Incidence and risk factors of fasting hyperglycaemia following first-attack acute pancreatitis before discharge: a retrospective study.

BACKGROUND: Pancreatic endocrine insufficiency is more likely to occur after acute pancreatitis (AP), but the risk factors affecting pancreatic endocrine function remain controversial. Therefore, exploring the incidence and risk factors of fasting hyperglycaemia following first-attack AP is important. METHODS: Data were collected from 311 individuals with first-attack AP without previous diabetes mellitus (DM) or impaired fasting glucose (IFG) history treated in the Renmin Hospital of Wuhan University. Relevant statistical tests were performed. A two-sided p-value < 0.05 was considered statistically significant. RESULTS: The incidence of fasting hyperglycaemia in individuals with first-attack AP was 45.3%. Univariate analysis showed that age (χ2 = 6.27, P = 0.012), aetiology (χ2 = 11.184, P = 0.004), serum total cholesterol (TC) (χ2 = 14.622, P < 0.001), and serum triglyceride (TG) (χ2 = 15.006, P < 0.001) were significantly different between the hyperglycaemia and non-hyperglycaemia groups (P < 0.05). The serum calcium concentration (Z=-2.480, P = 0.013) was significantly different between the two groups (P < 0.05). Multiple logistic regression analysis showed that age- ≥60 years (P < 0.001, OR = 2.631, 95%Cl = 1.529-4.527) and TG ≥ 5.65 mmol/L (P < 0.001, OR = 3.964, 95%Cl = 1.990-7.895) were independent risk factors for fasting hyperglycaemia in individuals with first-attack AP (P < 0.05). CONCLUSIONS: Old age, serum triglycerides, serum total cholesterol, hypocalcaemia, and aetiology are associated with fasting hyperglycaemia following first-attack AP. Age ≥ 60 years and TG ≥ 5.65 mmol/L are independent risk factors for fasting hyperglycaemia following first-attack AP.

Downregulation of Bmal1 Expression in Celiac Ganglia Protects against Hepatic Ischemia-Reperfusion Injury.

Hepatic ischemia-reperfusion injury (HIRI) significantly contributes to liver dysfunction following liver transplantation and hepatectomy. However, the role of the celiac ganglion (CG) in HIRI remains unclear. Adeno-associated virus was used to silence Bmal1 expression in the CG of twelve beagles that were randomly assigned to the Bmal1 knockdown group (KO-Bmal1) and the control group. After four weeks, a canine HIRI model was established, and CG, liver tissue, and serum samples were collected for analysis. The virus significantly downregulated Bmal1 expression in the CG. Immunofluorescence staining confirmed a lower proportion of c-fos+ and NGF+ neurons in TH+ cells in the KO-Bmal1 group than in the control group. The KO-Bmal1 group exhibited lower Suzuki scores and serum ALT and AST levels than the control group. Bmal1 knockdown significantly reduced liver fat reserve, hepatocyte apoptosis, and liver fibrosis, and it increased liver glycogen accumulation. We also observed that Bmal1 downregulation inhibited the hepatic neurotransmitter norepinephrine, neuropeptide Y levels, and sympathetic nerve activity in HIRI. Finally, we confirmed that decreased Bmal1 expression in CG reduces TNF-α, IL-1ß, and MDA levels and increases GSH levels in the liver. The downregulation of Bmal1 expression in CG suppresses neural activity and improves hepatocyte injury in the beagle model after HIRI.

Preexisting diabetes, serum calcium and D-dimer levels as predictable risk factors for pancreatic necrosis of patients with acute pancreatitis: a retrospective study.

BACKGROUND: Some individuals with acute pancreatitis (AP) suffer from pancreatic necrosis. Diabetes affects the severity of AP, but whether diabetes influences pancreatic necrosis is unclear. This study aims to investigate the clinical characteristics of AP patients with and without diabetes as well as analyze the risk factors of pancreatic necrosis. RESEARCH DESIGN AND METHODS: A total of 625 AP patients participated in the study. Clinical and laboratory data were retrieved. Multivariate logistic regression analysis was used to identify the risk factors for pancreatic necrosis. ROC curves assess the accuracy of indicators for predicting pancreatic necrosis in AP. RESULTS: AP patients with diabetes had high BMI, CTSI scores, pancreatitis severity, WBC, neutrophil, CRP, triacylglycerols and glucose levels. Diabetes, serum calcium and D-dimer were independent risk factors for pancreatic necrosis. Pancreatic necrosis in diabetes patients is also associated with sex and age. D-dimer is a better predictor of pancreatic necrosis in AP patients than serum calcium. CONCLUSIONS: Diabetic patients are more likely to suffer severe AP. Serum calcium and D-dimer are independent predictors for pancreatic necrosis. Furthermore, low serum calcium, high D-dimer levels, younger age and female sex are independent risk factors for pancreatic necrosis in AP patients with diabetes.

Inhibition of Notch activity suppresses hyperglycemia-augmented polarization of macrophages to the M1 phenotype and alleviates acute pancreatitis.

Acute pancreatitis (AP) is an acute inflammatory disorder characterized by acinar cell death and inflammation. Multiple factors cause hyperglycemia after AP. Macrophage polarization is involved in tissue injury and repair, and is regulated by Notch signaling during certain inflammatory diseases. The present study explores the relationship among hyperglycemia, macrophage polarization, and Notch signaling during AP and the related mechanisms. A cerulein-induced AP model was established in FVB/N mice, and AP with hyperglycemia was initiated by injection of 50% concentration glucose. Tissue damage, Notch activity, and macrophage polarization were assessed in pancreatic tissues. The role of Notch signaling in macrophage polarization during AP was also assessed in vitro by co-culturing primary macrophages and pancreatic acinar cells, and establishing a lipopolysaccharide (LPS)-induced inflammatory model in RAW264.7 cells. Pancreatic acinar cells were damaged and proinflammatory factor levels were increased in pancreatic tissues during AP. The hyperglycemic conditions aggravated pancreatic injury, increased macrophage infiltration, promoted macrophage polarization towards an M1 phenotype, and led to excessive up-regulation of Notch activity. Inhibition of Notch signaling by DAPT or Notch1 knockdown decreased the proportion of M1 macrophages and reduced the production of proinflammatory factors, thus mitigating pancreatic injury. These findings suggest that hyperglycemia induces excessive Notch signaling after AP and further aggravates AP by promoting pancreatic macrophage polarization towards the M1 phenotype. The Notch signaling pathway is a potential target for the prevention and treatment of AP.

PDE9 Inhibitor PF-04447943 Attenuates DSS-Induced Colitis by Suppressing Oxidative Stress, Inflammation, and Regulating T-Cell Polarization.

Ulcerative colitis (UC) is a form of inflammatory bowel disease, which manifests as irritation or swelling and sores in the large intestine in a relapsing and remitting manner. In a dextran sulfate sodium sulfate (DSS)-induced UC model in female mice, we found that the levels of cyclic guanosine monophosphate (cGMP) are reduced, while the expression of phosphodiesterase 9A (PDE9A) is highest among all phosphodiesterase (PDEs). Since PDE9 has the highest affinity toward cGMP, we evaluated the selective PDE9 inhibitor PF-04447943 (PF) as a potential candidate for UC treatment. PF has been extensively studies in cognitive function and in sickle cell disease, but not in models for inflammatory bowel disease (IBD). Therefore, we used female C57BL/6 mice treated with 3% DSS alone or co-treated with PF or sulfasalazine (SASP) to study the body weight, colon length, histopathology, and measure superoxide dismutase (SOD), malondialdehyde (MDA), and cGMP level, as well as cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-17 (IL-17), interleukin-12/23 (IL-12/23), interleukin-10 (IL-10), and pathways including nuclear factor kappa B (NF-κB), signal transducer and activator of transcription 3 (STAT3), and inflammasome activation. In addition, the number of dendritic cells (DC) and regulatory T cells (Treg cell) was assessed in the spleen, lymph node, and colon using flow cytometry. DSS reduced the number of goblet cells, decreased colon lengths and body weights, all of them were attenuated by PF treatment. It also suppressed the elevated level of inflammatory cytokines and increased level the anti-inflammatory cytokine, IL-10. PF treatment also reduced the DSS-induced inflammation by suppressing oxidative stress, NF-κB, STAT3, and inflammasome activation, by upregulating nuclear factor erythroid 2-related factor 2 (Nrf-2) and its downstream proteins via extracellular signal-regulated kinase (ERK) phosphorylation. Importantly, PF reversed imbalance in Treg/T helper 17 cells (Th17) cells ratio, possibly by regulating dendritic cells and Treg developmental process. In summary, this study shows the protective effect of a PDE9A inhibitor in ulcerative colitis by suppressing oxidative stress and inflammation as well as reversing the Treg/Th17 cells imbalance.

Airborne Bacteria Enriched PM2.5 Enhances the Inflammation in an Allergic Adolescent Mouse Model Induced by Ovalbumin.

Air pollution events frequently occur in China during the winter. Most investigations of pollution studies have focused on the physical and chemical properties of PM2.5. Many of these studies have indicated that PM2.5 exacerbates asthma or eosinophil inflammation. However, few studies have evaluated the relationship between bacterial loads in PM2.5, and especially pathogenic bacteria and childhood asthma. Airborne PM2.5 samples from heavily polluted air were collected in Hangzhou, China between December 2014 and January 2015. PM2.5 and ovalbumin (OVA) were intratracheally administered twice in 4-week intervals to induce the allergic pulmonary inflammation in adolescent C57/BL6 mice. PM2.5 exposure caused neutrophilic alveolitis and bronchitis. In the presence of OVA, the levels of the Th2 cytokines IL-4, IL-12, and IL-17 were significantly increased in bronchoalveolar lavage fluids (BALF) after PM2.5 exposure, while eosinophil infiltration and mucin secretion were also induced. In addition to adjuvant effects on OVA-induced allergic inflammation, PM2.5 exposure also led to the maturation of dendritic cells. These results suggest that PM2.5 exposure may aggravate lung eosinophilia and that PM2.5-bound microbial can exacerbate allergic and inflammatory lung diseases.