RESUMO
Acute pancreatitis (AP) is a local and/or systemic inflammatory disease that starts with acinar cell injury and necrosis; it has no effective medical treatment and thus remains a life-threatening condition. Interleukin-37 (IL-37), a natural immunomodulator, has demonstrated an antiinflammatory effect; however, the role of IL-37 in AP remains unknown. The serum IL-37 levels of 39 healthy controls and 94 patients with AP were measured. Cholecystokinin was applied to induce pancreatic acinar cell injury in vitro. Classical experimental AP models, such as caerulein, l-arginine, and taurolithocholic acid 3-sulfate disodium salt, were included in the in vivo study. A transgenic mouse model with the IL-37 gene and administration of recombinant IL-37 were used to further investigate the function of IL-37 in AP. Pancreas-specific gasdermin D-knockout (GSDMD-knockout) mice were used to explore the protective mechanism of IL-37. Our results showed that serum IL-37 levels in humans were negatively correlated with the severity of AP. Furthermore, IL-37-transgenic mice and supplementation with recombinant IL-37 could both protect against AP. Mechanistically, IL-37 was able to suppress pyroptosis of injured acinar cells, and specific depletion of GSDMD in the pancreas counteracted the protective effect of IL-37. Our study demonstrates that IL-37 protects against acinar cell pyroptosis in AP.
Assuntos
Células Acinares , Pancreatite , Animais , Humanos , Camundongos , Doença Aguda , Interleucinas/farmacologia , Camundongos Knockout , Camundongos Transgênicos , Pancreatite/tratamento farmacológico , PiroptoseRESUMO
BACKGROUND: The gastrointestinal microbiota is emerging as an important mediator in intestinal metabolism, such as vitamin D absorption. METHODS: To elucidate the causality of microbiota and vitamin D, we used linkage disequilibrium score (LDSC) regression and two-sample Mendelian randomization (MR) methods with largest genome-wide association study (GWAS) summary statistics to identify specific taxa that are linked to serum 25-hydroxyvitamin D (25(OH)D). RESULTS: We found that Ruminiclostridium9 was significantly genetically correlated with 25(OH)D at nominal significance (rg = 0.43, P = 0.04). Applying the inverse variance weighted (IVW) method, we identified that doubling the genetic liability of abundance of Erysipelotrichia, Erysipelotrichaceae and Erysipelotrichales reduced the concentration of 25(OH)D by 0.06 standard deviation (SD) (ßIVW = -0.06, s.e. = 0.01, P = 1.48 × 10-6, PFDR = 1.93 × 10-4) and, in turn, one SD increment in genetically determined serum 25(OH)D caused a 0.16 SD decrease in the relative abundance of Phascolarctobacterium (ßIVW = -0.16, s.e. = 0.04, P = 2.48 × 10-4, PFDR = 0.02) after removing pleiotropic instruments and outliers. Moreover, four MR methods were also used to evaluate causality, the results of which supported these findings. Leave-one-out analyses showed that the results were robust with regard to alterations in the single nucleotide polymorphisms (SNPs) we selected. CONCLUSIONS: In conclusion, our results support the hypothesis that the gut microbiota mediates the absorption of serum vitamin D supplementation and interacts with it closely. These microbiota are potential therapeutic targets for promoting serum vitamin D homeostasis.
Assuntos
Microbioma Gastrointestinal , Deficiência de Vitamina D , Microbioma Gastrointestinal/genética , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Vitamina D , Deficiência de Vitamina D/genética , VitaminasRESUMO
BACKGROUND: Danshen (Salvia miltiorrhiza Bunge) and its main active component Tanshinone IIA (TSA) are clinically used in China. However, the effects of TSA on acute pancreatitis (AP) and its potential mechanism have not been investigated. In this study, our objective was to investigate the protective effects of TSA against AP via three classic mouse models. METHODS: Mouse models of AP were established by caerulein, sodium taurocholate, and L-arginine, separately. Pancreatic and pulmonary histopathological characteristics and serum amylase and lipase levels were evaluated, and changes in oxidative stress injury and the ultrastructure of acinar cells were observed. The reactive oxygen species (ROS) inhibitor N-Acetylcysteine (NAC) and nuclear factor erythroid 2-related factor 2 (Nrf2) knockout mice were applied to clarify the protective mechanism of the drug. RESULTS: In the caerulein-induced AP model, TSA administration reduced serum amylase and lipase levels and ameliorated the histopathological manifestations of AP in pancreatic tissue. Additionally, TSA appreciably decreased ROS release, protected the structures of mitochondria and the endoplasmic reticulum, and increased the protein expression of Nrf2 and heme oxygenase 1 of pancreatic tissue. In addition, the protective effects of TSA against AP were counteracted by blocking the oxidative stress (NAC administration and Nrf2 knockout in mice). Furthermore, we found that TSA protects pancreatic tissue from damage and pancreatitis-associated lung injury in two additional mouse models induced by sodium taurocholate and by L-arginine. CONCLUSION: Our data confirmed the protective effects of TSA against AP in mice by inhibiting oxidative stress via the Nrf2/ROS pathway.