Lafutidine Ameliorates Indomethacin-Induced Small Intestinal Damage in Rats by Modifying the Intestinal Mucosal Barrier, Inflammation, and Microbiota.

INTRODUCTION: Nonsteroidal anti-inflammatory drug (NSAID)-induced small intestinal damage is a serious and escalating clinical problem without effective treatment. Lafutidine (LAF) is a novel histamine H2 receptor antagonist with a mucosal protective action. This study aimed to investigate the protective effect of LAF on indomethacin (IND)-induced enteropathy in rats. METHODS: Rats were treated with LAF for 10 days with concomitant IND treatment on the final 5 days. Changes in metabolism and hematological and biochemical parameters were measured, and intestinal damage was blindly scored. Intestinal mucosal tissue and luminal contents were collected for transcriptome and microbiota sequencing. Intestinal inflammation and barrier function were also evaluated. RESULTS: LAF treatment prevented anorexia and weight loss in rats and ameliorated reductions in hemoglobin, hematocrit, total protein, and albumin levels. LAF reduced the severity of IND-induced intestinal damage including macroscopic and histopathological damage score. Transcriptome sequencing results indicated that LAF might have positive effects on intestinal inflammation and the intestinal mucosal barrier. Further research revealed that LAF decreased neutrophil infiltration, and IL-1ß and TNF-α expression in intestinal tissue. Besides, the treatment increased mucus secretion, MUC2, Occludin, and ZO-1 expression, and decreased serum D-lactate levels. LAF treatment also ameliorates microbial dysbiosis in small intestine induced by IND and increased the abundance of Lactobacillus acidophilus. CONCLUSION: LAF may protect against NSAID enteropathy via enhancing the intestinal mucosal barrier, inhibiting inflammation, and regulating microbiota.

Large population-based study using the SEER database: is endoscopic resection appropriate for early gastric cancer patients in the United States?

AIM: To investigate whether endoscopic treatment is applicable to American patients and explores the predictors of lymph node metastasis (LNM) in early gastric cancer (EGC). METHODS: Patients with EGC confined to either mucosa (T1a, n = 1799) and submucosa (T1b, n = 1689) were identified from the Surveillance, Epidemiology, and End Result database. Multivariate logistic regression, Kaplan-Meier method, and univariate/multivariate Cox regression were used to assess the correlation between invasion depth and LNM or prognosis. A nomogram for predicting LNM was constructed and internally validated. RESULTS: EGC limited to T1a exhibited a 2.4% incidence of LNM, which increased to 11.1% when the depth invaded T1b.LNM was present at 1.4%, 5.2%, and 5.0% for sizes ≤2, 2-5, and >5cm of low-grade T1a EGC, respectively, (p = .019) and at 4.8%, 12.4%, and 28.6% of T1b EGC, respectively (p < .001).The multivariate logistic model revealed that older age, T1b invasion, larger tumor size, and high-grade lesions were associated with a higher risk of LNM. Moreover, the T1a EGC patients had better cancer-specific survival (OS) and overall survival(CSS) compared with the T1b EGC patients (5-year OS: 77.2% versus 67.4%, p < .001; 5-year CSS: 90.6% versus 81.4%, p < .001). The discrimination of the prediction model was 0.745. CONCLUSIONS: Endoscopic treatment may only be suitable for patients in the US population who have low-grade T1a lesions of less than 2 cm in size. Patients with T1a lesions of greater than 2 cm in size, lesions with high-grade, and all T1b lesions may benefit from radical surgical resection with lymphadenectomy.

Orchestration of MUC2 - The key regulatory target of gut barrier and homeostasis: A review.

The gut mucosa of human is covered by mucus, functioning as a crucial defense line for the intestine against external stimuli and pathogens. Mucin2 (MUC2) is a subtype of secretory mucins generated by goblet cells and is the major macromolecular component of mucus. Currently, there is an increasing interest on the investigations of MUC2, noting that its function is far beyond a maintainer of the mucus barrier. Moreover, numerous gut diseases are associated with dysregulated MUC2 production. Appropriate production level of MUC2 and mucus contributes to gut barrier function and homeostasis. The production of MUC2 is regulated by a series of physiological processes, which are orchestrated by various bioactive molecules, signaling pathways and gut microbiota, etc., forming a complex regulatory network. Incorporating the latest findings, this review provided a comprehensive summary of MUC2, including its structure, significance and secretory process. Furthermore, we also summarized the molecular mechanisms of the regulation of MUC2 production aiming to provide developmental directions for future researches on MUC2, which can act as a potential prognostic indicator and targeted therapeutic manipulation for diseases. Collectively, we elucidated the micro-level mechanisms underlying MUC2-related phenotypes, hoping to offer some constructive guidance for intestinal and overall health of mankind.

Synaptophysin-like 2 expression correlates with lymph node metastasis and poor prognosis in colorectal cancer patients.

BACKGROUND: Colorectal cancer (CRC) is one of the most common and fatal cancers worldwide. Synaptophysin-like 2 (SYPL2) is a neuroendocrine-related protein highly expressed in skeletal muscle and the tongue. The involvement of SYPL2 in CRC, including its level of expression and function, has not been evaluated. AIM: To evaluate the correlations of SYPL2 expression with lymph node metastasis (LNM) and prognosis in patients with CRC. METHODS: The levels of expression of SYPL2 in CRC and normal colorectal tissues were analyzed in multiple public and online databases. The associations between clinical variables and SYPL2 expression were evaluated statistically, and the associations between SYPL2 expression and prognosis in patients with CRC were analyzed using the Kaplan-Meier method and univariate/multivariate Cox regression analyses. SYPL2 expression was assessed in 20 paired CRC tissue and adjacent normal colorectal tissue samples obtained from Fuyang People's Hospital, and the associations between SYPL2 expression and the clinical characteristics of these patients were investigated. Correlations between the levels of expression of SYPL2 and key targeted genes were determined by Pearson's correlation analysis. The distribution of immune cells in these samples was calculated using the CIBERSORT algorithm. Gene set enrichment analysis (GSEA) was performed to evaluate the biofunction and pathways of SYPL2 in CRC. RESULTS: SYPL2 expression was significantly lower in CRC tissue samples than in normal colorectal tissue samples (P < 0.05). High SYPL2 levels in CRC tissues correlated significantly with LNM (P < 0.05) and a poorer patient prognosis, including significantly shorter overall survival (OS) [hazard ratio (HR) = 1.9, P < 0.05] and disease-free survival (HR = 1.6, P < 0.05). High SYPL2 expression was an independent risk factor for OS in both univariate (HR = 2.078, P = 0.014) and multivariate (HR = 1.754, P = 0.018) Cox regression analyses. In addition, SYPL2 expression correlated significantly with the expression of KDR (P < 0.0001, r = 0.47) and the BRAF V600E mutation (P < 0.05). Higher SYPL2 expression was associated with the enrichment of CD8 T-cells and M0 macrophages in the tumor microenvironment. GSEA revealed that SYPL2 was associated with the regulation of epithelial cell migration, vasculature development, pathways in cancer, and several vital tumor-related pathways. CONCLUSION: SYPL2 expression was lower in CRC tissue than in normal colorectal tissue. Higher SYPL2 expression in CRC was significantly associated with LNM and poorer survival.