Progress of pyroptosis in acute pancreatitis.
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ABSTRACT:
SUBMITTER: Li HY
PROVIDER: S-EPMC8478374 | biostudies-literature | 2021 Jul
REPOSITORIES: biostudies-literature
Publications
Progress of pyroptosis in acute pancreatitis.
Li Hong-Yao HY Lin Yu-Jie YJ Zhang Ling L Zhao Jing J Xiao Dan-Yang DY Huang Zhen-Zhen ZZ Li Pei-Wu PW
Chinese medical journal 20210722 18
Similar Datasets
Project description: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.
| S-EPMC9675483 | biostudies-literature
Project description:An international symposium entitled "Acute pancreatitis: progress and challenges" was held on November 5, 2014 at the Hapuna Beach Hotel, Big Island, Hawaii, as part of the 45th Anniversary Meeting of the American Pancreatic Association and the Japanese Pancreas Society. The course was organized and directed by Drs. Stephen Pandol, Tooru Shimosegawa, Robert Sutton, Bechien Wu, and Santhi Swaroop Vege. The symposium objectives were to: (1) highlight current issues in management of acute pancreatitis, (2) discuss promising treatments, (3) consider development of quality indicators and improved measures of disease activity, and (4) present a framework for international collaboration for development of new therapies. This article represents a compilation and adaptation of brief summaries prepared by speakers at the symposium with the purpose of broadly disseminating information and initiatives.
| S-EPMC4890478 | biostudies-literature
Project description:Objective: To investigate the protective effect of emodin in acute pancreatitis (AP)-associated lung injury and the underlying mechanisms. Methods: NaT-AP model in rats was constructed using 3.5% sodium taurocholate, and CER+LPS-AP model in mice was constructed using caerulein combined with Lipopolysaccharide. Animals were divided randomly into four groups: sham, AP, Ac-YVAD-CMK (caspase-1 specific inhibitor, AYC), and emodin groups. AP-associated lung injury was assessed with H&E staining, inflammatory cytokine levels, and myeloperoxidase activity. Alveolar macrophages (AMs) pyroptosis was evaluated by flow cytometry. In bronchoalveolar lavage fluid, the levels of lactate dehydrogenase and inflammatory cytokines were measured by enzyme-linked immunosorbent assay. Pyroptosis-related protein expressions were detected by Western Blot. Results: Emodin, similar to the positive control AYC, significantly alleviated pancreas and lung damage in rats and mice. Additionally, emodin mitigated the pyroptotic process of AMs by decreasing the level of inflammatory cytokines and lactate dehydrogenase. More importantly, the protein expressions of NLRP3, ASC, Caspase1 p10, GSDMD, and GSDMD-NT in AMs were significantly downregulated after emodin intervention. Conclusion: Emodin has a therapeutic effect on AP-associated lung injury, which may result from the inhibition of NLRP3/Caspase1/GSDMD-mediated AMs pyroptosis signaling pathways.
| S-EPMC9201345 | biostudies-literature
Project description:The functional relevance and effects of the pyroptosis executioner gasdermin D (GSDMD) on severe acute pancreatitis (SAP)-associated lung injury are unclear. We established caerulein-induced mouse models of SAP-associated lung injury, which showed that GSDMD-mediated pyroptosis was activated in both pancreatic and lung tissues. Compared with Gsdmd wild-type SAP mouse models, Gsdmd knockout (Gsdmd-/- ) ameliorated SAP-induced pancreas and related lung injury. Additionally, we investigated the effects of disulfiram on the treatment of SAP. Disulfiram is a Food and Drug Administration (FDA)-approved anti-alcoholism drug, which is reported as an effective pyroptosis inhibitor by either directly covalently modifying GSDMD or indirectly inhibiting the cleavage of GSDMD via inactivating Nod-like receptor protein 3 inflammasome. We demonstrated that disulfiram inhibited the cleavage of GSDMD, alleviated caerulein-induced SAP and related lung injury, and decreased the expression levels of proinflammatory cytokines (IL-1β and IL-18). Collectively, these findings disclosed the role of GSDMD-mediated pyroptosis in SAP and the potential application of disulfiram in the treatment of SAP.
| S-EPMC8632453 | biostudies-literature
Project description:Acute pancreatitis (AP) continues to pose a major challenge as targeted therapeutic interventions are absent. Mitochondrial dysfunction and inflammasome-dependent pyroptosis are involved in the pathogenic mechanisms of AP. CIRP is a stress-response protein and a damage-associated molecular pattern (DAMP) molecule. In our previous studies, we discovered that excessive CIRP can directly damage pancreatic acinar cells. Nonetheless, the precise involvement of CIRP in AP is still unexplored. The primary aim of this study was to examine the potential involvement of CIRP in the development of pyroptosis and mitochondrial dysfunction in AP. To study this, an L-arginine-induced AP mouse model was used. Our results showed that Caspase-1-mediated pyroptosis and mitochondria-derived reactive oxygen species (ROS) were crucial factors in the occurrence of tissue damage and inflammation in AP. A substantial increase in the CIRP serum levels was observed in AP mice. Blocking CIRP by either CIRP gene knockout or systemic administration of C23, a competing inhibitor of CIRP, reduced ROS accumulation and pyroptosis in AP mice. These effects were associated with attenuated pancreatic injury and inflammation. In addition, CIRP-triggered mitochondrial dysfunction, autophagy impairment, and pyroptosis in pancreatic acinar cells were prevented by TAK242, an inhibitor of CIRP receptor TLR4. In conclusion, CIRP can induce mitochondrial dysfunction and pyroptosis in pancreatic acinar cells, and blocking CIRP may be a valuable approach to treating patients with AP.
| S-EPMC10973482 | biostudies-literature
Project description:Purpose: The purpose of this study was to compare the hepatic transcriptome in the control group, acute pancreatitis, and severe acute pancreatitis, in order to identify metabolic gene changes during pancreatitis. Methods: 6-week Balb/c mice were subjected to AP (caerulein), SAP (caerulein and LPS) and control (saline), and mice liver tissues were harvested at 24 hours for RNA preparation (n=8 each group). Results: Among 11952 mapped genes, 8977 differentially expressed genes were identified by RNA-seq, including 351 genes induced in AP compare to Control and 5249 genes down regulated in SAP compare to AP. The genes up regulated were mainly related to fatty acid oxidation and ketone body synthesis especially Cpt2 and Acadvl, while genes that down regulated were associated with energy metabolism and inflammation. The overlap of two gene sets were 96 genes that involved in fatty acid metabolism. Conclusions: Our study revealed that in AP, genes associated with ketone body synthesis are upregulated in liver, in SAP, fatty acid oxidation related genes are downregulated in liver. Our data revealed the crosstalk between pancreas and liver, illustrated the difference of metabolism in AP and SAP.
2022-04-06 | GSE151927 | GEO
Project description:ObjectiveResearch is lacking on the natural history of acute pancreatitis (AP) progression to acute recurrent pancreatitis (ARP). The aim of this project was to study the progression from AP to ARP among pediatric patients with pancreatitis to better understand the presentation and natural history of pancreatitis.MethodsPatients presenting with AP were included in a prospective database in Research Electronic Data Capture. We enrolled 115 patients with AP from March 2013 to November 2016. Physicians completed surveys regarding clinical data for patients with first attack of AP. Patients were followed prospectively, with data on progression entered when patients presented with ARP.ResultsThe most common etiologies for the first attack of AP were idiopathic (31%), toxic/drug-related (23%), and biliary/gallstone (18%). Twenty of the 115 patients (17%) developed ARP during the follow-up period. Seventy percent (14/20) of patients with ARP progressed from AP to ARP within 5 months from first diagnosis. A comparison of patients who rapidly progressed to ARP within 3 months (n = 12) to those followed for >3 months without progression in 3 months (n = 97) revealed associations with a higher weight percentile for age (P = 0.045), male sex (P = 0.03), and presence of pancreatic necrosis during first AP attack (P = 0.004). Progression to ARP significantly differed by etiology group with genetics having the highest risk for ARP progression over time and patients with gallstone/biliary, viral/systemic, and obstructive (nongallstone) having the lowest risk for ARP progression over time (P = 0.02).ConclusionsMost patients who progressed from AP to ARP progressed within 5 months. The presence of a higher weight percentile for age, male sex, and pancreatic necrosis during the first AP attack are associated with rapid progression to ARP.
| S-EPMC6310081 | biostudies-literature
Project description:Our previous studies showed that Salidroside (Sal), a glucoside of the phenylpropanoid tyrosol isolated from Rhodiola rosea L, alleviated severe acute pancreatitis (SAP) by inhibiting inflammation. However, the detailed mechanism remains unclear. Recent evidence has indicated a critical role of Sal in ameliorating inflammatory disorders by regulating pyroptosis. The present study aimed to explore the involvement of Sal and pyroptosis in the pathogenesis of SAP and investigate the potential mechanism. The effects of Sal on pyroptosis were first evaluated using SAP rat and cell model. Our results revealed that Sal treatment significantly decreased SAP-induced pancreatic cell damage and pyroptosis in vivo and in vitro, as well as reduced the release of lactate dehydrogenase (LDH), IL-1β and IL-18. Search Tool for Interacting Chemicals (STITCH) online tool identified 4 genes (CASP3, AKT1, HIF1A and IL10) as candidate targets of Sal in both rattus norvegicus and homo sapiens. Western blot and immunohistochemistry staining validated that Sal treatment decreased the phosphorylation levels of Akt and NF-κB p65, as well as cleaved caspase-3 and N-terminal fragments of GSDME (GSDME-N), suggesting that Sal might suppress pyroptosis through inactivating Akt/NF-κB and Caspase-3/GSDME pathways. Furthermore, overexpression of AKT1 or CASP3 could partially reverse the inhibitory effects of Sal on cell injury and pyroptosis, while downregulation of AKT1 or CASP3 promoted the inhibitory effects of Sal. Taken together, our data indicate that Sal suppresses SAP-induced pyroptosis through inactivating Akt/NF-κB and Caspase-3/GSDME pathways.
| S-EPMC9898447 | biostudies-literature
Project description:Endogenous transfer RNA-derived small RNAs (tsRNAs) are newly identified RNAs that are closely associated with the pathogenesis of multiple diseases, but the involvement of tsRNAs in regulating acute pancreatitis (AP) development has not been reported. In this study, we screened out a novel tsRNA, tRF3-Thr-AGT, that was aberrantly downregulated in the acinar cell line AR42J treated with sodium taurocholate (STC) and the pancreatic tissues of STC-induced AP rat models. In addition, STC treatment suppressed cell viability, induced pyroptotic cell death and cellular inflammation in AP models in vitro and in vivo. Overexpression of tRF3-Thr-AGT partially reversed STC-induced detrimental effects on the AR42J cells. Next, Z-DNA-binding protein 1 (ZBP1) was identified as the downstream target of tRF3-Thr-AGT. Interestingly, upregulation of tRF3-Thr-AGT suppressed NOD-like receptor protein 3 (NLRP3)-mediated pyroptotic cell death in STC-treated AR42J cells via degrading ZBP1. Moreover, the effects of tRF3-Thr-AGT overexpression on cell viability and inflammation in AR42J cells were abrogated by upregulating ZBP1 and NLRP3. Collectively, our data indicated that tRF3-Thr-AGT suppressed ZBP1 expressions to restrain NLRP3-mediated pyroptotic cell death and inflammation in AP models. This study, for the first time, identified the role and potential underlying mechanisms by which tRF3-Thr-AGT regulated AP pathogenesis.
| S-EPMC8581331 | biostudies-literature
Project description:The currently used diagnostic criteria for acute pancreatitis in Japan are presentation with at least two of the following three manifestations: (1) acute abdominal pain and tenderness in the upper abdomen; (2) elevated levels of pancreatic enzyme in the blood, urine, or ascitic fluid; and (3) abnormal imaging findings in the pancreas associated with acute pancreatitis. When a diagnosis is made on this basis, other pancreatic diseases and acute abdomen can be ruled out. The purpose of this article is to review the conventional criteria and, in particular, the various methods of diagnosis based on pancreatic enzyme values, with the aim of improving the quality of diagnosis of acute pancreatitis and formulating common internationally agreed criteria. The review considers the following recommendations: Better even than the total blood amylase level, the blood lipase level is the best pancreatic enzyme for the diagnosis of acute pancreatitis and its differentiation from other diseases. A pivotal factor in the diagnosis of acute pancreatitis is identifying an increase in pancreatic enzymes in the blood. Ultrasonography (US) is also one of the procedures that should be performed in all patients with suspected acute pancreatitis. Magnetic resonance imaging (MRI) is one of the most important imaging procedures for diagnosing acute pancreatitis and its intraperitoneal complications. Computed tomography (CT) is also one of the most important imaging procedures for diagnosing acute pancreatitis and its intraabdominal complications. CT should be performed when a diagnosis of acute pancreatitis cannot be established on the basis of the clinical findings, results of blood and urine tests, or US, or when the etiology of the pancreatitis is unknown. When acute pancreatitis is suspected, chest and abdominal X-ray examinations should be performed to determine whether any abnormal findings caused by acute pancreatitis are present. Because the etiology of acute pancreatitis can have a crucial influence on both the treatment policy and severity assessment, it should be evaluated promptly and accurately. It is particularly important to differentiate between gallstone-induced acute pancreatitis, which requires treatment of the biliary system, and alcohol-induced acute pancreatitis, which requires a different form of treatment.
| S-EPMC2779365 | biostudies-other