Naringenin alleviates liver fibrosis by triggering autophagy-dependent ferroptosis in hepatic stellate cells.

Inhibition of activated hepatic stellate cells (HSCs) is a promising approach for treating liver fibrosis, and the ferroptosis has emerged as a pivotal mechanism to achieve this inhibition. The effects of naringenin, a flavonoid with anti-inflammatory properties, have not been thoroughly examined in liver fibrosis. Therefore, we used cholestasis model to study the effect of naringenin on liver fibrosis. Our findings demonstrated a significant exacerbation of liver tissue damage and fibrosis in mice subjected to bile duct ligation (BDL), accompanied by a substantial upregulation of fibrogenesis-related gene expression. Notably, naringenin administration markedly alleviated liver injury and fibrosis in these mice. Furthermore, naringenin exhibited inhibitory effects on the activation of HSCs, concurrently inducing ferroptosis. Importantly, naringenin significantly increased autophagic activity in HSCs. This effect was counteracted by co-administration of the autophagy inhibitor 3-MA, leading to a notable reduction in naringenin-induced HSC ferroptosis. In BDL model mice, naringenin demonstrated a mitigating effect on liver fibrosis, suggesting a potential correlation with naringenin-induced ferroptosis of HSCs. These results provide novel insights into the molecular mechanisms of naringenin-induced ferroptosis and highlight autophagy-dependent ferroptosis as a promising therapeutic strategy for liver fibrosis.

Differential Diagnosis of Post Pancreatitis Diabetes Mellitus Based on Pancreatic and Gut Hormone Characteristics.

CONTEXT: Distinguishing different types of diabetes is important in directing optimized treatment strategies and correlated epidemiological studies. OBJECTIVE: Through detailed analysis of hormone responses to mixed meal tolerance test (MMTT), we aimed to find representing characteristics of post-acute pancreatitis diabetes mellitus (PPDM-A) and post-chronic pancreatitis diabetes mellitus (PPDM-C). METHODS: Participants with PPDM-A, PPDM-C, type 1 diabetes, type 2 diabetes, and normal controls (NCs) underwent MMTT. Fasting and postprandial responses of serum glucose, C-peptide, insulin, glucagon, pancreatic polypeptide (PP), ghrelin, gastric inhibitory peptide (GIP), glucagon like peptide-1 (GLP-1), and peptide YY (PYY) were detected and compared among different groups. Focused analysis on calculated insulin sensitivity and secretion indices were performed to determine major causes of hyperglycemia in different conditions. RESULTS: Participants with PPDM-A were characterized by increased C-peptide, insulin, glucagon, and PP, but decreased ghrelin, GIP, and PYY compared with NCs. Patients with PPDM-C showed secretion insufficiency of C-peptide, insulin, ghrelin, and PYY, and higher postprandial responses of glucagon and PP than NCs. In particular, both fasting and postprandial levels of ghrelin in PPDM-C were significantly lower than other diabetes groups. PYY responses in patients with PPDM-A and PPDM-C were markedly reduced. Additionally, the insulin sensitivity of PPDM-A was decreased, and the insulin secretion for PPDM-C was decreased. CONCLUSION: Along with the continuum from acute to chronic pancreatitis, the pathological mechanism of PPDM changes from insulin resistance to insulin deficiency. Insufficient PYY secretion is a promising diagnostic marker for distinguishing PPDM from type 1 and type 2 diabetes. Absent ghrelin secretion to MMTT may help identify PPDM-C.

Ononin alleviates DSS-induced colitis through inhibiting NLRP3 inflammasome via triggering mitophagy.

BACKGROUND: Ononin, a flavonoid isolated from Astragalus membranaceus root, is the active ingredient of A. membranaceus and has potential anti-inflammatory properties, but its effect on colitis is unclear. AIMS: This study aimed to explore the anticolitis effect of Ononin by establishing a colitis model in mice induced by dextran sulfate sodium (DSS). METHODS: Male C57BL/6 mice were provided DSS, then treated with Ononin (10, 20, 40 mg/kg) or 5-ASA (40 mg/kg). The colitis symptoms were observed, the disease activity index (DAI) score were recorded daily, and colonic inflammation was evaluted by histopathological scoring. The expression of cytokines, inflammatory mediators, and mitophagy/NLRP3 inflammasome-related proteins were measured. RESULTS: Ononin significantly alleviated weight loss and colon shortening in mice with colitis (p < .01). Moreover, Ononin decreased the production of inflammatory cytokines and mediators associated with colitis (p < .05). In addition, Ononin inhibited macrophages infiltration and reduced caspase-1 activation in colitis mice. Caspase-1 activation is closely related to the NLRP3 inflammasome. Therefore, we investigated the effect of Ononin on NLRP3 inflammasome in vitro. The relevant results confirmed that Ononin inhibited NLRP3 inflammasome activation and inhibited mitochondrial damage (p < .05). Further studies revealed that Ononin inhibited mitochondrial damage through triggering mitophagy (p < .05). CONCLUSION: Ononin alleviates DSS-induced colitis by activating mitophagy to inhibit NLRP3 inflammasome.

Non-Alcoholic Fatty Liver Disease (NAFLD) Is an Independent Risk Factor for Developing New-Onset Diabetes After Acute Pancreatitis: A Multicenter Retrospective Cohort Study in Chinese Population.

Background: Numerous studies validated frequent glucose dysfunction in patients with acute pancreatitis (AP). However, the prevalence of new-onset diabetes in individuals after a first episode of AP varies widely among previous studies. This study aims to determine the incidence of post-acute pancreatitis diabetes mellitus (PPDM-A) in Chinese people and further identify potential risk factors that influence diabetes development in patients with AP. Methods: This was a multi-center retrospective cohort study including 6009 inpatients with a first attack of AP. A total of 1804 patients with AP without known endocrine pancreatic disorders or other pancreatic exocrine diseases were eligible for analysis. Data was collected from medical records by hospital information system and telephone follow-ups after discharge. The multiple logistic regression analysis was established to evaluate the potential influencing factors of PPDM-A. Results: The prevalence of newly diagnosed diabetes after a first episode of AP in China was 6.2%. Data showed that patients who developed PPDM-A were more likely to be younger (X2 = 6.329, P = 0.012), experienced longer hospital stays (X2 = 6.949, P = 0.008) and had a higher frequency of overweight or obesity (X2 = 11.559, P = 0.003) compared to those with normal glycemia. The frequency of stress hyperglycemia on admission (X2 = 53.815, P < 0.001), hyperlipidemia (X2 = 33.594, P < 0.001) and non-alcoholic fatty liver disease (NAFLD) (X2 = 36.335, P < 0.001) were significantly higher among individuals with PPDM-A compared with control group. Also, patients with PPDM-A were more likely to be hyperlipidemic AP (X2 = 16.304, P = 0.001) and show a higher degree of severity (X2 = 7.834, P = 0.020) and recurrence rate (X2 = 26.908, P < 0.001) of AP compared to those without diabetes. In addition, multiple logistic regression analysis indicated that stress hyperglycemia, hyperlipidemia, NAFLD and repeated attacks of AP were the independent influence factors for developing PPDM-A. Conclusion: Our study first demonstrated the prevalence of secondary diabetes in Chinese patients after AP. The disorder of glucose metabolism in individuals with AP should be regularly evaluated in clinical practice. Further studies are needed to verify the relationship between liver and pancreas in keeping glucose homeostasis under AP condition.

Peroral endoscopic myotomy treatment for symptomatic esophageal diverticulum: a systematic review and meta-analysis.

Peroral endoscopic myotomy (POEM) is a rapidly evolving technique for the treatment of esophageal diverticulum. The aim of this study was to perform a systematic review and meta-analysis of the literature focusing on POEM for symptomatic esophageal diverticula, including an in-depth evaluation of its efficacy, safety, and limitations. A comprehensive literature search was completed to identify articles that examined the efficacy and safety of POEM for esophageal diverticula. Heterogeneity among studies was assessed using the I2 statistic. Meta-regression and sensitivity analyses were performed to explore the sources of heterogeneity and assess potentially important covariates influencing the main outcomes. Primary endpoints such as rates of success, adverse events, and recurrences were evaluated. P values of ≤0.05 were considered statistically significant. Nine studies with a total of 153 patients were enrolled. Pooled technical success, clinical success, adverse events, and recurrence rates were 99% [95% confidence interval (CI), 97-100%; I2 = 0%), 94% (95% CI, 89-97%; I2 = 24%), 2% (95% CI, 0-6%, I2 = 0%), and 0% (95% CI, 0-1%; I2 = 0%), respectively. The pooled perforation rate was 6% (95% CI, 1-11%; I2 = 0%). Meta-regression analysis indicated that esophageal diverticula types and motility disorders were not associated with the clinical success rate (P > 0.05). POEM is a feasible, safe, and effective treatment for symptomatic esophageal diverticula, with low adverse events and recurrence rates.

The diagnostic value of EUS in pancreatic cystic neoplasms compared with CT and MRI.

BACKGROUND AND OBJECTIVES: Pancreatic cystic neoplasms (PCNs) are being increasingly identified. Recent reports have described the utility of endoscopic ultrasound (EUS) in the characterization of PCNs. This study presents the diagnostic value of EUS in PCNs. MATERIALS AND METHODS: A total of 108 patients (78 women and 30 men; average age, 50 years) who were confirmed pathologically to have PCNs were analyzed retrospectively. We analyzed the clinical characteristics of 108 patients and compared the diagnostic performance of computed tomography (CT), magnetic resonance imaging (MRI), and EUS with or without fine-needle aspiration (FNA). RESULTS: EUS with or without FNA significantly increased the accuracy for diagnosing PCNs compared with CT (P = 0.002) and MRI (P = 0.006). According to the tumor size, the further analysis of these impacts was provided. EUS was superior to CT in the characterization of PCNs in small (< 3 cm) lesions (P = 0.003), similarly superior to MRI in large (>3 cm) lesions (P = 0.030). Furthermore, EUS is valuable for precisely characterizing internal structures, for example, septa (P = 0.004, compared with CT; P = 0.033, compared with MRI) and mural nodules (P = 0.028, compared with CT). CONCLUSIONS: In our study, EUS with or without FNA is the ideal tool for providing detailed imaging of PCNs and performed better than MRI and CT.

Downregulation of FOXP3 inhibits invasion and immune escape in cholangiocarcinoma.

FOXP3 is known as a master control of regulatory T cells with recently studies indicating its expression in several tumor cells. In order to study the precise role of FOXP3 in cholangiocarcinoma, FOXP3 was knocked down in cholangiocarcinoma cell lines. Down regulation of FOXP3 inhibits tumor cell invasion by reducing the quantity of MMP-9 and MMP-2. With FOXP3 knocking down, IL-10 and TGF-ß1 secreted by cancer cells diminishes and the cell survival of T cells is significant up-regulation. These results suggest that FOXP3 plays an important role in tumor malignant phenotype, especially the invasion and immune escape.