PRMT7-Dependent Transcriptional Activation of Hmgb2 Aggravates Severe Acute Pancreatitis by Promoting Acsl1-Induced Ferroptosis.

Severe acute pancreatitis (SAP) is a highly fatal abdominal emergency, and its association with protein arginine methyltransferase 7 (PRMT7), the sole known type III enzyme responsible for the monomethylation of arginine residue, remains unexplored. In this study, we observe an increase in the PRMT7 levels in the pancreas of SAP mice and Cerulein-LPS-stimulated AR42J cells. Overexpression of Prmt7 exacerbated pancreatic damage in SAP, while the inhibition of PRMT7 improved SAP-induced pancreatic damage. Furthermore, PRMT7 overexpression promoted inflammation, oxidative stress, and ferroptosis during SAP. Mechanically, PRMT7 catalyzed monomethylation at histone H4 arginine 3 (H4R3me1) at the promoter region of high mobility group proteins 2 (HMGB2), thereby enhancing its transcriptional activity. Subsequently, HMGB2 facilitated Acyl CoA synthase long-chain family member 1 (ACSL1) transcription by binding to its promoter region, resulting in the activation of ferroptosis. Inhibition of PRMT7 effectively alleviated ferroptosis in Cerulein-LPS-induced AR42J cells by suppressing the HMGB2-ACSL1 pathway. Overall, our study reveals that PRMT7 plays a crucial role in promoting SAP through its regulation of the HMGB2-ACSL1 pathway to accelerate ferroptosis.

hP-MSCs attenuate severe acute pancreatitis in mice via inhibiting NLRP3 inflammasome-mediated acinar cell pyroptosis.

BACKGROUND: Severe acute pancreatitis (SAP) is a serious gastrointestinal disease that is facilitated by pancreatic acinar cell death. The protective role of human placental mesenchymal stem cells (hP-MSCs) in SAP has been demonstrated in our previous studies. However, the underlying mechanisms of this therapy remain unclear. Herein, we investigated the regularity of acinar cell pyroptosis during SAP and investigated whether the protective effect of hP-MSCs was associated with the inhibition of acinar cell pyroptosis. METHODS: A mouse model of SAP was established by the retrograde injection of sodium taurocholate (NaTC) solution in the pancreatic duct. For the hP-MSCs group, hP-MSCs were injected via the tail vein and were monitored in vivo. Transmission electron microscopy (TEM) was used to observe the pyroptosis-associated ultramorphology of acinar cells. Immunofluorescence and Western blotting were subsequently used to assess the localization and expression of pyroptosis-associated proteins in acinar cells. Systemic inflammation and local injury-associated parameters were evaluated. RESULTS: Acinar cell pyroptosis was observed during SAP, and the expression of pyroptosis-associated proteins initially increased, peaked at 24 h, and subsequently showed a decreasing trend. hP-MSCs effectively attenuated systemic inflammation and local injury in the SAP model mice. Importantly, hP-MSCs decreased the expression of pyroptosis-associated proteins and the activity of the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome in acinar cells. CONCLUSIONS: Our study demonstrates the regularity and important role of acinar cell pyroptosis during SAP. hP-MSCs attenuate inflammation and inhibit acinar cell pyroptosis via suppressing NLRP3 inflammasome activation, thereby exerting a protective effect against SAP.

Tectoridin alleviates caerulein-induced severe acute pancreatitis by targeting ERK2 to promote macrophage M2 polarization.

Severe acute pancreatitis (SAP) is an inflammatory disease of the pancreas with a high mortality rate. Macrophages play a crucial role in the pathogenesis of pancreatitis. Tectoridin (Tec) is a highly active isoflavone with anti-inflammatory pharmacological activity. However, the role of Tec in the SAP process is not known. The purpose of this study was to investigate the therapeutic effect and potential mechanism of Tec on SAP. To establish SAP mice by intraperitoneal injection of caerulein and Lipopolysaccharide (LPS), the role of Tec in the course of SAP was investigated based on histopathology, biochemical indicators of amylase and lipase and inflammatory factors. The relationship between Tec and macrophage polarization was verified by immunofluorescence, real-time quantitative PCR and Western blot analysis. We then further predicted the possible targets and signal pathways of action of Tec by network pharmacology and molecular docking, and validated them by in vivo and in vitro. In this study, we demonstrated that Tec significantly reduced pancreatic injury in SAP mice, and decreased serum levels of amylase and lipase. The immunofluorescence and Western blot analysis showed that Tec promoted macrophage M2 polarization. Network pharmacology and molecular docking predicted that Tec may target ERK2 for the treatment of SAP, and in vivo and in vitro experiments proved that Tec inhibited the ERK MAPK signal pathway. In summary, Tec can target ERK2, promote macrophage M2 polarization and attenuate pancreatic injury, Tec may be a potential drug for the treatment of SAP.

Circulating exosomal miR-155-5p contributes to severe acute pancreatitis-associated intestinal barrier injury by targeting SOCS1 to activate NLRP3 inflammasome-mediated pyroptosis.

Severe acute pancreatitis (SAP) represents a common and serious disease that can cause intestinal barrier dysfunction. However, the pathogenesis of this barrier dysfunction remains unclear. Exosomes are a new intercellular communication method involved in multiple diseases. Consequently, the present study sought to determine the function of circulating exosomes in barrier dysfunction associated with SAP. A rat model of SAP was established by injecting biliopancreatic duct with 5% sodium taurocholate. Circulating exosomes were purified from SAP (SAP-Exo) and sham operation rats (SO-Exo) using a commercial kit. In vitro, SO-Exo and SAP-Exo were cocultured with rat intestinal epithelial (IEC-6) cells. In vivo, naive rats were treated with SO-Exo and SAP-Exo. We found SAP-Exo-induced pyroptotic cell death and barrier dysfunction in vitro. In addition, miR-155-5p exhibited a remarkable increase in SAP-Exo than SO-Exo, and miR-155-5p inhibitor partially abolished the negative effect of SAP-Exo on IEC-6 cells. Furthermore, miRNA functional experiments revealed that miR-155-5p could induce pyroptosis and barrier loss in IEC-6 cells. Overexpression of suppressor of cytokine signaling 1 (SOCS1), a miR-155-5p target, could partially reverse IEC-6 cells from the harmful impact of miR-155-5p. In vivo, SAP-Exo significantly triggered pyroptosis in intestinal epithelial cells and caused intestinal injury. In addition, blocking exosome release with GW4869 attenuated intestinal injury in SAP rats. In summary, our study demonstrated that miR-155-5p is highly enriched in circulating exosomes from SAP rat plasma and can be transported to intestinal epithelial cells, where it targets SOCS1 to activate NOD-like receptor protein 3 (NLRP3) inflammasome-mediated pyroptosis leading to intestinal barrier damage.

Remission of organ failure in patients with predicted severe acute pancreatitis treated by somatostation, octreotide and cyclooxygenase-2 inhibitors.

BACKGROUND: /Objectives: Persistent organ failure (OF) in severe acute pancreatitis (SAP) is caused by activation of cytokine cascades, resulting in inflammatory injury. Anti-inflammation may be helpful in OF remission in early SAP. To assess the efficacy of anti-inflammatory regimens for OF prevention and remission in patients with predicted SAP and display clinical doctors' acceptance of these strategies, we conducted this retrospective study in the real world. METHODS: Clinical data of patients with predicted SAP from 2010 to 2017 were retrospectively reviewed. Cases were divided into conventional support (C), C+ somatostatin/octreotide (C + S/O), and C + S/O + Cyclooxygenase-2-inhibitors (C + S/O + COX-2-I). The occurrence of SAP, OF, changes of proportion for three strategies, length of hospital stay, meperidine injection, and cytokine levels were compared. The constituent ratios of the three schemes over eight years were evaluated. RESULTS: A total of 580 cases (C = 124, C + S/O = 290, C + S/O + COX-2-I = 166) were included. The occurrences of SAP in the C + S/O (28.3 %) and C + S/O + COX-2-I (18.1 %) groups were significantly lower than that in C group (60.5 %, P < 0.001), mainly by reducing persistent respiratory failure (P < 0.001) and renal failure (P = 0.002). C + S/O and C + S/O + COX-2-I regimens significantly decreased new onset OF and enhanced OF amelioration within 48 h when compared with C treatment (P < 0.001) in patients with OF score <2 and ≥ 2 on admission, respectively. C + S/O and C + S/O + COX-2-I as compared with C group significantly decrease OF occurrences in a multivariate logistic regression analysis (P < 0.05). CONCLUSIONS: Somatostatin or its analogs and cyclooxygenase-2 inhibitors are promising for OF prevention and remission in patients with predicted SAP. The acceptance of combined strategies in the real world has increased, and the occurrence of SAP has decreased annually.

Early detection of necrosis in low-enhanced pancreatic parenchyma using contrast-enhanced computed tomography was a better predictor of clinical outcomes than pancreatic inflammation: A multicentric cohort study of severe acute pancreatitis.

OBJECTIVES: We aim to assess the early use of contrast-enhanced computed tomography (CECT) of patients with severe acute pancreatitis (SAP) using the computed tomography severity index (CTSI) in prognosis prediction. The CTSI combines quantification of pancreatic and extrapancreatic inflammation with the extent of pancreatic necrosis. METHODS: Post-hoc retrospective analysis of a large, multicentric database (44 institutions) of SAP patients in Japan. The area under the curve (AUC) of the CTSI for predicting mortality and the odds ratio (OR) of the extent of pancreatic inflammation and necrosis were calculated using multivariable analysis. RESULTS: In total, 1097 patients were included. The AUC of the CTSI for mortality was 0.65 (95 % confidence interval [CI:] [0.59-0.70]; p < 0.001). In multivariable analysis, necrosis 30-50 % and >50 % in low-enhanced pancreatic parenchyma (LEPP) was independently associated with a significant increase in mortality, with OR 2.04 and 95 % CI 1.01-4.12 (P < 0.05) and OR 3.88 and 95 % CI 2.04-7.40 (P < 0.001), respectively. However, the extent of pancreatic inflammation was not associated with mortality, regardless of severity. CONCLUSIONS: The degree of necrosis in LEPP assessed using early CECT of SAP was a better predictor of mortality than the extent of pancreatic inflammation.

Construction and validation of a nomogram for predicting survival in elderly patients with severe acute pancreatitis: a retrospective study from a tertiary center.

PURPOSE: There is a lack of adequate models specifically designed for elderly patients with severe acute pancreatitis (SAP) to predict the risk of death. This study aimed to develop a nomogram for predicting the overall survival of SAP in elderly patients. METHODS: Elderly patients diagnosed with SAP between January 1, 2017 and December 31, 2022 were included in the study. Risk factors were identified through least absolute shrinkage and selection operator regression analysis. Subsequently, a novel nomogram model was developed using multivariable logistic regression analysis. The predictive performance of the nomogram was evaluated using metrics such as the receiver operating characteristic curve, calibration curve, and decision curve analysis (DCA). RESULTS: A total of 326 patients were included in the analysis, with 260 in the survival group and 66 in the deceased group. Multivariate logistic regression indicated that age, respiratory rate, arterial pH, total bilirubin, and calcium were independent prognostic factors for the survival of SAP patients. The nomogram demonstrated a performance comparable to sequential organ failure assessment (P = 0.065). Additionally, the calibration curve showed satisfactory predictive accuracy, and the DCA highlighted the clinical application value of the nomogram. CONCLUSION: We have identified key demographic and laboratory parameters that are associated with the survival of elderly patients with SAP. These parameters have been utilized to create a precise and user-friendly nomogram, which could be an effective and valuable clinical tool for clinicians.

An inflammation-based model for identifying severe acute pancreatitis: a single-center retrospective study.

BACKGROUND AND AIMS: Severe acute pancreatitis (SAP) is potentially lethal. Considering the role of inflammation in the progression of acute pancreatitis (AP), this study aims to develop a model based on inflammatory indexes for identifying the presence of SAP. METHODS: Overall, 253 patients with AP who were consecutively admitted between July 2018 and November 2020 were screened, of whom 60 had SAP. Systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), neutrophil-to-platelet ratio (NPR), systemic inflammation response index (SIRI), platelet-to-albumin ratio (PAR), C-reactive protein-to-albumin ratio (CAR), C-reactive protein-to-lymphocyte ratio (CLR), and triglyceride glucose (TyG) index were calculated. Multivariate logistic regression analyses were performed to identify independent risk factors of SAP. Then, inflammation-based models were established. Receiver operating characteristics (ROC) curve analyses were performed. Area under ROC curve (AUROC) was calculated. RESULTS: Diabetes mellitus, fatty liver, high white blood cell count (WBC), C-reactive protein (CRP), red blood cell distribution width (RDW), procalcitonin (PCT), SII, NLR, NPR, CAR, CLR, and TyG index, and a low LMR were significantly associated with SAP. Considering the collinearity among these variables, 10 multivariate logistic regression analyses were separately performed. Finally, four independent inflammation-based models were established. Of them, the best one, which was calculated as follows: 1.204*fatty liver (yes = 1; no = 0) + 0.419*PCT + 0.005*CLR - 2.629, had an AUROC of 0.795 with a specificity of 73.4% and a sensitivity of 71.7%. CONCLUSION: The inflammation-based model consisting of fatty liver, PCT, and CLR has a good diagnostic performance for SAP.

Predictive value of thrombin-antithrombin III complex and tissue plasminogen activator-inhibitor complex biomarkers in assessing the severity of early-stage acute pancreatitis.

BACKGROUND AND AIM: The development of acute pancreatitis (AP) is strongly linked to blood clotting and fibrinolysis issues. Modern clinical practices now utilize advanced blood markers like thrombin-antithrombin III complex (TAT), plasmin-α2-plasmin inhibitor complex, thrombomodulin (TM), and tissue plasminogen activator-inhibitor complex (t-PAIC) to assess thrombosis risk. Our study used a highly sensitive chemiluminescence technique to measure these markers in AP patients, aiming to determine their early predictive value for AP severity. METHODS: There were 173 patients with AP, all of whom developed symptoms within 72 h; 102 individuals had onset symptoms within 48 h. The biomarkers were measured upon admission before determining the severity of AP. RESULTS: The levels of TAT, plasmin-α2-plasmin inhibitor complex, TM, and t-PAIC were significantly higher in the severe acute pancreatitis (SAP) group compared with the mild acute pancreatitis and moderate severe acute pancreatitis groups. For the patients within 72 h of onset, TAT, TM, and t-PAIC predicted the occurrence of SAP. For the patients within 48 h of onset, TAT and t-PAIC predicted the occurrence of SAP. The area under the curve (AUC) of prediction models is similar to Bedside Index for Severity in Acute Pancreatitis (BISAP) but significantly higher than C-reactive protein (P < 0.05). Notably, t-PAIC had a larger AUC than TAT, BISAP, and C-reactive protein. CONCLUSION: In the initial 48 h, plasma TAT and t-PAIC levels may predict the development of SAP. Within 72 h, plasma levels of TAT, TM, and t-PAIC may predict the development of SAP, and the TAT + TM + t-PAIC prediction model achieved a maximum AUC of 0.915, comparable to BISAP.

Effect of STING signaling on intestinal barrier damage in severe acute pancreatitis.

BACKGROUND: Patients with severe acute pancreatitis (SAP) have a compromised intestinal barrier with decreased barrier function and increased cell death. Intestinal epithelial cells (IECs) create a physicochemical barrier that anchors bacteria in the intestine. Recent studies have shown that the stimulator of interferons genes (STING) signaling pathway plays an important function in a number of inflammatory conditions. METHODS: The rat SAP model was established by retrograde injection of freshly prepared sodium taurocholate into the biliopancreatic duct. Serum amylase (AMY), lipase (LIPA), interleukin (IL)-6, interferon (IFN)-ß, tumor necrosis factor (TNF)-α, intestinal-type fatty acid binding protein (FABP2), diamine oxidase (DAO) and endotoxin (ET) levels were measured in rats. H&E staining was used to assess histological changes in the intestine and pancreas. The expression of intestinal epithelial cell tight junction (TJ) proteins and STING signaling pathway proteins and genes were measured by RT- PCR, Western blot and immunofluorescence staining were used to analyze. The expression of STING signaling pathway proteins in pancreas were measured by Western blot were used to analyze. TUNEL was used to detect IECs death. RESULTS: Upregulation of STING pathway-related proteins and genes occurred after sap-induced IECs. In addition, C-176 reduced serum AMY, LIPA, TNF-α, IL-6, INF-ß, FABP2, DAO and endotoxin levels and decreased pancreatic and intestinal histopathological injury in SAP rats; DMXAA aggravated serum AMY, LIPA, TNF-α, IL-6, INF-ß, FABP2, DAO and endotoxin levels and increased pancreatic and intestinal histopathological injury in SAP rats. CONLUSIONS: The results suggest that inhibition of STING signaling can alleviate IECs after SAP, and activation of STING signaling can aggravate IECs after SAP.

Elevation of HO-1 expression protects the intestinal mucosal barrier in severe acute pancreatitis via inhibition of the MLCK/p-MLC signaling pathway.

In severe acute pancreatitis (SAP), intestinal mucosal barrier damage can cause intestinal bacterial translocation and induce or aggravate systemic infections. Heme oxygenase-1 (HO-1) is a validated antioxidant and cytoprotective agent. This research aimed to investigate the effect and mechanism of HO-1 on SAP-induced intestinal barrier damage in SAP rats. Healthy adult male Sprague-Dawley rats were randomly separated into the sham-operated group, SAP group, SAP + Hemin group, and SAP + Znpp group. The rat model of SAP was established by retrograde injection of sodium taurocholate (5%) into the biliopancreatic duct. Hemin (a potent HO-1 activator) and Znpp (a competitive inhibitor of HO-1) were injected intraperitoneally in the selected groups 24 h before SAP. Serum and intestinal tissue samples were collected for analysis after 24 h in each group. Hemin pretreatment significantly reduced systemic inflammation, intestinal oxidative stress, and intestinal epithelial apoptosis in SAP by increasing HO-1 expression. Meanwhile, pretreatment with Hemin abolished the inhibitory effect on the expression of the tight junction proteins and significantly inhibited the activation of the MLCK/P-MLC signaling pathway. Conversely, ZnPP completely reversed these effects. Our study indicates that upregulation of HO-1 expression attenuates the intestinal mucosal barrier damage in SAP. The protective effect of HO-1 on the intestine is attributed to MLCK/p-MLC signaling pathway inhibition.

Glycyrrhizin Ameliorates Cardiac Injury in Rats with Severe Acute Pancreatitis by Inhibiting Ferroptosis via the Keap1/Nrf2/HO-1 Pathway.

BACKGROUND: Severe acute pancreatitis (SAP) is a potential fatal gastrointestinal disease that is usually complicated by myocardial injury and dysfunction. Due to the lack of understanding of the mechanism of SAP-associated cardiac injury (SACI), there is still no complete treatment. AIMS: To explore the alleviative effect and anti-ferroptosis mechanism against SACI of glycyrrhizin (GL), an inhibitor of oxidative stress. METHODS: The SAP model was established by perfusing 5% sodium taurocholate into biliopancreatic duct in rats. H&E staining and serum assays were used to assess the injury changes of pancreas and heart. Echocardiography was used to evaluate the cardiac function. Transmission electron microscopy (TEM) and oxidative stress assays were used to investigate the ferroptosis-related morphological and biochemical changes. Western blot and immunofluorescence were performed to analyzed the expression of ferroptosis-related proteins. RESULTS: Significant myocardial impairment was found in SAP rats according to increased histopathological scores, serum creatine kinase-MB (CK-MB) and cardiac troponin-I (cTnI) levels, and a decreased fractional shortening and ejection fraction. The decreased mitochondrial cristae and significant expression changes of ferroptosis-related proteins confirmed the presence of ferroptosis in SACI. GL treatment attenuated above-mentioned cardiac tissues damage by inhibiting ferroptosis via restoring the expression of Nrf2 and HO-1 in vivo and in vitro. Treating with ML385 (a Nrf2 inhibitor) or transfecting with siRNA-Nrf2 reversed the protective effect of GL. CONCLUSIONS: Our findings demonstrate the involvement of ferroptosis in SACI and suggest a potential role for GL in the treatment of SACI by supressing ferroptosis via Keap1/Nrf2/HO-1 pathway.

The mitochondria-targeted Kaempferol nanoparticle ameliorates severe acute pancreatitis.

Kaempferol (KA), an natural antioxidant of traditional Chinese medicine (TCM), is extensively used as the primary treatment for inflammatory digestive diseases with impaired redox homeostasis. Severe acute pancreatitis (SAP) was exacerbated by mitochondrial dysfunction and abundant ROS, which highlights the role of antioxidants in targeting mitochondrial function. However, low bioavailability and high dosage of KA leading to unavoidable side effects limits clinical transformation. The mechanisms of KA with poor bioavailability largely unexplored, hindering development of the efficient strategies to maximizing the medicinal effects of KA. Here, we engineered a novel thioketals (TK)-modified based on DSPE-PEG2000 liposomal codelivery system for improving bioavailability and avoiding side effects (denotes as DSPE-TK-PEG2000-KA, DTM@KA NPs). We demonstrated that the liposome exerts profound impacts on damaging intracellular redox homeostasis by reducing GSH depletion and activating Nrf2, which synergizes with KA to reinforce the inhibition of inadequate fission, excessive mitochondrial fusion and impaired mitophagy resulting in inflammation and apoptosis; and then, the restored mitochondrial homeostasis strengthens ATP supply for PAC renovation and homeostasis. Interestingly, TK bond was proved as the main functional structure to improve the above efficacy of KA compared with the absence of TK bond. Most importantly, DTM@KA NPs obviously suppresses PAC death with negligible side effects in vitro and vivo. Mechanismly, DTM@KA NPs facilitated STAT6-regulated mitochondrial precursor proteins transport via interacting with TOM20 to further promote Drp1-dependent fission and Pink1/Parkin-regulated mitophagy with enhanced lysosomal degradation for removing damaged mitochondria in PAC and then reduce inflammation and apoptosis. Generally, DTM@KA NPs synergistically improved mitochondrial homeostasis, redox homeostasis, energy metabolism and inflammation response via regulating TOM20-STAT6-Drp1 signaling and promoting mitophagy in SAP. Consequently, such a TCM's active ingredients-based nanomedicine strategy is be expected to be an innovative approach for SAP therapy.

Exosomes from TNF-α preconditioned human umbilical cord mesenchymal stromal cells inhibit the autophagy of acinar cells of severe acute pancreatitis via shuttling bioactive metabolites.

Severe acute pancreatitis (SAP) is a common critical disease of the digestive system, with high mortality and a lack of effective prevention and treatment measures. Despite mesenchymal stromal cell transplantation having the potential to treat SAP, its clinical application prospect is limited, and the mechanism is unclear. Here, we reveal the therapeutic role of exosomes from TNF-α-preconditioned human umbilical cord mesenchymal stromal cells (HUCMSCs) in attenuating SAP and show that it is partly dependent on exosomal metabolites. Bioactive metabolomics analysis showed that 48 metabolites be significantly differentially expressed between the two groups (Exo-Ctrl group versus Exo-TNF-α group). Then, the further functional experiments indicated that 3,4-dihydroxyphenylglycol could be a key molecule mediating the therapeutic effect of TNF-α-preconditioned HUCMSCs. The animal experiments showed that 3,4-dihydroxyphenylglycol reduced inflammation and oxidative stress in the pancreatic tissue and inhibited acinar cell autophagy in a rat model of SAP. Mechanistically, we revealed that 3,4-dihydroxyphenylglycol activated the mTOR pathway to inhibit acinar cell autophagy and alleviate SAP. In summary, our study demonstrated that exosomes from TNF-α-preconditioned HUMSCs inhibit the autophagy of acinar cells of SAP by shuttling 3,4-dihydroxyphenylglycol and inhibiting the mTOR pathway. This study revealed the vital role and therapeutic potential of metabolite-derived exosomes in SAP, providing a new promising method to prevent and therapy SAP.

Mitochondrial (mt)DNA-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling promotes pyroptosis of macrophages via interferon regulatory factor (IRF)7/IRF3 activation to aggravate lung injury during severe acute pancreatitis.

BACKGROUND: Macrophage proinflammatory activation contributes to the pathology of severe acute pancreatitis (SAP) and, simultaneously, macrophage functional changes, and increased pyroptosis/necrosis can further exacerbate the cellular immune suppression during the process of SAP, where cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) plays an important role. However, the function and mechanism of cGAS-STING in SAP-induced lung injury (LI) remains unknown. METHODS: Lipopolysaccharide (LPS) was combined with caerulein-induced SAP in wild type, cGAS -/- and sting -/- mice. Primary macrophages were extracted via bronchoalveolar lavage and peritoneal lavage. Ana-1 cells were pretreated with LPS and stimulated with nigericin sodium salt to induce pyroptosis in vitro. RESULTS: SAP triggered NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation-mediated pyroptosis of alveolar and peritoneal macrophages in mouse model. Knockout of cGAS/STING could ameliorate NLRP3 activation and macrophage pyroptosis. In addition, mitochondrial (mt)DNA released from damaged mitochondria further induced macrophage STING activation in a cGAS- and dose-dependent manner. Upregulated STING signal can promote NLRP3 inflammasome-mediated macrophage pyroptosis and increase serum interleukin (IL)-6, IL-1ß, and tumor necrosis factor (TNF)-α levels and, thus, exacerbate SAP-associated LI (SAP-ALI). Downstream molecules of STING, IRF7, and IRF3 connect the mtDNA-cGAS-STING axis and the NLRP3-pyroptosis axis. CONCLUSIONS: Negative regulation of any molecule in the mtDNA-cGAS-STING-IRF7/IRF3 pathway can affect the activation of NLRP3 inflammasomes, thereby reducing macrophage pyroptosis and improving SAP-ALI in mouse model.

Soluble Fibrinogen-Like Protein 2 Downregulation and Th17/Treg Imbalance in a Taurocholate-Induced Murine Experimental Model of Severe Acute Pancreatitis.

BACKGROUND: Severe acute pancreatitis (SAP) is associated with tremendous systemic inflammation, T-helper 17 (Th17) cells, and regulatory T (Treg) cells play an essential role in the inflammatory responses. Meanwhile, soluble fibrinogen-like protein 2 (Sfgl2) is a critical immunosuppressive effector cytokine of Treg cells and modulates immune responses. However, the impact of SAP induction on Sfgl2 expression and the role of Sfgl2 in immunomodulation under SAP conditions are largely unknown. METHODS: A taurocholate-induced mouse SAP model was established. The ratios of CD4+CD25+Foxp3+ Treg cells or CD4+IL-17+ Th17 cells in blood and pancreatic tissues as well as surface expression of CD80, CD86, and major histocompatibility complex class II (MHC-II) were determined by flow cytometry. Gene mRNA expression was determined by qPCR. Serum amylase and soluble factors were quantitated by commercial kits. Bone marrow-derived dendritic cells (DCs) were generated, and NF-κB/p65 translocation was measured by immunofluorescence staining. RESULTS: SAP induction in mice decreased the Th17/Treg ratio in the pancreatic tissue and increased the Th17/Treg ratio in the peripheral blood. In addition, SAP was associated with a reduced level of Sfgl2 in the pancreatic tissue and blood: higher levels of serum IL-17, IL-2, IFN-α, and TNF-α, and lower levels of serum IL-4 and IL-10. Furthermore, the SAP-induced reduction in Sfgl2 expression was accompanied by dysregulated maturation of bone marrow-derived DCs. CONCLUSIONS: SAP causes reduced Sfgl2 expression and Th17/Treg imbalance, thus providing critical insights for the development of Sfgl2- and Th17/Treg balance-targeted immunotherapies for patients with SAP.

Albiflorin Alleviates Severe Acute Pancreatitis-Associated Liver Injury by Inactivating P38MAPK/NF-κB Signaling Pathway.

Albiflorin (Alb) is a monoterpenoid component that is commonly found in Paeonia lactiflora Pall. or Paeonia veitchii Lynch. It is known for its impressive anti-oxidant and anti-inflammatory properties. However, the effect of Alb on severe acute pancreatitis (SAP)-associated liver injury has not been fully understood. To investigate this, we conducted a study using a rat model of SAP induced by administering two intraperitoneal injections of 20% L-arginine (3.3 g/kg) over a period of 2 h. Subsequently, the SAP-induced rats were randomly assigned into different groups with the treatment of gradient doses of Alb (5, 10, and 20 mg/kg), with the normal saline as the sham group. The pathological changes in rat livers were evaluated through hematoxylin-eosin staining. Furthermore, the levels of amylase (AMY), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were determined using specific enzyme-linked immunosorbent assay kits. Moreover, the serum levels of inflammatory factors, such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1ß, were quantified. Finally, immunohistochemical and Western blot analyses were conducted to determine phosphorylation levels of nuclear factor kappa B (NF-κB) p65 and mitogen-associated protein kianse (MAPK) p38 in the liver tissues. TNF-α stimulated liver cells were used as a cell model to further confirm the involvement of NF-κB and p38 in the effect of Alb. Our study revealed that Alb effectively mitigated the hepatic pathological damage in a dose-dependent manner and reduced the levels of indicators associated with hepatic malfunction (AMY, AST, and ALT) in rats with SAP-induced liver injury. Additionally, Alb demonstrated its ability to suppress inflammation and oxidative stress markers in the liver tissues. Alb exerted dose-dependent inhibitory effects by modulating the P38MAPK/NF-κB signaling pathway. Overall, our findings strongly support the hepatoprotective effect of Alb in rats with SAP-induced liver injury, suggesting that Alb protects against SAP-induced liver injury through the suppression of inflammation and oxidative stress via the P38MAPK/NF-κB signaling pathway.

Comparison of Bedside Index for Severity in Acute Pancreatitis and Emergency Department SpO2, Age and Systemic Inflammatory Response Syndrome Scores in Predicting Severe Acute Pancreatitis in Patients with Acute Pancreatitis in the Emergency Department.

BACKGROUND: As the mortality of severe acute pancreatitis (SAP) is significantly higher than those with mild or moderate severity, it is of clinical significance to identify patients most likely to develop SAP at the time of emergency department (ED) presentation. OBJECTIVES: The aim of this study was to compare the performance of the Bedside Index for Severity in Acute Pancreatitis (BISAP) and the Emergency Department SpO2, Age and SIRS (ED-SAS) scoring systems as early risk assessment tools for identifying patients at high-risk of developing SAP. METHODS: We retrospectively reviewed adult patients with AP presented to ED between January 2019-September 2022. We calculated the scores of each patient with the parameters of the initial data. The primary outcome was SAP. The secondary outcomes were 30-day mortality, intensive care admission, and identifying low-risk patients without complications. RESULTS: Of 415 patients, 34 (8.2%) developed SAP and 15 (3.6%) died. With regard to predicting SAP, BISAP and ED-SAS scores had similar discriminative ability with area under the curves (AUCs) of 0.84 (95% confidence interval [CI]:0.80-0.88) and 0.83 (95% CI:0.79-0.86), respectively (p = 0.642). At a cut-off score of ≥2 for SAP, sensitivity/specificity values were 73.5%/82.4% for BISAP, 76.5%/83.2% for ED-SAS. BISAP and ED-SAS scores of ≥3, yielded sensitivity/specificity values of 50%/95.8% and 35.3%/95.5%, respectively. BISAP and ED-SAS were also similar in predicting mortality (AUCs of 0.92 vs. 0.90, respectively) and intensive care unit admission (AUCs 0.91 vs. 0.91). CONCLUSION: The BISAP and ED-SAS scores performed similarly in predicting SAP, mortality, and intensive care unit admission. As an easily calculated tool early in the ED, ED-SAS may be helpful in disposition decisions for emergency physicians.

Isorhamnetin Alleviates Mitochondrial Injury in Severe Acute Pancreatitis via Modulation of KDM5B/HtrA2 Signaling Pathway.

Severe acute pancreatitis (SAP), a widespread inflammatory condition impacting the abdomen with a high mortality rate, poses challenges due to its unclear pathogenesis and the absence of effective treatment options. Isorhamnetin (ISO), a naturally occurring flavonoid, demonstrates robust antioxidant and anti-inflammatory properties intricately linked to the modulation of mitochondrial function. However, the specific protective impact of ISO on SAP remains to be fully elucidated. In this study, we demonstrated that ISO treatment significantly alleviated pancreatic damage and reduced serum lipase and amylase levels in the mouse model of SAP induced by sodium taurocholate (STC) or L-arginine. Utilizing an in vitro SAP cell model, we found that ISO co-administration markedly prevented STC-induced pancreatic acinar cell necrosis, primarily by inhibiting mitochondrial ROS generation, preserving ATP production, maintaining mitochondrial membrane potential, and preventing the oxidative damage and release of mitochondrial DNA. Mechanistically, our investigation identified that high-temperature requirement A2 (HtrA2) may play a central regulatory role in mediating the protective effect of ISO on mitochondrial dysfunction in STC-injured acinar cells. Furthermore, through an integrated approach involving bioinformatics analysis, molecular docking analysis, and experimental validation, we uncovered that ISO may directly impede the histone demethylation activity of KDM5B, leading to the restoration of pancreatic HtrA2 expression and thereby preserving mitochondrial function in pancreatic acinar cells following STC treatment. In conclusion, this study not only sheds new light on the intricate molecular complexities associated with mitochondrial dysfunction during the progression of SAP but also underscores the promising value of ISO as a natural therapeutic option for SAP.

Investigating key factors of feeding intolerance in severe acute pancreatitis: A scoping review.

BACKGROUND: The complexity of severe acute pancreatitis (SAP) and the stress caused by the disease is associated with a high incidence of feeding intolerance. However, the factors influencing feeding incontinence in patients with SAP are diverse. AIMS: To systematically analyse relevant studies that investigate the occurrence of feeding intolerance in patients with SAP, identify the relevant factors of feeding intolerance in such patients and provide a reference for nursing staff to develop relevant intervention measures. DESIGN AND METHODS: This scoping review followed the approach proposed by Arksey and O'Malley. Seven electronic databases were searched from their establishment until August 2023. This included research on the factors influencing feeding intolerance in patients with SAP, determining research questions, completing literature screening and quality evaluation, extracting data and summarizing and analysing the data. The PRISMA extension for scoping reviews (PRISMA-ScR) statement has also been included. RESULTS: A total of 23 articles were included. The factors influencing feeding intolerance in patients with SAP included the patient's condition, disease, treatment, feeding management and follow-up care. CONCLUSIONS: The factors affecting feeding intolerance in patients with SAP are multifaceted. A personalized nursing care plan should be developed based on relevant risk factors to improve feeding tolerance and comfort in patients with SAP and shorten hospitalization time. RELEVANCE TO CLINICAL PRACTICE: Intensive care nurses should identify the risk factors for feeding intolerance in patients with SAP and implement appropriate interventions. To identify the risk factors, nurses must be updated with courses and training. Moreover, a systematic feeding intolerance prediction program can help intensive care nurses effectively identify the risk factors for feeding.