Identification of novel N7-methylguanine-related gene signatures associated with ulcerative colitis and the association with biological therapy.

OBJECTIVE: Ulcerative colitis (UC) is an inflammatory disease characterized by recurrent episodes of chronic intestinal inflammation. It is closely associated with immune dysregulation in the intestines. However, the mechanisms underlying the role of immune-related N7-methylguanosine (m7G) internal modification in UC remain unclear. METHODS: We conducted a screening of differentially expressed genes (DEGs) associated with m7G and performed immune infiltration analysis. We then investigated the correlation between m7G-related DEGs and immune cells or pathways. To further explore the functional implications, we conducted functional enrichment analysis to identify gene modules that strongly correlated with hub gene expression. In addition, we constructed a miRNA regulatory network for the hub genes in UC. Furthermore, we examined the association between hub genes and disease remission in UC patients undergoing biologic therapy. RESULTS: We obtained 13 m7G-related DEGs and conducted an in-depth analysis of immune infiltration. Among them, we identified five hub genes (NUDT7, NUDT12, POLR2H, QKI, and PRKCB) that showed diagnostic potential for UC. Through WGCNA and KEGG analysis, we found that gene modules strongly correlated with m7G hub gene expression were enriched in inflammation-related pathways. Furthermore, Kaplan-Meier survival analysis revealed a significant association between changes in hub gene expression levels and disease remission in UC patients undergoing biologic therapy. CONCLUSION: The findings of this study demonstrate that five m7G-related DEGs, including the m7G-modified recognition protein QKI, play a key role in the occurrence and progression of UC intestinal inflammation, which is closely related to intestinal immunity. These results provide valuable insights into the mechanisms of m7G modification in UC development and offer new perspectives for exploring novel therapeutic targets for UC.

Quantitative analysis of adipose tissue for predicting Crohn's disease postoperative endoscopic recurrence and anastomotic ulcer.

OBJECTIVE: Inflammation and ulcers at the anastomotic site are frequently observed after intestinal resection surgery for Crohn's disease (CD), which often signify postoperative recurrence. Crohn's disease causes abnormalities in whole-body fat metabolism, and alterations in subcutaneous and visceral fat are potential indicators of disease development. This study aimed to quantify the areas of subcutaneous (SFA) and visceral fat (VFA) and investigate the relationship between fat tissue and endoscopic recurrence and anastomotic ulceration after Crohn's disease surgery. METHODS: We conducted a retrospective analysis of clinical data from 279 patients diagnosed with Crohn's disease. Using abdominal CT (Computed Tomography) scans at the level of the umbilicus, we measured the area of subcutaneous and visceral fat, and calculated the Mesenteric Fat Index (MFI), which is defined as the ratio of the area of visceral fat to subcutaneous fat. We compared the changes in fat tissue between surgical Crohn's disease patients and non-surgical patients in remission, as well as changes in fat tissue before and after surgery, and between patients with and without endoscopic recurrence after surgery. RESULTS: The MFI value of the surgical group was higher than that of the non-surgical group(0.88(1.27 ± 1.26) VS 0.39(0.44 ± 0.21), P < 0.001), while the SFA value was lower(70.16(92.97 ± 78.23) VS 157.64(175.96 ± 101.58), P < 0.001). Of the 134 surgical patients who underwent abdominal CT examination after surgery, the SFA value was significantly higher after surgery(143.61 ± 81.86 VS 90.87 ± 71.93, P < 0.001), and the MFI value decreased accordingly(0.57 ± 0.36 VS 1.30 ± 1.35, P < 0.001). Multivariate Cox analysis indicated that high VFA and MFI values, smoking history, and preoperative biologic therapy were all risk factors for postoperative endoscopic recurrence(p < 0.05), while high MFI values and preoperative biologic therapy were also risk factors for anastomotic ulcers(p < 0.05). The Kaplan-Meier analysis showed that these factors increased the risk of reaching the endpoint with time(p < 0.05). The ROC curve results showed that MFI value had high diagnostic value for postoperative endoscopic recurrence [AUC:0.831, 95% CI: 0.75-0.91, p < 0.001] and anastomotic ulcers [AUC:0.801, 95% CI: 0.71-0.89, p < 0.001]. CONCLUSIONS: Surgical CD patients have significantly higher MFI values but the values decline after surgery. When the preoperative MFI value is > 0.82, the risk of postoperative endoscopic recurrence increases significantly, and when the MFI value is ≥ 1.10, the risk of anastomotic ulceration after surgery increases significantly. Meanwhile, biologic therapy preoperatively also is a high-risk factor for early postoperative endoscopic recurrence or anastomotic ulcers after intestinal resection surgery.

Surgical strategies for intestinal Crohn's disease. / è‚ é“å ‹ç½—æ©ç— çš„å¤–ç§‘æ²»ç–—ç­–ç•¥.

OBJECTIVES: As a type of inflammatory bowel disease, Crohn's disease (CD) is characterized by jumping lesions and transmural inflammation. The treatment goal is to control the development of inflammation with drugs such as 5-Amino Salicylic Acid, azathioprine and hormones, but most patients still need surgical treatment eventually. The surgical treatment of CD requires exquisite surgical design and solid surgical procedures to minimize the progression of intestinal lesions and preserve the normal bowel segment as much as possible. This study aims to summarize and discuss the surgical treatments for intestinal CD, and to provide references for the surgical treatment of intestinal CD. METHODS: Clinical data of 122 patients with CD were analyzed retrospectively. They all received surgical treatments in the Second Xiangya Hospital of Central South University between Jan. 1, 2015 and Jan. 1, 2021. The data included general information, clinical manifestations, preoperative examination, preoperative preparation, surgical methods, pathological examination, complications, and follow-up data. RESULTS: Except 1 case of emergency surgery, all the other patients met the surgical indications of intestinal CD after multi-disciplinary discussion (MDT) and they were transferred to surgery for elective surgery, and received high-quality intestinal preparation before surgery. Among them, 99 cases underwent one-stage abdominal operation and 23 cases underwent the second abdominal operation. All patients underwent successful surgery with good surgical results, with significantly alleviated clinical symptoms and the BMI significantly increased compared with those before surgery. There were 14 cases (11.5%) of postoperative complications. One case of delayed anastomotic fistula and one case of small intestinal cutaneous fistula which were successfully treated by conservative treatment, the other 12 cases were successfully treated by reoperation, and there were no complications with follow-up operation. The postoperative pathological diagnosis for all patients was clear. All patients received regular follow-up with 5-70 (median 36) months and no clinical recurrence was found. CONCLUSIONS: As the surgical treatment of intestinal CD, surgeons should strictly grasp the surgical indications based on the MDT. During the operation of small intestinal CD, it is advisable to preserve bowel segment as much as possible. For patients with short remaining normal bowel segment, the intestinal canal should be preserved as far as possible, even for the mildly diseased bowel, so as to avoid the occurrence of short bowel syndrome and leave room for possible reoperation. In the treatment of secondary duodenal CD, it is necessary to carefully identify the nature of the local lesions. Different surgical treatments should be performed according to whether there is an internal fistula and the size of this fistula. Meanwhile, duodenectomy or pancreaticoduodenectomy should be considered as the final surgical method in the treatment of primary duodenal CD.

Inhibitor of apoptosis-stimulating p53 protein protects against inflammatory bowel disease in mice models by inhibiting the nuclear factor kappa B signaling.

Drugs and therapies available for the treatment of inflammatory bowel disease (IBD) are not satisfactory. Our previous study has established the inhibitor of apoptosis-stimulating p53 protein (iASPP) as an oncogenic regulator in colorectal cancer by forming a regulatory axis or feedback loop with miR-124, p53, or p63. As iASPP could target and inhibit nuclear factor kappa B (NF-κB) activation, in this study the role and mechanism of iASPP in IBD was investigated. The aberrant up-regulation of iASPP in IBD was subsequently confirmed, based on online data sets, clinical sample examinations and 2,4,6-trinitrobenzene sulfonic acid (TNBS)- and dextran sulfate sodium (DSS)-induced colitis mice models. TNBS or DSS stimulation successfully induced colon shortness, body weight loss, mice colon oxidative stress and inflammation. In both types of colitis mice models, iASPP over-expression improved, whereas iASPP knockdown aggravated TNBS or DSS stimulation-caused colon shortness, body weight loss and mice colon oxidative stress and inflammation. Meanwhile, in both types of colitis mice models, iASPP over-expression inhibited p65 phosphorylation and decreased the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, C-X-C motif chemokine ligand (CXCL)1 and CXCL2 in mice colons, whereas iASPP knockdown exerted opposite effects.

Advance in Human Epithelial-Derived Organoids Research.

Organoids have complex three-dimensional structures that exhibit functionalities and feature architectures similar to those of in vivo organs and are developed from adult stem cells, embryonic stem cells, and pluripotent stem cells through a self-organization process. Organoids derived from adult epithelial stem cells are the most mature and extensive. In recent years, using organoid culture techniques, researchers have established various adult human tissue-derived epithelial organoids, including intestinal, colon, lung, liver, stomach, breast, and oral mucosal organoids, all of which exhibit strong research and application prospects. Studies have shown that epithelial organoids are mainly applied in drug discovery, personalized drug response testing, disease mechanism research, and regenerative medicine. In this review, we mainly discuss current organoid culture systems and potential applications of this technique with human epithelial tissue.

Letter regarding "MT1-MMP is not a good prognosticator of cancer survival: evidence from 11 studies" by Wu KP et al.

With great interest, we carefully read a meta-analysis entitled "MT1-MMP is not a good prognosticator of cancer survival: evidence from 11 studies" in Tumor Biology (by Wu KP et al.), in which the investigators aimed to assess the association between MT1-MMP expression and prognosis of patients with various types of cancers by calculating the pooled hazard ratio (HR) with corresponding 95 % confidence interval (95 % CI). They have reached an important conclusion that MT1-MMP overexpression indicated an unfavorable overall survival (OS) in cancers and the pooled HR (95 % CI) was 2.46 (95 % CI 1.75-3.47). In addition, subgroup analysis showed the HRs (95 % CI) were 3.73 (95 % CI 2.67-5.21) and 2.46 (95 % CI 1.69-3.59) for MT1-MMP in lung cancer and gastric cancer, respectively. Before these results can be accepted, we would like to address several concerns related to this meta-analysis.

Knockdown of p62/sequestosome 1 attenuates autophagy and inhibits colorectal cancer cell growth.

p62/sequestosome-1 is a multifunctional adapter protein implicated in selective autophagy, cell signaling pathways, and tumorigenesis, and plays an important role at the crossroad between autophagy and cancer. But, the connection between autophagy and cancer is complex and in some cases contradictory. Human colorectal cancer tissues from patients were analyzed for expression of p62 and Microtubule-associated protein light chain 3 (LC3, an autophagosome marker) using immunostaining, western blotting, real-time PCR, and confocal microscopy. To study the effects of p62 on autophagy and cell growth, shRNA for p62 was applied and cell growth curve was monitored in human colorectal cancer cell. In vivo experiments were done using the mouse xenograft model. We showed that up-regulated expression of p62 and LC3 in colorectal cancer tissues. We also demonstrated that specifically knockdown the expression of p62 showed significantly inhibitory effects not only on autophagy activation, but also on tumor growth both in vitro and xenograft tumors model. The ectopic overexpression of p62 and autophagy activation contributes to colorectal tumorigenesis. p62 and autophagy will be therapy targets for the treatment of colorectal cancer.

Timing of first abdominal operation in Crohn's disease based on a diagnostic model.

This study aims to develop a clinical diagnostic model for assessing the need for initial abdominal surgery in patients diagnosed with Crohn's disease (CD) and create a nomogram to facilitate clinical decision-making. A total of 164 surgical CD patients and 230 control CD patients were included in this retrospective analysis. Least Absolute Shrinkage and Selection Operator (Lasso) regression and binomial logistic regression were employed to select clinical variables. The 394 CD patients were randomly allocated to a training set and a validation set in a 7:3 ratio. The filtered variables were used to establish a diagnostic model and nomogram in the training set, subsequently validated in the testing set. Decision Curve Analysis (DCA) and clinical impact curve were constructed to validate the clinical applicability of the model. Binomial logistic regression analysis identified seven clinical variables with a p-value less than 0.01, including Biomarker (B), Waist-to-Height Ratio (WHtR), Intestinal obstruction, Albumin (ALB), Crohn's Disease Activity Index (CDAI), Myocardial Flow Index (MFI), and C-reactive protein (CRP). These variables were utilized to establish the diagnostic model. Calibration curves showed good alignment, with a C-index of 0.996 in the training set and 0.990 in the testing set. DCA and clinical impact curve demonstrated that the diagnostic model had good clinical efficiency and could provide clinical benefits. A validated diagnostic model for determining the timing of the first abdominal operation in CD patients was established and evaluated, showing high discriminative ability, calibration, and clinical efficiency. It can be utilized by clinicians to assess the optimal timing for transitioning CD patients from medical treatment to surgical intervention, providing valuable references for individualized treatment decisions for CD patients.

Restoration of klotho gene expression induces apoptosis and autophagy in gastric cancer cells: tumor suppressive role of klotho in gastric cancer.

BACKGROUND: The loss of tumor suppressor gene expression is involved in the carcinogenesis of gastric cancer (GC). Klotho is a recently identified tumor suppressor gene that epigenetically inactivated in gastric cancer. However, the signaling pathways involved in the suppressive role of klotho have rarely been reported in gastric cancer. In this study, we investigated the involvement of klotho in gastric cancer cell proliferation, apoptosis, and autophagy as well as the associated signaling. METHODS: Methylation of klotho gene promoter in GC-7901, MNK-45 and AGS gastric cancer cells as well as GES-1 normal gastric epithelial cells was detected by bisulfate-based PCR. Restoration of klotho gene expression was established by applying a demethylating agent and delivering aklotho gene expression vector into GC-7901 cells. Cell viability was measured by CCK-8 assay. Cell apoptosis and cycling were analyzed by flow cytometry. Autophagy was measured by detecting LC3-I and LC3-II expression. Protein levels and phosphorylation were measured by Western blot assay. RESULTS: Methylation of klotho gene promoter and expression of the klotho gene were detected in GC cells. Restoration of klotho gene expression significantly inhibited cell proliferation, induced cell apoptosis, and increased LC3-I/LC3-II expression in GC cells. Restoration of klotho gene expression downregulated the phosphorylation levels of IGF-1 receptor, IRS-1, PI3K, Akt, and mTOR proteins. Both apoptosis and autophagy inhibitors blocked klotho-induced apoptosis and autophagy. CONCLUSION: Klotho is a tumor suppressor in gastric cancer, which regulates IGF-1R phosphorylation and the subsequent activation of IRS-1/PI3K/Akt/mTOR signaling, tumor cell proliferation, apoptosis, and autophagy.

Correlation of S1P1 and ERp29 expression to progression, metastasis, and poor prognosis of gallbladder adenocarcinoma.

BACKGROUND: Gallbladder cancer (GBC) is one of the most aggressive malignant neoplasms with an extremely poor prognosis. Early diagnosis significantly increases the survival rate. The present study was undertaken to evaluate the diagnostic and prognostic value of sphingosine-1-phosphate receptor 1 (S1P1) and endoplasmic reticulum protein 29 (ERp29) in benign and malignant gallbladder lesions and to develop a possible alternative treatment for GBC. METHODS: A total of 100 gallbladder adenocarcinoma, 46 peritumoral, 30 gallbladder adenomatous, 15 gallbladder polyp, and 35 chronic cholecystitis tissues were included. S1P1 and ERp29 expressions were evaluated by immunohistochemistry. The correlation between S1P1 and ERp29 expression and tumor pathological features and prognosis was analyzed. RESULTS: S1P1 positive rate was significantly higher in gallbladder adenocarcinomas than that in peritumoral, adenomatous, polyp, and chronic cholecystitis tissues. On the contrary, ERp29 positive rate was significantly lower in adenocarcinomas than that in peritumoral, adenomatous, polyp, and chronic cholecystitis tissues. Benign lesions with positive S1P1 or negative ERp29 expression showed moderate or severe atypical hyperplasia in the gallbladder epithelium. The overexpression of S1P1 or non-expression of ERp29 was significantly associated with tumor differentiation, tumor mass, lymph node metastasis, and adenocarcinoma invasion. Univariate Kaplan-Meier analysis showed that the elevated S1P1 (P=0.008) or absence of ERp29 (P=0.043) was closely associated with decreased survival rate. Multivariate Cox regression analysis showed that S1P1 positive (P=0.004) or ERp29 negative (P=0.029) was an independent predictor of poor prognosis in gallbladder adenocarcinoma. CONCLUSION: S1P1 overexpression or ERp29 absence is related to the carcinogenesis and progression, and may be potential biomarkers for early detection of gallbladder adenocarcinoma.

Modified Primary Anastomosis Using an Intestinal Internal Drainage Tube for Crohn's Disease: A Pilot Study.

PURPOSE: Surgical treatment is an important part of the management of Crohn's disease (CD). However, the current recommended staged procedures require two operations, with long hospital stays and high costs, while traditional primary anastomosis has a high risk of complications. Therefore, the aim of this study was to compare the clinical efficacy and safety of modified primary anastomosis using intestinal internal drainage tubes for CD. METHODS: In this study, emergency and nonemergency CD patients were included separately. Then, the patients were divided into three subgroups: patients with intestinal internal drainage tubes (modified primary anastomosis), staged procedures, and traditional primary anastomosis. The main outcomes were the number of hospitalizations, length and cost of the first hospital stay, length and cost of total hospital stays, and complications. RESULTS: The outcomes of the three subgroups of emergency CD patients were not significantly different. For nonemergency CD patients, patients with intestinal internal drainage tubes had shorter total hospital stays and fewer hospitalizations compared with the staged procedures subgroup, while no significant differences in any outcomes were observed between the modified and traditional primary anastomosis subgroups. CONCLUSIONS: For emergency CD patients, no significant advantage in terms of the main outcomes was observed for modified primary anastomosis. For nonemergency CD patients, modified primary anastomosis reduced the length of total hospital stays and hospitalizations compared with staged procedures. The placement of intestinal internal drainage tubes allows some patients who cannot undergo primary anastomosis to undergo it, which is a modification of traditional primary anastomosis.

The predictive significance of a 5-m6A RNA methylation regulator signature in colorectal cancer.

Colorectal cancer attacks the colon or rectum, with increasing morbidity and mortality globally. The RNA modification 6-methyladenine (m6A) is related to RNA modifications, playing a critical role in colorectal cancer. We aimed to identify prognostic signatures for colorectal cancer using risk prediction algorithms, and to validate these signatures using independent datasets and clinical samples. In this study, 175 cases in GSE17536 were assigned into two clusters using consistent clustering and PCA analysis. A multivariate Cox risk regression model revealed that among 21 m6A RNA methylation regulators, RBM15B, FTO, IGF2BP2, ZCCHC4, and KIAA1429 were remarkably associated with colorectal cancer patients' overall survival (OS); however, Kaplan-Meier (KM) survival assessment showed no significant association between these five regulators and colorectal cancer patients' prognosis. A 5-m6A RNA methylation regulator signature was established using LASSO algorithm. Risk scores of cases in GSE17536, GSE17537 and GSE75500 were calculated, and lower risk scores were associated with better DSS/OS. receiver operating characteristic (ROC) curve and the nomogram revealed the satisfactory predictive efficiency of the risk score model. The risk score could distinguish cases in Cluster1 and Cluster2 and normal and tumor tissues based on GSE37182. The prognostic variables for colorectal cancer patients were assessed using both univariate and multivariate Cox's proportional hazard regression models, which revealed that the stage and risk score were significant risk factors. In this study, a comprehensive set of integrative bioinformatics analyses was conducted to investigate the prognostic and diagnostic potential of a panel of 5 m6A RNA methylated regulators in colorectal cancer patients. The conducted studies included the use of several statistical methods, such as the LASSO regression model, KM survival evaluation, ROC curve, and univariate and multivariate Cox's proportional hazard regression analyses. The findings from these analyses collectively established the prognostic marker, highlighting its significance in predicting patient outcomes and diagnosing colorectal cancer.

Ginsenoside Rg3 Ameliorates DSS-Induced Colitis by Inhibiting NLRP3 Inflammasome Activation and Regulating Microbial Homeostasis.

Ulcerative colitis (UC) is a recurrent inflammatory disease without a specific cure or treatment for improvement. Here, we investigated the potential therapeutic effect and mechanism of ginsenoside Rg3 (Gin Rg3) on UC. We constructed an in vitro cellular inflammatory model and a dextran sulfate sodium (DSS)-induced UC mouse model. We also used Gin Rg3, MCC950 (NLRP3 inhibitor), MSU (NLRP3 activator), and fecal transplantation (FMT) to intervene the model. The results showed that Gin Rg3 inhibited NLRP3 inflammasome activation, pyroptosis, and apoptosis in vitro and in vivo. DSS-induced changes in the abundance of gut microbiota at the phylum or genus level were partially restored by Gin Rg3. Furthermore, gin Rg3 affected intestinal metabolism in mice by inhibiting the activation of NLRP3 inflammasome. The gut microbiota treated with Gin Rg3 was sufficient to alleviate DSS-induced UC. In summary, Gin Rg3 alleviated DSS-induced UC by inhibiting NLRP3 inflammasome activation and regulating gut microbiota homeostasis.

Surgical management of duodenal Crohn's disease.

BACKGROUND: The case of Crohn's disease involving the duodenum is rare, and its surgical management requires a thorough understanding. AIM: To investigate the surgical management of duodenal Crohn's disease. METHODS: We systematically reviewed patients diagnosed with duodenal Crohn's disease who underwent surgery in the Department of Geriatrics Surgery of the Second Xiangya Hospital of Central South University from January 1, 2004, to August 31, 2022. The general information, surgical procedures, prognosis, and other information of these patients were collected and summarized. RESULTS: A total of 16 patients were diagnosed with duodenal Crohn's disease, where 6 cases had primary duodenal Crohn's disease, and 10 had secondary duodenal Crohn's disease. Among patients with primary disease, 5 underwent duodenal bypass and gastrojejunostomy, and 1 received pancreaticoduodenectomy. Among those with a secondary disease, 6 underwent closure of duodenal defect and colectomy, 3 received duodenal lesion exclusion and right hemicolectomy, and 1 underwent duodenal lesion exclusion and double-lumen ileostomy. CONCLUSION: Crohn's disease involving the duodenum is a rare condition. Different surgical management should be applied for patients with Crohn's disease presenting with different clinical manifestations.

Laparoscopic surgery contributes to a decrease in short-term complications in surgical ulcerative colitis patients during 2008-2017: a multicenter retrospective study in China.

BACKGROUND/AIMS: The aim of this study was to analyze the chronological changes in postoperative complications in surgical ulcerative colitis patients over the past decade in China and to investigate the potential parameters that contributed to the changes. METHODS: Ulcerative colitis patients who underwent surgery during 2008-2017 were retrospectively enrolled from 13 hospitals in China. Postoperative complications were compared among different operation years. Risk factors for complications were identified by logistic regression analysis. RESULTS: A total of 446 surgical ulcerative colitis patients were analyzed. Fewer short-term complications (24.8% vs. 41.0%, P=0.001) and more laparoscopic surgeries (66.4% vs. 25.0%, P<0.001) were found among patients who received surgery during 2014-2017 than 2008-2013. Logistic regression suggested that independent protective factors against short-term complications were a higher preoperative body mass index (odds ratio [OR], 0.870; 95% confidence interval [CI], 0.785-0.964; P=0.008), laparoscopic surgery (OR, 0.391; 95% CI, 0.217-0.705; P=0.002) and elective surgery (OR, 0.213; 95% CI, 0.067-0.675; P=0.009). The chronological decrease in short-term complications was associated with an increase in laparoscopic surgery. CONCLUSIONS: Our data revealed a downward trend of short-term postoperative complications among surgical ulcerative colitis patients in China during the past decade, which may be due to the promotion of minimally invasive techniques among Chinese surgeons.

MicroRNA-200c-5p targets NIMA Related Kinase 7 (NEK7) to inhibit NOD-like receptor 3 (NLRP3) inflammasome activation, MODE-K cell pyroptosis, and inflammatory bowel disease in mice.

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is characterized by chronic inflammation of the lower gastrointestinal tract with unknown etiology. In our previous study, NOD-like receptor 3 (NLRP3) inflammasome activation requiring the interaction of NLRP3 with NIMA Related Kinase 7 (NEK7) had been reported to regulate MODE-K cell pyroptosis and dextran sulfate sodium (DSS)-induced murine colitis. In the present study, miR-200c was closely related to IBD using weighted gene correlation network analysis (WGCNA). MicroRNA-200c (miR-200c) expression was down-regulated in IBD samples and negatively correlated with NLRP3. In MODE-K cells, miR-200c overexpression inhibited cellular inflammation; under adenosine triphosphate (ATP) and lipopolysaccharides (LPS) co-stimulation, miR-200c overexpression attenuated ATP and LPS-induced cell pyroptosis. In the DSS-induced IBD mice model, miR-200c overexpression alleviated DSS-induced IBD symptoms and improved physiological and biochemical indexes. Through direct targeting, miR-200c inhibited NEK7 expression. In MODE-K cells, NEK7 overexpression promoted cellular inflammation and ATP and LPS-induced cell pyroptosis; when co-transduced into MODE-K cells, NEK7 overexpression partially attenuated miR-200c agomir effects on cellular inflammation and ATP and LPS-induced cell pyroptosis. In conclusion, miR-200c, through targeting NEK7, could decrease cellular inflammation levels and NLRP3 inflammasome-related MODE-K cell pyroptosis in vitro and improve DSS-induced murine IBD symptoms in vivo.

METTL3 overexpression aggravates LPS-induced cellular inflammation in mouse intestinal epithelial cells and DSS-induced IBD in mice.

The inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are chronic inflammatory disorders of the intestine. Dysregulated cytokine secretion and signal transduction mechanisms via intestinal epithelial cells are involved in IBD pathogenesis, in which the transcription factor NF-κB plays a critical role. In this study, METTL3, which plays a key role in inflammation regulation, has been recognized significantly up-regulated in IBD samples, DSS-induced IBD mice, and LPS-treated MODE-K cells. Within LPS-treated MODE-K cells, METTL3 knockdown promoted cell viability, inhibited cell apoptosis, decreased apoptotic caspase3/9 cleavage, and decreased the levels of proinflammatory cytokines (IL-1ß, TNF-α, IL-6, and IL-18) and inflammatory enzymes (COX-2 and iNOS). Under the same conditions, METTL3 knockdown inhibited, whereas METTL3 overexpression promoted p65 phosphorylation in MODE-K cells; NF-κB inhibitor JSH-23 partially abolished the promotive effects of METTL3 overexpression upon p65 phosphorylation. Consistently, the effects of METTL3 overexpression upon LPS-stimulated MODE-K cells were partially abolished by JSH-23. Lastly, METTL3 knockdown in DSS-induced IBD mice significantly ameliorated DSS-induced IBD and inhibited DSS-induced p65 phosphorylation. In conclusion, METTL3 overexpression aggravates LPS-induced cellular inflammation in mouse intestinal epithelial cells and DSS-induced IBD in mice. The NF-κB signaling might be involved, and the regulatory mechanism remains to be investigated in our future study.

Transcriptomic landscape of sodium butyrate-induced growth inhibition of human colorectal cancer organoids.

Butyrate, a short-chain fatty acid, is predominantly produced by the decomposition of dietary fiber in the colon. Recent studies have shown that sodium butyrate (NaB) can inhibit cell proliferation and stimulate cell apoptosis in colorectal cancer (CRC) cells. However, the molecular mechanism behind NaB is still elusive. In this study, we aimed to explore the deeper mechanism of NaB in CRC by establishing a novel model - organoid. Organoids were generated from healthy and cancerous sites of CRC patients. RNA-seq experiments were undertaken using RNA isolated from the CRC organoids treated with NaB. Gene ontology analyses suggested that cell adhesion, cell-cell signaling, and extracellular matrix (ECM) organization were significantly enriched, with the manifested ECM related to the cell morphology variation in NaB-induced CRC organoids. The KEGG pathway and PPI analysis mainly focused on ECM-receptor interactions, as well as the PI3K-Akt signaling pathway. Interestingly, further analysis suggested that the upregulation of the expression of ITGB7 and ITGA2B was significantly associated with death by NaB-induced CRC organoids. In addition, NaB might further induce cell cycle arrest via the PI3K-Akt pathway, and thus cause cell death. Cumulatively, these results provide evidence that the ECM-integrin/PI3K axis may mediate phenotypic changes in the NaB-treated CRC organoid, which provides a broader perspective of the treatment and prognosis monitoring of CRC.

Role of a multidisciplinary team (MDT) in the diagnosis, treatment, and outcomes of inflammatory bowel disease: a single Chinese center's experience.

The incidence of inflammatory bowel disease (IBD) with a poor prognosis is increasing, and a single field is not capable of fully diagnosing and comprehensively treating IBD. The purpose of the current study was to explore the role of a multidisciplinary team (MDT) in the diagnosis and treatment of IBD. Subjects were 55 patients with IBD who underwent surgery at this hospital before the establishment of a MDT (before June 2016) and 276 patients who were discussed by a MDT; 72 of the latter patients underwent surgery. The preoperative rate of diagnosis, preoperative basic nutritional status, frequency of emergency surgery, and surgical complications in the two groups were compared to determine whether the MDT significantly affected the diagnosis and treatment of IBD and to explore trends in the types of patients with IBD and treatment decision-making since the establishment of MDT. Results revealed that the MDT significantly improved preoperative diagnostic accuracy for patients with IBD who underwent surgery (p < 0.005), and the frequency of elective surgery decreased significantly (p < 0.005). There were significant differences in the rate of clinical recurrence (p < 0.005) and the rate of additional surgery (p < 0.01) between the two groups, with higher rates in the control group. In terms of preoperative nutritional status, the proportion of decreased serum albumin and hemoglobin in the experimental group was significantly lower than that in the control group (p < 0.05). MDT plays a positive role in accurate preoperative diagnosis, improvement of preoperative preparations, and a reduction in postoperative adverse events for patients with IBD undergoing surgery.

Exosomal MicroRNA-181a Derived From Mesenchymal Stem Cells Improves Gut Microbiota Composition, Barrier Function, and Inflammatory Status in an Experimental Colitis Model.

Background: Mesenchymal stem cell (MSC)-derived exosomes (Exos) are recently proved to be a promising candidate for ulcerative colitis (UC), but the mechanism remains unclear. We investigated the effects of MSC-derived exosomal microRNA-181a (miR-181a) on gut microbiota, immune responses, and intestinal barrier function in UC. Methods: Human bone marrow MSC-derived Exos were extracted and identified via transmission electron microscopy (TEM), Nanoparticle Tracking Analysis (NTA), and Western blotting. Dextran sodium sulfate (DSS)-induced colitis model and lipopolysaccharide (LPS)-induced human colonic epithelial cell (HCOEPIC) model were established to determine the effect of MSC-Exos on gut microbiota, immune responses, and intestinal barrier function in vivo and in vitro. The relationship between miR-181a and UC was analyzed using the Gene Expression Omnibus (GEO) database. MSC-miR-181-inhibitor was used to reveal the role of exosomal miR-181a in DSS-induced colitis. Results: TEM and NTA results showed that Exos of a diameter of about 100 nm with the round and oval vesicle-like structure were successfully extracted. The expressions of the CD63, CD81, and TSG101 proteins were positive in these Exos. After MSC-Exo treatment, the colon length in colitis mice increased; colon inflammatory injury decreased; TNF-α, IL-6, IL-1ß, IL-17, and IL-18 levels decreased; and Claudin-1, ZO-1, and IκB levels increased. In addition, the structure of the gut microbiota in DSS-induced colitis mice was changed by MSC-Exos. MSC-Exos showed antiapoptotic effects on LPS-induced HCOEPIC. The protective effects decreased significantly by treatment with MSC-Exos interfered with miR-181a inhibitor in vivo and in vitro. Conclusion: MSC-derived exosomal miR-181a could alleviate experimental colitis by promoting intestinal barrier function. It exerted anti-inflammatory function and affected the gut microbiota. This indicated that MSC exosomal miR-181a may exhibit potential as a disease-modifying drug for UC.