Macrophages play a crucial role in the pathogenesis of pancreatitis that is a common gastrointestinal disease. Particularly, macrophages differentiate into different phenotypes and exert diverse functions in acute pancreatitis (AP) and chronic pancreatitis (CP), respectively. In AP, macrophages in the pancreas and other related organs are mainly activated and differentiated into a pro-inflammatory M1 phenotype, and furthermore secrete inflammatory cytokines and mediators, causing local inflammation of the pancreas, and even intractable systemic inflammatory response or multiple organ failure. In CP, macrophages often exhibit a M2 polarisation and interact with pancreatic stellate cells (PSCs) in an autocrine and paracrine cytokine-dependent manner to promote the progression of pancreatic fibrosis. As the severity of pancreatic fibrosis aggravates, the proportion of M2/M1 macrophage cytokines in the pancreas increases. The discovery of macrophages in the pathogenesis of pancreatitis has promoted the research of targeted drugs, which provides great potential for the effective treatment of pancreatitis. This paper provides an overview of the roles of various macrophages in the pathogenesis of pancreatitis and the current research status of pancreatitis immunotherapy targeting macrophages. The findings addressed in this review are of considerable significance for understanding the pivotal role of macrophages in pancreatitis.

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. Graphical

Vanin1 (VNN1) is an exogenous enzyme with pantetheinase activity that mainly exerts physiological functions through enzyme catalysis products, including pantothenic acid and cysteamine. In recent years, the crosstalk between VNN1 and metabolism and oxidative stress has attracted much attention. As a result of the ability of VNN1 to affect multiple metabolic pathways and oxidative stress to exacerbate or alleviate pathological processes, it has become a key component of disease progression. This review discusses the functions of VNN1 in glucolipid metabolism, cysteamine metabolism, and glutathione metabolism to provide perspectives on VNN1-targeted therapy for chronic diseases.

Pancreatic disorders cause a broad spectrum of clinical diseases, mainly including acute and chronic pancreatitis and pancreatic cancer, and are associated with high global rates of morbidity and mortality. Unfortunately, the pathogenesis of pancreatic disease remains obscure, and there is a lack of specific treatments. T lymphocytes (T cells) play a vital role in the adaptive immune systems of multicellular organisms. During pancreatic disease development, local imbalances in T-cell subsets in inflammatory and tumor environments and the circulation have been observed. Furthermore, agents targeting T cells have been shown to reverse the natural course of pancreatic diseases. In this review, we have discussed the clinical relevance of T-cell alterations as a potential outcome predictor and the underlying mechanisms, as well as the present status of immunotherapy targeting T cells in pancreatitis and neoplasms. The breakthrough findings summarized in this review have important implications for innovative drug development and the prospective use of immunotherapy for pancreatitis and pancreatic cancer.

Osteoporosis is becoming a highly prevalent disease in a large proportion of the global aged population. Serum metabolite markers may be important for the treatment and early prevention of osteoporosis. Serum samples from 32 osteoporosis and 32 controls were analyzed by untargeted metabolomics and lipidomic approaches performed on an ultra-high performance liquid chromatography and high-resolution mass spectrometry (UHPLC-HRMS) system. To find systemic disturbance of osteoporosis, weighted gene correlation network analysis (WGCNA) and statistical methods were employed for data-mining. Then, an in-depth targeted method was utilized to determine potential markers from the family of key metabolites. As a result, 1,241 metabolites were identified from untargeted methods and WGCNA indicated that lipids metabolism is deregulated and glycerol phospholipids, sphingolipids, fatty acids, and bile acids (BA) are majorly affected. As key metabolites of lipids metabolism, 66 bile acids were scanned and 49 compounds were quantified by a targeted method. Interestingly, hyocholic acids (HCA) were found to play essential roles during the occurrence of osteoporosis and may be potential markers. These metabolites may be new therapeutic or diagnosis targets for the screening or treatment of osteoporosis. Quantified measurement of potential markers also enables the establishment of diagnostic models for the following translational research in the clinic.

Objective: The intestinal barrier injury caused by severe acute pancreatitis (SAP) can induce enterogenous infection, further aggravating the inflammatory reactions and immune responses. This study aimed to test the hypothesis that emodin protects the intestinal function and is involved in the immune response in SAP. Methods: The network pharmacology was established using the Swiss target prediction and pathway enrichment analysis. The SAP mice model was induced by cerulein (50 μg/kg) and lipopolysaccharide (10 mg/kg) hyperstimulation. The pharmacological effect of emodin in treating SAP was evaluated at mRNA and protein levels by various methods. Results: The network analysis provided the connectivity between the targets of emodin and the intestinal barrier–associated proteins and predicted the BAX/Bcl-2/caspase 3 signaling pathway. Emodin alleviated the pathological damages to the pancreas and intestine and reduced the high concentrations of serum amylase and cytokines in vivo. Emodin increased the expression of intestinal barrier–related proteins and reversed the changes in the apoptosis-related proteins in the intestine. Simultaneously, emodin regulated the ratio of T helper type 1 (T_H1), T_H2, T_H17, γδ T cells, and interferon γ/interleukin 17 producing γδ T cells. Conclusions: These findings partly verified the mechanism underlying the regulation of the intestinal barrier and immune response by emodin.