Fraxinellone alleviates colitis-related intestinal fibrosis by blocking the circuit between PD-1+ Th17 cells and fibroblasts.

BACKGROUND: Excessive activation of colonic fibroblasts and differentiation of T helper 17 (Th17) cells are the key steps for intestinal fibrogenesis in the process of inflammatory bowel disease (IBD). Although both transforming growth factor-beta (TGF-ß)/Mothers Against Decapentaplegic Homolog (SMAD) 3-induced fibroblasts activation and interleukin (IL)-6/signal transducer and activator of transcription (STAT) 3-induced Th17 differentiation have been well studied, the crosstalk between fibroblasts and Th17 cells in the process of intestinal fibrogenesis needs to be unveiled. METHODS: In this study, the activation of colonic fibroblasts was induced with dextran sulfate sodium salt (DSS) and TGF-ß in vivo and in vitro respectively. P-SMAD3 and its downstream targets were quantified using RT-PCR, western blot and immunofluorescence. The differentiation of programmed death 1 (PD-1) + Th17 and activation of fibroblasts were quantified by FACS. PD-1+ Th17 cells and fibroblasts were co-cultured and cytokines in the supernatant were tested by ELISA. The anti-fibrosis effects of different chemical compounds were validated in vitro and further confirmed in vivo. RESULTS: The colonic fibroblasts were successfully activated by DSS and TGF-ß in vivo and in vitro respectively, as activation markers of fibroblasts (p-SMAD3 and its downstream targets such as Acta2, Col1a1 and Ctgf) were significantly increased. The activated fibroblasts produced more IL-6 compared with their inactivated counterparts in vivo and in vitro. The proinflammatory cytokine IL-6 induced PD-1+ Th17 differentiation and TGF-ß that in return promoted the activation of colonic fibroblasts. Fraxinellone inhibited TGF-ß+ PD-1+ Th17 cells via deactivating STAT3. CONCLUSIONS: The reciprocal stimulation constructed a circuit of PD-1+ Th17 cells and fibroblasts that accelerated the fibrosis process. Fraxinellone was selected as the potential inhibitor of the circuit of PD-1+ Th17 cells and fibroblasts in vivo and in vitro. Inhibiting the circuit of PD-1+ Th17 cells and fibroblasts could be a promising strategy to alleviate intestinal fibrosis.

Clinical manifestation, lifestyle, and treatment patterns of chronic erosive gastritis: A multicenter real-world study in China.

BACKGROUND: Although chronic erosive gastritis (CEG) is common, its clinical characteristics have not been fully elucidated. The lack of consensus regarding its treatment has resulted in varied treatment regimens. AIM: To explore the clinical characteristics, treatment patterns, and short-term outcomes in CEG patients in China. METHODS: We recruited patients with chronic non-atrophic or mild-to-moderate atrophic gastritis with erosion based on endoscopy and pathology. Patients and treating physicians completed a questionnaire regarding history, endoscopic findings, and treatment plans as well as a follow-up questionnaire to investigate changes in symptoms after 4 wk of treatment. RESULTS: Three thousand five hundred sixty-three patients from 42 centers across 24 cities in China were included. Epigastric pain (68.0%), abdominal distension (62.6%), and postprandial fullness (47.5%) were the most common presenting symptoms. Gastritis was classified as chronic non-atrophic in 69.9% of patients. Among those with erosive lesions, 72.1% of patients had lesions in the antrum, 51.0% had multiple lesions, and 67.3% had superficial flat lesions. In patients with epigastric pain, the combination of a mucosal protective agent (MPA) and proton pump inhibitor was more effective. For those with postprandial fullness, acid regurgitation, early satiety, or nausea, a MPA appeared more promising. CONCLUSION: CEG is a multifactorial disease which is common in Asian patients and has non-specific symptoms. Gastroscopy may play a major role in its detection and diagnosis. Treatment should be individualized based on symptom profile.

Lipid Metabolism-Related Gene Signature Predicts Prognosis and Indicates Immune Microenvironment Infiltration in Advanced Gastric Cancer.

Objective: Abnormal lipid metabolism is known to influence the malignant behavior of gastric cancer. However, the underlying mechanism remains elusive. In this study, we comprehensively analyzed the biological significance of genes involved in lipid metabolism in advanced gastric cancer (AGC). Methods: We obtained gene expression profiles from The Cancer Genome Atlas (TCGA) database for early and advanced gastric cancer samples and performed differential expression analysis to identify specific lipid metabolism-related genes in AGC. We then used consensus cluster analysis to classify AGC patients into molecular subtypes based on lipid metabolism and constructed a diagnostic model using least absolute shrinkage and selection operator- (LASSO-) Cox regression analysis and Gene Set Enrichment Analysis (GSEA). We evaluated the discriminative ability and clinical significance of the model using the Kaplan-Meier (KM) curve, ROC curve, DCA curve, and nomogram. We also estimated immune levels based on immune microenvironment expression, immune checkpoints, and immune cell infiltration and obtained hub genes by weighted gene co-expression network analysis (WGCNA) of differential genes from the two molecular subtypes. Results: We identified 6 lipid metabolism genes that were associated with the prognosis of AGC and used consistent clustering to classify AGC patients into two subgroups with significantly different overall survival and immune microenvironment. Our risk model successfully classified patients in the training and validation sets into high-risk and low-risk groups. The high-risk score predicted poor prognosis and indicated low degree of immune infiltration. Subgroup analysis showed that the risk model was an independent predictor of prognosis in AGC. Furthermore, our results indicated that most chemotherapeutic agents are more effective for AGC patients in the low-risk group than in the high-risk group, and risk scores for AGC are strongly correlated with drug sensitivity. Finally, we performed qRT-PCR experiments to verify the relevant results. Conclusion: Our findings suggest that lipid metabolism-related genes play an important role in predicting the prognosis of AGC and regulating immune invasion. These results have important implications for the development of targeted therapies for AGC patients.

Ileitis promotes MASLD progression via bile acid modulation and enhanced TGR5 signaling in ileal CD8+ T cells.

BACKGROUND & AIMS: Clinical evidence substantiates a link between inflammatory bowel disease, particularly Crohn's disease (CD), and metabolic dysfunction-associated steatotic liver disease (MASLD). This study aims to explore the underlying molecular mechanisms responsible for this association. METHODS: MASLD was induced by administering high-fat and western diets, while inflammatory bowel disease was induced using DSS (dextran sulfate sodium) and the Il10 knockout (KO) mouse model. The investigation into the role of secondary bile acids (SBAs) in ileitis involved employing metagenomic sequencing, conducting metabolomics detection, performing fecal microbiota transplantation, and constructing CD8+ T cell-specific gene knockout mice. RESULTS: In MASLD+DSS and Il10 KO MASLD mice, we observed ileitis characterized by T-cell infiltration and activation in the terminal ileum. This condition resulted in decreased bile acid levels in the portal vein and liver, inhibited hepatic farnesoid X receptor (FXR) activation, and exacerbated MASLD. Metagenomic and metabolomic analysis of ileal contents revealed increased Clostridium proliferation and elevated SBA levels in MASLD-associated ileitis. Experiments using germ-free mice and fecal microbiota transplantation suggested an association between SBA and MASLD-related ileitis. In vitro, SBAs promoted CD8+ T-cell activation via the TGR5, mTOR, and oxidative phosphorylation pathways. In vivo, TGR5 KO in CD8+ T cells effectively alleviated ileitis and reversed the MASLD phenotype. Clinical data further supported these findings, demonstrating a positive correlation between ileitis and MASLD. CONCLUSION: MASLD-induced changes in intestinal flora result in elevated levels of SBAs in the ileum. In the presence of a compromised intestinal barrier, this leads to severe CD8+ T cell-mediated ileitis through the TGR5/mTOR/oxidative phosphorylation signaling pathway. Ileitis-induced tissue damage impairs enterohepatic circulation, inhibits hepatic FXR activation, and exacerbates the MASLD phenotype. IMPACT AND IMPLICATIONS: Our study provides a comprehensive investigation of the interplay and underlying mechanisms connecting ileitis and metabolic dysfunction-associated steatotic liver disease (MASLD). Secondary bile acids produced by intestinal bacteria act as the critical link between MASLD and ileitis. Secondary bile acids exert their influence by disrupting liver lipid metabolism through the promotion of CD8+ T cell-mediated ileitis. In future endeavors to prevent and treat MASLD, it is essential to thoroughly account for the impact of the intestinal tract, especially the ileum, on liver function via the enterohepatic circulation.

Structure-based development of potent and selective type-II kinase inhibitors of RIPK1.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases. A number of allosteric RIPK1 inhibitors (RIPK1i) have been developed, and some of them have already advanced into clinical evaluation. Recently, selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge. Here, we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i. We also describe the structure-guided lead optimization of a potent, selective, and orally bioavailable RIPK1i, 62, which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases. Collectively, 62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.

RIPK1 activation in Mecp2-deficient microglia promotes inflammation and glutamate release in RTT.

Rett syndrome (RTT) is a devastating neurodevelopmental disorder primarily caused by mutations in the methyl-CpG binding protein 2 (Mecp2) gene. Here, we found that inhibition of Receptor-Interacting Serine/Threonine-Protein Kinase 1 (RIPK1) kinase ameliorated progression of motor dysfunction after onset and prolonged the survival of Mecp2-null mice. Microglia were activated early in myeloid Mecp2-deficient mice, which was inhibited upon inactivation of RIPK1 kinase. RIPK1 inhibition in Mecp2-deficient microglia reduced oxidative stress, cytokines production and induction of SLC7A11, SLC38A1, and GLS, which mediate the release of glutamate. Mecp2-deficient microglia release high levels of glutamate to impair glutamate-mediated excitatory neurotransmission and promote increased levels of GluA1 and GluA2/3 proteins in vivo, which was reduced upon RIPK1 inhibition. Thus, activation of RIPK1 kinase in Mecp2-deficient microglia may be involved both in the onset and progression of RTT.

STAT3 palmitoylation initiates a positive feedback loop that promotes the malignancy of hepatocellular carcinoma cells in mice.

Constitutive activation of the transcription factor STAT3 (signal transducer and activator of transcription 3) contributes to the malignancy of many cancers such as hepatocellular carcinoma (HCC) and is associated with poor prognosis. STAT3 activity is increased by the reversible palmitoylation of Cys108 by the palmitoyltransferase DHHC7 (encoded by ZDHHC7). Here, we investigated the consequences of S-palmitoylation of STAT3 in HCC. Increased ZDHHC7 abundance in HCC cases was associated with poor prognosis, as revealed by bioinformatics analysis of patient data. In HepG2 cells in vitro, DHHC7-mediated palmitoylation enhanced the expression of STAT3 target genes, including HIF1A, which encodes the hypoxia-inducible transcription factor HIF1α. Inhibiting DHHC7 decreased the S-palmitoylation of STAT3 and decreased HIF1α abundance. Furthermore, stabilization of HIF1α by cyclin-dependent kinase 5 (CDK5) enabled it to promote the expression of ZDHHC7, which generated a positive feedback loop between DHHC7, STAT3, and HIF1α. Perturbing this loop reduced the growth of HCC cells in vivo. Moreover, DHHC7, STAT3, and HIF1α were all abundant in human HCC tissues. Our study identifies a pathway connecting these proteins that is initiated by S-palmitoylation, which may be broadly applicable to understanding the role of this modification in cancer.

Erratum: Targeting sphingosine kinase 2 suppresses cell growth and synergizes with BCL2/BCL-XL inhibitors through NOXA-mediated MCL1 degradation in cholangiocarcinoma.

[This corrects the article on p. 546 in vol. 9, PMID: 30949409.].

Research progress on Limosilactibacilus reuteri in diseases.

Limosilactibacilus reuteri (L. reuteri) is a gram-positive probiotic that does not produce peroxidase. Certain strains of L. reuteri have been approved for use in human health products in China. The probiotic mechanism of L. reuteri in organisms can be divided into two directions: first, L. reuteri directly regulates the gut microbiota and indirectly affecting the host; second, L. reuteri secretes substances that directly affect the host. Numerous studies have shown that a deficiency in this commensal bacterium is associated with various diseases in different systems (such as inflammation in the digestive system, systemic lupus erythematosus in the autoimmune system, metabolic syndrome in the endocrine system, and mastitis in the reproductive system). However, although recent studies have found that L. reuteri can also promote disease progression, but overall, it is more beneficial than harmful in general. Further, more in-depth experiments are needed to determine whether L. reuteri should be removed from probiotics in the future. In this review, we provide an overview of the research history of L. reuteri and conclude with the main mechanisms through which this intestinal symbiont can improve health or aggravate diseases.

Single cell transcriptomic analyses implicate an immunosuppressive tumor microenvironment in pancreatic cancer liver metastasis.

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease refractory to all targeted and immune therapies. However, our understanding of PDAC microenvironment especially the metastatic microenvironment is very limited partly due to the inaccessibility to metastatic tumor tissues. Here, we present the single-cell transcriptomic landscape of synchronously resected PDAC primary tumors and matched liver metastases. We perform comparative analysis on both cellular composition and functional phenotype between primary and metastatic tumors. Tumor cells exhibit distinct transcriptomic profile in liver metastasis with clearly defined evolutionary routes from cancer cells in primary tumor. We also identify specific subtypes of stromal and immune cells critical to the formation of the pro-tumor microenvironment in metastatic lesions, including RGS5+ cancer-associated fibroblasts, CCL18+ lipid-associated macrophages, S100A8+ neutrophils and FOXP3+ regulatory T cells. Cellular interactome analysis further reveals that the lack of tumor-immune cell interaction in metastatic tissues contributes to the formation of the immunosuppressive microenvironment. Our study provides a comprehensive characterization of the transcriptional landscape of PDAC liver metastasis.

A nomogram based on clinical factors to predict calendar year readmission in patients with ulcerative colitis.

Background: Readmission shortly after discharge is indicative of an increased disease severity for patients with ulcerative colitis (UC) and ineffectiveness to medical therapy, which may contribute to a dismal prognosis. Objectives: This study aimed to explore prognostic variables with a nomogram to predict unplanned UC-related readmission within 1 year after discharge. Design: A retrospective cohort study. Methods: Electronic medical records of all UC patients treated at our center between 1 January 2014 and 31 June 2021 were reviewed. A comprehensive analysis of various characteristics, such as demographics, comorbidities, medical history, follow-up appointments, admission endoscopy, histopathologic features, etc., was used to determine the primary end point, which was unplanned UC-related calendar year readmission. Results: We found that the unplanned UC-related readmission rate within 1 year was 20.8%. In multivariable cox analysis, the predictors of the Elixhauser comorbidity index [Hazard ratio (HR): 3.50, 95% confidence interval (CI): 1.93-6.37], regular follow-up (HR: 0.29, 95% CI: 0.16-0.53), any history of corticosteroid use (HR: 3.38, 95% CI: 1.83-6.27), seral level of C-reactive protein (HR: 1.01, 95% CI: 1.00-1.02), and the UC endoscopic index of severity (HR: 1.29, 95% CI: 1.05-1.57) independently predicted calendar year readmission after discharge. The established nomogram had a consistently high accuracy in predicting calendar year readmission in the training cohort, with a concordance index of 0.784, 0.825, and 0.837 at 13, 26, and 52 weeks, respectively, which was validated in both the internal and external validation cohorts. Therefore, UC patients were divided into clinically low-, high-, and extremely high-risk groups for readmission, based on the calculated score of 272.5 and 378. Conclusion: The established nomogram showed good discrimination and calibration powers in predicting calendar year readmission in high-risk UC patients, who may need intensive treatment and regular outpatient visits.

The Characteristics and Treatment Outcomes of 71 Duodenal Brunner's Gland Adenomas with Endoscopic Submucosal Dissection.

INTRODUCTION: The aim of this study was to investigate outcomes of patients with duodenal Brunner's gland adenomas (BGAs) that were treated endoscopically. METHODS: We identified 71 consecutive patients treated at our center with endoscopic submucosal dissection (ESD) for their duodenal tumors diagnosed pathologically as BGAs over the period between January 1, 2011 and December 31, 2021. We retrospectively analyzed our experience and short- and long-term outcomes of ESD therapy on patients with BGAs. RESULTS: Among 71 BGA patients with an average age of 57 ± 11.7 years (range: 30-82), 48 (67.6%) were male and 23 (32.4%) were female. The accuracy of preoperative diagnosis with endoscopic ultrasonography was 44.0% (22/50). The H. pylori infection was found in 29 patients (29/71, 40.8%). The median size of BGAs was 1.5 cm (interquartile range [IQR] 0.8-2.7 cm). The most common location was the duodenum bulb (50/71, 64.8%). For the ESD procedure, the median operation time was 15.0 min (IQR 9.5-25.5 min). The en bloc and the complete resection rates were 97.2% and 92.3%, respectively. ESD-related mild acute obstructive pancreatitis was present in 2 patients (2/4, 50%) with BGAs located in the ampulla region. During the follow-up period, 1 patient with a positive peripheral margin experienced tumor recurrence 2 years after the initial ESD. There was no disease-related death for the cohort. CONCLUSION: ESD was an effective and safe therapeutic option for BGA patients with excellent outcomes. Long-term follow-up is needed.

Protein tyrosine phosphatase nonreceptor type 2 exerts antimetastatic functions in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly invasive tumor with a dismal prognosis. Recent studies have demonstrated PTPN2 (protein tyrosine phosphatase nonreceptor type 2) as a potential target for cancer therapy. However, the functions of PTPN2 in PDAC progression remain poorly understood. In this study, we found PTPN2 expression was downregulated in PDAC tissues, and decreased PTPN2 expression was associated with unfavorable prognosis. Functional studies indicated that PTPN2 knockdown promoted the migration and invasion abilities of PDAC cells in vitro, and the liver metastasis in vivo through epithelial-mesenchymal transition process. Mechanistically, MMP-1 was identified as a downstream target of PTPN2 via RNA-seq data and was responsible for the enhanced metastasis of PDAC cells upon PTPN2 knockdown. Moreover, according to chromatin immunoprecipitation and electrophoretic mobility shift assay, PTPN2 depletion transcriptionally activated MMP-1 via regulating the interaction of p-STAT3 with its distal promoter. This study, for the first time, demonstrated that PTPN2 inhibited PDAC metastasis, and presented a novel PTPN2/p-STAT3/MMP-1 axis in PDAC progression.

Risk factors of perforation in gastric stromal tumors during endoscopic resection: a retrospective case-control study.

BACKGROUND AND AIMS: Perforation is a common complication during endoscopic resection (ER) of gastric gastrointestinal stromal tumors (gGISTs) associated with secondary infections, sepsis, hospitalization time and cost. However, the risk factors of perforation remain controversial. This study aimed to investigate the risk factors for perforation during ER of gGISTs. METHODS: This retrospective case-control study included consecutive patients with gGISTs who underwent ER between June 2009 and November 2021 at the Nanjing Drum Tower Hospital. Univariate and multivariate analyses were performed to investigate the risk factors for perforation. Sensitivity analyses with propensity scoring (PS) were performed to evaluate the stability of the independent effects. RESULTS: In total, 422 patients with gGISTs were included. The following factors were associated with perforation during ER: in the non-intraluminal growth patterns (all confounders adjusted odds ratio [aOR]: 5.39, 95% CI 2.99-9.72, P < 0.001), in the gastric fundus (aOR 2.25, 95% CI 1.40-3.60, P = 0.007), sized ≥ 2 cm (aOR 1.70, 95% CI 1.04-2.77, P = 0.035), in the lesser curvature (aOR 0.12, 95% CI 0.05-0.27, P < 0.001), and in the gastric cardia (aOR 0.13, 95% CI 0.04-0.50, P = 0.003). The PS analysis confirmed the stable independent effects of these identified risk factors. CONCLUSIONS: ERs of gGISTs in non-intraluminal growth patterns, in the gastric fundus, and with larger tumor size were independent risk factors for perforation. While tumors in the lesser curvature or gastric cardia were independent protective factor for perforation.

Comparison of Modified Cap-Assisted Endoscopic Mucosal Resection and Endoscopic Submucosal Dissection in Treating Intraluminal Gastric Gastrointestinal Stromal Tumor (≤20 mm).

INTRODUCTION: A modified cap-assisted endoscopic mucosal resection (mEMR-C), introduced in this study, was a novel variation of the standard EMR. We aimed to compare the outcomes of mEMR-C and endoscopic submucosal dissection (ESD) for the treatment of small (≤20 mm) intraluminal gastric gastrointestinal stromal tumors (gGISTs). METHODS: This retrospective study included 43 patients who underwent mEMR-C and 156 patients who received ESD at Nanjing Drum Tower Hospital. Baseline characteristics, adverse events, and clinical outcomes were compared between the 2 groups. Univariate and multivariable analyses were conducted to adjust for confounders. After propensity score matching using sex, year, location, and tumor size, outcomes were compared with 41 patients in each group. RESULTS: A total of 199 patients underwent endoscopic resection and the en bloc resection rate was 100%. The complete resection rate was comparable in both groups ( P = 1.000). Approximately 9.5% of all patients had a positive margin. There was no significant difference in positive margin for patients undergoing mEMR-C or ESD (9.3% vs 9.6%, P = 1.000). No difference in adverse events in both groups ( P = 0.724). The mEMR-C was associated with shorter operation time and lower cost than the ESD. Recurrence was reported in 2 patients at 1 and 5 years after ESD during a median follow-up of 62 months. No metastasis and disease-related death were identified in both groups. Propensity score matching analysis revealed similar results. DISCUSSION: The mEMR-C was found to be the preferable technique for small (≤20 mm) intraluminal gGISTs with shorter operation time and lower cost as compared with ESD.

Copper Increases the Sensitivity of Cholangiocarcinoma Cells to Tripterine by Inhibiting TMX2-Mediated Unfolded Protein Reaction Activation.

Chemotherapy-induced adaptive resistance is a significant factor that contributes to low therapeutic efficacy in tumor cells. The unfolded protein response (UPR) is a key mechanism in the development of drug resistance and serves as a critical reactive system for endoplasmic reticulum stress. Cu(II) can reduce the abundance of 60S ribosomal subunits and inhibit rRNA processing, leading to a decrease in the translation efficiency of the GRP78/BiP mRNA, which serves as a primary sensor for UPR activation. In this study, CuET-Lipid@Cela, composed of CuET and tripterine (Cela), demonstrates a significant synergistic antitumor effect on cholangiocarcinoma (CCA) cells. RNA-Seq is used to investigate the underlying mechanism, which suggests that the transmembrane protein 2 (TMX2) gene may be crucial in Cu(II) regulation of UPR by inhibiting the activation of GRP78/BiP and PERK/eIF2α. The synergistic antitumor efficacy of CuET-Lipid@Cela via inhibition of TMX2 is also confirmed in a myrAKT/YapS127A plasmid-induced primary CCA mouse model, providing new insights into the reversal of acquired chemotherapy-induced resistance in CCA.

NNMT enriches for AQP5+ cancer stem cells to drive malignant progression in early gastric cardia adenocarcinoma.

OBJECTIVE: Early gastric cardia adenocarcinoma (EGCA) is a highly heterogeneous cancer, and the understanding of its classification and malignant progression is limited. This study explored the cellular and molecular heterogeneity in EGCA using single-cell RNA sequencing (scRNA-seq). DESIGN: scRNA-seq was conducted on 95 551 cells from endoscopic biopsies of low-grade intraepithelial neoplasia, well/moderately/poorly differentiated EGCA and their paired adjacent nonmalignant biopsy samples. Large-scale clinical samples and functional experiments were employed. RESULTS: Integrative analysis of epithelial cells revealed that chief cells, parietal cells and enteroendocrine cells were rarely detected in the malignant epithelial subpopulation, whereas gland and pit mucous cells and AQP5+ stem cells were predominant during malignant progression. Pseudotime and functional enrichment analyses showed that the WNT and NF-κB signalling pathways were activated during the transition. Cluster analysis of heterogeneous malignant cells revealed that NNMT-mediated nicotinamide metabolism was enriched in gastric mucin phenotype cell population, which was associated with tumour initiation and inflammation-induced angiogenesis. Furthermore, the expression level of NNMT was gradually increased during the malignant progression and associated with poor prognosis in cardia adenocarcinoma. Mechanistically, NNMT catalysed the conversion of nicotinamide to 1-methyl nicotinamide via depleting S-adenosyl methionine, which led to a reduction in H3K27 trimethylation (H3K27me3) and then activated the WNT signalling pathway to maintain the stemness of AQP5+ stem cells during EGCA malignant progression. CONCLUSION: Our study extends the understanding of the heterogeneity of EGCA and identifies a functional NNMT+/AQP5+ population that may drive malignant progression in EGCA and could be used for early diagnosis and therapy.

Bacillus subtilis and Bifidobacteria bifidum Fermentation Effects on Various Active Ingredient Contents in Cornus officinalis Fruit.

Microbial fermentation has been widely used to improve the quality and functional composition of food and edibles; however, the approach has rarely been applied to traditional Chinese medicines. In this study, to understand the effect of microbial fermentation on the active ingredients of traditional Chinese medicines, we used Bifidobacterium bifidum and Bacillus subtilis to ferment the traditional Chinese medicine, Cornus officinalis fruit (COF), and determined the levels of active ingredients using HPLC (high-performance liquid chromatography). According to the results, both B. subtilis and B. bifidum substantially increased the amount of gallic acid in the COF culture broth after fermentation; however, the two species of bacteria had no effect on the loganin content. Moreover, the B. subtilis fermentation reduced the contents of ursolic acid and oleanolic acid in the COF broth, whereas the B. bifidum fermentation did not. This study contributes to a better understanding of the mechanism by which microbial fermentation alters the active ingredient levels of traditional Chinese medicines, and suggests that fermentation may potentially improve their functional ingredients.

Sedation Is Associated with Higher Polyp and Adenoma Detection Rates during Colonoscopy: A Retrospective Cohort Study.

Background and Aims: Currently sedation is a common practice in colonoscopy to reduce pain of patients and improve the operator satisfaction, whereas its impact on examination quality, especially adenoma detection rate (ADR) is still controversial. Thus, we aimed to investigate the association of sedation with ADR. Methods: Consecutive patients receiving colonoscopy between January 2017 and January 2020 at the Nanjing Drum Tower Hospital, Nanjing, China, were collected. Univariate and multivariate logistic regression models were performed to investigate the association between sedation and ADR. Subgroup analysis and propensity score matching (PSM) analysis, as sensitivity analysis, were performed to validate the independent effect. Results: The ADR was significantly higher in cases with sedation (ADR: 36.9% vs. 29.1%, odds ratio [OR]: 1.42, 95% confidence interval [CI]: 1.31-1.55, P < 0.001). Multivariate analysis showed that the sedation was an independent factor associated with ADR (OR: 1.49, 95% CI: 1.35-1.65, P < 0.001). The effect was consistent in subgroup analyses (P > 0.05) and PSM analysis (ADR: 37.6% vs. 29.1%, OR: 1.47, 95% CI: 1.33-1.63, P < 0.001). Conclusion: Sedation was associated with a higher polyp and ADR s during colonoscopy, which can promote the quality of colonoscopy.