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Abstract Background Severe acute pancreatitis (SAP) is characterized by high mortality rates and various complications, including skeletal muscle atrophy, which significantly exacerbates its outcomes. Despite its clinical relevance, the mechanistic understanding of the relationship between skeletal muscle and the pancreas in SAP remains limited. Our study aimed to elucidate this “organ crosstalk” and its potential implications. Methods We established an SAP mouse model through pancreatic duct ligation (PDL) and evaluated pancreatic necrosis, skeletal muscle atrophy, and myonectin expression levels. Recombinant myonectin protein was administered in vivo and in vitro to assess its effects on acinar cell necrosis. Mechanistic insights were gained through RNA-seq data analysis and experimental validation. Serum samples from AP patients and healthy controls were collected to investigate the correlation between serum myonectin levels and disease severity. Results The mouse model exhibited severe pancreatic necrosis, skeletal muscle atrophy, and elevated myonectin levels, with myonectin administration exacerbating model severity. We identified iron accumulation-induced ferroptosis as a key pathway contributing to myonectin-mediated acinar cell necrosis. A total of 22 healthy controls and 52 patients with varying degrees of AP were included in the serum samples and clinical data (36.5% females, age 49.79 ± 16.53). Analysis of serum samples revealed significantly higher myonectin levels in AP patients, correlating with disease severity (R = 0.28, P = 0.041). Conclusions Our findings underscore the significant role of myonectin in SAP progression and its potential as a prognostic marker for disease severity in AP patients. This study contributes to a deeper understanding of the pathophysiology of SAP and highlights potential therapeutic targets for intervention.

The aging of pancreatic beta cells is closely associated with various diseases, such as impaired glucose tolerance, yet the underlying regulatory mechanisms remain unclear. In this study, we screened young and aged mouse pancreatic beta cells' high-throughput sequencing data from the GEO public database. Utilizing bioinformatics techniques, we identified the key regulatory factor YY1 in the aging process of pancreatic islets. We observed a significant decrease in the expression of YY1 in a D-gal-induced mouse model of pancreatic aging and an H2O2-induced MIN6 cell model of aging. Moreover, both vivo and vitro models, we found that the YY1 agonist eudesmin (EDN) improved glucose intolerance in mice, alleviated aging of pancreatic beta cells, and downregulated the expression of cell cycle protein P21. Mechanistically, we discovered that EDN inhibited the P38/JNK MAPK pathway in aging cells. In summary, our study confirms the regulatory role of the transcription factor YY1 in the aging process of pancreatic beta cells. This finding may provide a new approach for the clinical treatment of pancreatic aging-related diseases such as impaired glucose tolerance or diabetes.

Abstract Uncoupling protein 1 (UCP1) catalyzes the leak of protons across the mitochondrial inner membrane for thermogenesis. Compromised NK cell activity is involved in the occurrence of nonalcoholic liver fibrosis. Here, decreased UCP1 in NK cells was identified in patients with advanced nonalcoholic fatty liver disease. Although no obvious changes were observed in the NK cells of physiologic UCP1−/− mice (8–10 weeks old), impaired NK cell bioactivity was shown in methionine–choline-diet (MCD)-fed UCP1−/− mice and involved in the acerbation of nonalcoholic steatohepatitis (NASH) progress to liver fibrosis. Moreover, UCP1-deficient NK cells were responsible for the aggravation of liver fibrosis, as confirmed in MCD-fed UCP1flox/flox-NCR1cre mice. Acerbation of liver fibrosis was also seen in wild-type mice when their endogenous NK cells were replaced with UCP1−/− NK cells. Transcriptions of mitophagy-associated molecules in UCP1 −/− NK cells were enhanced according to RNA-seq. Electron microscopic results showed mitochondrial injuries and autophagic vesicles in MCD-fed NKWT cells, PA-treated NKWT cells, or physiologic NKKO cells. However, the co-existence of UCP1 deficiency and high lipid can synergistically induce NK cell necroptosis via DRP1S616 accompanied with reduced mitophagy. Finally, The UCP1 in NK cells was downregulated when treated by sustained high PA (600 μM) via the PPARγ/ATF2 axis. Thus, persistent high-lipid treatment not only decreases UCP1 expression but also combines with reduced UCP1 to promote NK cell necroptosis, and it is involved in NASH progression to fibrosis.

Abstract Adropin is encoded by the energy homeostasis-associated (ENHO) gene and widely present in liver, pancreas, heart, kidney, brain, and vascular tissues. Abnormal adropin is associated with metabolic, inflammatory, immune, and central nervous disorders. Whether adropin is involved in the development of colorectal cancer (CRC) is still unclear. Here, decreased adropin expression of tumor-nest cells in advanced-stage CRC was demonstrated. Adropin expressed by carcinoma cells was negatively correlated with macrophage infiltration in the matrix of CRC tissues. However, tumor macrophages enhanced adropin expression and were positively correlated with tumor invasion and metastasis. ENHO gene transfection into colon cancer (MC38) cells inhibited tumor growth in vivo, accompanying the increase of M1 macrophages. Treatment with low-dose adropin (

Abstract 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.

PurposeIn order to reduce the incidence and mortality of colorectal cancer, improving the quality of colonoscopy is the top priority. At present, the adenoma detection rate is the most used index to evaluate the quality of colonoscopy. So, we further verified the relevant factors influencing the quality of colonoscopy and found out the novel quality indicators by studying the relationship between the influencing factors and the adenoma detection rate.Materials/methodsThe study included 3824 cases of colonoscopy from January to December 2020. We retrospectively recorded the age and sex of the subjects; the number, size, and histological features of lesions; withdrawal time and the number of images acquired during colonoscopy. We analyzed the associated factors affecting adenoma and polyp detection, and verified their effectiveness with both univariate and multivariate logistic regression analyses.ResultsLogistic regression analyses showed that gender, age, withdrawal time and the number of images acquired during colonoscopy could serve as independent predictors of adenoma/polyp detection rate. In addition, adenoma detection rate (25.36% vs. 14.29%) and polyp detection rate (53.99% vs. 34.42%) showed a marked increase when the number of images taken during colonoscopy was ≥29 (P

Background The study aimed to detect the serum levels of fibroblast growth factor-21 (FGF-21) in fatty pancreas (FP) patients and to investigate their potential clinical value. Methods We screened patients with FP using transabdominal ultrasound. The anthropometric, biochemical and serum levels of FGF-21 were compared between the FP group and the normal control (NC) group. A receiver operating characteristic (ROC) curve was used to evaluate the predictive value of serum FGF-21 for FP patients. Results Compared with the NC group, body mass index, fasting blood glucose levels, uric acid levels and cholesterol levels of the FP group were significantly higher, while the high-density lipoprotein level was lower. In addition, levels of serum FGF-21, resistin, leptin and tumor necrosis factor-α were significantly higher than those in the NC group, while the serum adiponectin level was lower. Pearson analysis showed serum FGF-21 levels in FP patients were negatively correlated with leptin. The ROC curve showed the best critical value of the serum FGF-21 level in FP patients was 171 pg/mL (AUC 0.744, P = 0.002, 95% confidence intervals 0.636–0.852). Conclusion Serum FGF-21 was closely related to fatty pancreas. Detecting serum FGF-21 levels may help identify the population susceptible to FP.

The microRNAs miR-144/451 are highly conserved miRNA that is strongly induced during erythropoiesis. Despite the biological functions of miR-144/451 have been extensively studied in erythropoiesis and tumorigenesis, few studies have been conducted in immune responses. In this study, we showed that miR-144/451-/- DCs exhibit increased activation. Mechanistically, the miR-144 directly targets the 3`-UTR of IRF5 and represses the expression of IRF5 in DCs. Ectopic expression of miR-144/451 by lentiviruses downregulates the levels of IRF5 and suppresses DCs function. In addition, knockdown of IRF5 by shRNA significantly inhibits activities of the miR-144/451-/- DCs. Expression of miR144/451 was decreased in DCs from both patients with IBD and mice with DSS-colitis compared with controls. Human PBMC derived DCs were downregulated expression of miR144/451 after LPS stimulation. In the DSS-induced colitis mice model, we showed that ablation of the miR-144/451 gene causes severe colitis, and their DCs from both periphery and MLN expressed higher co-stimulatory molecules and pro-inflammatory cytokines than wild-type mice. In addition, DCs isolated from miR-144/451-/- mice transfusion exacerbates mice colitis. In the bone marrow transplanted chimeric mice model, we show that miR-144/451-/- bone marrow transplantation deteriorated DSS-induced colitis. At last, we treat the mice with miR-144/451 delivered by chitosan nanoparticles revealing protective effects in DSS-induced colitis mice. Thus, our results reveal a novel miR144/451-IRF5 pathway in DCs that protects experimental colitis. The manipulation of miR-144/451 expression and DCs activation in IBD patients may be a novel therapeutic approach for the treatment of inflammatory diseases.

Astilbin, as a compound of flavonoids, exerts anti-inflammation, antioxidation, and immune-suppression activities. Decreased activation of NF-κB and p38 MAPK and increased activation of SOCS3 and AMPK have been found in astilbin-treated cells. However, what molecules are docked by astilbin to initiate signaling cascades and result in functional changes remains unknown. In the study, we found that astilbin efficiently suppressed TNF-α production and increased CCR9 and CD36 expression of CD4+ T cells. In vivo administration of astilbin repressed the occurrence of type 1 diabetes mellitus in non-obese diabetic mice. The PPARγ/SOCS3, PPARγ/PTEN, and PPARγ/AMPK signaling pathways were substantially activated and played key roles in astilbin-induced downregulation of CD4+ T cell functions. Transcriptome sequencing results confirmed the changes of signaling molecules involved in the immune system, inflammatory responses, and indicated variations of multiple enzymes with oxidant or antioxidant activities. Astilbin directly induced cytoplasmic ROS production of CD4+ T cells ex vivo, but had no effects on mitochondrial ROS and mitochondrial weight. When cellular ROS was depleted, astilbin-treated CD4+ T cells remarkably reversed the expression of TNF-α, IFN-γ, CCR9, CD36, and signaling molecules (PPARγ, PTEN, p-AMPK, and SOCS3). Based on bioinformatics, two P450 enzymes (CYP1B1 and CYP19A1) were selected as candidate receptors for astilbin. CYP1B1 was identified as a real docking protein of astilbin in ROS production by AutoDock Vina software analysis and surface plasmon resonance assay. Collectively, astilbin downregulates effector CD4+ T cell activities via the CYP1B1/ROS/PPARγ pathway, which firmly supports its potential use in the treatment of inflammation.

Abstract Hypertriglyceridemic waist phenotype (HTWP) and its quantitative indicator, waist circumference-triglyceride index (WTI), are common quantitative indices of visceral obesity and are closely related to metabolic diseases. The purpose of this study was to investigate the relationship between fatty pancreas (FP) and HTWP in China. FP was diagnosed using trans-abdominal ultrasonography in all participants. According to the waist circumference and serum triglyceride levels, the participants were divided into four phenotype groups: normal waist circumference-normal triglyceride, normal waist circumference-elevated triglyceride, elevated waist circumference-normal triglyceride, and elevated waist circumference-elevated triglyceride (indicating HTWP). Clinical characteristics and biochemical indices were compared among the groups. Receiver operating characteristic (ROC) curves were used to evaluate the utility of WTI as a reference factor for FP screening. The HTWP group had a higher prevalence of metabolic syndrome (84.2%), FP (10.4%), fatty liver (64.5%), and hypertension (15.8%) than the other three phenotype groups. The occurrence rate of HTWP and the median WTI were significantly higher in participants with FP than in those without FP (54.7% vs 21.0%, 222 ± 135 vs 142 ± 141, p

Abstract Background To investigate the value of serum hydroxybutyrate dehydrogenase (HBDH) level, an isozyme of lactate dehydrogenase, in evaluating the severity of acute pancreatitis (AP). Methods Patients diagnosed with AP from January 2013 to December 2018 were included in this retrospective study. Patients were divided into the normal serum HBDH levels group (n-HBDH group) and the high serum HBDH levels group (h-HBDH group) according to the criteria HBDH ≥ 182 U/L after admission. The demographic parameters, laboratory data and the severity of AP in the two groups were compared. The receiver operating curve (ROC) was used to evaluate the efficacy of serum HBDH in predicting persistent organ failure and systemic inflammatory response syndrome (SIRS). Results A total of 260 AP patients were enrolled, including 176 cases in the n-HBDH group and 84 cases in the h-HBDH group. The incidence of SIRS and organ failure in the h-HBDH group were significantly higher than those in n-HBDH group (both P

BackgroundSince the outbreak of the coronavirus disease 2019 (COVID-19) pandemic first reported in Wuhan, China, several research on the psychological impact of the pandemic on patients with Crohn’s disease (CD) have been conducted. However, with the progression of the global pandemic and the emergence of the SARS-CoV-2 B.1.617.2 (Delta) variant, follow-up studies need to be performed to monitor the alterations of psychological status and health-related quality of life (HRQoL) among CD patients.AimsWe aimed to evaluate the impact of the SARS-CoV-2 Delta variant on the mental health and life quality among the CD population and tried to explore potent risk factors.MethodsThis observational study included 153 CD patients who responded to our pre-designed self-reported questionnaire. Demographic, clinical, and psychological information were collected and analyzed.ResultsQuite a number of CD patients were confronted with different levels of anxiety and depression, with incidence of 28.10 and 31.37% for anxiety and depression, respectively. Compared with non-pandemic circumstances, the life quality of CD patients due to the present situation was more often compromised. Isolation [odds ratio (OR): 4.71, P = 0.007] was verified as a risk factor for anxiety while use of telemedicine could help relieve anxiety (OR: 0.22, P < 0.001). Worsening of symptoms (OR: 4.92, P = 0.006), isolation (OR: 5.75, P = 0.005), and drug withdrawn (OR: 2.66, P = 0.026) were identified to be independent factors for developing depression. Likewise, use of telemedicine (OR: 0.13, P < 0.001) was negatively related to depression. Considering life quality, vaccination (OR: 3.07, P = 0.021) together with no medication (OR: 7.73, P = 0.010) was relevant to better life quality while worsening of symptoms (OR: 0.09, P = 0.034) were an independent risk factor for impaired life quality.ConclusionMany CD patients suffered from symptoms of anxiety and depression and impaired life quality during the COVID-19 pandemic. Those in isolation or with worsening of symptoms and drug withdrawn were more prone to experience psychological stress. Individualized management such as drug delivery and telemedicine should be promoted to maintain control of mental health and life quality during the pandemic.

Abstract Background The aim of this study was to evaluate the effect of a simple visceral obesity phenotype, known as the hypertriglyceridemic waist phenotype and its quantitative indicator waist circumference index on the severity of acute pancreatitis. Materials and methods Diagnosis and severity analysis of acute pancreatitis were determined according to the Atlanta classification guidelines, revised in 2012. We considered the hypertriglyceridemic waist phenotype as characterized by increased waist circumference and elevated triglyceride concentrations. We investigated the association between the acute pancreatitis severity and hypertriglyceridemic waist phenotype, including waist circumference index. Results The hypertriglyceridemic waist phenotype was significantly associated with systemic inflammatory response syndrome, organ failure, and severe acute pancreatitis. The median waist circumference index and demonstration of hypertriglyceridemic waist phenotype were positively correlated with acute pancreatitis severity. In addition, multivariate logistic analysis showed that patients with the hypertriglyceridemic waist phenotype had 1.664 times the risk of organ failure and 1.891 times the risk of systemic inflammatory response syndrome, compared with the other groups. Conclusion Upon admission, the hypertriglyceridemic waist phenotype was strongly associated with acute pancreatitis in patients. This phenotype, including waist circumference index, might be a simple method for evaluating individuals at high risk of severe acute pancreatitis.

Formononetin is a kind of isoflavone compound and has been reported to possess anti-inflammatory properties. In this present study, we aimed to explore the protective effects of formononetin on dextran sulfate sodium- (DSS-) induced acute colitis. By intraperitoneal injection of formononetin in mice, the disease severity of colitis was attenuated in a dose-dependent manner, mainly manifesting as relieved clinical symptoms of colitis, mitigated colonic epithelial cell injury, and upregulations of colonic tight junction proteins levels (ZO-1, claudin-1, and occludin). Meanwhile, our study found that formononetin significantly prevented acute injury of colonic cells induced by TNF-α in vitro, specifically manifesting as the increased expressions of colonic tight junction proteins (ZO-1, claudin-1, and occludin). In addition, the result showed that formononetin could reduce the NLRP3 pathway protein levels (NLRP3, ASC, IL-1β) in vivo and vitro, and MCC950, the NLRP3 specific inhibitor, could alleviate the DSS-induced mice acute colitis. Furthermore, in the foundation of administrating MCC950 to inhibit activation of NLRP3 inflammasome, we failed to observe the protective effects of formononetin on acute colitis in mice. Collectively, our study for the first time confirmed the protective effects of formononetin on DSS-induced acute colitis via inhibiting the NLRP3 inflammasome pathway activation.

Objective. This study aims to investigate the effects of reporting colonoscopy findings and the regular review of outcomes on adenoma detection rates. Methods. Patients who underwent colonoscopy from August 2013 to February 2014 were selected as the intervention group. The preintervention group included patients who underwent colonoscopy from January 2013 to July 2013, in which the procedure sheet for this group of patients was not accomplished. The primary outcome was adenoma detection rate (ADR), and secondary outcomes included the success rate of intubation and withdrawal time. Results. This study included 2,467 cases: 1,302 cases in the intervention group and 1,165 cases in the preintervention group. There was no significant difference in demographic characteristics between the two groups. In the intervention group, withdrawal time of colonoscopy was longer (P

Mitochondria are highly-dynamic organelles, but it is challenging to monitor quantitatively their dynamics in a living cell. Here we developed a novel approach to determine the global occurrence of mitochondrial fission and fusion events in living human epithelial cells (Hela) and mouse embryonic fibroblast cells (MEF). Distinct patterns of sequential events including fusion followed by fission (Fu-Fi), the so-called "kiss and run" model previously described, fission followed by fusion (Fi-Fu), fusion followed by fusion (Fu-Fu), and fission followed by fission (Fi-Fi) were observed concurrently. The paired events appeared in high frequencies with short lifetimes and large sizes of individual mitochondria, as compared to those for unpaired events. The high frequencies of paired events were found to be biologically significant. The presence of membrane uncoupler CCCP enhanced the frequency of paired events (from both Fu-Fi and Fi-Fu patterns) with a reduced mitochondrial size. Knock-out of mitofusin protein Mfn1 increased the frequency of fission with increased lifetime of unpaired events whereas deletion of both Mfn1 and Mfn2 resulted in an instable dynamics. These results indicated that the paired events were dominant but unpaired events were not negligible, which provided a new insight into mitochondrial dynamics. In addition to kiss and run model of action, our data suggest that, from a global visualization over an entire cell, multiple patterns of action appeared in mitochondrial fusion and fission.