High-fat diet (HFD) often increases oxidative stress and enhances inflammatory status in the body. Toll-like receptor 4 (TLR4) is widely expressed in the pancreatic tissues and plays an important role in pancreatitis. This study is aimed at investigating the effect of HFD on acute pancreatitis (AP) and the role of TLR4-mediated necroptosis and inflammation in this disease. Weight-matched rats were allocated for an 8-week feeding on the standard chow diet (SCD) or HFD, and then, the AP model was induced by infusion of 5% sodium taurocholate into the biliopancreatic duct. Rats were sacrificed at an indicated time point after modeling. Additionally, inhibition of TLR4 signaling by TAK-242 in HFD rats with AP was conducted in vivo. The results showed that the levels of serum free fatty acid (FFA) in HFD rats were higher than those in SCD rats. Moreover, HFD rats were more vulnerable to AP injury than SCD rats, as indicated by more serious pathological damage and much higher pancreatic malondialdehyde (MDA) and lipid peroxidation (LPO) levels as well as lower pancreatic superoxide dismutase (SOD) activities and reduced glutathione (GSH) contents and more intense infiltration of MPO-positive neutrophils and CD68-positive macrophages. In addition, HFD markedly increased the expressions of TLR4 and necroptosis marker (RIP3) and aggravated the activation of NF-κB p65 and the expression of TNF-α in the pancreas of AP rats at indicated time points. However, TLR4 inhibition significantly attenuated the structural and functional damage of the pancreas induced by AP in HFD rats, as indicated by improvement of the above indexes. Taken together, these findings suggest that HFD exacerbated the extent and severity of AP via oxidative stress, inflammatory response, and necroptosis. Inhibition of TLR4 signaling by TAK-242 alleviated oxidative stress and decreased inflammatory reaction and necroptosis, exerting a protective effect during AP in HFD rats.

Background The outbreak of COVID-19 has aroused global concerns. We aimed to describe the clinical characteristics of COVID-19 nonsurvivors and analyze possible causes for the rapid disease progress to death. Methods Patients with confirmed COVID-19 died in Renmin Hospital of Wuhan University before February 15, 2020, were identified. We obtained epidemiological, demographic, and clinical data from electronic medical records. Results Among 101 nonsurvivors, the median age was 71.0 years (IQR, 59.0-80.0), 59.4% were male, 79.2% had one or more comorbidities including hypertension (58.4%), cardiovascular disease (22.8%), diabetes (20.8%) etc. The most common symptoms were fever (76.2%), cough (58.4%) and dyspnea (54.5%). Respiratory failure (99.0%), acute cardiac injury (52.5%), sepsis (40.6%) and acute kidney injury (23.8%) were most common complications. Compared with patients died after 3 days of admission, patients died within 3 days of admission had significantly higher white blood cell count (10.8 vs 6.7*109/L, P=0.001) and neutrophil count (8.9 vs 5.5*109/L, P=0.001), longer prothrombin time (13.2 vs 12.5 s, P=0.040), higher D-dimer concentration (7.64 vs 2.82, P=0.040), higher lactate level (2.9 vs 2.2 mmol/L, P=0.042), lower oxygen saturation (85.0% vs 91.0%, P=0.008), and were more likely to suffer sepsis (52.1% vs 30.2%, P=0.025). Conclusions Older patients with underlying comorbidities suffering COVID-19 were at high risk of death. Respiratory failure, acute cardiac injury and acute kidney injury played crucial roles in the death of COVID-19 patients. Early development of sepsis was associated with the rapid disease progress to death.

Objective. For patients with severe acute pancreatitis (SAP), a high body mass index (BMI) increases the possibility of infection derived from the intestine. In this study, we evaluate whether TAK242 can alleviate severe acute pancreatitis-associated injury of intestinal barrier in high-fat diet-fed rats. Methods. A SAP model was established by retrograde injection of 5% sodium taurocholate into the biliary-pancreatic duct. Thirty Sprague-Dawley (SD) adult rats were randomly divided into five groups: standard rat chow (SRC) normal (SN), SRC SAP (SAP), high-fat diet normal (HN), HFD SAP (HSAP), and TLR4 inhibitor pretreatment HFD SAP (HAPT) groups. Intraperitoneal injection of 3 mg/kg TAK242 was administered 30 minutes before SAP model establishment in the HAPT group. Rats were sacrificed 12 hours after SAP modeling, followed by blood and pancreatic and distal ileum tissue collection for further analyses. Changes in the pathology responses of the rats in each group were assessed. Result. Analyses of serum amylase, lipase, cholesterol, triglyceride, IL-1β, IL-6, DAO, and serum endotoxin as well as tight junction protein expression including zonula occluden-1 and occludin indicated that high-fat diet aggravated SAP-induced intestinal barrier injury via increasing inflammatory response. In addition, the level of necroptosis was significantly higher in the SAP group compared with the SN group while the HSAP group exhibited more necroptosis compared with the SAP group, indicating the important role of necroptosis in pancreatitis-associated gut injury and illustrating that high-fat diet aggravated necroptosis of the ileum. Pretreatment with TLR4 inhibitor significantly alleviated inflammatory response and reduced necroptosis and level of oxidative stress while improving intestinal barrier function. Conclusion. High-fat diet aggravated SAP-induced intestinal barrier injury via inflammatory reactions, necroptosis, and oxidative stress. Inhibition of TLR4 by TAK242 reduced inflammation, alleviated necroptosis, and lowered the level of oxidative stress and then protected the intestinal barrier dysfunction from SAP in high-fat diet-fed rats.

The present study demonstrated that 4-PBA protected pancreas, lung, liver and kidney from injury in rat acute pancreatitis by regulating endoplasmic reticulum stress and mitigating inflammatory response to restrain cell death, and further suggested that 4-PBA may have potential therapeutic implications in the disease.

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