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Obstruction of bile ducts due to gallstones can lead to biliary acute pancreatitis (BAP). According to Perides et al., G protein-coupled bile acid receptor-1 (GPBAR1) mediates BAP. However, Zi's findings suggest that GPR39, rather than GPBAR1, mediates TLCAS-induced increases in cytosolic calcium and acinar cell necrosis, casting doubt on the role of GPBAR1 in BAP. Numerous G protein-coupled receptors on pancreatic acinar cells utilize Ca 2+ and cyclic adenosine monophosphate (cAMP) as second messengers to manage pancreatic exocrine secretion, with significant cross-talk between these signals. The primary bile acid cholic acid (CA) and its conjugated forms are predominant in the human gallbladder. This study aimed to clarify the role and physiological significance of GPBAR1 by investigating the physiological and pathological effects of CA activation on GPBAR1 in pancreatic acinar cells. Isolated rat pancreatic acinar cells were treated with CA and CCK in vitro to observe the effect of CA-induced cAMP signaling on CCK-induced physiological and pathological calcium signaling. In vivo evaluations involved reverse biliopancreatic duct injections of 5 % sodium taurocholate (STC) or 5 % CA in rats. CA induced intracellular cAMP signaling in a concentration-dependent manner without increasing the intracellular Ca 2+ concentration. CA did not independently cause calcium overload or enzyme activation, nor did it exacerbate calcium overload or enzyme activation from high-dose CCK. Reverse biliopancreatic duct injections of 5 % CA did not cause acute pancreatitis in the rats. Transcriptomic analysis revealed that 50 μM CA induced changes in gene expression related to protein synthesis in the endoplasmic reticulum and ribosomes. Furthermore, 50 μM CA accelerated the calcium waves and increased the enzyme secretion induced by CCK. GPBAR1 was found on the basolateral membrane in rat pancreatic tissue rather than near the apical region of acinar cells. GPBAR1 activation is not crucial for BAP activity but may play a role in bile acid regulation of pancreatic exocrine secretion, suggesting that GPBAR1 is a potential therapeutic target for pancreatic exocrine insufficiency., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jun Li reports financial support was provided by National Natural Science Foundation of China. Jun Li reports financial support was provided by Project of Shaanxi Administration of Traditional Chinese Medicine. Jun Li reports financial support was provided by Xi'an Science and Technology Program. Yudan Fan and Peng An reports financial support was provided by Key Research and Development Program of Shaanxi Province of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Yiyi decoction is a Chinese herbal formula for the treatment of acute pancreatitis that has been used in clinical practice for decades. A previous study has suggested that resveratrol, emodin, rhein and their derivatives might be the potential pharmacodynamic components in Yiyi decoction, and researchers have proposed that resveratrol, emodin and rhein are candidate markers for quality control. The present study investigated the intervention effect of Yiyi decoction and its effective components on murine acute pancreatitis using metabolomic approach that integrated global and unique metabolic characteristics. First, serum metabolomics based on the platform of ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry was performed to assess metabolic changes in experimental acute pancreatitis. Second, an in-depth analysis of bile acid metabolism was performed based on an in-house database. Finally, an integrated analysis of the intervention effect of Yiyi decoction and its effective components in response to these metabolic perturbations was performed. As a result, 39 potential biomarkers for the pathogenesis of acute pancreatitis, mainly phospholipids, fatty acids, bile acids and lipoylcarnitines, were screened and annotated. Integrated analysis revealed that the metabolic disorders in acute pancreatitis mice were reversed by Yiyi decoction primarily via regulating glycerophospholipid metabolism, bile acid biosynthesis, carnitine synthesis and fatty acid metabolism. Yiyi decoction components may effectively target the migratory metabolome. Histopathological and biochemical analyses suggested that Yiyi decoction maintained the gut barrier function and inhibited inflammatory cytokines, thus exert anti-acute pancreatitis effects. The present study utilized an approach that integrated global and unique metabolic characteristics to elucidate the underlying mechanisms of Chinese herbal formulas from a metabolomics perspective., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Gong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Acinar cells have been proposed as a cell-of-origin for pancreatic ductal adenocarcinoma (PDAC) after undergoing acinar-to-ductal metaplasia (ADM). ADM can be triggered by pancreatitis, causing acinar cells to de-differentiate to a ductal-like state. We identify FRA1 (gene name Fosl1) as the most active transcription factor during Kras G12D acute pancreatitis-mediated injury, and we have elucidated a functional role of FRA1 by generating an acinar-specific Fosl1 knockout mouse expressing Kras G12D . Using a gene regulatory network and pseudotime trajectory inferred from single-nuclei ATAC-seq and bulk RNA sequencing (RNA-seq), we hypothesized a regulatory model of the acinar-ADM-pancreatic intraepithelial neoplasia (PanIN) continuum and experimentally validated that Fosl1 knockout mice are delayed in the onset of ADM and neoplastic transformation. Our study also identifies that pro-inflammatory cytokines, such as granulocyte colony stimulating factor (G-CSF), can regulate FRA1 activity to modulate ADM. Our findings identify that FRA1 is a mediator of acinar cell plasticity and is critical for acinar cell de-differentiation and transformation., Competing Interests: Declaration of interests P.A.S. receives patent royalties from Guardant Health. A.M. is listed as an inventor on a patent that has been licensed by Johns Hopkins University to Thrive Earlier Detection. A.M. serves as a consultant for Freenome and Tezcat Biosciences., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Exogenous inhibition of neutrophil extracellular traps (NETs) was believed to alleviate acute pancreatitis (AP). This study aimed to comprehensively explore the key biological behavior of NETs including timing and pathogenesis in AP by integrating of single cell RNA sequencing(scRNA-seq) and bulk RNA-seq., Methods: Differentially expressed NETs-related genes and the hub genes of NETs were screened by bulk RNA-seq. ScRNA-seq was used to identify the cell types in pancreas of AP mice and to depict the transcriptomic maps in neutrophils. The mouse AP models were build to verify the timing of initiation of NETs and underlying pathogenesis of damage on pancreas acinar cells., Results: Tlr4 and Ccl3 were screened for hub genes by bulk RNA-seq. The trajectory analysis of neutrophils showed that high expression of Ccl3, Cybb and Padi4 can be observed in the middle stage during AP. Macrophages might be essential in the biological behavior of neutrophils and NETs. Through animal models, we presented that extensive NETs structures were formed at mid-stage of inflammation, accompanied by more serious pancreas and lung damage. NETs might promote necroptosis and macrophage infiltration in AP, and the damage on pancreatic injury could be regulated by Tlr4 pathway. Ccl3 was considered to recruit neutrophils and promote NETs formation., Conclusion: The findings explored the underlying timing and pathogenesis of NETs in AP for the first time, which provided gene targets for further studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Pancreatitis is a common, life-threatening inflammatory disease of the exocrine pancreas. Its pathogenesis remains obscure, and no specific or effective treatment is available. Gallstones and alcohol excess are major etiologies of pancreatitis; in a small portion of patients the disease is hereditary. Pancreatitis is believed to be initiated by injured acinar cells (the main exocrine pancreas cell type), leading to parenchymal necrosis and local and systemic inflammation. The primary function of these cells is to produce, store, and secrete a variety of enzymes that break down all categories of nutrients. Most digestive enzymes, including all proteases, are secreted by acinar cells as inactive proforms (zymogens) and in physiological conditions are only activated when reaching the intestine. The generation of trypsin from inactive trypsinogen in the intestine plays a critical role in physiological activation of other zymogens. It was proposed that pancreatitis results from proteolytic autodigestion of the gland, mediated by premature/inappropriate trypsinogen activation within acinar cells. The intra-acinar trypsinogen activation is observed in experimental models of acute and chronic pancreatitis, and in human disease. On the basis of these observations, it has been considered the central pathogenic mechanism of pancreatitis - a concept with a century-old history. This review summarizes the data on trypsinogen activation in experimental and genetic rodent models of pancreatitis, particularly the more recent genetically engineered mouse models that mimic mutations associated with hereditary pancreatitis; analyzes the mechanisms mediating trypsinogen activation and protecting the pancreas against its' damaging effects; discusses the gaps in our knowledge, potential therapeutic approaches, and directions for future research. We conclude that trypsin is not the culprit in the disease pathogenesis but, at most, a mediator of some pancreatitis responses. Therefore, the search for effective therapies should focus on approaches to prevent or normalize other intra-acinar pathologic processes, such as defective autophagy leading to parenchymal cell death and unrelenting inflammation., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Acute pancreatitis (AP) is a familiar emergency of digestive system characterized by pancreatic inflammation. Lonicerin (LCR) has been reported to exert anti-inflammatory and immunomodulatory characteristics in several inflammatory diseases. Nevertheless, its role and mechanism involved in AP are still unknown. This study was designed to explore the protective effect and potential mechanism of LCR in AP. In this study, LCR and ferrostatin-1 alleviated, but erastin aggravated caerulein (CAE) exposure-induced cytotoxicity and reduction of cell viability in AR42J cells. LCR exhibited a protective role in CAE-treated AR42J cells, as evidenced by alleviation of apoptosis, inflammation, and ferroptosis. Mechanistically, LCR decreased the phosphorylation level of nuclear factor-kappa B p65 and increased the levels of silent information regulator 1 (SIRT1) and glutathione peroxidase 4 (GPX4) in CAE-treated AR42J cells. Furthermore, functional rescue experiments manifested that knockdown of SIRT1 partially negated the inhibitory action of LCR against CAE-induced apoptosis, inflammation, and ferroptosis in AR42J cells. Overall, LCR mitigates apoptosis, inflammation, and ferroptosis in CAE-exposed AR42J cells, which is related to the activation of the SIRT1/GPX4 signaling pathway., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

A 10-y-old spayed female Cavalier King Charles Spaniel dog was presented to the Veterinary Teaching Hospital because of recurrent chronic abscesses on the distal pelvic limbs, fever, lethargy, lameness of unknown etiology, and chronic pancreatitis. Sterile nodular panniculitis was diagnosed after an extensive workup, and the dog initially responded to immunosuppressive therapy, but relapse and spread of cutaneous lesions and acute lameness occurred after 11 mo, and euthanasia was elected. Postmortem examination confirmed hyalinizing pancreatic adenocarcinoma with pancreatitis, panniculitis, polyarthritis (PPP), and osteomyelitis. Histopathology and bacterial and fungal cultures were supportive of a sterile process, specifically the PPP syndrome, which is a rare, potentially life-threatening, systemic manifestation of pancreatic disease in both people and animals. To our knowledge, a clinicopathologic description of a hyalinizing pancreatic adenocarcinoma associated with this rare syndrome has not been reported previously in a dog., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: The pathophysiology of Acute Pancreatitis (AP) may be complicated by endothelial activation. von Willebrand Factor (vWF)- ADAMTS13 axis is a marker of endothelial activation. The study aimed to investigate the axis in AP, comparing it in patients with and without persistent organ failure (OF), with and without pancreatic necrosis, and correlating it with the standard severity scores (CRP, APACHE II, BISAP, SOFA, and qSOFA) METHODS: vWF-Antigen (vWF:Ag), vWF-Collagen-Binding-Assay (vWF:CBA), and ADAMTS13 activity (ADAMTS13:act) levels were measured within 5 days of symptom onset in consecutive patients (n = 98), who were admitted with a first episode of AP (Dec 2021-May 2023)., Results: Of the 98 patients admitted with AP, 78(79.6 %) had no or transient OF; 20(20.4 %) had persistent OF. Age was comparable (43.73 ± 15.36 vs 38.65 ± 13.69) [mean ± SD](years), and males were predominant in both groups (70.5 % vs 80 %). Patientswith persistent OF had higher vWF:CBA(%)[323(279-486.5) vs 199.5(159.1-295.75)] and lower ADAMTS13:act(%)[35.4(23.8-56.85) vs 56.35(44.1-71.9)][median (25th - 75th percentile)](P = 0.001) than those with no or transient OF. Patients with pancreatic necrosis (n = 19) had lower ADAMTS13:act(%)[42.79 ± 18.69] than those without pancreatic necrosis (n = 18) [62.49 ± 22.64] (P < 0.01). ADAMTS13:act had a negative correlation(r = -0.2), whereas vWF:Ag and vWF:CBA had a positive correlation (r = 0.2) with the standard severity scores (P < 0.05). ADAMTS13:act could predict pancreatic necrosis [AUROC-0.737, P < 0.05] and persistent OF [AUROC-0.746, P < 0.001], while vWF:CBA could predict persistent OF [AUROC- 0.73, P < 0.001]., Conclusion: vWF-ADAMTS13 axis helps to predict severe disease and is associated with poor outcomes in acute pancreatitis., (Copyright © 2024 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

NLRP3 inflammasomes- pyroptosis axis is activated by microcirculation dysfunction and touched off severe acute pancreatitis (SAP). Activation of PGC-1α can improve microcirculation dysfunction by promoting mitochondrial biogenesis. Resveratrol (RSV), one typical SIRT1 agonist, possesses the ability of alleviating SAP and activing PGC-1α. Therefore, the study was designated to explore whether the protective effect of RSV in SAP was though suppressing NLRP3 inflammasomes- pyroptosis axis via advancing SIRT1/PGC-1α-dependent mitochondrial biogenesis. The models of SAP were induced by treating with sodium taurodeoxycholate in rats and AR42J cells. The pathological injury, water content (dry/wet ratio) and microcirculation function of pancreas, activity of lipase and amylase were used to evaluate pancreatic damage. The expression of inflammatory cytokine was measured by ELISA and RT-PCR. The damage of mitochondrial was evaluated by measuring the changes in Mitochondrial Membrane Potential (ΔΨm), mitochondrial ROS, ATP content and MDA as well as relocation of mtDNA and the activity of SOD and GSH. The expressions of NLRP3 inflammasomes- pyroptosis axis proteins were detected by Western blotting as well as SIRT1/PGC-1α/NRF1/TFAM pathway protein. Moreover, the modification of PGC-1α was measured by co-immunoprecipitation. The results displayed that RSV can significantly improve the damage of pancreas and mitochondrial, decrease the expression of pro-inflammatory factor and the activation of NLRP3 inflammasomes- pyroptosis axis, promote the expression of an-inflammatory factor and the deacetylation of PGC-1α together with facilitating SIRT1/PGC-1α-mediating mitochondrial biogenesis. Therefore, the protective effect of RSV in SAP is though inactivation of NLRP3 inflammasomes- pyroptosis axis via promoting mitochondrial biogenesis in a SIRT1/PGC-1α-dependent manner., (© 2024. The Author(s).)

Acute pancreatitis (AP) is a serious health problem that dysregulates intestinal microbiota. Angiotensin (Ang)-(1-7) plays a protective role in the intestinal barrier in AP, but its effect on intestinal microbiota remains clear. To investigate the impact of Ang-(1-7) on AP-induced intestinal microbiota disorder and metabolites. We collected blood and fecal samples from 31 AP patients within 48 h after admission to the hospital, including 11 with mild AP (MAP), 14 with moderately severe AP (MSAP), six with severe AP (SAP). Mice were divided into four groups: control, AP, AP + Ang-(1-7) via tail vein injection, and AP + Ang-(1-7) via oral administration. The samples of mice were collected 12 h after AP. Pancreatic and intestinal histopathology scores were analyzed using the Schmidt and Chiu scores. Fecal microbiota and metabolites analysis was performed via 16S rDNA sequencing and nontargeted metabolomics analysis, respectively. In patients, the abundance of beneficial bacteria (Negativicutes) decreased and pathogenic bacteria (Clostridium bolteae and Ruminococcus gnavus) increased in SAP compared with MAP. Ang-(1-7) levels were associated with changes in the microbiota. There were differences in the intestinal microbiota between control and AP mice. Ang-(1-7) attenuated intestinal microbiota dysbiosis in AP mice, reflecting in the increase in beneficial bacteria (Odoribacter and Butyricimonas) than AP, as well as pancreatic and intestinal injuries. Oral administration of Ang-(1-7) reversing AP-induced decreases in metabolisms: secondary bile acids, emodin, and naringenin. Ang-(1-7) may improve intestinal microbiota dysbiosis and modulate fecal metabolites in AP, thereby reducing the damage of AP., (© 2024 Federation of American Societies for Experimental Biology.)

This study aimed to elucidate the molecular mechanisms by which PLD2 controls apoptosis and edema in pancreatic cells via the Nrf2/NF-κB pathway. AR42J rat pancreatic cells were treated with 10 nM mitomycin to create an in vitro pancreatitis model (model group), with a control group receiving phosphate-buffered saline. Cells were transfected with a PLD2 overexpression plasmid using Lipofectamine 3000, forming the PLD2 overexpression group. PLD2 protein expression was assessed by Western blotting, and TNF-α, IL-6, and IL-10 levels were measured by RT-qPCR. Nrf2/NF-κB protein expressions were also analyzed. Apoptosis and necrosis were evaluated using Annexin V-FITC/PI staining and the LDH release test. Cell edema was assessed by cell volume, ion content, and membrane damage. Western blotting was used to analyze pan-apoptosis-related proteins. PLD2 expression was lower in the model group compared to controls (P < 0.05) but higher in the PLD2 overexpression group (P < 0.05). TNF-α, IL-6, and IL-10 levels were elevated in the model group (P < 0.05) and reduced in the PLD2 overexpression group (P < 0.05). Nrf2 expression decreased in the model group but increased with PLD2 overexpression (P < 0.05). NF-κB expression increased in the model group but decreased with PLD2 overexpression (P < 0.05). Apoptosis and necrosis rates were higher in the model group (P < 0.05) but lower in the PLD2 overexpression group (P < 0.05). Cell volume, Na + content, and LDH release increased in the model group (P < 0.05) but decreased with PLD2 overexpression (P < 0.05). RIPK1 expression decreased in the model group (P < 0.05) but increased with PLD2 overexpression (P < 0.05). CASP8, FADD, and ZBP1 levels were higher in the model group (P < 0.05) and reduced with PLD2 overexpression (P < 0.05). PLD2 exerts a protective effect in acute pancreatitis by activating Nrf2 and inhibiting NF-κB, reducing apoptosis, cell swelling, and membrane damage. This highlights potential therapeutic targets for pancreatic inflammation., (© 2024. The Author(s).)

Sphingosine-1-phosphate (S1P) is a sphingolipid metabolic product produced via the phosphorylation of sphingosine by sphingosine kinases (SPHKs), serving as a powerful modulator of various cellular processes through its interaction with S1P receptors (S1PRs). Currently, this incompletely understood mechanism in pancreatic diseases including pancreatitis and pancreatic cancer, largely limits therapeutic options for these disorders. Recent evidence indicates that S1P significantly contributes to pancreatic diseases by modulating inflammation, promoting pyroptosis in pancreatic acinar cells, regulating the activation of pancreatic stellate cells, and affecting organelle functions in pancreatic cancer cells. Nevertheless, no review has encapsulated these advancements. Thus, this review compiles information about the involvement of S1P signaling in exocrine pancreatic disorders, including acute pancreatitis, chronic pancreatitis, and pancreatic cancer, as well as prospective treatment strategies to target S1P signaling for these conditions. The insights presented here possess the potential to offer valuable guidance for the implementation of therapies targeting S1P signaling in various pancreatic diseases.

The exocrine pancreas is the main source of digestive enzymes which are released from secretory vesicles of acinar cells into the small intestine. Enzymes, including amylases, proteases and lipases, degrade the ingested food and thus determine the nutritional substrate for the gut microbiota. Acute (AP) and chronic pancreatitis (CP) are associated with a transitional or progressive exocrine pancreatic dysfunction, we analysed in the present study how an experimental induction of pancreatitis in mouse models affects the colonic and duodenal microbiome composition. Evaluation by 16 S rRNA gene sequencing revealed specific microbiome changes in colonic as well as in duodenal samples in different models of AP and CP. Mild acute pancreatitis, which is associated with a transient impairment of pancreatic secretion showed only minor changes in microbial composition, comparable to the ones seen in progressive dysfunctional mouse models of CP. The strongest changes were observed in a mouse model of severe AP, which suggest a direct effect of the immune response on gut microbiome in addition to a pancreatic dysfunction. Our data indicate that highly dysbiotic microbiome changes during pancreatitis are more associated with the inflammatory reaction than with a disturbed pancreatic secretion., (© 2024. The Author(s).)

Objective: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy because it is often diagnosed at a late-stage. Signal transducer and activator of transcription 5 (STAT5) is a transcription factor implicated in the progression of various cancer types. However, its role in KRAS-driven pancreatic tumourigenesis remains unclear., Design: We performed studies with LSL-Kras G12D ; Ptf1a-Cre ERT (KC ERT ) mice or LSL-Kras G12D ; LSL-Trp53 R172H ; Pdx1-Cre (KPC) mice crossed with conditional disruption of STAT5 or completed deficiency interleukin (IL)-22. Pancreatitis was induced in mice by administration of cerulein. Pharmacological inhibition of STAT5 on PDAC prevention was studied in the orthotopic transplantation and patient-derived xenografts PDAC model, and KPC mice., Results: The expression and phosphorylation of STAT5 were higher in human PDAC samples than control samples and high levels of STAT5 in tumour cells were associated with a poorer prognosis. The loss of STAT5 in pancreatic cells substantially reduces the KRAS mutation and pancreatitis-derived acinar-to-ductal metaplasia (ADM) and PDAC lesions. Mechanistically, we discovered that STAT5 binds directly to the promoters of ADM mediators, hepatocyte nuclear factor (HNF) 1β and HNF4α. Furthermore, STAT5 plays a crucial role in maintaining energy metabolism in tumour cells during PDAC progression. IL-22 signalling induced by chronic inflammation enhances KRAS-mutant-mediated STAT5 phosphorylation. Deficiency of IL-22 signalling slowed the progression of PDAC and ablated STAT5 activation., Conclusion: Collectively, our findings identified pancreatic STAT5 activation as a key downstream effector of oncogenic KRAS signalling that is critical for ADM initiation and PDAC progression, highlighting its potential therapeutic vulnerability., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate the correlation between the serum levels of ischaemia-modified albumin (IMA) and disease severity in rats with acute pancreatitis (AP)., Methods: A rat AP model was established and blood samples from each group were analysed at different time points. After the experiment, the pancreatic tissues of the rats were collected for pathological examination and the measurement of protein levels of NF-κB and NF-κB p65. Serum levels of amylase (α-AMY), tumour necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-8 were also compared between groups of rats., Results: The serum IMA concentration in the severe acute pancreatitis (SAP) group was greater than that in the mild acute pancreatitis (MAP) group. The levels of the NF-κB and NF-κB p65 proteins were increased in the MAP and SAP groups in a time-dependent manner. α-AMY, TNF-α and IL-6 were increased at all time points in the MAP and SAP groups. The increases were greatest at 24 h in the SAP group. In terms of pathological changes in the pancreas, renal and lung tissues, the damage in the SAP group was more obvious than that in the MAP group., Conclusions: Serum IMA level was associated with inflammatory markers and NF-κB p65 in rats with AP., Competing Interests: Declaration of conflicting interestThe authors declare that there are no conflicts of interest.

Severe acute pancreatitis (SAP) is an inflammatory disease with varying severity, ranging from mild local inflammation to severe systemic disease, with a high incidence rate and mortality. Current drug treatments are not ideal. Therefore, safer and more effective therapeutic drugs are urgently needed. 7α,14β-dihydroxy-ent-kaur-17-dimethylamino-3,15-dione DGA, a diterpenoid compound derivatized from glaucocalyxin A, exhibits anti-inflammatory activity. In this study, we demonstrated the therapeutic potential of DGA against SAP and elucidated the underlying mechanisms. Treatment with DGA markedly (1) inhibited death of RAW264.7 and J774a.1 cells induced by Nigericin and lipopolysaccharide, (2) alleviated edema, acinar cell vacuolation, necrosis, and inflammatory cell infiltration of pancreatic tissue in mice, and (3) inhibited the activity of serum lipase and the secretion of inflammatory factor IL-1β. DGA significantly reduced the protein expression of IL-1β and NLRP3 and inhibited the phosphorylation of NF-κB. However, DGA exhibited no inhibitory effect on the expression of caspase-1, gasdermin D (GSDMD), NF-κB, TNF-α, or apoptosis-associated speck-like protein (ASC) and on the cleavage of caspase-1 or GSDMD. Molecular docking simulation confirmed that DGA can bind to TLR4 and IL-1 receptor. In conclusion, DGA may effectively alleviate the symptoms of SAP in mice and macrophages by inhibiting the binding of TLR4 and IL-1 receptor to their ligands; therefore, DGA is a promising drug candidate for the treatment of patients with SAP., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background and Purpose: Acute pancreatitis (AP) is associated with acinar cell death and inflammatory responses. Ferroptosis is characterized by an overwhelming lipid peroxidation downstream of metabolic dysfunction, in which NADPH-related redox systems have been recognized as the mainstay in ferroptosis control. Nevertheless, it remains unknown how ferroptosis is regulated in AP and whether we can target it to restrict AP development., Experimental Approach: Metabolomics were applied to explore changes in metabolic pathways in pancreatic acinar cells (PACs) in AP. Using wild-type and Ptf1a CreERT2/+ IDH2 fl/fl mice, AP was induced by caerulein and sodium taurocholate (NaT). IDH2 overexpressing adenovirus was constructed for infection of PACs. Mice or PACs were pretreated with inhibitors of FSP1 or glutathione reductase. Pancreatitis severity, acinar cell injury, mitochondrial morphological changes and pancreatic lipid peroxidation were analysed., Key Results: Unsaturated fatty acid biosynthesis and the tricarboxylic acid cycle pathways were significantly altered in PACs during AP. Inhibition of ferroptosis reduced mitochondrial damage, lipid peroxidation and the severity of AP. During AP, the NADPH abundance and IDH2 expression were decreased. Acinar cell-specific deletion of IDH2 exacerbated acinar cell ferroptosis and pancreatic injury. Pharmacological inhibition of NADPH-dependent GSH/GPX4 and FSP1/CoQ 10 pathways abolished the protective effect of IDH2 overexpression on ferroptosis in acinar cells. CoQ 10 supplementation attenuated experimental pancreatitis via inhibiting acinar cell ferroptosis., Conclusion and Implications: We identified the IDH2-NADPH pathway as a novel regulator in protecting against AP via restricting acinar cell ferroptosis. Targeting the pathway and its downstream may shed light on AP treatment., (© 2024 British Pharmacological Society.)

The pancreas is a glandular organ with both endocrine and exocrine functions. Researchers have investigated the roles of several Rab proteins, which are major regulators of membrane trafficking, in pancreatic exocytosis of zymogen granules in exocrine cells, also known as acinar cells. However, detailed molecular mechanisms mediated by Rab proteins are not fully understood. RASEF/Rab45 is an atypical Rab GTPase that contains N-terminal EF-hand and coiled-coil domains, as well as a C-terminal Rab-GTPase domain. In this study, we investigated the in vivo role of RASEF in pancreatic acinar cells using RASEF-knockout (KO) mice. Morphological analyses revealed that pancreatic acinar cells in RASEF-KO mice had an increased number of zymogen granules and abnormal formations of organelles, such as the endoplasmic reticulum (ER) and lysosomes. Biochemical analyses showed that ER proteins were decreased, but digestive enzymes were increased in the RASEF-KO pancreas. Moreover, trypsinogen was activated and co-localized with the endo-lysosomal marker LAMP1 in RASEF-KO pancreas. Upon cerulein administration to induce acute pancreatitis, impaired enzyme release from the pancreas was observed in the serum of RASEF-KO mice. These findings suggest that RASEF likely regulates the formation and sorting of zymogen granules and secretion of digestive enzymes by pancreatic acinar cells., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Tomoko Kadowaki reports financial support was provided by Japan Society for the Promotion of Science. Keiko Sato reports financial support was provided by Japan Society for the Promotion of Science. Takayuki Tsukuba reports financial support was provided by Japan Society for the Promotion of Science. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Severe acute pancreatitis-acute lung injury (SAP-ALI) is a disease with high mortality. This study aims to explore the mechanism of baicalein on SAP-ALI in rats by blocking toll-like receptor-4 (TLR4)/myeloid differentiation primary response gene 88 (MyD88)/TIR-domain-containing adapter-inducing interferon-β (TRIF) signal pathway. The SAP-ALI rat model was established by intraperitoneal injection of 3% pentobarbital sodium (30 mg/kg), with pancreas and intestines turned over, injected with 3.5% sodium taurocholate backward into the bile-pancreatic duct at 0.1 mL/100 g for 12h, and treated with baicalein, lipopolysaccharide (LPS), miR-182 agomir, or miR-182 antagomir. The TLR4/MyD88/TRIF pathway was activated using LPS in SAP-ALI rats after baicalein treatment. Baicalein attenuated inflammatory cell infiltration, alveolar wall edema, decreased W/D ratio and levels of TLR4, MyD88, and TRIF in the lung tissues, reduced levels of inflammatory factors in pancreatic and lung tissues and BALF, diminished ROS, and elevated GSH, SOD and CAT in pancreatic and lung tissues of SAP-ALI rats. Activation of the TLR4/MyD88/TRIF pathway partly abrogated baicalein-mediated improvements in inflammation and oxidative stress in SAP-ALI rats. miR-182 targeted TLR4. miR-182 suppressed inflammation and oxidative stress in SAP-ALI rats by targeting TLR4. Inhibition of miR-182 partly nullified baicalein-mediated attenuation on inflammation and oxidative stress in SAP-ALI rats. In conclusion, baicalein can inhibit the TLR4/MyD88/TRIF pathway and alleviate inflammatory response and oxidative stress in SAP-ALI rats by upregulating miR-182 and suppressing TLR4, thus ameliorating SAP-ALI., (©The Author(s) 2024. Open Access. This article is licensed under a Creative Commons CC-BY International License.)

The current research was designed to investigate the impact of whole-process high-quality nursing on acute pancreatitis (AP) patients' quality of life as well as the mechanism of miR-126-5p/HOXC8 axis promoting AP progression. One hundred AP patients admitted to our hospital were chosen and separated into control group (CG, n=50) and study group (SG, n=50). The CG took the routine nursing, while the SG adopted the whole-process high-quality nursing. Besides, cerulein (CE) was treated in AR42J cells to establish an experimental model of AP. The proliferation, apoptosis along with inflammation of CE-treated AR42J cells were assessed. The outcomes manifested that in contrast to the CG, the recovery time of bowel sound, the improvement time of abdominal distension, the improvement time of abdominal pain, the exhaust time and the defecation time in the SG presented shorter, the anxiety and depression scores in the SG presented lower, the WHOQOL-100 scores of patients in the SG presented higher in the fields of physiology, psychology, environment and social relations, the total incidence of complications of the SG presented lower, and the total nursing satisfaction of the SG was better. Besides, miR-126-5p presented upregulation in CE-stimulated AR42J cells, and miR-126-5p inhibition increased the proliferation along with repressed the apoptosis and inflammation in CE-stimulated AR42J cells. Moreover, HOXC8 could be the target mRNA of miR-126-5p, and HOXC8 elevation promoted the proliferation along with repressed the apoptosis and inflammation in CE-stimulated AR42J cells. In addition, rescue assays further validated that HOXC8 silence offset the protective impact of miR-126-5p repression on AP cell damage. In conclusion, our study indicated that whole-process high-quality nursing could promote the quality of life of AP patients, and revealed that miR-126-5p inhibition relieved CE-stimulated AR42J cells injury caused by AP via targeting HOXC8. Our study might offer novel insights for AP treatment and nursing.

Acute pancreatitis (AP) is a multifaceted inflammatory disorder stemming from the aberrant activation of trypsin within the pancreas. Despite the contribution of various factors to the pathogenesis of AP, such as trypsin activation, dysregulated increases in cytosolic Ca 2+ levels, inflammatory cascade activation, and mitochondrial dysfunction, the precise molecular mechanisms underlying the disease are still not fully understood. Mitophagy, a cellular process that preserves mitochondrial homeostasis under stress, has emerged as a pivotal player in the context of AP. Research suggests that augmenting mitophagy can mitigate pancreatic injury by clearing away malfunctioning mitochondria. Elucidating the role of mitophagy in AP may pave the way for novel therapeutic strategies. This review article aims to synthesize the current research findings on mitophagy in AP and underscore its significance in the clinical management of the disorder., (© 2024. The Author(s).)

Acute pancreatitis (AP) is a common gastrointestinal disease with high morbidity and mortality rate. Unfortunately, neither the etiology nor the pathophysiology of AP are fully understood and causal treatment options are not available. Recently we demonstrated that heparanase (Hpa) is adversely involved in the pathogenesis of AP and inhibition of this enzyme ameliorates the manifestation of the disease. Moreover, a pioneer study demonstrated that Aspirin has partial inhibitory effect on Hpa. Another compound, which possesses a mild pancreato-protective effect against AP, is Trehalose, a common disaccharide. We hypothesized that combination of Aspirin, Trehalose, PG545 (Pixatimod) and SST0001 (Roneparstat), specific inhibitors of Hpa, may exert pancreato-protective effect better than each drug alone. Thus, the current study examines the pancreato-protective effects of Aspirin, Trehalose, PG545 and SST0001 in experimental model of AP induced by cerulein in wild-type (WT) and Hpa over-expressing (Hpa-Tg) mice. Cerulein-induced AP in WT mice was associated with significant rises in the serum levels of lipase (X4) and amylase (X3) with enhancement of pancreatic edema index, inflammatory response, and autophagy. Responses to cerulein were all more profound in Hpa-Tg mice versus WT mice, evident by X7 and X5 folds increase in lipase and amylase levels, respectively. Treatment with Aspirin or Trehalose alone and even more so in combination with PG545 or SST0001 were highly effective, restoring the serum level of lipase back to the basal level. Importantly, a novel newly synthesized compound termed Aspirlose effectively ameliorated the pathogenesis of AP as a single agent. Collectively, the results strongly indicate that targeting Hpa by using anti-Hpa drug combinations constitute a novel therapy for this common orphan disease., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

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., Competing Interests: Declaration of competing interest All authors have no conflicts of interests relevant to this article to disclose., (Copyright © 2024 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Objectives: This study aimed to evaluate the therapeutic effects of forsythoside A (FA) on brain injury induced by severe acute pancreatitis (SAP) using a murine model., Methods: Mice were induced with 3.5 % sodium taurocholate to model SAP-induced brain injury (SAP-IBI) and were randomly assigned to four distinct treatment regimens: the SAP-IBI model group (SAP-IBI), low-dose FA treatment group (FA L+SI), middle-dose FA treatment group (FA M+SI), and high-dose FA treatment group (FA H+SI). A sham-operation group (SO) served as a negative control. Serum levels of interleukin-1β (IL-1β) and IL-18 were quantified via ELISA, and serum amylase levels were assessed using optical turbidimetry. mRNA expression levels of AIM2, ASC, Caspase-1, and GAPDH in hippocampal brain tissue were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Protein levels of NLRP3, GSDMD, IL-1β, and IL-18 in hippocampal brain tissue were evaluated using Western blotting. Neurological function in surviving mice was assessed through modified neurological severity scores (mNSS). Transmission electron microscopy (TEM) provided ultrastructural analysis of the hippocampus. Additionally, water content and pathological changes in hippocampal brain tissue were examined 24 hours post-operation, along with other relevant indicators., Results: At 24 hours post-operation, the FA H+SI group exhibited significantly reduced levels of serum amylase, IL-1β, and IL-18, along with decreased expression of AIM2, ASC, and Caspase-1 mRNA. Furthermore, NLRP3 protein levels, water content, pancreas and hippocampal brain pathological scores, and mNSS were significantly lower compared to the SAP-IBI group (P<0.01)., Conclusions: FA demonstrates protective effects against SAP-IBI in mice, suggesting potential therapeutic benefits., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The serine protease chymotrypsin protects the pancreas against pancreatitis by degrading trypsinogen, the precursor to the digestive protease trypsin. Taking advantage of previously generated mouse models with either the Ctrb1 gene (encoding chymotrypsin B1) or the Ctrl gene (encoding chymotrypsin-like protease) disrupted, here we generated the novel Ctrb1-del × Ctrl-KO strain in the C57BL/6N genetic background, which harbors a naturally inactivated Ctrc gene (encoding chymotrypsin C). The newly created mice are devoid of chymotrypsin, yet the animals develop normally, breed well, and show no spontaneous phenotype, indicating that chymotrypsin is dispensable under laboratory conditions. When given cerulein, the Ctrb1-del × Ctrl-KO strain exhibited markedly increased intrapancreatic trypsin activation and more severe acute pancreatitis, relative to wild-type C57BL/6N mice. After the acute episode, Ctrb1-del × Ctrl-KO mice spontaneously progressed to chronic pancreatitis, whereas C57BL/6N mice recovered rapidly. The cerulein-induced pancreas pathology in Ctrb1-del × Ctrl-KO mice was highly similar to that previously observed in Ctrb1-del mice; however, trypsin activation was more robust and pancreatitis severity was increased. Taken together, the results confirm and extend prior observations demonstrating that chymotrypsin safeguards the pancreas against pancreatitis by limiting pathologic trypsin activity. In mice, the CTRB1 isoform, which constitutes about 90% of the total chymotrypsin content, is responsible primarily for the anti-trypsin defenses and protection against pancreatitis; however, the minor isoform CTRL also contributes to an appreciable extent. NEW & NOTEWORTHY Chymotrypsins defend the pancreas against the inflammatory disorder pancreatitis by degrading harmful trypsinogen. This study demonstrates that mice devoid of pancreatic chymotrypsins are phenotypically normal but become sensitized to secretagogue hyperstimulation and exhibit increased intrapancreatic trypsin activation, more severe acute pancreatitis, and rapid progression to chronic pancreatitis. The observations confirm and extend the essential role of chymotrypsins in pancreas health.

Objectives: Necroptosis, a programmed inflammatory cell death, is involved in the pathogenesis of acute pancreatitis (AP). We compared levels of interleukin (IL)-33 (released upon necroptosis), sST2 (soluble IL-33 receptor), MLKL, RIPK1 and RIPK3 (necroptosis executioner proteins), and proinflammatory cytokines IL-6, TNF and IL-1β at various severity categories and stages of AP., Methods: Plasma from 20 patients with early mild AP (MAP) (symptom onset < 72 h), 7 with severe AP (SAP) without and 4 with persistent organ failure (OF) at sampling, 8 patients with late SAP and 20 healthy controls (HC) were studied by ELISAs., Results: Early sST2 and IL-6 levels predicted the development of SAP and were higher in both MAP and early and late SAP than in HC. RIPK3 levels were higher than in HC in the patients who had or would later have SAP. MLKL levels were associated with the presence of OFs, particularly in the late phase, but were also higher in MAP than in HC., Conclusions: sST2, RIPK3 and IL-6 levels may have prognostic value in AP. Elevated MLKL levels are associated with OF in AP. Better understanding of necroptosis in AP pathophysiology is needed to evaluate whether inhibiting and targeting necroptosis is a potential therapeutic option in AP., (© 2024. The Author(s).)

Acute pancreatitis, an acute inflammatory injury of the pancreas, lacks a specific treatment. The circulatory protein renalase is produced by the kidney and other tissues and has potent anti-inflammatory and prosurvival properties. Recombinant renalase can reduce the severity of mild cerulein pancreatitis; the activity is contained in a conserved 20 aa renalase site (RP220). Here, we investigated the therapeutic effects of renalase on pancreatitis using two clinically relevant models of acute pancreatitis. The ability of peptides containing the RP220 site to reduce injury in a 1-day post-endoscopic retrograde cholangiopancreatography (ERCP) and a 2-day severe cerulein induced in mice was examined. The initial dose of renalase peptides was given either prophylactically (before) or therapeutically (after) the initiation of the disease. Samples were collected to determine early pancreatitis responses (tissue edema, plasma amylase, active zymogens) and later histologic tissue injury and inflammatory changes. In both preclinical models, renalase peptides significantly reduced histologic damage associated with pancreatitis, especially inflammation, necrosis, and overall injury. Quantifying inflammation using specific immunohistochemical markers demonstrated that renalase peptides significantly reduced overall bone marrow-derived inflammation and neutrophils and macrophage populations in both models. In the severe cerulein model, administering a renalase peptide with or without pretreatment significantly reduced injury. Pancreatitis and renalase peptide effects appeared to be the same in female and male mice. These studies suggest renalase peptides that retain the anti-inflammatory and prosurvival properties of recombinant renalase can reduce the severity of acute pancreatitis and might be attractive candidates for therapeutic development. NEW & NOTEWORTHY Renalase is a secretory protein. The prosurvival and anti-inflammatory effects of the whole molecule are contained in a 20 aa renalase site (RP220). Systemic treatment with peptides containing this renalase site reduced the severity of post-endoscopic retrograde cholangiopancreatography (ERCP) and severe cerulein pancreatitis in mouse models.

Objectives: Acute pancreatitis (AP) has a high incidence of hospitalizations, morbidity, and mortality worldwide. A growing number of studies on AP pathogenesis are based on cerulein-induced experimental model, which simulates human AP in vivo. It has been demonstrated that both pancreatic acinar cells and peritoneal macrophages are involved in pancreatic inflammation and damage. However, their connection has not been well understood., Methods: A cerulein-induced AP model was established on the pancreatic acinar cell line AR42J. Rat macrophages were isolated from the peritoneal cavity. The effects of cerulein-induced pancreatic exosomes on the peritoneal macrophage and pancreas in vivo and in vitro were examined. The underlying molecular mechanism was investigated by exploring the regulatory role of downstream molecules., Results: We found that exosomes derived from cerulein-treated AR42J cells induced rat peritoneal macrophage M1 polarization and pyroptosis. miR-24-3p was upregulated in cerulein-stimulated exosomes, whereas the miR-24-3p inhibitor counteracted the effect of pancreatic exosomes on peritoneal macrophage M1 polarization and pyroptosis. Furthermore, miR-24-3p inhibited March3 expression, whereas MARCH3 mediated NLRP3 ubiquitination in rat peritoneal macrophages, which, in turn, contributed to the apoptosis, reactive oxygen species production, and inflammation in AR42J cells., Conclusions: Exosomes derived from cerulein-stimulated pancreatic acinar cells mediate peritoneal macrophage M1 polarization and pyroptosis via an miR-24-3p/MARCH3/NLRP3 axis in AP., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background & Aims: Acinar-to-ductal metaplasia (ADM) is crucial in the development of pancreatic ductal adenocarcinoma. However, our understanding of the induction and resolution of ADM remains limited. We conducted comparative transcriptome analyses to identify conserved mechanisms of ADM in mouse and human., Methods: We identified Sox4 among the top up-regulated genes. We validated the analysis by RNA in situ hybridization. We performed experiments in mice with acinar-specific deletion of Sox4 (Ptf1a: CreER; Rosa26 -LSL-YFPLSL-YFP ; Sox4 fl/fl ) with and without an activating mutation in Kras (Kras LSL-G12D/+ ). Mice were given caerulein to induce pancreatitis. We performed phenotypic analysis by immunohistochemistry, tissue decellularization, and single-cell RNA sequencing., Results: We demonstrated that Sox4 is reactivated in ADM and pancreatic intraepithelial neoplasias. Contrary to findings in other tissues, Sox4 actually counteracts cellular dedifferentiation and helps maintain tissue homeostasis. Moreover, our investigations unveiled the indispensable role of Sox4 in the specification of mucin-producing cells and tuft-like cells from acinar cells. We identified Sox4-dependent non-cell-autonomous mechanisms regulating the stromal reaction during disease progression. Notably, Sox4-inferred targets are activated upon KRAS inactivation and tumor regression., Conclusions: Our results indicate that our transcriptome analysis can be used to investigate conserved mechanisms of tissue injury. We demonstrate that Sox4 restrains acinar dedifferentiation and is necessary for the specification of acinar-derived metaplastic cells in pancreatic injury and cancer initiation and is activated upon Kras ablation and tumor regression in mice. By uncovering novel potential strategies to promote tissue homeostasis, our findings offer new avenues for preventing the development of pancreatic ductal adenocarcinoma., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Acute pancreatitis (AP) is an inflammatory disorder that occurs in the exocrine pancreas associated with tissue injury and necrosis. Experimental models of AP typically involve rodents, such as rats or mice. However, rodents exhibit divergent pathophysiological responses after the establishment of AP between themselves and in comparison, with human. The experiments conducted for this manuscript aimed to standardize a new AP model in zebrafish and validate it. Here, we provide a protocol for inducing AP in zebrafish through intraperitoneal injections of synthetic caerulein. Details are provided for solution preparation, pre-injection procedures, injection technique, and monitoring animal survival. Subsequently, validation was performed through biochemical and histological analyses of pancreatic tissue. The administered dose of caerulein for AP induction was 10 μg/kg applied four times in the intraperitoneal region. The histological validation study demonstrated the presence of necrosis within the first 12 h post-injection, accompanied by an excess of zymogen granules in the extracellular milieu. These observations align with those reported in conventional rodent models. We have standardized and validated the AP model in zebrafish. This model can contribute to preclinical and clinical studies of new drugs for AP treatment. Therefore, this novel model expands the toolkit for exploring faster and more effective preventive and therapeutic strategies for AP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Severe acute pancreatitis (SAP) is a prevalent acute inflammatory disease that is clinically manifested by systemic inflammation dysregulation, resulting in a significantly elevated mortality rate. Bufalin has been verified to have potent pharmacological properties, including analgesic, anti-tumor and anti-inflammatory effects. However, it remains unclear whether bufalin inhibits SAP. Thus, we aim to explore the impact of bufalin in SAP rats and to evaluate the potential mechanisms of action. In addition to analyzing serum biochemistry and pancreatic tissue pathology, we elucidated its mechanisms of action through enzyme-linked immunosorbent assay (ELISA), immunohistochemical analysis, Western blot, and quantitative real-time PCR. The results demonstrated that bufalin dose-dependently reversed the elevation of serum Amylase (Amy) and Lipase (LPS) levels in SAP rats, alleviating pancreatic tissue pathological damage. Bufalin exhibited potent antioxidant effects by reducing malondialdehyde (MDA) levels, decreasing Superoxide dismutase (SOD) and glutathione(GSH) consumption, inhibiting the interaction of Keap1-Nrf2, and increasing HO-1 expression. Furthermore, bufalin inhibited TNF-α, IL-6, IL-1β, p-NF-κB-p65, p-IκBα, and NF-κB-p65 expression, while enhancing IκBα expression, ultimately confirming its anti-inflammatory effects on SAP. In summary, our findings suggest that bufalin exerts anti-inflammatory and antioxidant actions in NaT-SAP rats by inhibiting NF-κB and activating the Keap1-Nrf2/HO-1 pathway. This study represents the inaugural application of bufalin in NaT-induced SAP rats, indicating its potential as an effective therapeutic agent for SAP patients., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Severe acute pancreatitis (SAP) is a common digestive system disorder in clinical practice, and it is often associated with liver damage in patients with severe acute pancreatitis. Several studies have indicated that pyroptosis plays a role in liver damage following severe acute pancreatitis (SAP). However, the precise mechanisms remain unclear. This study aims to elucidate the association and specific mechanisms between liver injury following SAP and pyroptosis, providing theoretical support for research on SAP-induced liver injury., Methods: A rat model of SAP with concomitant liver injury was successfully established. The expression levels of miR-103-3p across different liver tissue groups were quantified using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Bioinformatic analyses and dual-luciferase reporter assays confirmed that NLRP1 is a direct target of miR-103-3p. In vivo assessments of miR-103-3p levels were performed, and the extent of cell pyroptosis during liver injury post-SAP was evaluated through western blotting, qRT-PCR, scanning electron microscopy, histopathology, immunofluorescence, and immunohistochemistry. The role of miR-103-3p in regulating NLRP1-mediated pyroptosis and its impact on SAP-induced liver injury were validated., Results: This study reports that following SAP-induced liver injury, the expression of miR-103-3p in liver tissue was significantly decreased, and cell pyroptosis was involved in the process of liver injury. Experimental validation indicated that NLRP1 was a downstream target of miR-103-3p. Overexpression of miR-103-3p in vitro significantly alleviated the severity of liver injury following SAP, while simultaneously inhibiting cell pyroptosis., Conclusion: These findings indicate that pyroptosis may be linked to SAP-induced liver injury and that miR-103-3p mitigates hepatocyte pyroptosis by reducing liver injury through the suppression of NLRP1 expression., Competing Interests: Conflicts of Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Acute pancreatitis (AP) is a lethal inflammatory disease of the pancreas. Its pathogenesis remains obscure and specific treatments are lacking. An increase in Interleukin-10 (IL-10) in the early stage of AP patients is closely related to AP severity. In Coxsackievirus B3 (CVB3) induced murine AP model, we found early IL-10 increased viral replication and pancreatic inflammation, yet the cellular source of IL-10 and the immunomodulatory role of neutrophils during viral infection remains unknown. Here we show that CVB3 infection enhanced neutrophil infiltration and IL-10 expression in the pancreas at day3 post infection (p.i.). Neutrophils served as an important early source of pancreatic IL-10 at the initiation of infection. Day3 pancreas extracts (D3P) also induced bone-marrow derived neutrophils (BMneu) to secrete IL-10. Adoptive transfer of D3P-pretreated BMneu into IL-10 KO mice increased viral replication and pancreas histopathology, which effect was blunted by the absence of IL-10 in BMneu. Mechanically, IL-10 + neutrophil increased IL-10R1 expression on MΦs and activated STAT3-IL-6/IL-10 signaling cascade while decreased IL-12 and MHC II expression in MΦs, thus impairing IFN-γ + Granzyme B + CD8 + T cell activation and viral clearance. Adoptive transferring infected mice with activated CD8 + T cells 4 days p.i. attenuated viral load and AP pathology indicating an AP-protective effect. Our findings document a novel immunoregulatory function of neutrophils in acute CVB3 infection, in which neutrophil-derived IL-10 impairs anti-viral CD8 + T activation, and amplifies intrapancreatic inflammation via activating MΦ STAT3-IL-6 signaling cascade. An IL-10-targeting option is suggested for the future treatment of viral AP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Abstract: A 54-year-old man presented with left lower quadrant pain. CT showed no cause for his pain but identified an incidental 2.0-cm enhancing lesion in the pancreatic tail. On MRI, this lesion was hyperenhancing and diffusion-restricting, suspicious for a neuroendocrine tumor. However, EUS-guided biopsy yielded only benign pancreatic tissue. Due to this discordance, 64 Cu-DOTATATE PET/CT was performed. The pancreatic tail lesion was tracer-avid, suggesting a well-differentiated neuroendocrine tumor. Based on the PET findings, the patient underwent distal pancreatectomy. Surgical pathology revealed only focal chronic pancreatitis with islet aggregation, a previously undescribed mimic of neuroendocrine tumor on DOTATATE PET/CT., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Acute pancreatitis (AP) is a sudden-onset disease of the digestive system caused by abnormal activation of pancreatic enzymes. Dual oxidase 2 (DUOX2) has been found to be elevated in the progression of a variety of inflammatory diseases. Therefore, we analyzed the specific roles of DUOX2 in AP development. Blood samples were collected from of AP patients and healthy people, and the caerulein- stimulated human pancreatic duct cells (H6C7) were utilized to establish an AP cell model. Cell growth and apoptosis were measured using an MTT assay and TUNEL staining. Additionally, RT-qPCR and western blot assays were conducted to assess the RNA and protein expressions of the cells. ELISA kits were used to determine TNF-α, IL-6, IL-8, and IL-1β levels. The interaction between DUOX2 and miR-605-3p was predicted using the Targetscan database and confirmed by dual-luciferase report assay. We found that DUOX2 increased while miR-605-3p decreased in the blood of AP patients and caerulein-stimulated H6C7 cells. DUOX2 was targeted by miR-605-3p. Furthermore, DUOX2 knockdown or miR-605-3p overexpression promoted cell viability, decreased the TNF-α, IL-6, IL-8, and IL-1β levels, and inhibited apoptosis rate in caerulein-stimulated H6C7 cells. DUOX2 knockdown or miR-605-3p overexpression also increased the Bcl-2 protein levels and down-regulated Bax, cleaved-caspase-1, NLRP3 and p-p65. Interestingly, DUOX2 overexpression reversed the miR-605-3p mimic function in the caerulein-treated H6C7 cells. In conclusion, our research demonstrated that DUOX2 knockdown relieved the injury and inflammation in caerulein-stimulated H6C7 cells., Competing Interests: The authors declare there are no competing interests., (©2024 Zhang et al.)

Intestinal dysfunction plays a pivotal role in the development of acute pancreatitis (AP), however, the underlying mechanisms of intestinal dysfunction on severity of hyperlipidemic acute pancreatitis (HLAP) are still unclear. Herein, we explored the role of intestinal function on the severity of HLAP. We found that HLAP patients exhibit higher lipid and inflammatory response than AP patients. Hyperlipidemia significantly elevates serum lipids and worsen pancreatic damage in AP mice. In addition, significant exacerbated intestinal barrier damage and inflammation were observed in experimental HLAP mice, as evidenced by increased serum amylase and lipase levels, and pancreatic edema. Further, RNA-Seq showed that a markedly decrease of glutathione S-transferase pi (GSTpi) in colonic tissue of HLAP mice compared with AP mice, accompanied with increased serum lipopolysaccharides level. However, colonic GSTpi overexpression by adeno-associated virus significantly attenuated intestinal damage and subsequent pancreatic inflammation in HLAP mice. Mechanistically, GSTpi mitigated HLAP-mediated colonic NLRP3 inflammasome activation and barrier dysfunction. These results suggest that intestinal GSTpi deficiency exacerbates the severity of experimental HLAP, providing new insights for the clinical treatment of HLAP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Acute pancreatitis (AP) is an inflammatory disease of the pancreas and the main cause of hospital admissions for gastrointestinal diseases. Here, the work studied the circular RNA DTNB/microRNA-485-5p/MCL1 axis in AP and hoped to unravel the related mechanism. Caerulein exposure replicated an AP model in AR42J cells, and caerulein-mediated expression of circDTNB, miR-485-5p, and MCL1 was recorded. After exposure, cells were intervened with transfection plasmids and tested for LDH release, apoptosis, and inflammation. To determine the interwork of circDTNB, miR-485-5p, and MCL1, prediction results and verification experiments were conducted. Caerulein exposure reduced circDTNB and MCL1, while elevated miR-485-5p levels in AR42J cells. Upregulating circDTNB protected AR42J cells from caerulein-induced LDH cytotoxicity, apoptosis, and inflammation, but circDTNB upregulation-induced protections could be muffled by inhibiting MCL1. On the contrary, downregulating circDTNB further damaged AR42J cells under caerulein exposure, however, this phenomenon could be partially rescued after silencing miR-485-5p. miR-485-5p was mechanistically verified to be a target of circDTNB to mediate MCL1. Overall, the circDTNB/miR-485-5p/MCL1 axis protects inflammatory response and apoptosis in caerulein-exposed AR42J cells, promisingly identifying circDTNB as a novel molecule for AP treatment., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Acute pancreatitis (AP) is an inflammatory disease initiated by the death of exocrine acinar cells, but its pathogenesis remains unclear. Signal transducer and activator of transcription 3 (STAT3) is a multifunctional factor that regulates immunity and the inflammatory response. The protective role of STAT3 is reported in Coxsackievirus B3 (CVB3)-induced cardiac fibrosis, yet the exact role of STAT3 in modulating viral-induced STAT1 activation and type I interferon (IFN)-stimulated gene (ISG) transcription in the pancreas remains unclarified. In this study, we tested whether STAT3 regulated viral-induced STAT1 translocation. We found that CVB3, particularly capsid VP1 protein, markedly upregulated the phosphorylation and nuclear import of STAT3 (p-STAT3) while it significantly impeded the nuclear translocation of p-STAT1 in the pancreases and hearts of mice on day 3 postinfection (p.i.). Immunoblotting and an immunofluorescent assay demonstrated the increased expression and nuclear translocation of p-STAT3 but a blunted p-STAT1 nuclear translocation in CVB3-infected acinar 266-6 cells. STAT3 shRNA knockdown or STAT3 inhibitors reduced viral replication via the rescue of STAT1 nuclear translocation and increasing the ISRE activity and ISG transcription in vitro. The knockdown of STAT1 blocked the antiviral effect of the STAT3 inhibitor. STAT3 inhibits STAT1 activation by virally inducing a potent inhibitor of IFN signaling, the suppressor of cytokine signaling-3 ((SOCS)-3). Sustained pSTAT1 and the elevated expression of ISGs were induced in SOCS3 knockdown cells. The in vivo administration of HJC0152, a pharmaceutical STAT3 inhibitor, mitigated the viral-induced AP and myocarditis pathology via increasing the IFNβ as well as ISG expression on day 3 p.i. and reducing the viral load in multi-organs. These findings define STAT3 as a negative regulator of the type I IFN response via impeding the nuclear STAT1 translocation that otherwise triggers ISG induction in infected pancreases and hearts. Our findings identify STAT3 as an antagonizing factor of the IFN-STAT1 signaling pathway and provide a potential therapeutic target for viral-induced AP and myocarditis.

Acute pancreatitis, a common exocrine inflammatory disease affecting the pancreas, is characterized by intense abdominal pain and multiple organ dysfunction. However, the alterations in retinal blood vessels among individuals with acute pancreatitis remain poorly understood. This study employed optical coherence tomography angiography (OCTA) to examine the superficial and deep retinal blood vessels in patients with pancreatitis. Sixteen patients diagnosed with pancreatitis (32 eyes) and 16 healthy controls (32 eyes) were recruited from the First Affiliated Hospital of Nanchang University for participation in the study. Various ophthalmic parameters, such as visual acuity, intraocular pressure, and OCTA image for retina consisting of the superficial retinal layer (SRL) and the deep retinal layer (DRL), were recorded for each eye. The study observed the superficial and deep retinal microvascular ring (MIR), macrovascular ring (MAR), and total microvessels (TMI) were observed. Changes in retinal vascular density in the macula through annular partitioning (C1-C6), hemispheric quadrant partitioning (SR, SL, IL, and IR), and early diabetic retinopathy treatment studies (ETDRS) partitioning methods (R, S, L, and I). Correlation analysis was employed to investigate the relationship between retinal capillary density and clinical indicators. Our study revealed that in the superficial retinal layer, the vascular density of TMI, MIR, MAR, SR, IR, S, C2, C3 regions were significantly decreased in patients group compared with the normal group. For the deep retinal layer, the vascular density of MIR, SR, S, C1, C2 regions also reduced in patient group. The ROC analysis demonstrated that OCTA possesses significant diagnostic performance for pancreatitis. In conclusion, patients with pancreatitis may have retinal microvascular dysfunction, and OCTA can be a valuable tool for detecting alterations in ocular microcirculation in pancreatitis patients in clinical practice., (© 2024. The Author(s).)

Objective: It was targeted to assess the efficacy of certolizumab on pancreas and target organs via biochemical parameters and histopathologic scores in experimental acute pancreatitis (AP)., Materials and Methods: Forty male Sprague Dawley rats were divided into the following 5 equal groups: group 1 (sham group), group 2 (AP group), group 3 (AP + low-dose certolizumab group), group 4 (AP + high-dose certolizumab group), and group 5 (placebo group). Rats in all groups were sacrificed 24 hours after the last injection and amylase, tumor necrosis factor α, transforming growth factor β, interleukin 1β, malondialdehyde, superoxide dismutase, and glutathione peroxidase levels were studied in blood samples. Histopathological investigation of both the pancreas and target organs (lungs, liver, heart, kidneys) was performed by a pathologist blind to the groups. In silico analysis were also accomplished., Results: The biochemical results in the certolizumab treatment groups were identified to be significantly favorable compared to the AP group (P < 0.001). The difference between the high-dose group (group 4) and low-dose treatment group (group 3) was found to be significant in terms of biochemical parameters and histopathological scores (P < 0.001). In terms of the effect of certolizumab treatment on the target organs (especially on lung tissue), the differences between the low-dose treatment group (group 3) and high-dose treatment group (group 4) with the AP group (group 2) were significant., Conclusions: Certolizumab has favorable protective effects on pancreas and target organs in AP. It may be a beneficial agent for AP treatment and may prevent target organ damage., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The rapidly aging population is consuming more alcohol, leading to increased alcohol-associated acute pancreatitis (AAP) with high mortality. However, the mechanisms remain undefined, and currently there are no effective therapies available. This study aims to elucidate aging- and alcohol-associated spatial transcriptomic signature by establishing an aging AAP mouse model and applying Visium spatial transcriptomics for understanding of the mechanisms in the context of the pancreatic tissue. Upon alcohol diet feeding and caerulein treatment, aging mice (18 months) developed significantly more severe AAP with 5.0-fold increase of injury score and 2.4-fold increase of amylase compared to young mice (3 months). Via Visium spatial transcriptomics, eight distinct tissue clusters were revealed from aggregated transcriptomes of aging and young AAP mice: five acinar, two stromal, and one islet, which were then merged into three clusters: acinar, stromal, and islet for the comparative analysis. Compared to young AAP mice, > 1300 differentially expressed genes (DEGs) and approximately 3000 differentially regulated pathways were identified in aging AAP mice. The top five DEGs upregulated in aging AAP mice include Mmp8, Ppbp, Serpina3m, Cxcl13, and Hamp with heterogeneous distributions among the clusters. Taken together, this study demonstrates spatial heterogeneity of inflammatory processes in aging AAP mice, offering novel insights into the mechanisms and potential drivers for AAP development. KEY MESSAGES: Mechanisms regarding high mortality of AAP in aging remain undefined. An aging AAP mouse model was developed recapturing clinical exhibition in humans. Spatial transcriptomics identified contrasted DEGs in aging vs. young AAP mice. Top five DEGs were Mmp8, Ppbp, Serpina3m, Cxcl13, and Hamp in aging vs. young AAP mice. Our findings shed insights for identification of molecular drivers in aging AAP., (© 2024. The Author(s).)

Background: Ferroptosis is a newly recognized form of regulatory cell death characterized by severe lipid peroxidation triggered by iron overload and the production of reactive oxygen species (ROS). However, the role of ferroptosis in severe acute pancreatitis(SAP) has not been fully elucidated., Methods: We established four severe acute pancreatitis models of rats including the sham control group, the SAP group, the Fer -1-treated SAP (SAP + Fer-1) group, the 3-MA-treated SAP (SAP + 3-MA) group. The SAP group was induced by retrograde injection of sodium taurocholate into the pancreatic duct. The other two groups were intraperitoneally injected with ferroptosis inhibitor (Fer-1) and autophagy inhibitor (3-MA), respectively. The model of severe acute pancreatitis with amylase crest-related inflammatory factors was successfully established. Then we detected ferroptosis (GPX4, SLC7A1 etc.) and autophagy-related factors (LC3II, p62 ect.) to further clarify the relationship between ferroptosis and autophagy., Results: Our study found that ferroptosis occurs during the development of SAP, such as iron and lipid peroxidation in pancreatic tissues, decreased levels of reduced glutathione peroxidase 4 (GPX 4) and glutathione (GSH), and increased malondialdehyde(MDA) and significant mitochondrial damage. In addition, ferroptosis related proteins such as GPX4, solute carrier family 7 member 11(SLC7A11) and ferritin heavy chain 1(FTH1) were significantly decreased. Next, the pathogenesis of ferroptosis in SAP was studied. First, treatment with the ferroptosis inhibitor ferrostatin-1(Fer-1) significantly alleviated ferroptosis in SAP. Interestingly, autophagy occurs during the pathogenesis of SAP, and autophagy promotes the occurrence of ferroptosis in SAP. Moreover, 3-methyladenine (3-MA) inhibition of autophagy can significantly reduce iron overload and ferroptosis in SAP., Conclusions: Our results suggest that ferroptosis is a novel pathogenesis of SAP and is dependent on autophagy. This study provides a new theoretical basis for the study of SAP., (© 2024. The Author(s).)

Acute pancreatitis (AP) is a frequent but severe abdominal emergency in general surgery with intestinal barrier dysfunction. Heat shock protein 70 (HSP70) is a ubiquitous molecular chaperone that has been proposed to exert favorable effects on AP. Nonetheless, the detailed impacts of HSP70 on the intestinal barrier function in AP are unknown, which will be investigated here. After the injection of sodium taurocholate into the biliopancreatic duct, the rat models of AP were established. After modeling, HSP70 expression was up-regulated through lentivirus infection. Western blot was used to detect HSP70 expression. H&E staining was used to examine the histological changes in the pancreatic and intestinal tissues. The levels of pancreatic biochemical markers and oxidative stress markers were detected using corresponding assay kits. ELISA was used to detect the levels of inflammatory cytokines and gastrointestinal function indicators. Immunofluorescence staining and Western blot were used to detect the expression of tight junction proteins. DCFH-DA probe and MitoSOX Red probe were used to detect total reactive oxygen species (ROS) and mitochondrial ROS (mtROS), respectively. TUNEL assay and Western blot were used to detect apoptosis. During the model construction, severe pancreatic and abnormal intestinal tissue abnormalities were observed, inflammatory response was activated and the intestinal barrier was disrupted. HSP70 expression was down-regulated in the intestinal tissues AP rat models. HSP70 ameliorated the morphological damage of pancreatic and intestinal tissues of AP rats. In addition, HSP70 significantly reduced intestinal barrier damage, inflammatory response, oxidative stress and apoptosis in the intestinal tissues of AP rat models. Collectively, HSP70 might attenuate AP through exerting anti-inflammatory, anti-oxidant, anti-apoptotic effects and inhibiting intestinal barrier disruption., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier Masson SAS.)

Ferroptosis, characterized by lipid peroxidation, plays a significant role in the pathogenesis of acute pancreatitis (AP). While sterol O-acyltransferase 2 (Soat2) is known for its crucial regulatory role in cholesterol homeostasis, its involvement in the development of AP remains unreported. We conducted this study to identify the pivotal role of Soat2 in AP using transcriptomic databases. Subsequently, we confirmed its alterations through both in vitro and in vivo experimental models. Furthermore, we performed intervention with the Soat2 inhibitor avasimibe to evaluate pancreatic tissue pathology and serum enzymatic levels and observe inflammatory cell infiltration through immunohistochemistry. Additionally, changes in indicators related to ferroptosis were also observed. The results showed that in the AP mouse model, the protein and mRNA levels of Soat2 were significantly increased. Following avasimibe administration, there was a decrease in serum amylase levels, reduction in pancreatic tissue pathological damage, and attenuation of inflammatory cell infiltration. Furthermore, avasimibe administration resulted in downregulation of ferroptosis-related indicators. In conclusion, our findings suggest that the Soat2 inhibitor avasimibe protects against AP in mice through inhibition of the ferroptosis., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Dyslipolysis of adipocytes plays a critical role in various diseases. Adipose triglyceride lipase (ATGL) is a rate-limiting enzyme in adipocyte autonomous lipolysis. However, the degree of adipocyte lipolysis related to the prognoses in acute pancreatitis (AP) and the role of ATGL-mediated lipolysis in the pathogenesis of AP remain elusive. Herein, the visceral adipose tissue consumption rate in the acute stage was measured in both patients with AP and mouse models. Lipolysis levels and ATGL expression were detected in cerulein-induced AP models. CL316,243, a lipolysis stimulator, and adipose tissue-specific ATGL knockout mice were used to further investigate the role of lipolysis in AP. The ATGL-specific inhibitor, atglistatin, was used in C57Bl/6N and ob/ob AP models. This study indicated that increased visceral adipose tissue consumption rate in the acute phase was independently associated with adverse prognoses in patients with AP, which was validated in mouse AP models. Lipolysis of adipocytes was elevated in AP mice. Stimulation of lipolysis aggravated AP. Genetic blockage of ATGL specifically in adipocytes alleviated the damage to AP. The application of atglistatin effectively protected against AP in both lean and obese mice. These findings demonstrated that ATGL-mediated adipocyte lipolysis exacerbates AP and highlighted the therapeutic potential of ATGL as a drug target for AP., Competing Interests: Disclosure Statement None declared., (Copyright © 2024 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Hyperlipidemic pancreatitis (HP) is an inflammatory injury of the pancreas triggered by elevated serum triglyceride (TG) levels. The mechanistic target of rapamycin (mTOR) signaling pathway plays a crucial role in regulating lipid homeostasis and inflammation. This study aimed to investigate whether the activity of mTOR complex 2 (mTORC2) affects the progression of HP and its underlying mechanisms. In vivo, a high-fat diet and retrograde administration of sodium taurocholate were employed to establish the HP models in rats, with pancreatic tissue pathology evaluated. The expression of Rictor and peroxisome proliferator-activator receptor (PPAR) was examined. The serum levels of TG, fatty acid metabolites, inflammatory and lipid metabolism-related factors were determined. In vitro, pancreatic acinar cells (PACs) were exposed to palmitic acid and cholecystokinin-8. PAC apoptosis, pyroptosis, and ferroptosis were assessed. In the HP models, rats and PACs exhibited upregulated Rictor and downregulated PPARα, and Rictor knockdown promoted PPARα expression. In vivo, Rictor knockdown decreased the serum levels of TG, α-amylase, total cholesterol, low-density lipoprotein cholesterol, lactate dehydrogenase, and inflammatory factors, while increasing high-density lipoprotein cholesterol levels. Rictor knockdown increased ACOX1 and CPT1α and decreased SREBP-1, CD36, SCD1, ACLY, and ACACA. Rictor knockdown reduced damage to pancreatic tissue structure. In vitro, Rictor knockdown inhibited PAC apoptosis, pyroptosis, and ferroptosis. Treatment with the PPARα antagonist GW6471 abolished the beneficial effects of Rictor knockdown. Rictor/mTORC2 deficiency reduces serum TG levels, maintains lipid homeostasis, and suppresses inflammation by inhibiting PPARα expression. Weakening mTORC2 activity holds promise as a novel therapeutic strategy for HP., (© 2024 Wiley Periodicals LLC.)

Cathepsin B (CTSB) and inflammatory cytokines are critical in initiating and developing pancreatitis. Calcineurin, a central calcium (Ca 2+ )-responsive signaling molecule, mediates acinar cell death and inflammatory responses leading to pancreatitis. However, the detailed mechanisms for regulating CTSB activity and inflammatory cytokine production are unknown. Myricetin (MC) exhibits various biological activities, including anti-inflammatory effects. Here, we aimed to investigate MC effects on pancreatitis and the underlying mechanisms. Prophylactic and therapeutic MC treatment ameliorated the severity of cerulein-, L-arginine-, and PDL-induced acute pancreatitis (AP). The inhibition of CTSB activity by MC was mediated via decreased calcineurin activity and macrophage infiltration, not neutrophils infiltration, into the pancreas. Additionally, calcineurin activity inhibition by MC prevented the phosphorylation of Ca 2+ /CaM-dependent protein kinase kinase 2 (CaMKK2) during AP, resulting in the inhibition of CaMKIV phosphorylation and adenosine monophosphate-activated protein kinase (AMPK) dephosphorylation. Furthermore, MC reduced nuclear factor-κB activation by modulating the calcineurin-CaMKIV-IKKα/β-Iκ-Bα and calcineurin-AMPK-sirtuin1 axes, resulting in reduced production of tumor necrosis factor-α, interleukin (IL)-1β, and IL-6. Our results showed that MC alleviated AP severity by inhibiting acinar cell death and inflammatory responses, suggesting that MC as a calcineurin and CaMKK2 signaling modulator may be a potential treatment for AP., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Developing strategies to target injured pancreatic acinar cells (PACs) in conjunction with primary pathophysiology-specific pharmacological therapy presents a challenge in the management of acute pancreatitis (AP). We designed and synthesized a trypsin-cleavable organosilica precursor bridged by arginine-based amide bonds, leveraging trypsin's ability to selectively identify guanidino groups on arginine via Asp189 at the active S1 pocket and cleave the carboxy-terminal (C-terminal) amide bond via catalytic triads. The precursors were incorporated into the framework of mesoporous silica nanoparticles (MSNs) for encapsulating the membrane-permeable Ca 2+ chelator BAPTA-AM with a high loading content (∼43.9%). Mesenchymal stem cell membrane coating and surface modification with PAC-targeting ligands endow MSNs with inflammation recruitment and precise PAC-targeting abilities, resulting in the highest distribution at 3 h in the pancreas with 4.7-fold more accumulation than that of naked MSNs. The outcomes transpired as follows: After bioinspired MSNs' skeleton biodegradation by prematurely and massively activated trypsin, BAPTA-AM was on-demand released in injured PACs, thereby effectively eliminating intracellular calcium overload (reduced Ca 2+ level by 81.3%), restoring cellular redox status, blocking inflammatory cascades, and inhibiting cell necrosis by impeding the IκBα/NF-κB/TNF-α/IL-6 and CaMK-II/p-RIP3/p-MLKL/caspase-8,9 signaling pathways. In AP mice, a single dose of the formulation significantly restored pancreatic function (lipase and amylase reduced more by 60%) and improved the survival rate from 50 to 91.6%. The formulation offers a potentially effective strategy for clinical translation in AP treatment.

Severe acute pancreatitis (SAP) is a complicated inflammatory reaction that impacts the pancreas, often resulting in damage to numerous organs. This disorder encompasses a range of processes such as inflammation, oxidative stress, and pancreatitis. The hormone melatonin (MT) is primarily secreted by the pineal gland and plays a crucial role in mitigating inflammation, countering the harmful effects of free radicals, and regulating oxidative stress. The aim of this research was to investigate the potential protective impact and the underlying mechanism of melatonin in mice afflicted with SAP. The biochemical and histological assessments unequivocally demonstrated that melatonin effectively inhibited necrosis, infiltration, edema and cell death in pancreatic tissues, thereby suppressing acute pancreatitis. Notably, melatonin also alleviated the consequent harm to distant organs, notably the lungs, liver, and kidneys. Furthermore, both preventive and therapeutic administration of melatonin prompted nuclear factor E2-related factor 2 (Nrf2) activation followed by Nrf2 target gene expression. Nrf2 initiates the activation of antioxidant genes, thereby providing defense against oxidative stress. Conversely, Nrf2 reduction may contribute to impaired antioxidant protection in SAP. The beneficial impact of Nrf2 on antioxidants was absent in Nrf2-knockout mice, leading to the accumulation of LDH and exacerbation of cell death. This deterioration in both pancreatitis and injuries in distant organs intensified significantly. The results indicate that melatonin has an enhanced ability to protect against multiorgan damage caused by SAP, which is accomplished through the increase in Nrf2 expression. Additionally, Nrf2 initiates the activation of antioxidant genes that offer defense against cell death., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Acute pancreatitis (AP) is a life-threatening inflammatory disease with no specific therapy. Excessive cytoplasmic Ca2+ elevation and intracellular ATP depletion are responsible for the initiation of AP. Inhibition of Ca2+ release-activated Ca2+ (CRAC) channels has been proposed as a potential treatment, and currently, a novel selective CRAC channel inhibitor CM4620 (Auxora, CalciMedica) is in Phase 2b human trials. While CM4620 is on track to become the first effective treatment for AP, it does not produce complete protection in animal models. Recently, an alternative approach has suggested reducing ATP depletion with a natural carbohydrate galactose. Here, we have investigated the possibility of using the smallest effective concentration of CM4620 in combination with galactose. Protective effects of CM4620, in the range of 1-100 n m, have been studied against necrosis induced by bile acids, palmitoleic acid, or l-asparaginase. CM4620 markedly protected against necrosis induced by bile acids or asparaginase starting from 50 n m and palmitoleic acid starting from 1 n m. Combining CM4620 and galactose (1 m m) significantly reduced the extent of necrosis to near-control levels. In the palmitoleic acid-alcohol-induced experimental mouse model of AP, CM4620 at a concentration of 0.1 mg/kg alone significantly reduced edema, necrosis, inflammation, and the total histopathological score. A combination of 0.1 mg/kg CM4620 with galactose (100 m m) significantly reduced further necrosis, inflammation, and histopathological score. Our data show that CM4620 can be used at much lower concentrations than reported previously, reducing potential side effects. The novel combination of CM4620 with galactose synergistically targets complementary pathological mechanisms of AP., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Physiological Society.)