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.

Engineering of Pore Design and Oxygen Vacancy on High-Entropy Oxides by a Microenvironment Tailoring Strategy.

High-entropy oxides (HEOs) exhibit abundant structural diversity due to cationic and anionic sublattices with independence, rendering them superior in catalytic applications compared to monometallic oxides. Nevertheless, the conventional high-temperature calcination approach undermines the porosity and reduces the exposure of active sites (such as oxygen vacancies, OVs) in HEOs, leading to diminished catalytic efficiency. Herein, we fabricate a series of HEOs with a large surface area utilizing a microenvironment modulation strategy (m-NiMgCuZnCo: 86 m2/g, m-MnCuCoNiFe: 67 m2/g, and m-FeCrCoNiMn: 54 m2/g). The enhanced porosity in m-NiMgCuZnCo facilitates the presentation of numerous OVs, exhibiting an exceptional catalytic performance. This tactic creates inspiration for designing HEOs with rich porosity and active species with vast potential applications.

Deficiency of angiopoietin-like 4 enhances CD8+ T cell bioactivity via metabolic reprogramming for impairing tumour progression.

Angiopoietin-like 4 (ANGPTL4) is a secreted metabolism-modulating glycoprotein involved in the progression of tumours, cardiovascular diseases, metabolic syndrome and infectious diseases. In this study, more CD8+ T cells were activated to be effector T cells in ANGPTL4-/- mice. Impaired growth of tumours implanted in 3LL, B16BL6 or MC38 cells and reduced metastasis by B16F10 cells were observed in ANGPTL4-/- mice. Bone marrow (BM) transplantation experiments displayed that deficiency of ANGPTL4 in either host or BM cells promoted CD8+ T cell activation. However, ANGPTL4 deficiency in CD8+ T cells themselves showed more efficient anti-tumour activities. Recombinant ANGPTL4 protein promoted tumour growth in vivo with the less CD8+ T cell infiltration and it directly downregulated CD8+ T cell activation ex vivo. Transcriptome sequencing and metabolism analysis identified that ANGPTL4-/- CD8+ T cells increased glycolysis and decreased oxidative phosphorylation, which was dependent on the PKCζ-LKB1-AMPK-mTOR signalling axis. Reverse correlation of elevated ANGPTL4 levels in sera and tumour tissues with activated CD8+ T cells in the peripheral blood was displayed in patients with colorectal cancer. These results demonstrated that ANGPTL4 decreased immune surveillance in tumour progression by playing an immune-modulatory role on CD8+ T cells via metabolic reprogramming. Efficient blockade of ANGPTL4 expression in tumour patients would generate an effective anti-tumour effect mediated by CD8+ T cells.

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.

Low-dose adropin stimulates inflammasome activation of macrophage via mitochondrial ROS involved in colorectal cancer progression.

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 (< 100 ng/mL) on macrophages ex vivo directly increased mitochondrial reactive oxygen species for inflammasome activation. Furthermore, ENHO-/- mice had less M1 macrophages in vivo, and ENHO-/- macrophages were inert to be induced into the M1 subset ex vivo. Finally, low-dose adropin promoted glucose utilization, and high-dose adropin enhanced the expression of CPT1α in macrophages. Therefore, variations of adropin level in carcinoma cells or macrophages in tumor tissues are differently involved in CRC progression. Low-dose adropin stimulates the antitumor activity of macrophages, but high-dose adropin facilitates the pro-tumor activity of macrophages. Increasing or decreasing the adropin level can inhibit tumor progression at different CRC stages.

Embedding Hierarchical Pores by Mechanochemistry in Carbonates with Superior Chemoselective Catalysis and Stability.

Hierarchical porosity of carbonates can facilitate their performance in massive applications as compared to their corresponding bulk samples. Traditional solution-based precipitation is typically utilized to fabricate porous carbonates. However, this tactic is generally employed under humid conditions, which demand soluble metal precursors, solvents, and extended dry periods. A salt-assisted mechanochemistry is exploited in contemporary work to settle the shortcomings. Enlighted by solid-state technology, this approach eliminates the utilization of solvents, and the process of ball milling can create pores in 5 min. A range of highly porous carbonates and their derivatives are acquired, with several materials surpassing recording surface areas (e.g., H-CaCO3: 108 m2/g, SrCO3: 125 m2/g, BaCO3: 172 m2/g, Pd/H-CaCO3 catalyst: 101 m2/g). The results display that Pd/H-CaCO3 shows superior catalytic efficiency in the synthesis of aniline (turnover frequency [TON] = 1.33 × 104/h-1, yield ≥ 99%, and recycle stability: 11 cycles) and dye degradation. Combining mechanochemistry and salt-assisted tactic provides a facile and efficient pathway for processing porous materials.

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.

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.

Self-Stirring Microcatalysts: Large-Scale, High-Throughput, and Controllable Preparation and Application.

Herein, we introduce a strategy to develop a kind of unprecedented microcatalyst, which owns self-stirring and catalytic performance based on pneumatic printing and magnetic field induction technology. A spindle-shaped microcatalyst based on metal-organic frameworks (MOFs) with a certain aspect ratio and size can be obtained by tuning the printing parameters and the intensity of the magnetic field. One nozzle can print 18 000 microcatalysts per hour, which provides a prerequisite for the realization of large-scale production in the industrial field. Furthermore, this strategy can be widely applied to a variety of other heterogeneous catalysts, such as mesoporous SiO2, zeolite, metallic oxide, and so on. To demonstrate the superiority of the printed catalyst, the series of printed microcatalysts were evaluated by various catalytic reactions including liquid-phase hydrogenation, microdroplet dye-fading, and photocatalytic degradation in microreactor, all of which exhibited excellent catalytic performance.

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.

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.

Deficiency of miR-15a/16 upregulates NKG2D in CD8+ T cells to exacerbate dextran sulfate sodium-induced colitis.

The miR-15a/16 gene cluster is located in human chromosome 13 (13q14.3) and mouse chromosome 14 (14qC3). These genes are involved in cancer development and immune regulation. Our group has previously verified the binding of the 3'-untranslated region of NKG2D gene by miR-16 through dual-luciferase reporter assay. Herein, we found that miR-16 overexpression inhibited the NKG2D expression of CD8+ T cells, and that CD8+ NKG2D+ T cell frequency increased in miR-15/16-/- mice. CD8+ NKG2D+ T cells derived of miR-15/16-/- mice displayed activatory phenotype with enhanced IFN-γ production and cytotoxicity. The transfection of lentivirus containing antago-miR-16 sequences enhanced the NKG2D expression level of CD8+ T cells. However, no significant differences in CD8+ NKG2D+ T cell frequencies existed between wild-type and miR-15/16-transgenic mice because NKG2D was not expressed on the rest CD8+ T cells. When CD8+ T cells of miR-15/16-transgenic mice were treated with IL-2 in vitro, the magnitude of NKG2D expression and activation of CD8+ T cells was lower than that of wild-type mice. miR-15/16-/- mice showed that the exacerbation of colitis induced by dextran sulfate sodium (DSS) with more CD8+ T cells accumulated in inflamed colons, whereas miR-15/16-transgenic mice ameliorated DSS-induced colitis with less infiltration of CD8+ T cells. When NKG2D+ cells were depleted with NKG2D antibody in miR-15/16-/- mice, the aggravated colitis disappeared. All these results demonstrated that NKG2D could be upregulated by decreased miR-16 in CD8+ T cells to mediate inflammation. Thus, gene therapy based on the overexpression of miR-16 in CD8+ T cells can be used for patients with inflammatory diseases.

A 2-Fold Interpenetrated Nitrogen-Rich Metal-Organic Framework for Rapid and Selective Adsorption of Congo Red.

A new metal-organic framework was prepared based on a mixed ligand system of the designed nitrogen-rich 3,6-bis(2-methylimidazole)pyrimidine (b2mpm) and benzophenone 4,4'-dicarboxylic acid (H2bpndc). The prepared material shows a three-dimensional 2-fold interpenetrated pcu framework and features rectangular channels decorated with nitrogen sites. Thanks to the abundant hydrogen bonding and π-π stacking interactions, the titled material can rapidly adsorb Congo red (CR) and presents ultrahigh adsorption capacity (2348 mg g-1). Moreover, this material has an adsorptive selectivity toward CR and can be regenerated by simply washing it with ethanol. The adsorption kinetic and isotherm of the titled material were also determined, indicating that the adsorption kinetic conforms to the pseudo-second-order model and the adsorption isotherm obeys the Langmuir model. Additionally, the titled material exhibits the suitable adsorption ability toward CO2 (15.2 cm3 g-1 under 1 atm at 298 K). These results demonstrate that the titled material would be an effective and easily regenerated adsorbent for CR removal from wastewater.

Serum hydroxybutyrate dehydrogenase as an early predictive marker of the severity of acute pancreatitis: a retrospective study.

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 < 0.001). In addition, the HBDH level was significantly decreased in 110 patients who were re-measured after AP treatment. The serum HBDH levels were positively correlated with Atlanta classification, Ranson score, and BISAP score (all P < 0.05). ROC analysis showed that a serum HBDH cut-off point of 195.0 U/L had optimal predictive value for the development of persistent organ failure (AUC = 0.778) and 166.5 U/L for the development of SIRS (AUC = 0.724). CONCLUSION: The elevated serum HBDH in early stage of AP is closely related to the adverse prognosis of AP patients, which can be used as a potential early biomarker for predicting the severity of AP.

Grape Seed Polyphenols Ameliorated Dextran Sulfate Sodium-Induced Colitis via Suppression of Inflammation and Apoptosis.

BACKGROUND: Ulcerative colitis (UC) is an inflammatory bowel disease. Its onset is typically gradual, usually followed by periods of spontaneous remission and subsequent relapses. Grape seed polyphenols (GSP), a natural product extracted from grape seeds, have strong anti-inflammatory functions. OBJECTIVES: In this study, we investigated whether GSP has an inhibitory effect on UC and its related mechanism or not. METHODS: We induced UC by 2.5% dextran sulfate sodium (DSS) and GSP at different doses (500 and 750 mg/kg body weight per day) was administrated to the mice by gavage. Body weight, diarrhea, and bloody stool were recorded every day to evaluate disease activity index. Hemotoxylin-eosin staining and immunohistochemical staining were used to identify the histological damages and inflammatory infiltration in colon tissues. Real-time polymerase chain reaction was used to evaluate mRNA expression of interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α and the expression of phosphorylated-signal transducer and activator of transcription 3 (STAT3) and STAT3 were assessed by western blot. The immunofluorescent assay was used to evaluate the apoptosis of intestinal epithelial cells (IECs). RESULTS: GSP could alleviate the loss of body weight, diarrhea, bloody stool, the mucosal damage, and inflammatory infiltration. GSP could also downregulate the mRNA expression of inflammatory cytokines IL-6, IL-1ß, and TNF-α as well as the phosphorylation of STAT3 and ameliorate the apoptosis of IECs. CONCLUSIONS: Our study suggests that GSP has protective effects against DSS-induced UC, which may through suppression of inflammation and apoptosis.

NQDI-1 protects against acinar cell necrosis in three experimental mouse models of acute pancreatitis.

NQDI-1, an inhibitor of ASK1, has been reported to have protective effects in several experimental human disease models. However, the role of NQDI-1 in acute pancreatitis (AP) has not been reported. In this study, we found that NQDI-1 could attenuate histological damage of pancreatic tissue as well as the levels of serum amylase and lipase in a mouse model of AP induced by caerulein. Moreover, the production of reactive oxygen species (ROS) and the expression of necrosis-related proteins (RIP3 and p-MLKL) were also reduced after NQDI-1 administration. Correspondingly, we elucidated the effect of NQDI-1 in vitro and found that NQDI-1 protected against pancreatic acinar cells necrosis via decreasing the ROS production and RIP3 and p-MLKL expression. In addition, we identified the protective effect of NQDI-1 on AP through two other mouse models induced by l-arginine and pancreatic duct ligation. Taken together, these findings showed that NQDI-1 could reduce the acinar cells necrosis and alleviate the severity of AP, which may afford a new therapeutic target on pancreatic necrosis in AP clinically.

Association of the hypertriglyceridemic waist phenotype and severity of acute pancreatitis.

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.

Dynamic changes of proteasome and protective effect of bortezomib, a proteasome inhibitor, in mice with acute pancreatitis.

The proteasome is involved in the activation of NF-κB and can regulate the progression of inflammatory diseases. However, the role of proteasome in acute pancreatitis (AP) has not been demonstrated. In this study, we first observed that the protein level and activity of proteasome 20S were increased significantly in pancreatic injury tissues after caerulein-induced mild acute pancreatitis (MAP) induction, which was in consistent with the expression of the NF-κB nucleoprotein and positively correlated with the severity of AP. Then, bortezomib, a classical proteasome inhibitor, was used to intervene the progression of MAP in mice. The results showed that bortezomib administration reduced the serum amylase and lipase levels and mitigated histopathological manifestation of pancreatic injury in mice. Meanwhile, bortezomib decreased the expression of NF-κB p65 nucleoprotein as well as total proteasome 20S protein, and inhibited the activity of 20S in pancreatic tissues. In addition, we found that bortezomib could protect pancreatic acinar cell against necrosis and mitigate the severity of AP in a severe acute pancreatitis model induced by sodium taurocholate hydrate. Taken together, our study for the first time confirmed that the proteasome participated in the pathogenesis of AP and its inhibitor bortezomib could protect against AP in mice.