Search Results (4,131)

Fermentation is widely used to enhance the bioactivity of herbal phytochemicals through microbial bioconversion. Rehmannia glutinosa contains catalpol, an iridoid glycoside with metabolic and immunomodulatory potential; however, its efficacy in the unfermented form is limited. This study investigated whether fermentation enhances catalpol production and improves metabolic and immune-regulating functions via glucagon-like peptide-1 receptor (GLP-1R) signaling. Rehmannia glutinosa extract was fermented under optimized conditions, and catalpol and iridoid precursor levels were quantified to assess bioconversion efficiency. Biological effects were evaluated in intestinal epithelial cells, macrophages, and an Artemia model, focusing on glucose transport, GLP-1 secretion, dipeptidyl peptidase-4 (DPP-4) expression, mucosal defense, and GLP-1R/protein kinase A/cAMP response element-binding protein (PKA/CREB) signaling. Fermentation significantly increased catalpol content while reducing iridoid precursors. The fermented extract suppressed intestinal glucose absorption by downregulating sodium–glucose cotransporter 1 (SGLT1) and glucose transporter 2 (GLUT2). It also enhanced GLP-1 secretion and reduced DPP-4 expression, leading to activation of GLP-1R/PKA/CREB signaling. This activation increased mucin 2 (MUC2) expression and promoted anti-inflammatory. Full article

Hyaluronan (HA) receptors are expressed in a wide variety of different tissues and have long been known to support the critical cellular functions of adhesion and motility, in addition to a range of different physiological and pathological processes, including immunity, inflammation and tumour metastasis. In recent years, LYVE-1, an HA receptor largely but not exclusively restricted to the endothelia of lymphatic capillaries, has been shown to mediate the entry of immune cells through lymphatic endothelial junctions by engaging with their surface HA glycocalyx, itself anchored to the immune cell membrane by the closely related receptor CD44. Although similar to CD44 in primary sequence, LYVE-1 is functionally distinct, with a mutually exclusive pattern of tissue expression and a marked dependence on avidity for engagement with the long chains of HA—achieved primarily through receptor clustering. Here, we review key data that have defined the in vitro and in vivo functions of LYVE-1, including recent high-resolution crystal structures that have revealed its unusual and reversible “sliding” mode of interaction with HA, as distinct from the conventional “sticking” interaction in CD44. Lastly, we consider the emerging functions of LYVE-1 in sites beyond the lymphatics, namely tissue-resident macrophages and the specialised blood vessels of certain organs, and its potential as a therapeutic target. Full article

Diabetic peripheral neuropathy (DPN) remains a leading cause of disability in diabetes, yet current care is largely symptomatic and does not directly address early neurovascular-immune pathology. This narrative review synthesizes clinical, redox, vascular, and immunological evidence into a peripheral nerve neurovascular unit (PNVU)/blood–nerve barrier (BNB)-centered framework for DPN. First, the review outlines the diagnostic and translational endpoint landscape of DPN, emphasizing that commonly used clinical, neurophysiological, small-fiber, and imaging-based tools capture important disease domains but do not directly assess early BNB dysfunction. It then reviews the anatomical and functional basis of the PNVU and BNB, including endoneurial microvascular endothelial cells, pericytes, basement membrane components, immune cells, and tight-junction proteins. Next, it discusses how chronic hyperglycemia and dyslipidemia drive metabolic-to-vascular coupling, redox imbalance, antioxidant defense failure, advanced glycation end products (AGEs), receptor for AGEs (RAGE), and nuclear factor-κB (NF-κB) signaling, endothelial activation, leukocyte recruitment, macrophage polarization, and junctional disassembly, culminating in increased BNB permeability and exposure of peripheral nerves to pro-inflammatory and neurotoxic mediators. Finally, it evaluates incretin-based therapies—including glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors, DPP-4is), and emerging multi-agonists—as potential modulators of oxidative and inflammatory stress within this framework. Although semaglutide and related agents show mechanistic plausibility and preclinical promise, direct evidence for incretin-mediated BNB stabilization in human DPN remains limited. By reframing DPN as a redox-driven neurovascular-immune disorder, this review highlights barrier-focused biomarkers, translational endpoints, and hypothesis-generating therapeutic opportunities that require clinical validation. Full article

Regulatory T cells (Tregs, CD4⁺ CD25⁺ Foxp3⁺) play a crucial role as a core cell subset in maintaining immune homeostasis in the ocular immune-privileged microenvironment. This review systematically summarizes the stage-specific regulatory mechanisms of Treg cells in common inflammatory diseases such as keratitis, uveitis, and dry eye syndrome, including intercellular interactions, signal pathway mediation, and cytokine network regulation, as well as key experimental evidence (animal/cell models and clinical sample data) and research progress in targeted therapy. Studies have shown that Treg cells maintain ocular immune balance by secreting anti-inflammatory cytokines (such as IL-10 and TGF-β), regulating signaling pathways (STAT, PI3K/AKT, SIRT1, etc.), and interacting with immune cells (macrophages, dendritic cells). Their functions are regulated by multiple factors such as cytokine networks, epigenetic modifications, and delivery vectors. Targeted interventions based on Treg cells (cell therapy, drug intervention, and signaling pathway regulation) and combined treatment strategies have shown good anti-inflammatory potential. This article, in light of current research limitations (such as insufficient analysis of cell heterogeneity and the disconnect between basic and clinical research), proposes future research directions, providing a theoretical basis for the understanding of the pathogenesis of inflammatory eye diseases and the development of new immunomodulatory therapies, and establishing a complete research framework of “mechanism–evidence–treatment”. Full article

Butyrophilin-like 2 (BTNL2) is an immunomodulatory molecule critically involved in regulating the host immune response to infection with the avirulent Mycobacterium tuberculosis strain H37Ra. However, its functional role in modulating pyroptosis and associated inflammatory responses remains incompletely characterized. Here, we demonstrate that BTNL2 deficiency exacerbates pyroptosis and the inflammatory response in H37Ra-infected murine peritoneal macrophages via two distinct pathways. First, the loss of BTNL2 induces excessive mitochondrial damage, which leads to aberrant release of mitochondrial DNA (mtDNA) and accumulation of mitochondrial reactive oxygen species (mtROS), thereby triggering NLRP3 (NOD-like receptor family pyrin domain containing 3) inflammasome activation and gasdermin D (GSDMD)-mediated pyroptosis. Second, cytosolic mtDNA accumulation hyperactivates the cGAS–STING signaling axis, resulting in transcriptional upregulation of NLRP3 and consequent amplification of pro-inflammatory cytokine production. Collectively, these findings demonstrate that BTNL2 acts as a regulator of mitochondrial homeostasis and innate immune balance during H37Ra infection in primary peritoneal macrophages. The results provide mechanistic insights into BTNL2 function in the context of H37Ra-induced pyroptosis. Full article

The aqueous extract of Diaphragma Juglandis Fructus (AED), a by-product of Juglans regia L., represents a promising food-derived functional ingredient with potential benefits for intestinal health. This study evaluated the anti-colitis effects of AED and explored its underlying mechanisms using LPS-stimulated RAW264.7 macrophages and a DSS-induced colitis mouse model. In DSS-induced colitis in mice, AED at 10 μg/mL suppressed pro-inflammatory cytokine production and inhibited JAK1/STAT3 signaling. In DSS-induced colitis in mice, AED at 600 mg/kg for 7 days mitigated DSS-induced colonic injury, restored tight junction proteins, and improved epithelial barrier integrity. Integrated transcriptomic and metabolomic analyses identified AED-associated alterations in arginine-polyamine and taurine-hypotaurine metabolism, while network pharmacology and molecular docking suggested angiotensin-converting enzyme (ACE) and von Willebrand factor (VWF) as candidate functional targets for further investigation. Collectively, these findings indicate that AED exerts anti-colitis effects in association with coordinated changes in inflammatory signaling, metabolic pathways, and barrier-related markers, supporting its potential as a food-derived functional ingredient candidate for ulcerative colitis management. Full article

Glyphosate, the most widely used herbicide worldwide, is now ubiquitous in the environment, posing a growing threat to human health. While accumulating evidence has linked glyphosate exposure to liver injury, the underlying mechanisms remain unclear. In this study, based on data from NHANES 2013–2018, we identified significant associations between glyphosate exposure and abnormal liver function parameters in the general US population. A glyphosate-exposed mouse model was further established, and the results showed that hepatic accumulation of glyphosate induced direct histopathological damage and increased serum AST, ALT, and ALP levels in mice. Combined network toxicology and gene set analyses revealed that glyphosate activated liver macrophages, upregulating genes related to lipid metabolism, inflammation, and pyroptosis. The activation of the pyroptosis pathway was further confirmed by Western blot analysis of NLRP3 inflammasome-associated proteins. Mechanistically, glyphosate disrupted mitochondrial membranes and compromised mitochondrial function, leading to the release of mtDNA, which subsequently activated the cGAS-STING pathway in mouse livers and RAW264.7 macrophages. Moreover, glyphosate-induced NLRP3 activation in RAW264.7 cells was attenuated by the cGAS inhibitor. These findings provide a novel mechanistic insight into glyphosate-induced hepatotoxicity and reinforce the growing concern over its association with liver injury in humans. Full article

Myocardial infarction (MI) triggers excessive oxidative stress, a detrimental immune response, and insufficient angiogenesis, which collectively impede effective cardiac repair. This study developed a multifunctional composite polysaccharide hydrogel, termed KgXd^gel, based on konjac glucomannan (KGM) and xanthan gum (XG) functionalized with gallic acid (GA) and dopamine (DA), respectively, to integrate reactive oxygen species (ROS) scavenging, macrophage polarization, and pro-angiogenic activities. In vitro assays demonstrated that the KgXd^gel hydrogel exhibited excellent cytocompatibility, effectively scavenged ROS, promoted the polarization of macrophages towards the reparative M2 phenotype, and enhanced the migration and tube formation of human umbilical vein endothelial cells. In a rat MI model, treatment with KgXd^gel significantly improved cardiac function (e.g., left ventricular ejection fraction, LVEF; left ventricular fractional shortening, LVFS), attenuated left ventricular dilation (LVIDs), and favorably modulated the post-infarction microenvironment. This was evidenced by the upregulation of the M2 marker CD163 and the angiogenic factor VEGF, alongside the downregulation of pro-inflammatory cytokines (e.g., IL-1β, TNF-α) and the M1 marker iNOS. These findings conclusively demonstrate that the KgXd^gel hydrogel synergistically promotes cardiac repair post-MI through its integrated antioxidant, immunomodulatory, and pro-angiogenic functions, presenting a promising multi-targeted therapeutic strategy. Full article

Copper is essential for the proper functioning of immune cells and participates in diverse biochemical processes. The maintenance of copper ion homeostasis is critical for normal host physiology, while dysregulation of copper metabolism is closely linked to various diseases. Emerging evidence indicates that disease-associated elevations in copper levels significantly enhance macrophage functions, including the expression of inflammatory cytokines, phagocytosis, and bactericidal activity. As key innate immune cells, macrophages not only eliminate invading pathogens but also contribute to immune regulation, tissue repair, and angiogenesis. In this review, we summarize current knowledge of copper transport and homeostatic mechanisms in macrophages and highlight how copper regulates their antimicrobial activity, inflammatory responses, and reparative functions. A deeper understanding of these mechanisms may provide new insights into therapeutic strategies targeting macrophage regulation through copper metabolism in the context of infectious and inflammatory diseases. Full article

Background: The NLRP3 inflammasome drives pathological inflammation in various diseases. PINK1/Parkin-associated mitophagy serves as a critical negative regulator of NLRP3 activation, yet pharmacological enhancers remain scarce. Muscone, a natural macrocyclic ketone with blood–brain barrier permeability, exhibits potent anti-inflammatory properties; however, its mechanistic role within the NLRP3-mitophagy axis remains undefined. Methods: LPS/ATP-stimulated macrophages were employed to assess stage-specific effects of muscone on NLRP3 priming (NF-κB signaling, NLRP3, and pro-IL-1β expression) and activation (ASC oligomerization, ASC–pro-caspase 1 complex formation, and IL-1β secretion). RNA sequencing and bioinformatic analysis were performed for pathway enrichment. Mitophagy was characterized by MitoSOX Red staining for mt-ROS detection, electron microscopy, Western blotting of LC3B-II in isolated mitochondria and PINK1 and Parkin in whole-cell lysates, and live-cell mitochondria–lysosome tracking. In vivo protective efficacy was assessed in an LPS-induced endotoxemia mouse model. Results: Muscone dose-dependently suppressed both the priming and activation stages of the NLRP3 inflammasome, maximally reducing IL-1β secretion by ~60% at 50 μM. Mechanistically, muscone amplified PINK1/Parkin-associated mitophagy, scavenging excessive mt-ROS and attenuating NLRP3 activation. These effects were corroborated by RNA-seq and comprehensive functional assays. In vivo, muscone (30 mg/kg) significantly improved survival (3/8 mice alive at 98 h when all LPS controls had died; 2/8 survived to the 132-h endpoint), with concomitant enhancement of mitophagy markers in peritoneal macrophages. Conclusions: Muscone functions as a PINK1/Parkin-associated mitophagy enhancer that maintains mitochondrial quality control during NLRP3-driven inflammatory responses. Its unique macrocyclic structure and blood–brain barrier permeability provide a promising scaffold for developing therapeutics against inflammatory disorders associated with NLRP3 inflammasome activation. Full article

Endotoxemia represents a life-threatening clinical disorder driven by an aberrant host immune response to pathogenic infection, often resulting in severe multiple organ dysfunction. Among its most devastating complications are acute lung injury (ALI) and endotoxemia-associated encephalopathy (EAE), both of which are associated with elevated mortality and currently lack effective targeted interventions. This study evaluated the therapeutic efficacy and underlying molecular mechanisms of recombinant human thymosin β4 (rhTβ4) in a murine model of lipopolysaccharide (LPS)-induced endotoxemia. Our results showed that treatment with rhTβ4 markedly enhanced survival rates and diminished the systemic overproduction of diverse proinflammatory cytokines and chemokines in endotoxemic mice. These systemic protective actions were achieved through the inhibition of the TLR4/NF-κB signaling cascade, the reduction in M1 macrophage polarization, and the simultaneous alleviation of mitochondrial impairment and oxidative stress. Moreover, rhTβ4 treatment significantly rescued EAE-related cognitive deficits and attenuated neuronal damage, primarily through the suppression of neuroinflammation and microglial overactivation. Integrative transcriptomic profiling and functional assays identified lysophosphatidic acid receptor 3 (LPAR3) as an important contributor, suggesting that rhTβ4 suppresses microglial-mediated neurotoxicity at least in part through LPAR3 downregulation. In conclusion, rhTβ4 confers robust multi-organ protection against endotoxemic injury by orchestrating the inhibition of systemic and central neuroinflammatory cascades, positioning it as a promising candidate for the treatment of endotoxemia-induced ALI and EAE. Full article

This study integrates multidimensional computational approaches—network toxicology, machine learning, molecular docking, and molecular dynamics simulation—to systematically elucidate the toxic mechanism by which the environmental pollutant diisononyl cyclohexane-1,2-dicarboxylate (DINCH) contributes to atherosclerosis. By jointly mining multiple databases, we obtained 246 targets common to DINCH and atherosclerosis. LASSO regression and support vector machine–recursive feature elimination (SVM-RFE) then identified 8 significantly upregulated core targets (CSF1R, CD36, CCL3, CCR2, ADAM8, TLR1, CTSS, and MMP1). Functional enrichment analysis showed that these core targets were significantly associated with key signaling pathways, including lipid and atherosclerosis, the PPAR signaling pathway, the PI3K–Akt signaling pathway, and the AGE–RAGE signaling pathway in diabetic complications. Differential gene analysis confirmed that these genes were significantly upregulated in diseased tissues, and receiver operating characteristic (ROC) analysis demonstrated excellent diagnostic performance (AUC = 0.87–0.96). Immune cell infiltration analysis further revealed a strong association between the core targets and immune cell populations, notably macrophages and T cells. Molecular docking and molecular dynamics simulations showed that DINCH had high affinity for the core targets, and its binding to CCR2 was the most stable (binding free energy = −7.6 kcal/mol). The final AOP framework systematically presented the cascade by which DINCH may contribute to atherosclerosis through metabolic disruption and immune activation. This study provides new mechanistic insights into the development of DINCH-induced atherosclerosis and offers a theoretical basis for health risk assessment of environmental pollutants. Full article

Background: Ovarian cancer (OVCA) remains the most lethal gynecologic malignancy, with poor prognosis largely due to late-stage diagnosis and therapy resistance. Pyroptosis, a pro-inflammatory form of programmed cell death, has recently emerged as a regulator of tumor progression and immune regulation. This study aimed to systematically profile pyroptosis-related genes and identify robust biomarkers for OVCA. Methods: Microarray data from the GSE54388 dataset were analyzed to characterize pyroptosis-related gene expression. Immune cell infiltration was assessed using xCell, and pathway enrichment was performed via Gene Set Enrichment Analysis (GSEA). Weighted Gene Co-expression Network Analysis (WGCNA) identified hub genes, followed by Gene Ontology (GO) and Reactome enrichment. Machine learning algorithms (Support Vector Machine, XGBoost, and Generalized Linear Model) were employed for feature selection and biomarker identification. Validation was conducted across independent bulk and scRNA-seq datasets, with GEPIA2 used to compare OVCA and normal samples and KMplot for survival analysis. Results: OVCA samples showed significantly reduced infiltration of CD4⁺ and CD8⁺ T cells, mast cells, monocytes, neutrophils, and immature dendritic cells compared to normal samples. GSEA revealed enrichment of cell cycle-related pathways, implicating pyroptosis-related genes as key regulators of mitotic progression. From 1097 differentially expressed genes, 22 pyroptosis-related DEGs (PYRDEGs) were identified, with nine hub genes (CASP1, CEP55, CHMP4C, HTRA1, IL18, MELK, PKM, PTX3, TNFSF13B) strongly associated with OVCA. Functional enrichment linked these genes to cytokinesis, inflammasome activity, and immune signaling. Machine learning consistently identified CEP55 as the core biomarker, demonstrating high diagnostic accuracy (AUC up to 0.972) and significant upregulation in OVCA samples. Correlation analysis linked CEP55 expression to altered immune cell populations, including positive associations with Th1 and class-switched memory B-cells and negative associations with iDCs, Tregs, and M2 macrophages. CEP55 was highly expressed across bulk and scRNA-seq datasets (cancer epithelial and CD8+ TEMRA cells) and negatively correlated with overall survival (OS) and progression-free survival (PFS). Conclusions: Pyroptosis-related genes play pivotal roles in OVCA pathogenesis. CEP55 emerges as a promising biomarker for early detection and a potential therapeutic target, bridging cell cycle regulation with immune modulation. Full article

This translational synthesis highlights the potential role of obesity-induced low-grade chronic inflammation in modulating clinical outcomes among patients with spondyloarthritis (SpA). Obesity transforms adipose tissue into a pro-inflammatory endocrine organ, where hypertrophic adipocytes release adipokines such as leptin alongside cytokines including TNF-α and IL-6, potentially contributing to macrophage polarization toward an M1 phenotype and activating NF-κB signaling pathways. This systemic immunometabolic priming may lower activation thresholds at the enthesis—the primary pathological site in SpA—potentially amplifying IL-23/IL-17 axis activity via Th17 bias, innate-like lymphocyte responses, and stromal–immune crosstalk under mechanical stress. Clinically, patients with SpA and obesity have been reported to demonstrate heightened disease activity (BASDAI, ASDAS), impaired function (BASFI), accelerated radiographic progression (syndesmophytes, enthesophytes), and diminished biologic response rates, potentially attributable to pharmacokinetic alterations (e.g., subtherapeutic TNF inhibitor levels) and pharmacodynamic resistance. Multisystem comorbidities, including non-alcoholic fatty liver disease, cardiovascular events, metabolic syndrome, sleep disturbances, and depression, further exacerbate morbidity and diminish quality of life. Therapeutic implications emphasize obesity as a modifiable disease modifier. Weight loss interventions, including hypocaloric diets, anti-inflammatory regimens (e.g., Mediterranean diet), multicomponent exercise, GLP-1 receptor agonists, and bariatric surgery, have been associated with reductions in inflammatory biomarkers, improved remission rates (MDA, DAPSA), and prolonged drug survival by restoring adipokine balance and disrupting mechano-inflammatory loops. Future randomized controlled trials should prioritize long-term evaluations of integrated multidisciplinary strategies that combine metabolic optimization with immunomodulatory therapies, addressing adherence challenges through psychological support and patient-tailored protocols, while elucidating dose–response relationships for GLP-1RAs and exercise in diverse SpA subtypes to establish precision management paradigms that mitigate cardiometabolic burden and improve holistic outcomes. Full article

Oxidative stress is a key contributor to aging and chronic diseases, highlighting the need for safe and effective natural antioxidants. Monascus yellow pigments (MYPs) and ginsenoside Rg3 exhibit antioxidant activity, but their applications are restricted by low solubility and limited natural abundance. In this research, a bidirectional liquid fermentation system of Monascus ruber using ginseng decoction was established for the simultaneous production of water-soluble MYPs (WSMYPs) and ginsenoside Rg3. Process conditions were optimized to enhance the yields and the antioxidant activity of the system. Antioxidant assays and H₂O₂-induced RAW264.7 cell models confirmed that WSMYPs were strongly correlated with antioxidant capacity, with ABTS and DPPH scavenging activities showing 2.28-fold and 3.33-fold increases, respectively, compared to the control. Their combination with Rg3 exerted synergistic protective effects by enhancing the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT). Network pharmacology and molecular docking further revealed that Monapurone C, a representative WSMYP, and Rg3 act through a multi-target, multi-pathway antioxidant network involving signaling pathways such as PI3K-Akt. This study demonstrates a cost-effective strategy for co-producing WSMYPs and Rg3, providing new insights into the value-added utilization of edible and medicinal resources. Full article