The TRIM28/miR133a/CD47 axis acts as a potential therapeutic target in pancreatic necrosis by impairing efferocytosis.

Efferocytosis, the clearance of apoptotic cells by macrophages, plays a crucial role in inflammatory responses and effectively prevents secondary necrosis. However, the mechanisms underlying efferocytosis in acute pancreatitis (AP) remain unclear. In this study, we demonstrated the presence of efferocytosis in injured human and mouse pancreatic tissues. We also observed significant upregulation of CD47, an efferocytosis-related the "do not eat me" molecule in injured acinar cells. Subsequently, we used CRISPR-Cas9 gene editing, anti-adeno-associated virus (AAV) gene modification, and anti-CD47 antibody to investigate the potential therapeutic role of AP. CD47 expression was negatively regulated by upstream miR133a, which is controlled by the transcription factor TRIM28. To further investigate the regulation of efferocytosis and reduction of pancreatic necrosis in AP, we used miR-133a-agomir and pancreas-specific AAV-shTRIM28 to modulate CD47 expression. Our findings confirmed that CD47-mediated efferocytosis is critical for preventing pancreatic necrosis and suggest that targeting the TRIM28-miR133a-CD47 axis is clinically relevant for the treatment of AP.

Associations of Intrapancreatic Fat Deposition With Incident Diseases of the Exocrine and Endocrine Pancreas: A UK Biobank Prospective Cohort Study.

INTRODUCTION: To investigate whether increased intrapancreatic fat deposition (IPFD) heightens the risk of diseases of the exocrine and endocrine pancreas. METHODS: A prospective cohort study was conducted using data from the UK Biobank. IPFD was quantified using MRI and a deep learning-based framework called nnUNet. The prevalence of fatty change of the pancreas (FP) was determined using sex- and age-specific thresholds. Associations between IPFD and pancreatic diseases were assessed with multivariate Cox-proportional hazard model adjusted for age, sex, ethnicity, body mass index, smoking and drinking status, central obesity, hypertension, dyslipidemia, liver fat content, and spleen fat content. RESULTS: Of the 42,599 participants included in the analysis, the prevalence of FP was 17.86%. Elevated IPFD levels were associated with an increased risk of acute pancreatitis (hazard ratio [HR] per 1 quintile change 1.513, 95% confidence interval [CI] 1.179-1.941), pancreatic cancer (HR per 1 quintile change 1.365, 95% CI 1.058-1.762) and diabetes mellitus (HR per 1 quintile change 1.221, 95% CI 1.132-1.318). FP was also associated with a higher risk of acute pancreatitis (HR 3.982, 95% CI 2.192-7.234), pancreatic cancer (HR 1.976, 95% CI 1.054-3.704), and diabetes mellitus (HR 1.337, 95% CI 1.122-1.593, P = 0.001). DISCUSSION: FP is a common pancreatic disorder. Fat in the pancreas is an independent risk factor for diseases of both the exocrine pancreas and endocrine pancreas.

Association of MASLD with the risk of extrahepatic cancers: A systematic review and meta-analysis of 18 cohort studies.

BACKGROUND: Numerous recent studies have explored the association between metabolic dysfunction-associated steatotic liver disease (MASLD) and the risk of various extrahepatic cancers. However, the conclusions were inconclusive. The aim of this study was to clarify this relationship by conducting a robust meta-analysis. METHODS: Systematic searches were conducted on PubMed, Embase and Web of Science databases to identify relevant cohort studies published prior to February 2024. Hazard ratios (HRs) and their corresponding 95% confidence intervals (95% CIs) were combined using a random-effects model in this meta-analysis. RESULTS: Eighteen cohort studies (approximately 16.7 million participants) were finally included in this meta-analysis. MASLD was linked to a higher risk of extrahepatic cancers, such as gastric (n = 10, HR = 1.47, 95% CI: 1.07-2.01), colorectal (n = 13, HR = 1.33, 95% CI: 1.16-1.53), pancreatic (n = 8, HR = 1.41, 95% CI: 1.11-1.79), biliary tract (n = 5, HR = 1.27, 95% CI: 1.18-1.37), thyroid (n = 6, HR = 1.46, 95% CI: 1.02-2.09), urinary system (n = 10, HR = 1.45, 95% CI: 1.25-1.69), breast (n = 11, HR = 1.17, 95% CI: 1.08-1.26) and female genital organ cancers (n = 10, HR = 1.36, 95% CI: 1.11-1.66). However, there was no statistically significant association between MASLD and the risk of head and neck (n = 6, HR = 1.03, 95% CI: 99-1.07), oesophageal (n = 9, HR = 1.26, 95% CI: 0.86-1.86), lung (n = 9, HR = 1.01, 95% CI: 0.92-1.10), prostate (n = 9, HR = 1.06, 95% CI: 0.94-1.19) or small intestine cancer (n = 2, HR = 1.75, 95% CI: 1.00-3.06). CONCLUSIONS: This latest large-scale meta-analysis indicated that MASLD was associated with an increased risk of various extrahepatic cancers, such as gastric, colorectal, pancreatic, biliary duct, thyroid, urinary system, breast, skin and female genital cancers. Further research is needed to investigate the mechanisms underlying these associations.

Vonoprazan-amoxicillin dual therapy versus bismuth-containing quadruple therapy for Helicobacter pylori eradication: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: Recently, vonoprazan-amoxicillin (VA) dual therapy has been reported as a promising approach for Helicobacter pylori (H. pylori) eradication. However, the effects of VA therapy versus bismuth-containing quadruple therapy (BQT) on H. pylori eradication remains unclear. The objective of this meta-analysis was to compare the effects of VA dual therapy with BQT for H. pylori eradication. METHODS: A comprehensive search of the literature was conducted from the beginning to September 2023, utilizing PubMed, Embase, the Cochrane Library and Web of Science database. A random-effects model was used to perform a meta-analysis to determine the pooled relative risk (RR) with 95% confidence intervals (CIs). Moreover, trial sequential analysis (TSA) was conducted to evaluate the conclusiveness of the H. pylori eradication rate. RESULTS: Six randomized controlled trials (RCTs) with 1233 patients were included. The VA therapy has similar eradication rate (ITT analysis: 87% vs. 85.7%, RR = 1.01, 95% CI: 0.93-1.09, p = 0.84; PP analysis: 92.5% vs. 93.2%, RR = 1.00, 95% CI: 0.94-1.06, p = 0.97) and compliance (RR = 1.01, 95% CI: 0.99-1.03, p = 0.32) compared to BQT. The VA therapy group had a significantly lower incidence of total adverse events than the BQT group (16.3% vs. 40.0%, RR = 0.45, 95% CI: 0.37-0.55, p < 0.00001). The TSA result showed that the effect was conclusive. CONCLUSIONS: Current evidence indicated that VA therapy is just as successful as BQT in eliminating H. pylori, yet it has fewer adverse events and similar compliance.

Non-alcoholic fatty liver disease and gestational diabetes mellitus: a bidirectional two-sample mendelian randomization study.

PURPOSE: Previous observational studies have revealed a potential link between non-alcoholic fatty liver disease (NAFLD) and gestational diabetes mellitus (GDM), but their causal relationship remains unclear. Thus, this study aimed to examine whether a causal link exists between genetically determined NAFLD and GDM. METHODS: Utilizing publicly accessible genome-wide association studies (GWAS), a two-sample bidirectional Mendelian randomization (MR) analysis was conducted. The GWASs data pertaining to NAFLD and GDM were obtained from the UK Biobank Consortium and FinnGen database in primary analysis, respectively. The random-effects inverse variance weighted (IVW) method was utilized as primary analysis method. Several sensitivity analyses were utilized to verify the robustness of the results. Additionally, we also analyzed the causal effect of potential shared influencing factors on these two conditions. RESULTS: The result of the IVW method showed that there was no significant causal relationship between genetically determined NAFLD and GDM (OR = 0.98, 95% CI: 0.90-1.07, P = 0.691). Similarly, our reverse MR analysis failed to detect a significant causal effect of GDM on NAFLD (OR = 1.14, 95% CI: 0.97-1.36, P = 0.118). Sensitivity analyses further confirmed the robustness of the results. Moreover, we found that genetically determined body mass index, waist-to-hip ratio, triglycerides, and television viewing time may be positively correlated with NAFLD and GDM, while high-density lipoprotein cholesterol and apolipoprotein A-I may both be negatively correlated with NAFLD and GDM. CONCLUSIONS: The current bidirectional MR study failed to provide sufficient genetic evidence for the causal relationship between NAFLD and GDM.

Inhibition of Gasdermin D blocks the formation of NETs and protects acute pancreatitis in mice.

The persistent activation of neutrophils and the excessive neutrophil extracellular traps (NETs) formation are the main determinants of pancreatic tissue injury and systemic inflammatory response in acute pancreatitis (AP). Thus, inhibiting the release of NETs can effectively prevent the aggravation of AP. Here, our study showed that the pore-forming protein gasdermin D (GSDMD) was activity in neutrophils of AP mice and patients and played the vital role in NETs formation. Through the application of GSDMD inhibitor or the construction of neutrophil GSDMD specific knockout mice, it was found in vivo and in vitro that inhibition of GSDMD could block the NETs formation, reduce pancreatic injury, systemic inflammatory reaction and organ failure in AP mice. To sum up, our findings confirmed that neutrophil GSDMD was the therapeutic target for improving the occurrence and development of AP.

Apolipoprotein C-III itself stimulates the Syk/cPLA2-induced inflammasome activation of macrophage to boost anti-tumor activity of CD8+ T cell.

Increased prevalence of cancer in obese individuals is involved with dyslipidemia- induced chronic inflammation and immune suppression. Although apolipoprotein C-III (ApoC3)-transgenic mice (ApoC3TG mice) or poloxamer 407 (P407)-treated mice had hyperlipidemia, CD8+ T cells with upregulated antitumor activities were observed in ApoC3TG mice, and decreased CD8+ T cell activities were observed in P407-treated mice. Increased ApoC3 expression in hepatocellular carcinoma was associated with increased infiltration of CD8+ T cells and predicted survival. Recombinant ApoC3 had no direct effects on CD8+ T cells. The upregulation of CD8+ T cells in ApoC3TG mice was due to cross-talk with context cells, as indicated by metabolic changes and RNA sequencing results. In contrast to dendritic cells, the macrophages of ApoC3TG mice (macrophagesTG) displayed an activated phenotype and increased IL-1ß, TNF-α, and IL-6 production. Coculture with macrophagesTG increased CD8+ T cell function, and the adoptive transfer of macrophagesTG suppressed tumor progression in vivo. Furthermore, spleen tyrosine kinase (Syk) activation induced by TLR2/TLR4 cross-linking after ApoC3 ligation promoted cellular phospholipase A2 (cPLA2) activation, which in turn activated NADPH oxidase 2 (NOX2) to promote an alternative mode of inflammasome activation. Meanwhile, mitochondrial ROS produced by increased oxidative phosphorylation of free fatty acids facilitated the classical inflammasome activation, which exerted an auxiliary effect on inflammasome activation of macrophagesTG. Collectively, the increased antitumor activity of CD8+ T cells was mediated by the ApoC3-stimulated inflammasome activation of macrophages, and the mimetic ApoC3 peptides that can bind TLR2/4 could be a future strategy to target liver cancer.

Development, validation, and evaluation of a risk assessment tool for personalized screening of gastric cancer in Chinese populations.

BACKGROUND: Effective risk prediction models are lacking for personalized endoscopic screening of gastric cancer (GC). We aimed to develop, validate, and evaluate a questionnaire-based GC risk assessment tool for risk prediction and stratification in the Chinese population. METHODS: In this three-stage multicenter study, we first selected eligible variables by Cox regression models and constructed a GC risk score (GCRS) based on regression coefficients in 416,343 subjects (aged 40-75 years) from the China Kadoorie Biobank (CKB, development cohort). In the same age range, we validated the GCRS effectiveness in 13,982 subjects from another independent Changzhou cohort (validation cohort) as well as in 5348 subjects from an endoscopy screening program in Yangzhou. Finally, we categorized participants into low (bottom 20%), intermediate (20-80%), and high risk (top 20%) groups by the GCRS distribution in the development cohort. RESULTS: The GCRS using 11 questionnaire-based variables demonstrated a Harrell's C-index of 0.754 (95% CI, 0.745-0.762) and 0.736 (95% CI, 0.710-0.761) in the two cohorts, respectively. In the validation cohort, the 10-year risk was 0.34%, 1.05%, and 4.32% for individuals with a low (≤ 13.6), intermediate (13.7~30.6), and high (≥ 30.7) GCRS, respectively. In the endoscopic screening program, the detection rate of GC varied from 0.00% in low-GCRS individuals, 0.27% with intermediate GCRS, to 2.59% with high GCRS. A proportion of 81.6% of all GC cases was identified from the high-GCRS group, which represented 28.9% of all the screened participants. CONCLUSIONS: The GCRS can be an effective risk assessment tool for tailored endoscopic screening of GC in China. Risk Evaluation for Stomach Cancer by Yourself (RESCUE), an online tool was developed to aid the use of GCRS.

Association between inflammatory bowel disease and risk of incident prostate cancer: a systematic review and meta-analysis of cohort studies.

BACKGROUND AND OBJECTIVE: Numerous observational studies have been conducted to investigate the potential association between inflammatory bowel disease (IBD) and prostate cancer (PCa). However, a definitive conclusion has yet to be established. We therefore performed a meta-analysis to explore the relationship between these two conditions. METHODS: PubMed, Embase, and Web of Science databases were systematically searched to identify all relevant cohort studies that investigated the association between IBD and risk of incident PCa published from inception to February 2023. The pooled hazard ratios (HRs) with 95% confidence intervals (CI) was calculated as effect size for the outcome based on random-effects model meta-analysis. RESULTS: A total of 18 cohort studies with 592,853 participants were included. The meta-analysis revealed that IBD was linked to an elevated risk of incident PCa (HR = 1.20, 95% CI: 1.06-1.37, P = 0.004). Further subgroup analyses revealed that ulcerative colitis (UC) was linked to an increased risk of incident PCa (HR = 1.20, 95% CI: 1.06-1.38, P = 0.006), while Crohn's disease (CD) is not significantly associated with a higher risk of PCa (HR = 1.03, 95% CI: 0.91-1.17, P = 0.65). There was a significant correlation between IBD and an elevated risk of incident PCa in the European population, but such a correlation was not observed in the Asian and North American populations. Sensitivity analyses indicated that our results were robust. CONCLUSIONS: Our latest evidence indicates that IBD was linked to an elevated risk of incident PCa, especially in UC patients and the European population.

Number of recurrences is significantly associated with the post-acute pancreatitis diabetes mellitus in a population with hypertriglyceridemic acute pancreatitis.

BACKGROUND: Twenty-three percent of patients are diagnosed with diabetes mellitus after the first episode of acute pancreatitis. The incidence of post-acute pancreatitis diabetes mellitus is significantly higher than that of type 1 diabetes mellitus. Some studies have concluded that the all-cause mortality and worse prognosis of diabetes after pancreatitis are higher. We predicted that number of recurrences of pancreatitis would be significantly associated with the incidences of metabolic syndrome, abdominal obesity, and post-acute pancreatitis diabetes mellitus. METHODS: Patients admitted to our hospital for hypertriglyceridemic acute pancreatitis from 2013-2021 were selected for a cross-sectional study. Statistical analysis methods were used to analyze the effect of recurrences on the long-term prognosis of patients with hypertriglyceridemic acute pancreatitis. RESULTS: In this study, 101 patients with hypertriglyceridemic acute pancreatitis were included: 60 (59.41%) in the recurrent acute pancreatitis group and 41 (40.59%) in the only one episode of acute pancreatitis group. Among all hypertriglyceridemic acute pancreatitis patients, approximately 61.4% were diagnosed with abdominal obesity, 33.7% of patients are diagnosed with metabolic syndrome, 34.7% of patients are diagnosed with diabetes mellitus, and 21.8% of patients are diagnosed with post-acute pancreatitis diabetes mellitus. Recurrent acute pancreatitis were independent risk factors for post-acute pancreatitis diabetes mellitus in patients with hypertriglyceridemic acute pancreatitis (odds ratio [OR] = 3.964, 95% confidence interval [CI] = 1.230-12.774) and the risk of post-acute pancreatitis diabetes mellitus in patients with three or more recurrent episodes was 6.607 times higher than that in patients without recurrent episodes (OR = 6.607, 95% CI = 1.412-30.916). CONCLUSIONS: Recurrence is an independent risk factor for the development of post-acute pancreatitis diabetes mellitus and is significantly associated with the number of recurrences.

Activation of bivalent factor DLX5 cooperates with master regulator TP63 to promote squamous cell carcinoma.

To reconstruct systematically hyperactive transcription factor (TF)-dependent transcription networks in squamous cell carcinomas (SCCs), a computational method (ELMER) was applied to 1293 pan-SCC patient samples, and 44 hyperactive SCC TFs were identified. As a top candidate, DLX5 exhibits a notable bifurcate re-configuration of its bivalent promoter in cancer. Specifically, DLX5 maintains a bivalent state in normal tissues; its promoter is hypermethylation, leading to DLX5 transcriptional silencing in esophageal adenocarcinoma (EAC). In stark contrast, DLX5 promoter gains active histone marks and becomes transcriptionally activated in ESCC, which is directly mediated by SOX2. Functionally, silencing of DLX5 substantially inhibits SCC viability both in vitro and in vivo. Mechanistically, DLX5 cooperates with TP63 in regulating ∼2000 enhancers and promoters, which converge on activating cancer-promoting pathways. Together, our data establish a novel and strong SCC-promoting factor and elucidate a new epigenomic mechanism - bifurcate chromatin re-configuration - during cancer development.

[Network Meta-analysis of Chinese medicine injections for activating blood and resolving stasis in adjuvant treatment of acute ischemic stroke].

Network Meta-analysis was employed to compare the efficacy of Chinese medicine injections for activating blood and resolving stasis combined with conventional western medicine in the treatment of acute ischemic stroke and the effects on platelet aggregation rate, fibrinogen(FIB), and hypersensitive C-reactive protein(hs-CRP), with a view to providing evidence-based medicine reference for clinical medication. CNKI, Wanfang, VIP, SinoMed, PubMed, Web of Science, Cochrane Library, and EMbase were searched for randomized controlled trial(RCT) on the treatment of acute ischemic stroke with Salvia Miltiorrhiza Ligustrazine Injection, Danhong Injection, Shuxuetong Injection, Xueshuantong Injection, Shuxuening Injection, Safflower Yellow Pigment Injection, and Ginkgo Diterpene Lactone Meglumine Injection combined with conventional western medicine. The retrieval time was from database inception to March 18, 2023. The articles were extracted by two researchers and their quality was evaluated. R 4.2.2 was used for network Meta-analysis. A total of 87 RCTs involving 8 580 patients were included. Network Meta-analysis showed that, in terms of reducing National Institutes of Health stroke scale(NIHSS) scores, the surface under the cumulative ranking curve(SUCRA) showed the order of Xueshuantong Injection + conventional western medicine(88.7%) > Salvia Miltiorrhiza Ligustrazine Injection + conventional western medicine(73.7%) > Shuxuetong Injection + conventional western medicine(69.7%) > Shuxuening Injection + conventional western medicine(51.8%) > Danhong Injection + conventional western medicine(43.7%) > Safflower Yellow Pigment Injection + conventional western medicine(36.8%) > Ginkgo Diterpene Lactone Meglumine Injection + conventional western medicine(35.3%) > conventional western medicine(1.7%). In terms of improving clinical total effective rate, SUCRA showed the order of Danhong Injection + conventional western medicine(63.0%) > Shuxuening Injection + conventional western medicine(59.0%) > Salvia Miltiorrhiza Ligustrazine Injection + conventional western medicine(58.9%) > Safflower Yellow Pigment Injection + conventional western medicine(57.1%) > Xueshuantong Injection + conventional western medicine(56.8%) > Shuxuetong Injection + conventional western medicine(54.6%) > Ginkgo Diterpene Lactone Meglumine Injection + conventional western medicine(50.5%) > conventional western medicine(0.03%). In terms of improving Barthel index, SUCRA showed the order of Danhong Injection + conventional western medicine(84.7%) > Shuxuetong Injection + conventional western medicine(72.4%) > Safflower Yellow Pigment Injection + conventional western medicine(61.6%) > Salvia Miltiorrhiza Ligustrazine Injection + conventional western medicine(44.6%) > Ginkgo Diterpene Lactone Meglumine Injection + conventional western medicine(43.2%) > Shuxuening Injection + conventional western medicine(42.2%) > conventional western medicine(1.4%). In terms of reducing platelet aggregation rate, SUCRA showed the order of Salvia Miltiorrhiza Ligustrazine Injection + conventional western medicine(82.4%) > Shuxuetong Injection + conventional western medicine(81.6%) > Ginkgo Diterpene Lactone Meglumine Injection + conventional western medicine(40.7%) > Danhong Injection + conventional western medicine(37.3%) > conventional western medicine(8.0%). In terms of reducing FIB, SUCRA showed the order of Danhong Injection + conventional western medicine(81.0%) > Salvia Miltiorrhiza Ligustrazine Injection + conventional western medicine(71.9%) > Ginkgo Diterpene Lactone Meglumine Injection + conventional western medicine(70.0%) > Shuxuetong Injection + conventional western medicine(46.7%) > Xueshuantong Injection + conventional western medicine(22.6%) > conventional western medicine(8.7%). In terms of reducing hs-CRP, SUCRA showed the order of Shuxuening Injection + conventional western medicine(89.9%) > Salvia Miltiorrhiza Ligustrazine Injection + conventional western medicine(78.8%) > Ginkgo Diterpene Lactone Meglumine Injection + conventional western medicine(52.4%) > Danhong Injection + conventional western medicine(47.6%) > Xueshuantong Injection + conventional western medicine(43.5%) > Shuxuetong Injection + conventional Western medicine(35.6%) > conventional western medicine(2.3%). The results indicated that Xueshuantong Injection + conventional western medicine, Danhong Injection + conventional western medicine, and Salvia Miltiorrhiza Ligustrazine Injection + conventional western medicine ranked the top three. Xueshuantong Injection + conventional western medicine had the best effect on reducing NIHSS scores. Danhong Injection + conventional western medicine showed the best performance of improving clinical total effective rate, improving Barthel index, and reducing FIB in the blood. Salvia Miltiorrhiza Ligustrazine Injection + conventional western medicine had the best effect on reducing platelet aggregation rate in the blood. Shuxuening Injection + conventional western medicine had the best effect on reducing hs-CRP. However, more high-quality RCTs are needed for verification in the future to provide more reliable evidence-based medical reference.

Increased angiopoietin-like 4 expression ameliorates inflammatory bowel diseases via suppressing CD8+ T cell activities.

Angiopoietin-like 4 (ANGPTL4) is involved in inflammation-associated diseases, such as rheumatoid arthritis, type 2 diabetes, atherosclerosis, and chronic obstructive pulmonary disease. The role of ANGPTL4 in the pathogenesis of inflammatory bowel disease (IBD) remains unknown. Here, the plasma ANGPTL4 levels peaked on days 3 and 5, and expression of ANGPTL4 of inflamed colons peaked on days 5 and 7 in mice with dextran sulfate sodium (DSS)-induced colitis. Simultaneously, CD8+T cells in the inflamed colons peaked at day 5 but declined at day 7. However, the ANGPTL4-/- mice treated with DSS exhibited exacerbated colitis with more CD8+T cells and macrophages infiltrating the colons. The exogenous ANGPTL4 protein protected the mice against DSS-induced colitis with less CD8+T cell and macrophage recruitment in the colons. In addition, recombinant ANGPTL4 directly downregulated the IFN-γ and NKG2D expression of CD8+T cells but had no effects on the CD86 expression and TNF-α secretion of macrophages ex vivo. Adding ANGPTL4 protein into ANGPTL4-/- mice almost blocked the onset of DSS-induced colitis. In parallel, the plasma ANGPTL4 levels were elevated in patients with Crohn's disease and ulcerative colitis at mild/moderate stage and restored to normal levels in IBD patients at a severe stage. The higher ANGPTL4 expression in the inflamed colons of patients with IBD was correlated with lower CD8+ cell infiltration, whereas no associations with macrophages. Our results demonstrated the compensatory protective effect of ANGPTL4 on IBD development at least via the downregulation of CD8+T cell activities. Adding the ANGPTL4 protein would have beneficial effects to retard the progression of IBD.

Paeonol protects against acute pancreatitis by inhibiting M1 macrophage polarization via the NLRP3 inflammasomes pathway.

The excessive inflammatory response mediated by macrophage is one of the key factors for the progress of acute pancreatitis (AP). Paeonol (Pae) was demonstrated to exert multiple anti-inflammatory effects. However, the role of Pae on AP is not clear. In the present study, we aimed to investigate the protective effect and mechanism of Pae on AP in vivo and vitro. In the caerulein-induced mild acute pancreatitis (MAP) model, we found that Pae administration reduced serum levels of amylase, lipase, IL-1ß and IL-6 and alleviated the histopathological manifestations of pancreatic tissue in a dose-dependent manner. And Pae decrease the ROS generated, restore mitochondrial membrane potential (ΔΨm), inhibit M1 macrophage polarization and NLRP3 inflammasome in bone marrow-derived macrophages (BMDMs) in vitro. In addition, specific NLRP3 inhibitor MCC950 eliminated the protective effect of Pae on AP induced by caerulein in mice. Correspondingly, the inhibitory effect of Pae on ROS generated and M1 polarization was not observed in BMDMs with MCC950 in vitro. Taken together, our datas for the first time confirmed the protective effects of Pae on AP via the NLRP3 inflammasomes Pathway.

Elevated serum ferritin levels are associated with severity and prognosis of severe acute pancreatitis: a preliminary cohort study.

BACKGROUND: Serum ferritin (SF), as an acute-phase response protein, is used to reflect the degree of oxidative stress and systemic inflammatory responses. This study was designed to assess the effect of elevated SF levels on the severity of acute pancreatitis (AP). METHODS: From January 2013 to December 2020, 200 consecutive patients with AP were retrospectively reviewed to analyze the relationships among the etiologies of pancreatitis, the severity of the disease and SF levels. The receiver operating characteristic (ROC) curve and logistic regression analysis were used to assess whether elevated SF levels could predict the onset of organ failure in AP. RESULTS: 92 (46%) had high SF levels (> 275 ng/ml). SF levels were not associated with the etiology of AP disease. Among patients with high SF levels, there was a significant increase in the proportion of patients with severe AP (23.1% vs. 76.9%) and a higher proportion of systemic inflammatory response scores (25.9% vs. 44.6%) in comparison to patients with normal SF levels. The area under the ROC curve for SF in predicting persistent organ failure was 0.812 [95% confidence interval 0.721-0.904]. CONCLUSIONS: F concentrations were positively correlated with the severity of AP, and quantitative assessment of SF can predict disease severity and organ failure in patients with AP.

Emerin knockdown induces the migration and invasion of hepatocellular carcinoma cells by up-regulating the cytoplasmic p21.

Emerin (EMD) plays diverse roles in cellular polarity organization, nuclear stability, and cell motility, however, the biological role of EMD relevant to the migration and invasion of hepatocellular carcinoma (HCC) cells has not yet been illustrated. In the present study, we initially found that the upregulation of EMD in HCC tissues, and EMD expression was negatively correlated with the spontaneous metastatic potential of HCC cell lines. Loss of EMD in HCC cells facilitated cell migration and invasion in vitro and metastasis in vivo. Meanwhile, we demonstrated that EMD knockdown induced EMT but enhanced p21 expression in HCC cells. Notably, silencing of EMD in HCC cells increased the cytoplasmic localization of p21 protein, whereas p21 knockdown partially abrogated the migratory and invasive ability, EMT, and the actin cytoskeleton rearrangement induced by EMD knockdown in HCC cells. Our results indicated a significant role of EMD knockdown in the HCC cell motility and metastasis through upregulating the cytoplasmic p21, unveiling a novel mechanism of cell motility regulation induced by EMD.

Inhibition of hypoxia-inducible factor-1α alleviates acinar cell necrosis in a mouse model of acute pancreatitis.

Hypoxia-inducible factor-1α (Hif1α) is activated in hypoxia and is closely related to oxidative stress, immunity and cell metabolism. Recently, it is reported that Hif1α is involved in atherosclerosis, ischemia-reperfusion (I/R) injury, alcoholic liver disease and pancreatic tumors. In this study, we found that Hif1 signal pathway is significantly changed in pancreas of acute pancreatitis (AP) mice. Meanwhile, we verified that the high expression of Hif1α injured pancreatic tissues of cerulean-induced AP mice, which prompting that Hif1α participated in the progress of histopathology on AP. We applied a Hif1α inhibitor PX478 and observed that it could alleviate histological injury of pancreas as well as the levels of serum amylase, lipase and proinflammatory cytokine in the murine model of AP induced by caerulein. In addition, PX478 could reduce the formation of necrosome (RIP3 and p-MLKL) and the generation of reactive oxygen species (ROS) in AP mice. Correspondingly, we further confirmed the effectiveness of PX478 in vitro and found that inhibiting Hif1α could mitigated the necrosis of pancreatic acinar cells via reducing the RIP3 and p-MLKL expression and the ROS production. In conclusion, inhibiting Hif1α could protect against acinar cells necrosis in AP, which may provide a new target for the prevention and treatment of AP clinically.

[Overview of systematic reviews of Panax notoginseng saponins in treatment of acute cerebral infarction].

To overview the systematic reviews of Panax notoginseng saponins in the treatment of acute cerebral infarction. CNKI, CBM, Wanfang, VIP, PubMed, Cochrane Library and EMbase databases were retrieved to collect the systematic reviews of the efficacy of P. notoginseng saponins in the treatment of acute cerebral infarction. The retrieval time was from the time of database establishment to January 2021. After two researchers independently screened out the literature and extracted the data, AMSTAR-2 scale was used to evaluate the methodological quality of the included systematic reviews, GRADE system was used to grade the quality of evidences of the outcome indicators, and the efficacy evaluation was summarized. A total of 5 systematic reviews were included. AMSTAR-2 evaluation results showed that 3 items were relatively complete, while 4 items had a poor overall quality. P. notoginseng saponins combined with conventional Western medicine therapy was superior to single conventional therapy in the recovery of neurological function, enhancement of the total effective rate in clinic, and improvement of activities of daily living. GRADE evaluation results showed that the quality of evidence was from low quality to very low quality. In conclusion, in the treatment of acute cerebral infarction, P. notoginseng saponins can improve the clinical efficacy, with a good safety but a not high methodological quality and a low evidence quality. It is suggested that high-quality clinical studies shall be further carried out to provide evidence-based basis for the application of P. notoginseng saponins in the treatment of acute cerebral infarction.

Meta-analysis of genome-wide association studies and functional assays decipher susceptibility genes for gastric cancer in Chinese populations.

OBJECTIVE: Although a subset of genetic loci have been associated with gastric cancer (GC) risk, the underlying mechanisms are largely unknown. We aimed to identify new susceptibility genes and elucidate their mechanisms in GC development. DESIGN: We conducted a meta-analysis of four genome-wide association studies (GWASs) encompassing 3771 cases and 5426 controls. After targeted sequencing and functional annotation, we performed in vitro and in vivo experiments to confirm the functions of genetic variants and candidate genes. Moreover, we selected 33 promising variants for two-stage replication in 7035 cases and 8323 controls from other five studies. RESULTS: The meta-analysis of GWASs identified three loci at 1q22, 5p13.1 and 10q23.33 associated with GC risk at p<5×10-8 and replicated seven known loci at p<0.05. At 5p13.1, the risk rs59133000[C] allele enhanced the binding affinity of NF-κB1 (nuclear factor kappa B subunit 1) to the promoter of PRKAA1, resulting in a reduced promoter activity and lower expression. The knockout of PRKAA1 promoted both GC cell proliferation and xenograft tumour growth in nude mice. At 10q23.33, the rs3781266[C] and rs3740365[T] risk alleles in complete linkage disequilibrium disrupted and created, respectively, the binding motifs of POU2F1 and PAX3, resulting in an increased enhancer activity and expression of NOC3L, while the NOC3L knockdown suppressed GC cell growth. Moreover, two new loci at 3q11.2 (OR=1.21, p=4.56×10-9) and 4q28.1 (OR=1.14, p=3.33×10-11) were associated with GC risk. CONCLUSION: We identified 12 loci to be associated with GC risk in Chinese populations and deciphered the mechanisms of PRKAA1 at 5p13.1 and NOC3L at 10q23.33 in gastric tumourigenesis.

Genetic risk, incident gastric cancer, and healthy lifestyle: a meta-analysis of genome-wide association studies and prospective cohort study.

BACKGROUND: Genetic variants and lifestyle factors have been associated with gastric cancer risk, but the extent to which an increased genetic risk can be offset by a healthy lifestyle remains unknown. We aimed to establish a genetic risk model for gastric cancer and assess the benefits of adhering to a healthy lifestyle in individuals with a high genetic risk. METHODS: In this meta-analysis and prospective cohort study, we first did a fixed-effects meta-analysis of the association between genetic variants and gastric cancer in six independent genome-wide association studies (GWAS) with a case-control study design. These GWAS comprised 21 168 Han Chinese individuals, of whom 10 254 had gastric cancer and 10 914 geographically matched controls did not. Using summary statistics from the meta-analysis, we constructed five polygenic risk scores in a range of thresholds (p=5 × 10-4 p=5 × 10-5 p=5 × 10-6 p=5 × 10-7, and p=5 × 10-8) for gastric cancer. We then applied these scores to an independent, prospective, nationwide cohort of 100 220 individuals from the China Kadoorie Biobank (CKB), with more than 10 years of follow-up. The relative and absolute risk of incident gastric cancer associated with healthy lifestyle factors (defined as not smoking, never consuming alcohol, the low consumption of preserved foods, and the frequent intake of fresh fruits and vegetables), was assessed and stratified by genetic risk (low [quintile 1 of the polygenic risk score], intermediate [quintile 2-4 of the polygenic risk score], and high [quintile 5 of the polygenic risk score]). Individuals with a favourable lifestyle were considered as those who adopted all four healthy lifestyle factors, those with an intermediate lifestyle adopted two or three factors, and those with an unfavourable lifestyle adopted none or one factor. FINDINGS: The polygenic risk score derived from 112 single-nucleotide polymorphisms (p<5 × 10-5) showed the strongest association with gastric cancer risk (p=7·56 × 10-10). When this polygenic risk score was applied to the CKB cohort, we found that there was a significant increase in the relative risk of incident gastric cancer across the quintiles of the polygenic risk score (ptrend<0·0001). Compared with individuals who had a low genetic risk, those with an intermediate genetic risk (hazard ratio [HR] 1·54 [95% CI 1·22-1·94], p=2·67 × 10-4) and a high genetic risk (2·08 [1·61-2·69], p<0·0001) had a greater risk of gastric cancer. A similar increase in the relative risk of incident gastric cancer was observed across the lifestyle categories (ptrend<0·0001), with a higher risk of gastric cancer in those with an unfavourable lifestyle than those with a favourable lifestyle (2·03 [1·46-2·83], p<0·0001). Participants with a high genetic risk and a favourable lifestyle had a lower risk of gastric cancer than those with a high genetic risk and an unfavourable lifestyle (0·53 [0·29-0·99], p=0·048), with an absolute risk reduction of 1·12% (95% CI 0·62-1·56). INTERPRETATION: Chinese individuals at an increased risk of incident gastric cancer could be identified by use of our newly developed polygenic risk score. Compared with individuals at a high genetic risk who adopt an unhealthy lifestyle, those who adopt a healthy lifestyle could substantially reduce their risk of incident gastric cancer. FUNDING: National Key R&D Program of China, National Natural Science Foundation of China, 333 High-Level Talents Cultivation Project of Jiangsu Province, and China Postdoctoral Science Foundation.