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Background: Patients with acute pancreatitis (AP) exhibit specific phenotypes of gut microbiota associated with severity. Gut microbiota and host interact primarily through metabolites; regrettably, little is known about their roles in AP biological networks. This study examines how enterobacterial metabolites modulate the innate immune system in AP aggravation., Methods: In AP, alterations in gut microbiota were detected via microbiomics, and the Lactobacillus metabolites of tryptophan were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). By culturing Lactobacillus with tryptophan, differential metabolites were detected by LC-MS/MS. Lipopolysaccharide (LPS)-stimulated RAW264.7 cells and mice with cerulein plus LPS-induced AP were used to evaluate the biological effect of norharman on M1 macrophages activation in AP development. Further, RNA sequencing and lipid metabolomics were used for screening the therapeutic targets and pathways of norharman. Confocal microscopy assay was used to detect the structure of lipid rafts. Molecular docking was applied to predict the interaction between norharman and HDACs. Luciferase reporter assays and chromatin immunoprecipitation (ChIP) were used to explore the direct mechanism of norharman promoting Rftn1 expression. In addition, myeloid-specific Rftn1 knockout mice were used to verify the role of Rftn1 and the reversed effect of norharman., Results: AP induced the dysfunction of gut microbiota and their metabolites, resulting in the suppression of Lactobacillus-mediated tryptophan metabolism pathway. The Lactobacillus metabolites of tryptophan, norharman, inhibited the release of inflammatory factor in vitro and in vivo, as a result of its optimal inhibitory action on M1 macrophages. Moreover, norharman blocked multiple inflammatory responses in AP exacerbation due to its ability to maintain the integrity of lipid rafts and restore the dysfunction of lipid metabolism. The mechanism of norharman's activity involved inhibiting the enzyme activity of histone deacetylase (HDACs) to increase histone H3 at lysine 9/14 (H3K9/14) acetylation, which increased the transcription level of Rftn1 (Raftlin 1) to inhibit M1 macrophages' activation., Conclusions: The enterobacterial metabolite norharman can decrease HDACs activity to increase H3K9/14 acetylation of Rftn1, which inhibits M1 macrophage activation and restores the balance of lipid metabolism to relieve multiple inflammatory responses. Therefore, norharman may be a promising prodrug to block AP aggravation., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background and Purpose: Microbiome dysfunction is known to aggravate acute pancreatitis (AP); however, the relationship between this dysfunction and metabolite alterations is not fully understood. This study explored the crosstalk between the microbiome and metabolites in AP mice., Methods: Experimental AP models were established by injecting C57/BL mice with seven doses of cerulein and one dose of lipopolysaccharide (LPS). Metagenomics and untargeted metabolomics were used to identify systemic disturbances in the microbiome and metabolites, respectively, during the progression of AP., Results: The gut microbiome of AP mice primarily included Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria, and "core microbiota" characterized by an increase in Proteobacteria and a decrease in Actinobacteria. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis found that significantly different microbes were involved in several signaling networks. Untargeted metabolomics identified 872 metabolites, of which lipids and lipid-like molecules were the most impacted. An integrated analysis of metagenomics and metabolomics indicated that acetate kinase ( ackA ) gene expression was associated with various gut microbiota, including Alistipes , Butyricimonas , and Lactobacillus , and was strongly correlated with the metabolite daphnoretin. The functional gene, O -acetyl-L-serine sulfhydrylase ( cysK ), was associated with Alistipes , Jeotgalicoccus , and Lactobacillus , and linked to bufalin and phlorobenzophenone metabolite production., Conclusion: This study identified the relationship between the gut microbiome and metabolite levels during AP, especially the Lactobacillus-, Alistipes- , and Butyricimonas -associated functional genes, ackA and cysK . Expression of these genes was significantly correlated to the production of the anti-inflammatory and antitumor metabolites daphnoretin and bufalin., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhou, Tao, Guo, Zhu, Wu, Xiang and Shang.)

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant lethal disease due to its asymptomatic at its early lesion of the disease and drug resistance. Target therapy associated with molecular pathways so far seems not to produce reasonable outcomes. Understanding of the molecular mechanisms underlying inflammation-initiated tumorigenesis may be helpful for development of an effective therapy of the disease. A line of studies showed that pancreatic tumorigenesis was resulted from pancreatitis, which was caused synergistically by various pancreatic cells. This review focuses on those players and their possible clinic implications, such as exocrine acinar cells, ductal cells, and various stromal cells, including pancreatic stellate cells (PSCs), macrophages, lymphocytes, neutrophils, mast cells, adipocytes and endothelial cells, working together with each other in an inflammation-mediated microenvironment governed by a myriad of cellular signaling networks towards PDAC., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Recent studies have proven that the overall pathophysiology of pancreatitis involves not only the pancreatic acinar cells but also duct cells, however, pancreatic duct contribution in acinar cells homeostasis is poorly known and the molecular mechanisms leading to acinar insult and acute pancreatitis (AP) are unclear. Our previous work also showed that S100A9 protein level was notably increased in AP rat pancreas through iTRAQ-based quantitative proteomic analysis. Therefore, we investigated the actions of injured duct cells on acinar cells and the S100A9-related effects and mechanisms underlying AP pathology in the present paper. Methods: In this study, we constructed S100A9 knockout (s100a9 -/- ) mice and an in vitro coculture system for pancreatic duct cells and acinar cells. Moreover, a variety of small molecular inhibitors of S100A9 were screened from ChemDiv through molecular docking and virtual screening methods. Results: We found that the upregulation of S100A9 induces cell injury and inflammatory response via NLRP3 activation by targeting VNN1-mediated ROS release; and loss of S100A9 decreases AP injury in vitro and in vivo . Moreover, molecular docking and mutant plasmid experiments proved that S100A9 has a direct interaction with VNN1 through the salt bridges formation of Lys57 and Glu92 residues in S100A9 protein. We further found that compounds C 42 H 60 N 4 O 6 and C 28 H 29 F 3 N 4 O 5 S can significantly improve AP injury in vitro and in vivo through inhibiting S100A9-VNN1 interaction. Conclusions: Our study showed the important regulatory effect of S100A9 on pancreatic duct injury during AP and revealed that inhibition of the S100A9-VNN1 interaction may be a key therapeutic target for this disease., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Acute pancreatitis (AP) is an aseptic inflammation characterized with an annual incidence rate, and ~20% patients progressing to severe AP (SAP) with a high mortality rate. Although Qingyi decoction has been frequently used for SAP treatment over the past 3 decades in clinic, the actual mechanism of its protective effects remains unknown. As the major active ingredient of Qingyi decoction, emodin was selected in the present study to investigate the effect of emodin against severe acute pancreatitis (SAP) in rats through NOD‑like receptor protein 3 (NLRP3) inflammasomes. The rats were randomly divided into a sham operation group, an SAP model group induced by a standard retrograde infusion of 5.0% sodium taurocholate into the biliopancreatic duct, and low‑dose (30 mg/kg) and high‑dose (60 mg/kg) emodin‑treated groups. At 12 h after the event, the plasma amylase, lipase, interleukin (IL)‑1β, IL‑18 and myeloperoxidase (MPO) activities were examined. Furthermore, the pathological scores of pancreases were evaluated by hematoxylin and eosin staining. The expression levels of P2X ligand‑gated ion channel 7 (P2X7), NLRP3, apoptosis‑associated speck‑like protein containing a C‑terminal caspase recruitment domain and caspase‑1 were also analyzed by western blot analysis. The data demonstrated that, compared with the SAP group, emodin could significantly relieve the pancreatic histopathology and acinar cellular structure injury, and notably downregulate the plasma amylase and lipase levels, as well as the MPO activities in pancreatic tissues, in a dose‑dependent manner. Furthermore, emodin inhibited the P2X7/NLRP3 signaling pathway followed by the decrease of pro‑inflammatory factors, and the latter is beneficial for the recovery of SAP. Collectively, the data indicated that emodin may be an efficient candidate natural product for SAP treatment.