Acute pancreatitis (AP) is an inflammatory disease that can progress to systemic immune responses and multi-organ damage in its severe forms. Anoectochilus roxburghii (Wall.) Lindl. (AR), a traditional Chinese medicinal plant, has been reported to exhibit anti-inflammatory, hypoglycemic, hepatoprotective, and analgesic properties. Kinsenoside (KD), the primary bioactive glycoside in AR, is responsible for many of its therapeutic effects. Given its anti-inflammatory and immunomodulatory properties, KD may have the potential to mitigate pancreatic inflammation in AP. However, its protective role in AP has not yet been investigated.

This study aimed to investigate the protective effects of the natural active compound KD against acute pancreatitis (AP) and its associated molecular mechanisms.

Two AP mouse models were established: one by intraperitoneal injection of caerulein combined with lipopolysaccharide (LPS) and the other by retrograde injection of sodium taurocholate (NaT) into the biliopancreatic duct. KD (2.5, 5, 10 mg/kg) was administered as a pre-treatment 1 h before the induction of AP. The severity of AP was evaluated through histopathological analysis, while macrophage infiltration and phenotypic changes in pancreatic tissues were examined using immunofluorescence staining and flow cytometry. Bone marrow-derived macrophages (BMDMs) were polarized into the M1 phenotype through two distinct methods: stimulation with LPS and interferon-γ (IFNγ) and indirect co-culture with pancreatic acinar cells. Changes in macrophage phenotype after KD supplementation (100, 200, and 400 μM) were analyzed using quantitative Reverse Transcription PCR (qRT-PCR) and flow cytometry. Network pharmacology and transcriptomic sequencing were utilized to identify potential targets and pathways affected by KD, with validation of key signaling pathways performed through qPCR and Western blot analysis.

In two models of AP mice, KD at a high dose (10 mg/kg) significantly alleviated pancreatic damage. It reduced pancreatic edema, necrosis, and inflammatory cell infiltration, with a notable decrease in macrophage infiltration. Furthermore, KD (10 mg/kg) administration significantly reduced serum lipase by 53.62% in the Caerulein + LPS model and 41.14% in the NaT model, as well as amylase by 28.13% and 27.99%, respectively. Additionally, KD (10 mg/kg) administration mitigated systemic inflammation and lung injury during AP. Both in vivo and in vitro experiments demonstrated that KD (400 μM) significantly reduced the proportion of M1 macrophages. Furthermore, KD (400 μM) downregulated the mRNA expression of M1-associated genes, including Nos2, Tnf, Il1b, and Il6, in macrophages stimulated by both LPS + IFNγ and pancreatic acinar cell-conditioned media. Network pharmacology and transcriptomic analyses identified toll-like receptor 4 (TLR4) as a potential target of KD in the context of AP. KD (400 μM) was shown to inhibit the activation of the TLR4/STAT1 signaling pathway in macrophages exposed to inflammatory stimuli.

KD administration mitigated experimental AP induced by diverse etiologies through the inhibition of M1 macrophage polarization via the TLR4/STAT1 signaling pathway. These findings highlight KD as a promising therapeutic candidate with potential clinical applications in the management of AP.

The process of apoptosis plays a crucial role in tissue homeostasis, immune system regulation, and organ formation. Apoptotic vesicles (ApoEVs) are involved in efferocytosis, the process by which phagocytes ingest dead cells. ApoEVs also have potential therapeutic applications in cancer treatment, ischemic diseases, and their anti-inflammatory properties make them incredibly versatile for medical applications. These vesicles can induce apoptosis in cancer cells, provide tumor antigens for cancer vaccines, and even serve as effective drug delivery systems. Moreover, they can target hypoxic cells, inhibit inflammatory cell death pathways, and promote tissue regeneration. Also, their potential in addressing inflammatory disorders such as gastrointestinal ailments, osteoarthritis, and diabetes is promising. Additionally, ApoEVs can polarize anti-inflammatory immune cells and suppress inflammatory immune responses which make them a viable option for addressing the unmet need for novel anti-inflammatory medications. Despite a wealth of reviews examining the applications of ApoEVs, very few have thoroughly investigated the mechanisms underlying their anti-inflammatory effects. This distinctive approach positions the current review as timely and immensely relevant, illuminating the intriguing ways these entities function beyond their established advantages.

Obesity is a pandemic of the 21st century, and the prevalence of this metabolic condition has enormously increased over the past few decades. Obesity is associated with a number of comorbidities and complications, such as diabetes and cardiovascular disorders, which can be associated with severe and fatal outcomes. Adipose tissue is an endocrine organ that secretes numerous molecules and proteins that are capable of modifying immune responses. The progression of obesity is associated with adipose tissue dysfunction, which is characterised by enhanced inflammation and apoptosis. Increased fat-tissue mass is associated with the dysregulated secretion of substances by adipocytes, which leads to metabolic alterations. Importantly, the adipose tissue contains immune cells, the profile of which changes with the progression of obesity. For instance, increasing fat mass enhances the presence of the pro-inflammatory variants of macrophages, major sources of tumour necrosis factor α and other inflammatory mediators that promote insulin resistance. The pathogenesis of obesity is complex, and understanding the pathophysiological mechanisms that are involved may provide novel treatment methods that could prevent the development of serious complications. The aim of this review is to discuss current evidence describing the involvement of various inflammatory mediators in the pathogenesis of obesity.

Macrophage proinflammatory activation contributes to the pathology of severe acute pancreatitis (SAP) and, simultaneously, macrophage functional changes, and increased pyroptosis/necrosis can further exacerbate the cellular immune suppression during the process of SAP, where cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) plays an important role. However, the function and mechanism of cGAS-STING in SAP-induced lung injury (LI) remains unknown.

Lipopolysaccharide (LPS) was combined with caerulein-induced SAP in wild type, cGAS -/- and sting -/- mice. Primary macrophages were extracted via bronchoalveolar lavage and peritoneal lavage. Ana-1 cells were pretreated with LPS and stimulated with nigericin sodium salt to induce pyroptosis in vitro.

SAP triggered NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation-mediated pyroptosis of alveolar and peritoneal macrophages in mouse model. Knockout of cGAS/STING could ameliorate NLRP3 activation and macrophage pyroptosis. In addition, mitochondrial (mt)DNA released from damaged mitochondria further induced macrophage STING activation in a cGAS- and dose-dependent manner. Upregulated STING signal can promote NLRP3 inflammasome-mediated macrophage pyroptosis and increase serum interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α levels and, thus, exacerbate SAP-associated LI (SAP-ALI). Downstream molecules of STING, IRF7, and IRF3 connect the mtDNA-cGAS-STING axis and the NLRP3-pyroptosis axis.

Negative regulation of any molecule in the mtDNA-cGAS-STING-IRF7/IRF3 pathway can affect the activation of NLRP3 inflammasomes, thereby reducing macrophage pyroptosis and improving SAP-ALI in mouse model.

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.

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.

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.

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.

Chronic pancreatitis (CP) is an inflammatory, irreversible disorder of the pancreas which leads to organ atrophy and poses high risk for the development of pancreatic cancer. Given the lack of clinically approved therapy, we explored the pharmacological potential of the nanoparticles of cerium oxide (nanoceria, NC) against animal models of CP. Nanoceria ameliorated the features of CP as evident from biochemical parameters. It inhibited the inflammatory cytokines and chemokines by abrogation of macrophage signaling. Further, NC attenuated the fibrogenesis by inhibition of TGF-β signaling, endoplasmic reticulum stress, and epithelial-to-mesenchymal transition. Our findings reveal the anti-CP potential of the novel redox regenerative nanoceria against two models of CP.

Pancreatitis is an inflammatory reaction of pancreatic tissue digestion, edema, bleeding and even necrosis caused by activation of pancreatin due to various causes. In particular, patients with severe acute pancreatitis (SAP) often suffer from secondary infection, peritonitis and shock, and have a high mortality rate. Chronic pancreatitis (CP) can cause permanent damage to the pancreas. Due to the innate characteristics, structure and location of the pancreas, there is no effective treatment, only relief of symptoms. Especially, AP is an unpredictable and potentially fatal disease, and the timely diagnosis and treatment remains a major challenge. With the rapid development of nanomedicine technology, many potential tools can be used to address this problem. In this review, we have introduced the pathophysiological processes of pancreatitis to understanding its etiology and severity. Most importantly, the current progress in the diagnosis and treatment tools of pancreatitis based on nanomedicine is summarized and prospected.