Search Results (670)

The endocannabinoid system (ECS) is increasingly recognized as a central regulator of immune homeostasis, integrating neural, metabolic, and immune signaling to maintain physiological equilibrium. This Perspective examines the “therapeutic paradox” of endocannabinoid immunomodulation, whereby anti-inflammatory and tissue-protective effects are mechanistically linked to transient immunosuppression. Although cannabinoid receptor 2 (CB2) is the primary mediator of immune regulation, growing evidence indicates that cannabinoid receptor 1 (CB1) also contributes to inflammatory control in both the central nervous system and peripheral tissues. Activation of CB2 suppresses inflammatory signaling through Gi/o-mediated inhibition of adenylate cyclase, reduced cyclic adenosine monophosphate (cAMP) signaling, and repression of nuclear factor kappa B (NF-κB)-dependent transcription. While these mechanisms limit pathological inflammation and promote tissue protection, they simultaneously attenuate innate and adaptive immune functions required for effective pathogen clearance. Across neuroinflammatory disorders, inflammatory bowel disease, hepatic injury, sepsis, cancer, and systemic inflammatory syndromes, the ECS shifts immune responses toward resolution at the cost of reduced antimicrobial readiness. We synthesize the molecular mechanisms underlying this therapeutic paradox, including macrophage polarization, lymphocyte reprogramming, and tissue-specific immune adaptations, and discuss strategies for developing endocannabinoid-based therapeutics that preserve anti-inflammatory efficacy while minimizing immunosuppressive liabilities. Full article

As a natural purine metabolite, inosine’s impact on kidney-related diarrhea through its influence on gut microbiota and associated metabolic functions remains unclear. Kidney-related diarrhea was induced in male KM mice. Histopathological alterations and inflammatory infiltration were assessed using hematoxylin and eosin (HE) staining. ELISA was used to measure corticosterone (CORT), antidiuretic hormone (ADH), and adenosine triphosphate (ATP) to assess metabolic status and fluid homeostasis. Immunohistochemistry (IHC) staining techniques, Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR), and Western blot (WB) were used to analyze the expression of aquaporin-4 (AQP4), AMP-activated protein kinase (AMPK), nuclear factor kappa-B (NF-κB), and adenosine A2A Receptor (A2AR). Gut microbiota composition and predicted functional pathways were analyzed using 16S rRNA sequencing and KEGG-based functional prediction, followed by correlation analyses between the microbiota and factors. Inosine improved renal function, alleviated renal and colonic histopathological damage, and reduced inflammatory infiltration. It also increased ATP, ADH, and CORT levels, indicating improvements in metabolic and fluid-balance-related factors. Inosine also increased A2AR, AMPK, and AQP4 expression while decreasing NF-κB expression. Moreover, inosine altered gut microbial composition and was associated with differences in predicted microbial functional pathways. Significant correlations were observed between specific bacterial taxa and host indicators. Inosine alleviated kidney-related diarrhea in mice, accompanied by improvements in metabolic status and fluid homeostasis, reduced inflammation, modulation of A2AR/AMPK/NF-κB-related signaling pathway, and alterations in gut microbial composition. Further studies are required to clarify the causal contributions of gut microbial composition and functional activity to the beneficial effects of inosine. Full article

Redox homeostasis is essential for intestinal and systemic health and is regulated by antioxidant defense systems and redox-sensitive signaling pathways such as the nuclear factor erythroid 2-related factor 2 (Nrf2) and the nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells (NF-κB). Disturbances in this balance promote oxidative stress, chronic inflammation, and disease progression. Increasing evidence indicates that microbiota-derived metabolites act as key modulators of redox biology by shaping host gene expression through receptor-mediated signaling, metabolic regulation, and chromatin-associated mechanisms, including histone modifications, DNA methylation, and changes in chromatin accessibility. This review discusses how major classes of microbiota-derived and microbiota-modulated metabolites, including short-chain fatty acids (SCFAs), secondary bile acids, tryptophan-derived metabolites, polyphenol metabolites, hydrogen sulfide, and lipid mediators, influence redox-sensitive signaling and epigenetic regulation. We highlight their effects on intestinal barrier integrity and immune cell function, with particular emphasis on macrophage polarization and T-cell differentiation. Finally, we consider the emerging translational relevance of the microbiota–metabolite–epigenetic axis, while emphasizing that biomarker development and therapeutic applications require further mechanistic validation and clinical studies. Full article

Background: Acute liver injury (ALI) is commonly caused by acetaminophen (APAP) overdose, which drives oxidative stress alongside activation of innate immune signaling. Casticin, a naturally occurring flavonoid, has anti-inflammatory and antioxidant properties. Focusing on the toll-like receptor 4 (TLR4)/myeloid differentiation primary response 88 (MyD88)/tumor necrosis factor receptor-associated factor 6 (TRAF6)/nuclear factor kappa B (NF-κB) pathway, this study assessed casticin’s ability to protect mice from APAP-induced hepatotoxicity. Methods: APAP-induced ALI was established in mice randomly assigned to the following six groups: normal control, casticin control, APAP, APAP plus N-acetylcysteine (NAC), APAP plus low-dose casticin, and APAP plus high-dose casticin. Casticin was administered for three consecutive days before APAP to evaluate its preventive rather than therapeutic potential. Biochemical and histological analyses were performed, with molecular assessments using Western blotting, ELISA, quantitative real-time PCR (qPCR), and immunohistochemistry. Results: APAP significantly elevated serum ALT, AST, and ALP and markedly deteriorated hepatic architecture, confirming hepatotoxicity. APAP also induced lipid peroxidation and depleted antioxidant defenses. Hepatic TNF-α and IL-6 increased, IL-10 decreased, and the abundance of TLR4, MyD88, TRAF6, and NF-κB p65 was elevated. Casticin reduced these pathway components, lowered TNF-α and IL-6, and increased IL-10 dose-dependently, with effects approaching those of NAC. Conclusions: Casticin protected the liver against APAP toxicity, restraining oxidative injury while damping TLR4/MyD88/TRAF6/NF-κB signaling. Full article

Metabolic diseases are characterized by a complex interplay between metabolic dysregulation and chronic low-grade inflammation. Fetuin-A (FetA), a liver-derived hepatokine, has emerged as a key mediator linking these processes through its pro-inflammatory and insulin resistance-promoting effects. Accumulating evidence indicates that FetA not only serves as a biomarker but also actively contributes to disease pathogenesis by modulating multiple signaling pathways. In this review, we present an overview of the molecular mechanisms underlying FetA-induced suppression of peroxisome proliferator-activated receptor (PPAR) signaling, a central regulator of metabolic homeostasis. Emerging evidence suggests that FetA may promote Toll-like receptor 4 (TLR4)-mediated inflammation, activate nuclear factor kappa B (NF-κB) signaling, suppress key energy regulators such as Sirtuin 1 (SIRT1) and AMP-activated protein kinase (AMPK), and inhibit PPAR activity through Wnt and extracellular signal-regulated kinase (ERK) pathways. These interconnected mechanisms may contribute to impaired lipid metabolism, increased insulin resistance, and metabolic inflammation. Furthermore, we highlight the role of FetA glycosylation, particularly fucosylation, as a regulatory layer influencing its biological activity. Fucosylated FetA may more effectively activate TLR4 signaling and suppress PPAR activity, suggesting functional heterogeneity among glycoforms. Overall, the FetA–PPAR interaction may represent a key mechanistic link between metabolic inflammation and disease progression. Full article

Medical ozone has emerged as a potential redox-modulating intervention in inflammatory and degenerative conditions, particularly in dermatological contexts characterized by chronic oxidative imbalance and impaired tissue remodeling. Unlike conventional pharmacological agents, ozone exerts its biological activity through rapid chemical reactions generating transient reactive and electrophilic species that activate endogenous adaptive signaling pathways. Controlled oxidative perturbations activate antioxidant transcriptional programs, primarily mediated by the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, while modulating inflammatory signaling networks, including nuclear factor kappa B (NF-κB) and the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. This dual behavior reflects hormetic responses in which low-dose exposure promotes adaptive cellular signaling, whereas excessive oxidative burden leads to structural and functional damage. This review summarizes current knowledge on the molecular mechanisms underlying ozone-induced redox modulation, with emphasis on chemical reactivity, spatiotemporal signaling dynamics, thiol-based sensing, and metabolic reinforcement of antioxidant defenses. Particular attention is given to skin and subcutaneous adipose tissue, where oxidative stress, immune activation, and extracellular matrix remodeling converge. Dose dependency, safety constraints, and methodological variability are critically discussed, highlighting the narrow threshold between adaptive signaling and oxidative injury and the need for rigorous mechanistic and clinical validation. Full article

Emerging evidence links gut microbiota (GM) dysbiosis to hyperuricemia (HUA). The GM plays a critical role in regulating host health and homeostasis by producing a diverse array of metabolites, including short-chain fatty acids, bile acids and uremic toxins. Dysregulation of the microbial metabolite profile has been implicated in the pathogenesis of HUA. Given the urgent need for green and safe urate-lowering therapies for HUA, recent years have seen an increasing focus on interpreting the ability of natural products to modulate these microbial metabolites. Such interventions enhance beneficial metabolites and suppress uremic toxins, thereby alleviating HUA through coordinated regulation of urate transporters, restoration of intestinal barrier integrity, reprogramming of systemic metabolic disturbances, and inhibition of inflammation via Toll-like receptor 4 (TLR4)/ nuclear factor kappa B (NF-κB), Janus kinase (JAK)/ signal transducer and activator of transcription (STAT), and Phosphatidylinositol-3-kinase (PI3K)/ protein kinase B (AKT) pathways. Furthermore, a comprehensive translational roadmap has been proposed, grounded in a critical appraisal of current trial limitations. Overall, this review consolidates evidence for the protective effects of natural products against HUA and related comorbidities, with an emphasis on GM-derived metabolites, aiming to expand clinical applications and provide insights for future studies. Full article

Background/Objectives: Estrogen is a key female hormone; however, its role in periodontitis remains poorly understood. This study investigated the effects of 17β-estradiol (E2) on experimental periodontitis using an ovariectomy (OVX) model with E2 administration. Methods: Female mice aged 8–10 weeks underwent OVX, followed by induction of ligature-induced periodontitis, and subsequent quantification of alveolar bone resorption. Additional groups received an aromatase inhibitor or E2 supplementation after OVX, with subsequent induction of periodontitis and evaluation of bone resorption. Histological analysis assessed multinucleated giant cells and tartrate-resistant acid phosphatase-positive osteoclasts on the bone surface. Gingival tissue was analyzed for gene expression related to osteoclastogenesis. The effect of E2 on osteoclast differentiation from bone marrow cells was also examined. Results: OVX significantly reduced serum E2 levels and decreased alveolar bone resorption. Aromatase inhibitor administration similarly reduced bone loss. Histological evaluation revealed a reduced number of resorbing osteoclasts in OVX mice, whereas E2 supplementation increased osteoclast numbers. No significant changes in inflammatory cytokine or receptor activator of nuclear factor-kappa B ligand (RANKL) expression were observed. E2 promoted osteoclast differentiation in vitro, and treatment with E2 prior to RANKL stimulation further increased the number of osteoclasts. This effect was suppressed by an estrogen receptor antagonist. Moreover, E2 enhanced the expression of osteoclast differentiation–associated genes in the presence of RANKL, an effect abolished by tamoxifen. Conclusions: E2 increased alveolar bone resorption in experimental periodontitis, likely by promoting osteoclast differentiation, independent of inflammatory cytokine or RANKL gene expression. Full article

Periodontitis is a chronic inflammatory disease driven largely by dysregulated host responses that lead to destruction of periodontal tissues. Integrins are heterodimeric transmembrane receptors that regulate cell adhesion and bidirectional signaling in epithelial cells, immune cells, periodontal ligament fibroblasts, and osteoclasts. During disease progression, integrin-related responses may shift across overlapping molecular phases. Epithelial integrins such as α3β1 and α6β4 support barrier integrity, whereas α5β1 may facilitate microbial interaction and inflammatory signaling. β2 integrins and α4β1 contribute to leukocyte recruitment and inflammatory amplification, whereas increased α9β1-associated signaling and reduced αvβ6-mediated regulation of transforming growth factor β (TGF-β) may promote inflammatory persistence. Matrix-associated integrins, including α2β1 and α11β1, support extracellular matrix (ECM) organization and mechanotransduction, whereas αvβ3 cooperates with Receptor activator of nuclear factor kappa B ligand (RANKL) to promote osteoclast activity and alveolar bone resorption. Impaired β1 integrin-dependent signaling and potentially reduced αvβ5-associated efferocytosis may contribute to defective resolution and regeneration. Importantly, integrin expression, activation, and downstream signaling are distinct, and the strength of evidence varies among integrin subtypes. This review proposes a conceptual framework in which periodontitis reflects a dynamic imbalance in integrin-mediated processes that link inflammation, bone resorption, and regenerative failure, rather than being a direct equivalent of clinical periodontal stages or grades. Full article

The present study aimed to evaluate the role of ascorbic acid in alleviating ammonia-induced muscle quality deterioration and to clarify its regulatory effects on apoptosis, texture, and flavor-related metabolites in rainbow trout (Oncorhynchus mykiss). The results demonstrated that ascorbic acid alleviated ammonia stress-induced inflammatory and apoptotic damage by regulating toll like receptor 5 (TLR5), myeloid differentiation primary response 88 (MyD88), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) expression, thereby contributing to the restoration of myofibrillar integrity, reduced extracellular gaps, and increased shear force from 14.18 N to 18.26 N (p < 0.05). Ascorbic acid modulated ammonia handling and ion-exchange responses by upregulating glutamine synthetase (GS) expression from approximately 2.3-fold to 6.7-fold and increasing ornithine and citrulline accumulation. Alterations in tricarboxylic acid cycle-related metabolites further suggested that energy metabolism may be involved in the physiological adaptation to ammonia stress. Meanwhile, the ascorbic acid reduced the accumulation of key off-flavor compounds (1-octene-3-alcohol and (E)-2-nonenal), attenuating the earthy–moldy and fishy flavor. This research proposes a potential strategy to improve muscle quality in live transportation. Full article

Women with polycystic ovary syndrome (PCOS) and insulin resistance (IR) commonly have elevated serum advanced glycation end-products (AGEs) that accumulate in their ovaries, potentially altering ovarian function. AGEs have been shown to interfere with insulin signaling in granulosa cells (GCs) by suppressing the translocation of glucose transporters. Additionally, PCOS has been associated with insulin receptor substrate (IRS)-1 polymorphisms and upregulation in IRS-1 gene expression in GCs. We hypothesize that AGEs are partly responsible for ovarian IR by altering IRS-1 in human GCs. Cumulus granulosa cells from women undergoing IVF were cultured in control media or media containing human glycated albumin (HGA) as a source of AGEs. The quantification of mRNA expression was compared using RT-PCR for receptors for AGEs (RAGE), IRS-1, IRS-2, Glucose Transporter Type (GLUT)-1, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). In addition, IRS-1 protein intensity was assessed by immunofluorescence. Compared to the control group, HGA-treated GCs showed a statistically significant upregulation in RAGE mRNA by 314% and in IRS-1 mRNA by 423%. Even though there was a 183% increase in GLUT-1 mRNA, it did not reach statistical significance. There was no change in IRS-2 or NF-κB mRNA expression levels. Immunofluorescence showed that IRS-1 deposition was visualized in GCs, and the addition of HGA resulted in a significant increase in the intensity of IRS-1 protein compared to control cells. The AGE-induced upregulation in IRS-1, the primary insulin receptor substrate, in GCs could indicate compensation for insulin action deficiency and potentially IR. Additionally, immunofluorescence analysis of GLUT-4 revealed a statistically significant reduction in cytoplasmic GLUT-4 signal in HGA-treated GCs compared to controls (2.10 ± 0.21 vs. 3.81 ± 0.22 arbitrary units; p = 0.010), consistent with AGE-mediated disruption of glucose transporter localization. These results suggest that AGE exposure may initiate early molecular changes consistent with altered insulin signaling, but do not establish insulin resistance per se. Full article

Background/Objectives: Exposure to particulate matter (PM) containing bacterial endotoxins triggers inflammation and oxidative stress in the respiratory epithelium. In this study, we investigated chitosan nanoparticle-loaded Cordyceps militaris grown on germinated Rhynchosia nulubilis (GCN) as a potential functional food-derived ingredient against PM- and lipopolysaccharide (LPS)-induced cellular damage in human lung epithelial cells. Methods: This study employed an integrative approach combining GCN analysis with bioinformatics methods using a PM- and LPS-induced pulmonary cellular inflammation model. Gene Expression Omnibus (GEO) transcriptomic datasets and Cytoscape-based network analysis were utilized to identify key hub genes and signaling pathways associated with PM- and LPS-induced pulmonary inflammation, which were subsequently validated by RT-PCR and Western blotting. Results: Nano-encapsulation significantly improved the antioxidant capacity and storage stability of the extract compared with non-encapsulated Cordyceps militaris grown on germinated Rhynchosia nulubilis (GRC). GCN markedly attenuated PM- and LPS-induced cytotoxicity and intracellular reactive oxygen species (ROS) production in a dose-dependent manner, resulting in a therapeutic index approximately 4.5-fold higher than that of GRC under PM and LPS co-exposure. Bioinformatics analysis identified inflammation-related genes and pathways associated with PM- and LPS-induced pulmonary responses, primarily enriched in tumor necrosis factor (TNF)-related inflammatory pathways, Toll-like receptor signaling, and cytokine signaling. Consistent with these findings, GCN suppressed the expression of C-X-C motif chemokine ligand 2 (CXCL-2) and tumor necrosis factor-alpha (TNF-α) mRNA and inhibited mitogen-activated protein kinase (MAPK)-mediated activator protein-1 (AP-1) and nuclear factor-kappa B (NF-κB) signaling pathways in human type II alveolar epithelial cells (A549). Conclusions: Collectively, nano-encapsulation enhanced the stability and bioactivity of Cordyceps militaris-based extracts, suggesting that GCN may have potential as a functional food-derived candidate ingredient to protect airway epithelial cells against inflammation and oxidative stress induced by PM and LPS. As this study was conducted using an in vitro A549 epithelial cell model, further validation in physiologically relevant systems is needed to confirm its translational applicability. Full article

Background/Objectives: This prospective observational cohort study aimed to evaluate the influence of heated tobacco (HT) and electronic cigarettes (ECs) on bone remodeling markers such as receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG), and periodontal status, at baseline and at 3 months after initial periodontal therapy. Methods: The sample comprised 236 participants (130 women, 106 men; mean age 38.96 ± 7.69 years), distributed across non-smokers (n = 72), heated tobacco/HT product users (n = 83), and electronic cigarette/EC users (n = 81). For each patient, the periodontal charting included periodontal probing depth (PPD), bleeding on probing (BOP), and clinical attachment loss (CAL). Unstimulated saliva samples were analyzed for RANKL and OPG levels. All patients underwent nonsurgical periodontal therapy (scaling and root planing). Between-group comparisons were performed using the Kruskal–Wallis test followed by Bonferroni-adjusted pairwise comparisons, while within-group changes over time were assessed using the Wilcoxon signed-rank test. To complement the primary nonparametric analyses, two-way mixed-design ANOVA and ANCOVA models adjusted for baseline values and periodontitis stage were performed as sensitivity analyses. Statistical significance was set at p < 0.05. Results: At baseline, both product user groups exhibited significantly higher PPD (p = 0.005) and CAL (p = 0.001) compared with non-smokers, with no differences between HT and EC users. Salivary RANKL levels were significantly higher in HT and EC users than in non-smokers, and OPG levels did not differ significantly. Following non-surgical periodontal therapy, all parameters improved significantly across groups (p < 0.001). At the 3-month follow-up, both product user groups maintained higher PPD (p = 0.008), CAL (p = 0.001), and salivary RANKL levels, compared with non-smoking individuals (p < 0.001). The RANKL/OPG ratio remained significantly different only for EC users compared with non-smokers (p < 0.001). Conclusions: HT and EC use were associated with differences in periodontal parameters and higher RANKL levels, while differences in the RANKL/OPG ratio were observed in EC users compared with non-smokers. Non-surgical periodontal therapy improved clinical parameters and reduced the RANKL/OPG ratio, highlighting the importance of biofilm control. Full article

Inflammaging is defined as chronic low-grade inflammation associated with aging and is increasingly recognized as a dynamic and mechanistically driven biological process rather than a state adequately described by circulating biomarkers alone. Traditional inflammatory markers alone, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and C-reactive Protein (CRP), fail to capture the complexity, tissue specificity, and causal architecture of inflammaging. Recent experimental evidence has demonstrated that diverse upstream drivers, including immunosenescence, gut microbiome dysbiosis, metabolic dysfunction, and cellular senescence, converge on a limited number of central inflammatory hubs, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, GMP–AMP synthase–stimulator of interferon genes (cGAS–STING), Janus kinase/signal transducer and activator of transcription (JAK/STAT), and p38 mitogen-activated protein kinase (p38 MAPK) signaling. These mechanistic nodes represent promising therapeutic targets, potentially modifiable biological processes, and support the emerging concept of ‘druggable inflammaging’, whereby senotherapeutics, inflammasome inhibitors, innate immune modulators, and metabolic interventions may actively modify aging-associated inflammatory biology rather than simply monitor it through biomarkers. This review highlights a paradigm shift from biomarker-based assessment toward mechanism-based intervention, where inflammaging can be characterized as a modifiable biological process and a central target for precision pharmacological strategies in aging-related diseases. Full article

Chronic low-grade inflammation is a hallmark of aging and a major driver of metabolic and degenerative diseases. While systemic immune dysfunction has been widely investigated, the contribution of barrier tissues to persistent inflammatory signaling remains incompletely defined. The oral mucosa represents a uniquely exposed barrier, continuously challenged by microbial, mechanical, and metabolic stressors and characterized by a specialized immune architecture. Here, we synthesize current evidence supporting the oral barrier as an active immunometabolic interface linking local immune activation to systemic inflammatory tone. Spatially organized epithelial, neutrophil, and antigen-presenting cell (APC) compartments coordinate immune responses tightly coupled to metabolic reprogramming, including hypoxia-inducible factor-1α (HIF-1α)-dependent glycolysis and mitochondrial reactive oxygen species (mtROS) production. In parallel, the oral microbiota provides ligands and metabolites such as lipopolysaccharide (LPS), short-chain fatty acids (SCFAs), and succinate, which activate pattern-recognition receptors (PRRs), including toll-like receptors (TLRs) and the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, thereby sustaining nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB)-mediated inflammatory signaling. Barrier disruption and dysbiosis promote microbial translocation and persistent innate immune activation, while saliva and gingival crevicular fluid facilitate systemic dissemination of inflammatory mediators. Overall, sustained immunometabolic engagement at the oral barrier emerges as a key driver of chronic low-grade systemic inflammation and a potential therapeutic target in inflammaging. Full article