To evaluate temporal trends in gender, etiology, severity, outcomes, cost and median length of stay (MLS) in patients with acute pancreatitis (AP) in a third-tier Chinese city.

Patients with AP admitted to a university hospital between January 2013 and December 2021. Relationships between etiology, prevalence of severe acute pancreatitis (SAP) and survey years were investigated by joinpoint regression analysis.

A total of 5459 (male 62.3%) patients with AP were included. Between January 2013 and December 2021, we observed: (a) the prevalence of biliary diseases-related AP was stable, while the prevalence of hypertriglyceridemia (HTG)-associated AP (Ptrend = 0.04) and alcohol-associated AP (Ptrend < 0.0001) both increased; (b) there was an increase in crude prevalence of SAP from 4.97% to 12.2% between 2013 and 2021 (Ptrend < 0.0001); (c) compared to female populations, male gender had a higher prevalence of AP; (d) there was a decrease in MLS from 11 days to 8 days (Ptrend < 0.0001) and in median cost of hospitalization (MCH) for all patients (from 20,166 to 12,845 YUAN) (Ptrend < 0.0001); (e) the overall in-hospital mortality rate was 1.28% (70/5459) for patients with AP. There was no statistically significant in the time trend of mortality during the study period (Ptrend = 0.5873). At multivariate analysis, survey year was associated with prevalence of SAP after adjustment by age and biliary diseases (OR: 1.07; 95% CI: 1.03-1.12). Based on the stratification by severity of disease, the decrease of MLS and MCH was more significant in non-SAP vs. SAP patients.

Over the observational period, the proportion of male patients with AP, prevalence of age-adjusted rate of HTG and alcohol-associated AP and SAP increased, while MLS and MCH for all patients decreased, and the time trend of mortality of AP was stable.

Acute pancreatitis (AP) is an acute inflammation of the pancreas, which is considered a prevalent gastrointestinal emergency characterized by rapid progression and significant mortality. Currently available medications primarily serve as adjunctive therapies, yielding suboptimal therapeutic outcomes. Consequently, there remains a dearth of specific and efficient treatment modalities for AP. In recent years, nanomedicine-based treatment strategies have exhibited significant potential as drug therapy approaches for pancreatitis. The distinctive features of the AP microenvironment encompass aberrant activation of pancreatic enzymes, oxidative stress induced by elevated reactive oxygen species levels, and excessive production of pro-inflammatory cytokines; these factors offer promising targeted sites for early diagnosis and treatment using nanomedicine. This article comprehensively delineates the pathological microenvironmental characteristics associated with AP while highlighting the application of microenvironment-responsive strategies in nanodrug delivery systems for its treatment, thereby providing insights into future prospects.

Acute pancreatitis (AP) is an abrupt inflammation of the pancreatic tissue. The severity of AP varies from mild and self-limiting to severe, potentially fatal, and can affect several organ systems. The most severe type of AP causes multiple organ damage (MOD) due to systemic inflammation. In this study, ambrisentan (AMB), an endothelin A receptor antagonist (ETA), was investigated for its potential to ameliorate L-arginine (L-Arg) induced AP and MOD in rats. AP was induced using L-Arg (100 mg/100 g). Two doses of AMB were tested and compared to N-acetylcystiene (NAC) effect. AMB restored the normal structure of the pancreatic, hepatic, pulmonary, and renal tissues. In addition, it normalized the levels of pancreatic enzymes, lactate dehydrogenase (LDH), serum liver enzymes, and kidney biomarkers. Furthermore, AMB corrected the imbalance in the levels of oxidants/antioxidants caused by L-Arg. In contrast, AMB (5 mg/kg) significantly upregulated the protein levels of adenosine monophosphate protein kinase (AMPK), nuclear factor erythroid 2-related factor 2 (NRF2), heme oxidase-1(HO-1) and thioredoxin reductase 1 (TXNRD1) by approximately 69.59 %, 85.14 %, 688 % and 96 % respectively, compared with those in rats treated with L-Arg. Furthermore, AMB (5 mg/kg) significantly lowered the thioredoxin-interacting protein (TXNIP), nod-like Receptor Protein 3 (NLRP3), glycogen synthase kinase-3β (GSK-3β), inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), CD68, autophagic markers (P62 and LC3) and apoptotic marker caspase 3 by around 62.43 %, 73.56 %, 62.5 %,70 %, 80.3 %, 93 %, 96.7 %, 95 %, 39.6 % respectively, compared to the group treated with L-Arg. AMB effectively improved the AP and MOD produced by L-Arg through its anti-inflammatory and antioxidant properties. NRF2/HO-1 and TXNIP/NLRP3 pathways play major roles in these protective effects.

Acute pancreatitis (AP) is a serious pancreatic inflammatory disease that results in pancreatic enzyme activation and autodegradation. Betulinic acid (BA), a pentacyclic triterpene of natural origin that was isolated from several plants, has anti-inflammatory, immunomodulatory and antioxidant effects that can help with AP. With this study, we aimed to investigate the potential positive effects of BA on l-arginine-induced AP. A total of 24 male rats were divided into four groups (control, BA, AP and BA + AP). Animals in the BA group were given BA 50 mg/kg/day for 7 days. AP was induced by administering two doses of 250-mg/100-g l-arginine to animals in the AP group. The animals in the BA + AP group were administered 50-mg/kg/day BA (gavage) for 7 days and two doses of 250-mg/100-g l-arginine on the seventh day. BA pretreatment inhibited the increased lipase activity caused by AP and showed protective activity against oxidative damage to pancreatic tissue. It decreased the severity of inflammation by suppressing the release of pro-inflammatory cytokines while increasing the level of the anti-inflammatory cytokine IL-10. It showed a protective effect on pancreatic tissue by inhibiting tumour necrosis factor (TNF-α) and Bax expression. The findings of the study show that BA exhibits multifaceted protective activity in experimental AP induced with l-arginine.

Severe acute pancreatitis (SAP) is a life-threatening condition characterized by excessive reactive oxygen species (ROS) production and impaired mitochondrial function, resulting from disrupted autophagic flux. Current clinical treatment for SAP fails to address the condition comprehensively, with the treatment targeting only a single pathogenesis. Herein, we report an innovative acid-responsive biomimetic nanozyme. This system features a hollow Prussian blue (PB) core, serving as an ROS scavenger encapsulated within a porous ZIF-8 shell, enabling the efficient delivery of celastrol that activates autophagic flux. Encased in a macrophage membrane, this system selectively targets inflamed pancreatic tissues and is readily internalized by pancreatic acinar cells. This dual-scavenging mechanism effectively attenuates inflammatory cytokine levels and restores mitochondrial homeostasis in three distinct SAP mouse models. Overall, this study presents a promising synergistic strategy for the dual scavenging of damaged mitochondria and ROS, offering a novel therapeutic approach to the treatment of SAP.

Acute pancreatitis (AP) is a common disease in the digestive tract and is characterized by elevated serum pancreatic proteases and abdominal pain. AP, especially severe AP, is still a deadly disease; thus, identifying potential therapies and exploring the underlying mechanism are essential for AP patients. Galangin, a flavonoid extracted from traditional medicinal herbs, shows robust anti-inflammatory and cell protection abilities in various diseases, but its role in AP has not been unveiled. We explored the function and mechanism of galangin in AP using caerulein-induced mouse, isolated acinar cell and bone marrow-derived macrophage models. The pancreas was analyzed using histology and immunofluorescent staining; cytokine levels, the activity of amylase and lipase, and reactive oxygen species (ROS) levels were determined; infiltrating macrophages were analyzed by flow cytometry; certain proteins and RNAs were analyzed; and the safety of galangin was also evaluated. We found that galangin significantly attenuated AP in mice and acinar cells by decreasing ROS and apoptosis via the promotion of Srxn1 expression through an NRF2-dependent pathway. Galangin significantly reduced the number of infiltrating macrophages and inhibited the activation of M1-type macrophages by negatively regulating NF-κB signaling. Compared to the control, no obvious side effects were observed in the galangin-treated group. Thus, our study demonstrated that galangin is a safe and efficient drug to treat AP by preventing injury to acinar cells and inhibiting M1-type macrophages, suggesting a potential therapy for AP in the future.

The stroma of healthy pancreases contains various non-hematopoietic, non-endothelial mesenchymal cells. It is altered by chronic inflammation which in turn is a major contributor to the development of pancreatic adenocarcinoma (PDAC). In PDAC, the stroma plays a decisive and well-investigated role for tumor progression and therapy response. This review addresses the central role of stromal cells in the early inflammation-driven development of PDAC. It focuses on major subpopulations of pancreatic mesenchymal cells, i.e., fibroblasts, pancreatic stellate cells, and multipotent stroma cells, particularly their activation and functional alterations upon chronic inflammation including the development of different types of carcinoma-associated fibroblasts. In the second part, the current knowledge on the impact of activated stroma cells on acinar-to-ductal metaplasia and the transition to pancreatic intraepithelial neoplasia is summarized. Finally, putative strategies to target stroma cells and their signaling in early pancreatic carcinogenesis are reflected. In summary, the current data show that the activation of pancreatic stroma cells and the resulting fibrotic changes has pro- and anti-carcinogenetic effects but, overall, creates a carcinogenesis-promoting microenvironment. However, this is a dynamic process and the therapeutic targeting of specific pathways and cells requires in-depth knowledge of the molecular interplay of various cell types.

Acute pancreatitis (AP) is associated with multiple cellular mechanisms that trigger and or are triggered by the inflammatory injury and death of the acinar cells. One of the key mechanisms is the endoplasmic reticulum (ER) stress, which manifests as an accumulation of misfolded proteins within ER, an event that has proinflammatory and proapoptotic consequences. Hence, the degree of cell insult during AP could considerably depend on the signaling pathways that are upregulated during ER stress and its resulting dyshomeostasis such as C/EBP homologous protein (CHOP), cJUN NH2-terminal kinase (JNK), nuclear factor kappa B (NF-κB), and NOD-like receptor protein 3 (NLRP3) inflammasome. Exploring these molecular pathways is an interesting area for translational medicine as it may lead to identifying new therapeutic targets in AP. This review of the literature aims to shed light on the different roles of ER stress in the etiopathogenesis and pathogenesis of AP. Then, it specifically focuses on the therapeutic implications of ER stress in this context.

Systemic inflammatory response syndrome (SIRS) is a frequent and serious complication of acute pancreatitis (AP), often associated with increased mortality. This study aims to leverage automated machine learning (AutoML) algorithms to create a model for the early and precise prediction of SIRS in AP.

This study retrospectively analyzed patients diagnosed with AP across multiple centers from January 2017 to December 2021. Data from the First Affiliated Hospital of Soochow University and Changshu Hospital were used for training and internal validation, while testing was conducted with data from the Second Affiliated Hospital. Predictive models were constructed and validated using the least absolute shrinkage and selection operator (LASSO) and AutoML. A nomogram was developed based on multivariable logistic regression (LR) analysis, and the performance of the models was assessed through receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA). Additionally, the AutoML model's effectiveness and interpretability were assessed through DCA, feature importance, SHapley Additive exPlanation (SHAP) plots, and locally interpretable model-agnostic explanations (LIME).

A total of 1,224 patients were included, with 812 in the training cohort, 200 in validation, and 212 in testing. SIRS occurred in 33.7% of the training cohort, 34.0% in validation, and 22.2% in testing. AutoML models outperformed traditional LR, with the deep learning (DL) model achieving an area under the ROC curve of 0.843 in the training set, and 0.848 and 0.867 in validation and testing, respectively.

The AutoML model using the DL algorithm is clinically significant for the early prediction of SIRS in AP.

Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive and fatal cancer. M1 macrophages are generally considered to have anti-tumor properties, capable of suppressing tumor growth and metastasis by secreting pro-inflammatory cytokines and enhancing the immune response.

The objective of this research was to pinpoint crucial genes associated with M1 macrophages and search for a new way to activate the M1 phenotype of macrophages in PDA.

The level of immune cell infiltration was assessed using CIBERSORT in TCGA-PAAD cohort and ICGC-PACA cohort. We performed weighted gene co-expression network analysis (WGCNA) to identify the module most correlated with M1 macrophages and we identified hub genes through protein-protein interaction (PPI) analyse. Through survival analysis, correlation analysis and single cell analysis, we obtained the relationship between hub genes and prognosis, and the relationship between key genes and immune cells, as well as its expression in various cells.

PRSS1 (Cationic trypsinogen) and CTRB1 (Chymosinogen B) were hub genes of the M1 macrophage-associated WGCNA module (211genes) and are closely related to the extension of survival time, which are also verified as cell growth-related genes by DepMap database. Through single-cell sequencing analysis, we determined that the expression levels of PRSS1 and CTRB1 in the acinar cells of tumor tissues were diminished. PRSS1 and CTRB1 are considered to be the signature genes of acinar cells. The proportion of acinar cells was also correlated with the infiltration of CD8T cells and M1 cells. Immunostaining revealed elevated expression levels of PRSS1 and CTRB1 in adjacent normal tissues. Cell line experiments confirmed that macrophages polarize towards M1 by engulfing pancreatic enzyme granules, thereby inhibiting the malignant phenotype of tumor cells.

Our findings highlight the critical role of acinar cells in modulating the immune microenvironment of pancreatic tumors by influencing macrophage polarization. This insight may provide novel opportunities for therapeutic interventions in cancer treatment.

Severe acute pancreatitis (SAP) is a critical inflammatory disease with high morbidity and mortality. Current treatments focused on symptomatic relief but failed to prevent inflammation progression in cellular level.

In order to develop an SAP-targeting drug delivery system to alleviate SAP in cellular level and illustrate its mechanism, we explored the use of proanthocyanidin (PYD) and pentoxifylline (PTX) loaded into macrophage membrane-coated self-assembly nanoparticles (FePTX@CM NPs) for targeted SAP treatment. The combination application of these two drugs was innovative in SAP aid.

We developed the NPs by self-assembly strategy and cell membrane coating. Its particle size and zeta potential were measured by dynamic light scatter (DLS). The morphology of the NPs was observed by transmission electron microscopy (TEM). And the encapsulation efficiency was evaluated by nano-flow cytometry. The total protein profile was determined via Coomassie brilliant blue. We explore the mechanism of our NPs against SAP in cellular and animal levels. Bioinformatics approaches, TEM, immunofluorescent assay and co-immunoprecipitation were performed to comprehensively explain the specific anti-SAP mechanism of FePTX@CM NPs.

After inflammation-driven targeting, PYD in the NPs inhibited pancreatic amylase and lipase release by suppressing mitochondrial reactive oxygen species (mtROS)/Golgi stress, while PTX prevented SAP-associated macrophage PANoptosis by inhibiting Zbp1 signal pathway. The protection effect of these biomimetic NPs worked from different aspects to alleviate SAP symptoms and inflammation progression in relative cells.

The FePTX@CM NPs demonstrated effective pancreas targeting, reduced systemic inflammation especially pro-inflammatory cell recruitment and activation, and minimized tissue damage in SAP mouse models, offering a promising therapeutic strategy for clinical SAP management.

Macrophage infiltration and activation is a critical step during acute pancreatitis (AP). NLRP3 inflammasomes in macrophages plays a critical role in mediating pancreatic inflammatory responses. Qing-Yi Decoction(QYD)has been used for many years in clinical practice of Nankai Hospital combined with traditional Chinese and western medicine treatment of acute pancreatitis. Although QYD has a well-established clinical efficacy, little is known about its bioactive ingredients, how they interact with different therapeutic targets and the pathways to produce anti-inflammatory effects. Here, we elucidate the therapeutic effects of QYD against acute pancreatitis and reveal its mechanism of action.

The main components of QYD were identified using UHPLC-Q-Orbitrap MS. Network pharmacology was employed to predict potential therapeutic targets and their mechanisms of action. C57BL/6 mice were randomly divided into control group, model group, low, medium and high dose (6, 12, 24 g/kg) QYD groups, with 10 mice in each group. The therapeutic effect of QYD on cerulein-induced acute pancreatitis. (CER-AP) was evaluated by histopathological score, immunohistochemistry, serum amylase and cytokines detection by ELISA. The protein expressions of MyD88/NF-κB/NLRP3 signaling pathway were detected by Western blotting. Along with molecular docking of key bioactive compounds and targets, RAW264.7 cells stimulated with 1μg/ml LPS is used to screen components with more potent effects on target proteins. AR42 J cells were stimulated with 100 nM dexamethasone (dexa) combined with 10 nM cerulein (CN) as s a cell-culture model of acute pancreatitis. Inhibitory effects of the main chemical composition Wogonoside on NLRP3 inflammasomes were analyzed by qRT-PCR and Western blots.

Using UHPLC-Q-Orbitrap MS, 217 compounds were identified from QYD, including Wogonoside, Catechins, Rhein, etc. A visualization network of QYD-compounds-key targets-pathways-AP show that QYD may modulate PI3K-Akt signaling pathway, NOD-like receptor signaling pathway, MAPK signaling pathway, Ras signaling pathway and Apoptosis signaling pathway by targeting TNF, IL1β, AKT1, TP53 and STAT3 exerting a therapeutic effect on AP. QYD administration effectively mitigated CER-induced cytokine storm, pancreas edema and serum amylase. QYD (12 mg/kg) showed better effect. The protein expression levels of MyD88, NF-κB, NLRP3, Caspase-1 and GSDMD in pancreatic tissue were significantly decreased. Through molecular docking and LPS-RAW264.7 inflammation model, the selected Wogonoside significantly decreased IL-1β mRNA. The expression levels of NLRP3/Caspase-1/GSDMD pathway-related proteins were also decreased on AR42J-AP.

The results of network pharmacology indicate that QYD can inhibit AP through multiple pathways and targets. This finding was validated through in vivo tests, which demonstrated that QYD can reduce AP by inhibiting NLRP3 inflammasomes, additionally, it should be noted that 12mg/kg was a relatively superior dose. One of the main chemical compositions Wogonoside regulated NLRP3 inflammasome activation to protect against AP. This study is the first to verify the intrinsic molecular mechanism of QYD in treating AP by combining network pharmacology and animal experiments. The findings can provide evidence for subsequent clinical research and drug development.

Severe acute pancreatitis (SAP) poses significant challenges due to its complex pathophysiology, which includes inflammatory-immune responses that cause considerable damage to both the pancreas and other tissues. In this study, we explored the role of Annexin A1 (Anxa1), a glucocorticoid-regulated protein recognized for its anti-inflammatory properties, in regulating inflammation during acute pancreatitis. Using flow cytometry, single-cell RNA sequencing, and gene expression analysis, we examined how Anxa1 expression is regulated in myeloid cells throughout acute pancreatitis, employing various animal models to evaluate the consequences of modulating Anxa1 on injuries induced by SAP. Our findings revealed dynamic regulation of Anxa1 expression in myeloid cells, with mice lacking Anxa1 exhibiting worsened pancreatic injury and heightened systemic inflammation, resulting in significant damage to extra-pancreatic organs such as the lungs, liver, and kidneys. In contrast, treatment with Ac2-26, a synthetic peptide derived from Anxa1, effectively mitigated both pancreatic and extra-pancreatic inflammation and tissue damage. Overall, this study highlights the critical role of Anxa1 in modulating inflammatory responses during acute pancreatitis. Targeting Anxa1 presents a promising therapeutic strategy to mitigate pancreatic injury and prevent systemic complications associated with severe acute pancreatitis.

Ariel Dynamic Acute Pancreatitis Tracker (ADAPT) is an artificial intelligence tool using mathematical algorithms to predict severity and manage fluid resuscitation needs based on the physiologic parameters of individual patients. Our aim was to assess whether adherence to ADAPT fluid recommendations vs standard management impacted clinical outcomes in a large prospective cohort.

We analyzed patients consecutively admitted to the Los Angeles General Medical Center between June 2015 and November 2022 whose course was richly characterized by capturing more than 100 clinical variables. We inputted these data into the ADAPT system to generate resuscitation fluid recommendations and compared with the actual fluid resuscitation within the first 24 hours from presentation. The primary outcome was the difference in organ failure in those who were over-resuscitated (>500 mL) vs adequately resuscitated (within 500 mL) with respect to the ADAPT fluid recommendation. Additional outcomes included intensive care unit admission, systemic inflammatory response syndrome (SIRS) at 48 hours, local complications, and pancreatitis severity.

Among the 1,083 patients evaluated using ADAPT, 700 were over-resuscitated, 196 were adequately resuscitated, and 187 were under-resuscitated. Adjusting for pancreatitis etiology, gender, and SIRS at admission, over-resuscitation was associated with increased respiratory failure (odd ratio [OR] 2.73, 95% confidence interval [CI] 1.06-7.03) as well as intensive care unit admission (OR 2.40, 1.41-4.11), more than 48 hours of hospital length of stay (OR 1.87, 95% CI 1.19-2.94), SIRS at 48 hours (OR 1.73, 95% CI 1.08-2.77), and local pancreatitis complications (OR 2.93, 95% CI 1.23-6.96).

Adherence to ADAPT fluid recommendations reduces respiratory failure and other adverse outcomes compared with conventional fluid resuscitation strategies for acute pancreatitis. This validation study demonstrates the potential role of dynamic machine learning tools in acute pancreatitis management.

Acute pancreatitis (AP) an inflammatory condition caused by the premature activation of pancreatic proteases, leads to organ damage, systemic inflammation, and multi-organ failure. Severe acute pancreatitis (SAP) has high morbidity and mortality, affecting the liver, kidneys, and lungs. Autophagy maintains pancreatic homeostasis, with VMP1-mediated selective autophagy (zymophagy) preventing intracellular zymogen activation and acinar cell death. This study examines the protective role of VMP1 (Vacuole Membrane Protein 1)-induced autophagy using ElaI-VMP1 transgenic mice in a necrohemorrhagic SAP model (Hartwig's model). ElaI-VMP1 mice show significantly reduced pancreatic injury, including lower necrosis, edema, and inflammation, compared to wild-type (WT) mice. Biochemical markers (lactate dehydrogenase-LDH-, amylase, and lipase) and histopathology confirm that VMP1 expression mitigates pancreatic damage. Increased zymophagy negatively correlates with acinar necrosis, reinforcing its protective role. Beyond the pancreas, ElaI-VMP1 mice exhibit preserved liver, kidney, and lung histology, indicating reduced systemic organ damage. The liver maintains normal architecture, kidneys show minimal tubular necrosis, and lung inflammation features are reduced compared to WT mice. Our results confirm that zymophagy functions as a protective pathophysiological mechanism against pancreatic and extrapancreatic tissue injury in SAP. Further studies on the mechanism of VMP1-mediated selective autophagy in AP are necessary to determine its relevance and possible modulation to prevent the severity of AP.

Severe acute pancreatitis (SAP) is associated with metabolic disorders, hypocalcemia, and multiple organ failure. The objective of this study was to investigate changes in thyroid ultrastructure and function in rats with SAP and to provide a theoretical basis for the clinical treatment of thyroid injury in patients with SAP. 64 male SPF Wistar rats were randomly divided into the SAP group and the control group. Pancreatic enzymatic indicators and thyroid hormones were detected, pathology scores were evaluated, and morphological changes were observed under light microscopy and transmission electron microscopy (TEM) in both groups. The serum levels of triiodothyronine (T3), tetraiodothyronine (T4) and Ca2+ were significantly lower in the SAP group than in the control group (P<0.05), whereas the level of calcitonin (CT) was significantly higher than that in the control group (P<0.05). The thyroid structure (pathology and electron microscopy) of the SAP rats was seriously damaged and worsened over time. SAP can cause thyroid injury through a variety of mechanisms, which can also retroact to pancreatitis to aggravate the inflammatory response. This study may have theoretical significance for basic research on SAP. Key words Severe acute pancreatitis, Thyroid, Structure and functional changes, Transmission electron microscopy.

The exocrine pancreas has a limited regenerative capacity, but to what extent all acinar cells are involved in this process is unclear. Nevertheless, the heterogenous nature of acinar cells suggests that cells exhibiting higher plasticity might play a more prominent role in acinar regeneration. In that regard, Stmn1 -expressing acinar cells have been identified as potential facultative progenitor-like cells in the adult pancreas. Here, we studied Stmn1-progeny under physiological conditions, during regeneration, and in the context of Kras G12D expression.

We followed the fate of Stmn1-progenies both under baseline conditions, following caerulein-induced acute or chronic pancreatitis, pancreatic duct ligation, and in the context of Kras G12D expression.

The Stmn1-lineage contributes to baseline acinar cell turnover under physiological conditions. Furthermore, these cells rapidly proliferate and repopulate the acinar compartment in response to acute injury in an ADM-independent manner. Moreover, acinar regeneration during chronic pancreatitis progression is in conjunction with a decline in the proliferative capacity of the Stmn1-lineage. Interestingly, newly generated acinar cells display increased susceptibility to additional injury during recurrent acute pancreatitis (RAP). Finally, given their inability to form ADMs, the Stmn1-lineage fails to form PanINs upon oncogenic Kras expression.

Our findings establish the Stmn1-lineage as a pivotal subpopulation for acinar tissue homeostasis and regeneration. The ability of these cells to restore acinar tissue in an ADM-independent manner distinguishes them as a critical regenerative population. This study presents a new paradigm for acinar regeneration and repair in the context of pancreatitis and neoplasia.

Acute pancreatitis (AP) initiates as primarily sterile local inflammation that triggers pro-inflammatory response, which is subsequently counterbalanced by an anti-inflammatory response. Immune checkpoints, such as PD-1/PD-L1, play a pivotal role in modulating these responses to prevent excessive immune activation and associated inflammatory damage. This study aimed to investigate the underlying mechanisms of these processes in both murine and human AP.

We conducted a comprehensive integration of data from cerulein-induced AP mouse models (CER-AP), utilizing single-cell RNA sequencing and digital spatial profiling for pancreatic samples, as well as single-cell Cytometry by Time Of Flight (CyTOF) for blood samples. Additionally, bulk-RNA sequencing performed on blood samples from AP patients was employed to investigate innate and adaptive immune changes at early stage of the disease.

Across the four analytical approaches, we observed consistent immune cell type distributions. Our integrative analysis revealed a significant imbalance between increased innate immune cells, including neutrophils, macrophages, and monocytes, and decreased adaptive immune cells, including CD4+ and CD8+ T cells, in early-stage AP. Notably, the PD-1/PD-L1 related pathway exhibited substantial alterations, especially in the acinar cells, T cells, B cells, macrophages, and neutrophils at the early stage of disease. Moreover, we observed a significant reduction in PD-L1 expression in the blood and regulatory T cells of CyTOF mice at the CyTOF level.

This multi-omics analysis deciphers a distinct imbalance between increased innate immunity and decreased adaptive immunity during the early phase of AP. The PD-L1 checkpoint emerges as a key regulator of immune homeostasis and a critical factor in the pathogenesis of AP.

We aimed to assess whether patients with rheumatoid arthritis (RA) have a higher risk of developing acute and chronic pancreatitis compared to individuals without RA. We identified 54,910 individuals with RA between 2010 and 2017. After exclusion, they were matched in a 1:3 ratio based on age and gender to control population without RA. Cox regression analyses were performed to estimate hazard ratio. During a median follow-up of 5.5 years, 0.18% of the patients with RA and 0.14% of the matched control developed acute pancreatitis. The risk acute pancreatitis was higher in the RA cohort compared to matched control (adjusted hazard ratio [aHR] 1.33; 95% confidence interval [CI] 1.02-1.74). In the case of chronic pancreatitis, 0.11% of patients with RA and 0.09% of the matched control developed chronic pancreatitis. Patients with RA appear to have a marginally elevated risk of chronic pancreatitis compared to matched controls (aHR 1.25, 95% CI 0.90-1.74), though this increase did not achieve statistical significance. The risk of acute pancreatitis is slightly higher in individuals with RA than in matched controls. The risk of chronic pancreatitis did not show statistical significance, but it tended to increase marginally in patients with RA.

Pancreatitis is a prominent and severe type of inflammatory disorder that has grabbed a lot of scientific and clinical interest to prevent its onset. It should be detected early to avoid the development of serious complications, which occur due to long-term damage to the pancreas. The accurate measurement of biomarkers that are released from the pancreas during inflammation is essential for the detection and early treatment of patients with severe acute and chronic pancreatitis, but this is sub-optimally performed in clinically relevant practices, mainly due to the complexity of the procedure and the cost of the treatment. Clinically available tests for the early detection of pancreatitis are often time-consuming. The early detection of pancreatitis also relates to disorders of the exocrine pancreas, such as cystic fibrosis in the hereditary form and cystic fibrosis-like syndrome in the acquired form of pancreatitis, which are genetic disorders with symptoms that can be correlated with the overexpression of specific markers such as creatinine in biological fluids like urine. In this review, we studied how to develop a minimally invasive system using hydrogel-based biosensors, which are highly absorbent and biocompatible polymers that can respond to specific stimuli such as enzymes, pH, temperature, or the presence of biomarkers. These biosensors are helpful for real-time health monitoring and medical diagnostics since they translate biological reactions into quantifiable data. This paper also sheds light on the possible use of Ayurvedic formulations along with hydrogels as a treatment strategy. These analytical devices can be used to enhance the early detection of severe pancreatitis in real time.

Acute liver injury (ALI) is a vital factor in the early progression of severe acute pancreatitis (SAP). It exacerbates systemic inflammation, impairs the liver's capacity to clear inflammatory mediators and cytokines, and contributes to systemic organ dysfunction syndrome (SODS). However, the mechanisms driving SAP-associated liver injury (SAP-ALI) are poorly understood, and effective therapeutic options remain limited. Chaperone-mediated autophagy (CMA), a selective form of autophagy, plays an essential role in reducing inflammation and oxidative stress by clearing damaged or dysfunctional proteins. This study examines the role of CMA in SAP-ALI and evaluates its therapeutic potential. In a sodium taurocholate-induced SAP-ALI rat model, CMA dysfunction was observed, characterized by reduced LAMP2A expression and the accumulation of CMA substrate proteins in pancreatic and hepatic tissues. The activator AR7 successfully restored CMA function, enhanced anti-inflammatory and antioxidant responses, and mitigated pancreatic and liver damage in SAP rat. In contrast, the CMA inhibitor PPD exacerbated liver injury, underscoring CMA's protective role in SAP-ALI. Mechanistic analyses demonstrated that CMA reactivation activated the Keap1/Nrf2 signaling pathway, leading to increased expression of antioxidant-related genes and suppression of NLRP3 inflammasome activation. Specifically, the protective effects of AR7-induced CMA activation were significantly reversed by the Nrf2 inhibitor ML385, which inhibited Nrf2 signaling and its associated protein levels. These findings show AR7-induced CMA reactivation as a promising therapeutic strategy for SAP-ALI, primarily through its enhancement of Keap1/Nrf2-regulated antioxidant pathways and inhibition of NLRP3 inflammasome activation.

Acute pancreatitis (AP) is a common digestive emergency with high morbidity and mortality. Over the past decade, significant progress has been made in understanding the mechanisms of AP, including oxidative stress, disruptions in calcium homeostasis, endoplasmic reticulum stress, inflammatory responses, and various forms of cell death. This review provides an overview of the typical signaling pathways involved and proposes the latest clinical translation prospects. These strategies are important for the early management of AP, preventing multi-organ injury, and improving the overall prognosis of the disease.

Acute pancreatitis (AP) is an acute inflammatory disease that can lead to multiple system dysfunction, including acute kidney injury (AKI). AKI occurs in 10%-42% of AP patients, and studies have shown that early (48 hours) acute pancreatitis associated acute kidney injury (AP-AKI) can increases the risk of death in acute pancreatitis. Anion gap (AG) is a common index in clinical evaluation of acid-base imbalance and an important index in critically ill patients. The aim of this study was to investigate the relationship between baseline anion gap values and early acute kidney injury in patients with acute pancreatitis in intensive care unit.

Our data were derived from inpatients admitted to Beth Israel Deaconess Medical Center (BIDMC) in the United States between 2008 and 2019. A total of 4,017 adult patients with acute pancreatitis admitted to the ICU were enrolled in the study, and 475 were enrolled according to the exclusion and inclusion criteria. Only the baseline value and one day after arrival to the intensive care unit (ICU) were considered for all laboratory test values. According to previous literature and clinical significance, AG was divided into two groups: low value (< 16mmol/L) group and high value (≥16mmol/L) group, and logistics univariate and multifactor regression analysis was applied to verify the relationship between anion gap and AKI risk.

Only 157 of the 475 AP cases had an AG level below 16 mmol/L, whereas 318 patients had an AG level over 16 mmol/L. Within 48 hours, 89 and 240 cases (56.7% and 75.5%) and the low- and high-AG groups had AKI. In AP cases, an elevated AG was related to an increased risk of AKI [odds ratio (OR) = 1.06, 95% confidence interval (CI): 1.03-1.1], and is a nonlinear relationship. When controlling for other factors, this correlation was still significant. Compared to the lower group, high-AG (≥16mmol/L) values can increase the risk of early acute kidney injury in patients with acute pancreatitis (OR = 2.35, CI: 1.57-3.53).

Anion gap (AG) is an independent risk factor for early acute kidney injury in patients with acute pancreatitis, and has a nonlinear relationship with 48-hour AKI. Higher AG(≥16mmol/L) values can significantly increase the risk of AP-AKI.

Acute pancreatitis (AP) is a highly fatal pancreatic inflammation. In recent years, synthetic nanoparticles have been extensively developed as drug carriers to address the challenges of systemic adverse reactions and lack of specificity in drug delivery. However, systemically administered nanoparticle therapy is rapidly cleared from circulation by the mononuclear phagocyte system (MPS), leading to suboptimal drug concentrations in inflamed tissues and suboptimal pharmacokinetics. To address this challenge, we herein demonstrate a surface masking strategy that involves coating the surface of selenylated Poria cocos polysaccharide nanoparticles with a layer of macrophage plasma membrane to circumvent MPS sequestration, thereby enhancing the therapeutic efficacy of selenylated Poria cocos polysaccharide nanoparticles. Nanoparticles encapsulated with macrophage membranes can simulate the active homing efficacy of macrophages to inflamed lesions during AP, resulting in excessive infiltration of macrophages in pancreatic inflammation sites and prolonged tissue retention time. This technique converts non-adhesive lipid nanoparticles into bioadhesive nanoparticles, increasing local tissue accumulation under inflammatory conditions, including the pancreas and vulnerable lungs. The mechanism is related to targeting pro-inflammatory macrophages. In murine models of mild and severe AP, intravenous treatment with macrophage-mimicking nanoparticles effectively reduces systemic inflammation level and diminishes the recruitment of macrophages and neutrophils. Mechanistic studies elucidate that macrophage membrane-biomimetic selenylated Poria cocos polysaccharide nanoparticles primarily mitigate pancreatic inflammation by inhibiting the AKT/mTOR pathway to reverse autophagic flux impairment. This allows us to envision that the developed biomimetic nanotherapy approach could potentially serve as a novel strategy for pancreatic drug therapy.

Mitophagy serves as a mitochondrial quality control mechanism to maintain the homeostasis of mitochondria and the intracellular environment. Studies have shown that there is a close relationship between mitophagy and apoptosis. Sestrin2 (Sesn2) is a highly conserved class of stress-inducible proteins that play important roles in reducing oxidative stress damage, inflammation, and apoptosis. However, the potential mechanism of how Sesn2 regulates mitophagy and apoptosis in severe acute pancreatitis (SAP) remains unclear. In the study, RAW264.7 (macrophage cell Line) cellular inflammation model established by lipopolysaccharide (LPS) treatment as well as LPS and CAE-induced SAP mouse model (wild-type and Sen2 Knockout mouse) were used. Our study showed that LPS stimulation significantly increased the level of Sesn2 in RAW264.7 cells, Sesn2 increased mitochondrial membrane potential, decreased inflammation levels, mitochondrial superoxide levels and apoptosis, and also promoted monocyte macrophages toward the M2 anti-inflammatory phenotype, suggesting a protective effect of Sesn2 on mitochondria. Further, Sesn2 increased mitophagy and decreased apoptosis via modulating the PINK1-Parkin signaling. Meanwhile, knockout of Sesn2 exacerbated pancreatic, mitochondrial damage and inflammation in a mouse model of SAP. In addition, the protective effect of Sesn2 against SAP was shown to be associated with mitophagy conducted by the PINK1-Parkin pathway via inhibiting apoptosis. These findings reveal that Sesn2 in balancing mitochondrial autophagy and apoptosis by modulating the PINK1-Parkin signaling may present a new therapeutic strategy for the treatment of SAP.

Both the clinical management and study of recurrent acute pancreatitis and chronic pancreatitis are complicated by significant heterogeneity in the etiology, mechanisms, symptoms, and complications of pancreatitis. The National Institutes of Diabetes and Digestive and Kidney Disease recently convened a workshop to address current knowledge and knowledge gaps in the field. Preclinical models that better replicate human disease are important for development of new therapies. Pain is often the most common and most difficult symptom to treat, as the causes are multifactorial and effective treatment may vary depending on whether pain is neuropathic or nociceptive in origin, and the placebo effect can complicate evaluation of the efficacy of medical and procedural interventions. Novel technologies like functional magnetic resonance imaging and virtual reality may offer novel means for assessing and treating pain, respectively. Clinical trial designs will need to consider best approaches to addressing the heterogeneity of chronic pancreatitis, including careful attention to designing eligibility criteria, and establishing accepted and validated core outcomes criteria for the field. The latter may be informed by consensus in pain research. Recruitment of participants into clinical trials has been challenging, often requiring multiple centers. Establishment of a clinical trials network would facilitate greater opportunities for therapeutic trials in pancreatitis.

The mechanism of cell damage during acute pancreatitis (AP) has not been fully elucidated, and there is still a lack of specific or effective treatments. Increasing evidence has implicated mitochondrial dysfunction as a key event in the pathophysiology of AP. Mitochondrial dysfunction is closely related to calcium (Ca2+) overload, intracellular adenosine triphosphate depletion, mitochondrial permeability transition pore openings, loss of mitochondrial membrane potential, mitophagy damage and inflammatory responses. Mitochondrial dysfunction is an early triggering event in the initiation and development of AP, and this organelle damage may precede the release of inflammatory cytokines, intracellular trypsin activation and vacuole formation of pancreatic acinar cells. This review provides further insight into the role of mitochondria in both physiological and pathophysiological aspects of AP, aiming to improve our understanding of the underlying mechanism which may lead to the development of therapeutic and preventive strategies for AP.

Severe acute pancreatitis (SAP) is a severe clinical condition associated with high rates of morbidity and mortality. Multiple organ dysfunction syndrome that follows systemic inflammatory response syndrome is the leading cause of SAP‑related death. Since the inflammatory mechanism of SAP remains unclear, there is currently a lack of effective drugs available for its treatment. Therefore, it is important to study effective therapeutic drugs and their molecular mechanisms based on studying the inflammatory mechanism of SAP. In the present study, in vivo, a mouse model of AP induced by cerulein (CR) combined with lipopolysaccharide (LPS) was established to clarify the therapeutic effect of artesunate (AS) in AP mice by observing the gross morphological changes of the pancreas and surrounding tissues, calculating the pancreatic coefficient, and observing the histopathology of the pancreas. The serum amylase activity in AP mice was detected by iodine colorimetry and the superoxide dismutase activity in the pancreas was detected by WST‑1 assay. The levels of proinflammatory cytokines in the serum, the supernatant of pancreatic tissue homogenates and the peritoneal lavage fluid were detected by ELISA assay. The total number of peritoneal macrophages was assessed using the cellular automatic counter, and the expression of proteins related to autophagy, and the TLR4 pathway was detected by immunohistochemistry and western blotting. In vitro, the effect of trypsin (TP) combined with LPS was observed by detecting the release of proinflammatory cytokine levels from macrophages by ELISA assay, and detecting the expression of proteins related to autophagy and the TLR4 pathway by immunofluorescence and western blotting. The present study revealed that AS reduced pancreatic histopathological damage, decreased pancreatic TP and serum amylase activities, increased superoxide dismutase activity, and inhibited pro‑inflammatory cytokine levels in a mouse model of AP induced by cerulein combined with lipopolysaccharide. In vitro, TP combined with LPS was found to synergistically induce pro‑inflammatory cytokine release from mouse macrophages and RAW264.7 cells, while AS could inhibit cytokine release. Furthermore, CR combined with LPS synergistically increased amylase activity in acinar cells, whereas AS decreased amylase activity. Autophagy serves an important role in the release of pro‑inflammatory cytokines. In the present study, it was revealed that the autophagy inhibitor LY294002 suppressed the release of pro‑inflammatory cytokines from macrophages treated with TP combined with LPS, and pro‑inflammatory cytokine release was not further reduced by AS combined with LY294002. Furthermore, AS not only inhibited the expression of important molecules in the Toll‑like receptor 4 (TLR4) signaling pathway, but also inhibited autophagy proteins and reduced the number of autolysosomes in mice with AP and in macrophages. In conclusion, these results suggested that AS may protect against AP in mice via inhibition of TLR4‑dependent autophagy; therefore, AS may be considered a potential therapeutic agent against SAP.

The necrosis of pancreatic acinar cells is a key molecular event in the progression of acute pancreatitis (AP), with disturbances in mitochondrial energy metabolism considered to be a direct causative factor of acinar cell necrosis. Histidine triad nucleotide-binding protein 2 (HINT2) has been implicated in the development of various diseases, whereas its involvement in the progression of AP remains unclear. This study aims to investigate the role of HINT2 in AP. HINT2 expression in pancreatic tissues was significantly downregulated after AP. The results of glutathione-S-transferase (GST) pull-down and proteomics analyses revealed the involvement of HINT2 in regulating mitochondrial oxidative phosphorylation (OXPHOS) in AP mice. Moreover, lentivirus-mediated HINT2 overexpression not only alleviated AP-induced ATP depletion, but also relieved inflammatory responses and cell necrosis. Mechanistically, HINT2 interacted with cytochrome C oxidase II (MTCO2) to promote mitochondrial OXPHOS, thereby reducing ROS accumulation and inhibiting the activation of inflammatory signaling pathway. Besides, HINT2 act as a direct pharmacological target of Emo to elicit protective effects on AP. Importantly, Emo upregulates the expression of HINT2 and OXPHOS complex proteins and enhances the interaction between HINT2 and MTCO2. Furthermore, CRISPR/Cas9-mediated HINT2 knockout significantly impaired the protective effects of Emo against AP-induced mitochondrial energy metabolism disorders, inflammatory responses, and acinar cell necrosis. Overall, these results uncover a previously unexplored role for HINT2 in maintaining mitochondrial energy metabolism in pancreatic acinar cells and reveals novel mechanism and target for Emo-mediated AP remission.

Oxidative stress (OS) injury is pivotal in acute pancreatitis (AP) pathogenesis, contributing to inflammatory cascades. Irisin, a ubiquitous cytokine, exhibits antioxidant properties. However, the role of irisin in AP remains inconclusive. Our study aims to elucidate irisin expression in AP patients and investigate its mechanism of action to propose a novel treatment strategy for AP. Serum irisin levels in 65 AP patients were quantified using an enzyme-linked immunosorbent assay and correlated with disease severity scores. Core genes implicated in AP-related oxidative stress were identified and screened via bioinformatics analysis. The therapeutic efficacy of irisin in AP was confirmed using a murine cerulein-induced AP model. The intrinsic mechanism of irisin's antioxidative stress action was investigated and verified in pancreatic AR42J cells (Supplementary Fig. 1). Common targets shared by irisin and AP were further validated using a molecular docking model which was constructed for virtual docking analysis. This study investigated alterations in redox status in AP and found a significant reduction in serum irisin levels, correlating inversely with AP severity. In a murine AP model, we showed that irisin triggers an antioxidative stress program via the KEAP1 gene; this process helps reestablish redox balance by decreasing the buildup of reactive oxygen species (ROS) and suppressing the secretion of inflammatory mediators within pancreatic tissues Notably, increased KEAP1 expression counteracted the antioxidative effects of irisin. Our findings unveil a novel therapeutic mechanism for AP, wherein irisin inhibits KEAP1 to alleviate OS. Increasing irisin levels in vivo presents a promising strategy for AP treatment.

Neutrophil extracellular traps (NETs) play a significant role in the development of acute pancreatitis (AP). The actin-binding protein LASP1 regulates proteins associated with the cytoskeleton, yet its precise involvement in NETs and AP remains to be elucidated.

To investigate the role of LASP1 in NETs and AP, several bioinformatics methods, such as weighted gene co-expression network analysis (WGCNA), differential analysis, and least absolute shrinkage and selection operator (LASSO) regression, were utilized to screen for feature genes based on the Gene Expression Omnibus (GEO) dataset. To further assess the impact of LASP1, both an in vitro model of 12-myristic-13-acetate phobolol (PMA)-induced NETs and a caerulein-induced AP model were employed.

Through WGCNA, AP-related module genes were screened, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses were conducted to identify enriched pathways and functions. Six characteristic genes were identified through LASSO regression screening, with LASP1 being the most distinct. LASP1 reduces the generation of NETs induced by PMA in vitro. Mechanistically, LASP1 may increase F-actin protein levels by inhibiting the depolymerization of F-actin. Furthermore, our study utilizing a mouse AP model demonstrated that the LSAP1 recombinant protein effectively alleviated pancreatic necrosis in mice afflicted with AP.

LASP1 inhibits the formation of NETs and may alleviate AP by increasing the level of F-actin protein.

The WD40 domain (WDD) of ATG16L1 plays a pivotal role in non-canonical autophagy. This study examined the role of recently identified LAP-like non-canonical autophagy (LNCA) in acute pancreatitis. LNCA involves rapid single-membrane LC3 conjugation to endocytic vacuoles in pancreatic acinar cells. The rationale for this study was the previously observed presence of trypsin in the organelles undergoing LNCA; aberrant trypsin formation is an important factor in pancreatitis development. Here we report that the deletion of WDD (attained in ATG16L1[E230] mice) eliminated LNCA, aggravated caerulein-induced acute pancreatitis and suppressed the fast trypsin degradation observed in both a rapid caerulein-induced disease model and in caerulein-treated isolated pancreatic acinar cells. These experiments indicate that LNCA is a WDD-dependent mechanism and suggest that it plays not an activating but a protective role in acute pancreatitis. Furthermore, palmitoleic acid, another inducer of experimental acute pancreatitis, strongly inhibited LNCA, suggesting a novel mechanism of pancreatic lipotoxicity.Abbreviation: AMY: amylase; AP: acute pancreatitis; CASM: conjugation of Atg8 to single membranes; CCK: cholecystokinin; FAEE model: fatty acid and ethanol model; IL6: interleukin 6; LA: linoleic acid; LAP: LC3-associated phagocytosis; LMPO: lung myeloperoxidase; LNCA: LAP-like non-canonical autophagy; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MPO: myeloperoxidase; PMPO: pancreatic myeloperoxidase; POA: palmitoleic acid; WDD: WD40 domain; WT: wild type.

Acute pancreatitis (AP) is an inflammatory disease of the pancreas and a complex process involving multiple factors, with mitochondrial damage playing a crucial role. Mitochondrial dysfunction is now considered a key driver in the development of AP. This dysfunction often presents as increased oxidative stress, altered membrane potential and permeability, and mitochondrial DNA damage and mutations. Under stress conditions, mitochondrial dynamics and mitochondrial ROS production increase, leading to decreased mitochondrial membrane potential, imbalanced calcium homeostasis, and activation of the mitochondrial permeability transition pore. The release of mitochondrial DNA (mtDNA), recognized as damage-associated molecular patterns, can activate the cGAS-STING1 and NF-κB pathway and induce pro-inflammatory factor expression. Additionally, mtDNA can activate inflammasomes, leading to interleukin release and subsequent tissue damage and inflammation. This review summarizes the relationship between mitochondria and AP and explores mitochondrial protective strategies in the diagnosis and treatment of this disease. Future research on the treatment of acute pancreatitis can benefit from exploring promising avenues such as antioxidants, mitochondrial inhibitors, and new therapies that target mitochondrial dysfunction.

Acute pancreatitis (AP) is a common acute inflammatory abdominal condition. Severe acute pancreatitis (SAP) can provoke a systemic inflammatory response and lead to multiple organ failure. The S100A9 protein, recognized as a major inflammatory biomarker, plays a significant role in both infection and inflammatory responses. Despite its known role in inflammation, the precise role of S100A9 in AP remains poorly understood. This study aimed to elucidate the potential role of S100A9 in AP and investigate the underlying mechanism. We employed a mouse model of AP and the AR42J cell line to investigate the functional role of S100A9. The effect of S100A9 on pancreatic injury and the expression of inflammatory factors (IL-6, IL-1β, and TNF-α) was assessed through targeted inhibition of S100A9 expression in the mouse model of AP. Furthermore, the modulatory effect of cerulein-induced inflammatory responses on AR42J cells was assessed after adding the S100A9 recombinant protein. In the mouse model of AP, targeted inhibition of S100A9 markedly ameliorated pancreatic injury and significantly decreased the expression levels of IL-6, IL-1β, and TNF-α. Moreover, increased levels of S100A9 were positively correlated with elevated expression of receptor for advanced glycation endproducts (RAGE) in pancreatic acinar cells. In AR42J cells, the introduction of S100A9 recombinant protein enhanced RAGE expression and exacerbated cerulein-induced inflammatory response. S100A9 inhibition significantly alleviated the pancreatic inflammatory response by downregulating RAGE expression, thereby improving AP.

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-1β, 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.

The initial stages of acute pancreatitis (AP) are characterized by a significant event - acinar ductal metaplasia (ADM). This process is a crucial feature of both acute and chronic pancreatitis, serving as the first step in the development of pancreatic cancer. Ion channels are integral transmembrane proteins that play a pivotal role in numerous biological processes by modulating ion flux. In many diseases, the expression and activity of ion channels are often dysregulated. Metal ions, including calcium ions (Ca2+), ferrous ions (Fe2+), and Copper ions (Cu2+), assume a distinctive role in cellular metabolism. These ions possess specific biological properties relevant to cellular function. However, the interactions among these ions exacerbate the imbalance within the intracellular environment, resulting in cellular damage and influencing the progression of AP. A more in-depth investigation into the mechanisms by which these ions interact with acinar cells is essential for elucidating AP's pathogenesis and identifying novel therapeutic strategies. Currently, treatment for AP primarily focuses on pain relief, complications prevention, and prognosis improvement. There are limited specific treatments targeting acinous cell dedifferentiation or ion imbalance. This study aims to investigate potential therapeutic strategies by examining ion crosstalk within acinar cells in the context of acute pancreatitis.