multiple genes and environmental factors that accelerate the disturbance of the immune-gut-microbiome axis.Lesions often involve multiple organs and systems.Biological agents are an important means of treating IBD and its extraintestinal manifestations.Current studies suggest that biologics can bring benefits to patients,but paradoxical skin lesions,joint lesions,and ocular lesions appear during the treatment.Diseases,pulmonary lesions and other manifestations or lesions are easily ignored in clinical practice,thereby delaying the patient's condition and affecting the patient's quality of life.Therefore,by summarizing the clinical characteristics and diagnosis and treatment experience of contradictory extraintestinal manifestations in the current application of biological agents,this review aims to improve the understanding of clinicians,identify this clinical manifestation early,and avoid delaying the patient's condition.

Objective To investigate the influencing factors for chronic pancreatitis(CP)complicated by pancreatogenic portal hypertension(PPH),and to establish a predictive model.Methods A retrospective analysis was performed for the clinical data of 99 patients with CP complicated by PPH who were hospitalized in The First Affiliated Hospital of Kunming Medical University,Chuxiong Yi Autonomous Prefecture People's Hospital,Wenshan People's Hospital,and Puer People's Hospital from January 2017 to December 2022,and these patients were enrolled as PPH group.The incidence density sampling method was used to select 198 CP patients from databases as control group.The independent-samples t test was used for comparison of normally distributed continuous data between two groups,and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups;the chi-square test or the Fisher's exact test was used for comparison of categorical data between two groups.The Least Absolute Shrinkage and Selection Operator(LASSO)regression model was used to identify the potential predictive factors for CP complicated by PPH,and the predictive factors obtained were included in the multivariate Logistic regression analysis to obtain independent risk factors,which were used to establish a nomogram prediction model.The receiver operating characteristic(ROC)curve,the calibration curve,and the Hosmer-Lemeshow goodness-of-fit test were used to perform internal validation of the model,and the clinical decision curve was used to assess the clinical practicability of the model.Results There were significant differences between the two groups in sex,history of recurrent acute pancreatitis attacks,acute exacerbation of CP,bile duct stones,peripancreatic fluid accumulation,pseudocysts,pulmonary infection,elevated C-reactive protein(CRP),elevated procalcitonin,fibrinogen(FIB),neutrophil-lymphocyte ratio(NLR),gamma-glutamyl transpeptidase,total bilirubin,direct bilirubin,low-density lipoprotein(LDL),serum amylase,D-dimer,and serum albumin(all P<0.05).The predictive variables obtained by the LASSO regression analysis included sex,recurrent acute pancreatitis attacks,bile duct stones,peripancreatic fluid accumulation,pulmonary infection,pseudocysts,CRP,NLR,FIB,and LDL.The multivariate Logistic regression analysis showed that sex(odds ratio[OR]=2.716,P<0.05),recurrent acute pancreatitis attacks(OR=2.138,P<0.05),peripancreatic fluid accumulation(OR=2.297,P<0.05),pseudocysts(OR=2.805,P<0.05),and FIB(OR=1.313,P<0.05)were independent risk factors for CP complicated by PPH.The above factors were fitted into the model,and the Bootstrap internal validation showed that the nomogram model had an area under the ROC curve of 0.787(95%confidence interval:0.730—0.844),and the calibration curve was close to the reference curve.The Hosmer-Lemeshow goodness-of-fit test showed that the model had a good degree of fitting(χ2=7.469,P=0.487).The clinical decision curve analysis showed that the prediction model had good clinical practicability.Conclusion Male sex,recurrent acute pancreatitis attacks,peripancreatic fluid accumulation,pseudocysts,and FIB are independent risk factors for CP complicated by PPH,and the nomogram model established has good discriminatory ability,calibration,and clinical practicability.

Objective:To investigate the current status of endoscopic treatment for gastroesophageal varices in portal hypertension in China, and to provide supporting data and reference for the development of endoscopic treatment.Methods:In this study, initiated by the Liver Health Consortium in China (CHESS), a questionnaire was designed and distributed online to investigate the basic condition of endoscopic treatment for gastroesophageal varices in portal hypertension in 2022 in China. Questions included annual number and indication of endoscopic procedures, adherence to guideline for preventing esophagogastric variceal bleeding (EGVB), management and timing of emergent EGVB, management of gastric and isolated varices, and improvement of endoscopic treatment. Proportions of hospitals concerning therapeutic choices to all participant hospitals were calculated. Guideline adherence between secondary and tertiary hospitals were compared by using Chi-square test.Results:A total of 836 hospitals from 31 provinces (anotomous regions and municipalities) participated in the survey. According to the survey, the control of acute EGVB (49.3%, 412/836) and the prevention of recurrent bleeding (38.3%, 320/836) were major indications of endoscopic treatment. For primary [non-selective β-blocker (NSBB) or endoscopic therapies] and secondary prophylaxis (NSBB and endoscopic therapies) of EGVB, adherence to domestic guideline was 72.5% (606/836) and 39.2% (328/836), respectively. There were significant differences in the adherence between secondary and tertiary hospitals in primary prophylaxis of EGVB [71.0% (495/697) VS 79.9% (111/139), χ2=4.11, P=0.033] and secondary prophylaxis of EGVB [41.6% (290/697) VS 27.3% (38/139), χ2=9.31, P=0.002]. A total of 78.2% (654/836) hospitals preferred endoscopic therapies treating acute EGVB, and endoscopic therapy was more likely to be the first choice for treating acute EGVB in tertiary hospitals (82.6%, 576/697) than secondary hospitals [56.1% (78/139), χ2=46.33, P<0.001]. The optimal timing was usually within 12 hours (48.5%, 317/654) and 12-24 hours (36.9%, 241/654) after the bleeding. Regarding the management of gastroesophageal varices type 2 and isolated gastric varices type 1, most hospitals used cyanoacrylate injection in combination with sclerotherapy [48.2% (403/836) and 29.9% (250/836), respectively], but substantial proportions of hospitals preferred clip-assisted therapies [12.4% (104/836) and 26.4% (221/836), respectively]. Improving the skills of endoscopic doctors (84.2%, 704/836), and enhancing the precision of pre-procedure evaluation and quality of multidisciplinary team (78.9%, 660/836) were considered urgent needs in the development of endoscopic treatment. Conclusion:A variety of endoscopic treatments for gastroesophageal varices in portal hypertension are implemented nationwide. Participant hospitals are active to perform emergent endoscopy for acute EGVB, but are inadequate in following recommendations regarding primary and secondary prophylaxis of EGVB. Moreover, the selection of endoscopic procedures for gastric varices differs greatly among hospitals.

Background:The burden of Crohn's disease(CD)is rising globally,and the efficacy and safety of ustekinumab(UST)in treatment of CD need to be further verified.Aims:To assess the short-term efficacy and safety of UST in CD patients.Methods:A single-center retrospective observational study was conducted in the First Affiliated Hospital of Kunming Medical University.The clinical data of CD patients treated with UST from January 2020 to December 2023 were analyzed retrospectively.The clinical activity and endoscopic severity of the disease were assessed using Crohn's disease activity index(CDAI)and simple endoscopic score for Crohn's disease(SES-CD),respectively.The primary outcomes were clinical response(CDAI score decreased≥70 points,or CDAI score decreased<70 points but the total score<150)and clinical remission(CDAI score<150),while the secondary outcomes included endoscopic response(SES-CD decreased≥50%),endoscopic remission(SES-CD≤2),changes of inflammatory and nutritional indicators,and the adverse events.Results:Twenty-seven CD patients were included,of which,16 were males,and 11 were females,with median disease duration of 3.00 years.After treatment with UST,the median CDAI score decreased from 213.00(178.83,302.98)at baseline to 129.83(89.67,151.33)at week 16/20 and 95.07(67.45,178.34)at week 32(all P<0.017).The clinical response rate and remission rate at week 16/20 were 92.6%and 70.4%,respectively,and those at week 32 were 95.5%and 72.7%,respectively.When patients were stratified as biologic na?ve and exposure,or as with and without dose optimization,no significant differences were found in clinical response and remission rates among various subgroups.Seventeen patients reviewed endoscopy at week 16/20,the SES-CD decreased significantly from baseline(5.47±4.53 vs.9.88±4.58,P<0.05),with the endoscopic response rate and remission rate of 35.3%and 23.5%,respectively.C-reactive protein decreased significantly from baseline at week 16/20 and week 32 of treatment(all P<0.017),while the platelet count,hemoglobin,albumin and body mass index only showed insignificant improving trends.No serious adverse events were observed during the medication period.Conclusions:UST can improve the clinical symptoms,endoscopic manifestations,and systemic inflammation effectively in CD patients in short-term follow-up,and represents a good safety profile.

Objective:To investigate the risk factors of moderately severe acute pancreatitis (MSAP) and severe acute pancreatitis (SAP) complicated with pancreatogenic portal hypertension (PPH) and to establish a prediction model.Methods:From January 1, 2016 to December 31, 2022, a total of 1 095 patients diagnosed with MSAP or SAP at the First Affiliated Hospital of Kunming Medical University were enrolled and divided into PPH group (145 cases) and non-PPH group (950 cases) according to the presence or absence of concomitant PPH. The general data (gender, etiology of acute pancreatitis, days of hospitalization, etc.), complications (portal vein thrombosis, pancreatic pseudocyst, pancreatic encapsulated necrosis, etc.), laboratory indicators (albumin, D-dimer, etc.), and scores of modified computed tomography severity index (MCTSI) were collected in the two groups. The least absolute shrinkage and selection operator(LASSO) and multivariate logistic regression analysis were performed to analyze the independent risk factors of MSAP and SAP complicated with PPH, and the nomogram prediction model was established. The area under the curve of the receiver operating characteristic curve was calculated to evaluate the discrimination of the calibration curve and Hosmer-Lemeshow goodness of fit test were used to assess the predictive accuracy of the model, and clinical decision curve analysis (DCA) was used to evaluate the clinical practicability of the model.Results:The results of LASSO and multivariate logistic regression analysis showed that portal vein thrombosis, pancreatic pseudocyst, pancreatic encapsulated necrosis, days of hospitalization, MCTSI and decreased albumin were independent risk factors of MSAP and SAP complicated with PPH ( OR=7.013, 2.085, 1.846, 1.030, 1.235 and 0.955; 95% confidence interval 4.061 to 12.112, 1.255 to 3.463, 1.066 to 3.199, 1.013 to 1.047, 1.123 to 1.357 and 0.927 to 0.983; all P<0.05). The area under the curve of the model was 0.820 (95% confidence interval 0.780 to 0.859), the calibration curve was close to the reference curve, and the Hosmer-Lemeshow goodness-fit test showed that the model had a good fit ( χ2=9.82, P=0.278). The result of DCA indicated that the model had a high net benefit in a wide range of risk threshold (threshold probability 0.1 to 0.9), and had certain clinical practicability. Conclusions:Portal vein thrombosis, pancreatic pseudocyst, pancreatic encapsulated necrosis, days of hospitalization, MCTSI and decreased albumin are the independent risk factors of MSAP and SAP complicated with PPH. The established nomogram model has good differentiation, calibration and clinical practicability.

The gut microbiota is closely related to the occurrence and development of colitis.Enterotoxigenic Bacteroides fragilis secretes enterotoxins,which can stimulate the body to induce colitis,while the type Ⅵ secretion system and antimicrobial proteins of non-enterotoxigenic Bacteroides fragilis are engaged in competition among the Bacteroides.The bacterial products of non-enterotoxigenic Bacteroides fragilis,such as polysaccharide A,short-chain fatty acids,and α-galactosylceramide,can mediate beneficial interactions with the host.This article reviewed the biological characteristics of non-enterotoxigenic Bacteroides fragilis and its mechanism of action in colitis,with the aim of providing theoretical basis for its future clinical application as a probiotics.

The gut microbiota is closely related to the occurrence and development of colitis.Enterotoxigenic Bacteroides fragilis secretes enterotoxins,which can stimulate the body to induce colitis,while the type Ⅵ secretion system and antimicrobial proteins of non-enterotoxigenic Bacteroides fragilis are engaged in competition among the Bacteroides.The bacterial products of non-enterotoxigenic Bacteroides fragilis,such as polysaccharide A,short-chain fatty acids,and α-galactosylceramide,can mediate beneficial interactions with the host.This article reviewed the biological characteristics of non-enterotoxigenic Bacteroides fragilis and its mechanism of action in colitis,with the aim of providing theoretical basis for its future clinical application as a probiotics.

Background:The burden of Crohn's disease(CD)is rising globally,and the efficacy and safety of ustekinumab(UST)in treatment of CD need to be further verified.Aims:To assess the short-term efficacy and safety of UST in CD patients.Methods:A single-center retrospective observational study was conducted in the First Affiliated Hospital of Kunming Medical University.The clinical data of CD patients treated with UST from January 2020 to December 2023 were analyzed retrospectively.The clinical activity and endoscopic severity of the disease were assessed using Crohn's disease activity index(CDAI)and simple endoscopic score for Crohn's disease(SES-CD),respectively.The primary outcomes were clinical response(CDAI score decreased≥70 points,or CDAI score decreased<70 points but the total score<150)and clinical remission(CDAI score<150),while the secondary outcomes included endoscopic response(SES-CD decreased≥50%),endoscopic remission(SES-CD≤2),changes of inflammatory and nutritional indicators,and the adverse events.Results:Twenty-seven CD patients were included,of which,16 were males,and 11 were females,with median disease duration of 3.00 years.After treatment with UST,the median CDAI score decreased from 213.00(178.83,302.98)at baseline to 129.83(89.67,151.33)at week 16/20 and 95.07(67.45,178.34)at week 32(all P<0.017).The clinical response rate and remission rate at week 16/20 were 92.6%and 70.4%,respectively,and those at week 32 were 95.5%and 72.7%,respectively.When patients were stratified as biologic na?ve and exposure,or as with and without dose optimization,no significant differences were found in clinical response and remission rates among various subgroups.Seventeen patients reviewed endoscopy at week 16/20,the SES-CD decreased significantly from baseline(5.47±4.53 vs.9.88±4.58,P<0.05),with the endoscopic response rate and remission rate of 35.3%and 23.5%,respectively.C-reactive protein decreased significantly from baseline at week 16/20 and week 32 of treatment(all P<0.017),while the platelet count,hemoglobin,albumin and body mass index only showed insignificant improving trends.No serious adverse events were observed during the medication period.Conclusions:UST can improve the clinical symptoms,endoscopic manifestations,and systemic inflammation effectively in CD patients in short-term follow-up,and represents a good safety profile.