Search Results (289)

RARγ is expressed during embryogenesis by stem/primitive progenitor cells, indicating a role in controlling their development. Supporting this view is that a physiological level of 10 nM of the RARγ agonist AGN205327 blocked stem/progenitor cell differentiation during zebrafish embryogenesis, mouse gastruloid development, and adult chondro- and osteogenesis. Similarly, transgene expression of RARγ or the use of the RARγ agonist CD437 enhanced the generation of induced pluripotent stem cells (iPSCs) from human and mouse somatic cells. RARγ regulates many events that control the behavior of stem/progenitor cells regarding whether they develop to give rise to mature cells. RARγ positively regulates the expressions of NOTCH ligands and their receptors, transforming growth factors (TGFs), and molecules pertaining to cell identity, extracellular matrix communication, and all-trans retinoic acid synthesis and catabolism. The genes that are repressed by RARγ include RARγ, PPARγ, and RXRα. RARγ integrates into Wnt/β-catenin and TGFβ signaling by acting as a co-factor to the gene co-activator β-catenin and transcription factor Smad3, respectively. Within the cytoplasm, RARγ regulates Akt/NF-κB signaling. As a model, we propose that ATRA ligand-activated RARγ acts as a gatekeeper to stem cell developmental progression during embryogenesis and that this role extends to stem/progenitor cell homeostasis within adult tissues. Full article

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively triggers apoptosis in malignant, infected, or stressed cells while sparing normal tissues, making it an attractive therapeutic candidate. However, many tumors exhibit intrinsic or acquired resistance to TRAIL, driven by reduced DR4/DR5 surface expression, elevated decoy receptor levels, dysregulated DISC assembly, overexpression of c-FLIP and anti-apoptotic Bcl-2 family proteins, or activation of survival pathways such as NF-κB, PI3K/Akt, and MAPK. Moreover, TRAIL receptors can initiate non-canonical signaling pathways that promote migration, invasion, and metastasis in specific oncogenic contexts, thereby further limiting therapeutic efficacy. We aimed to integrate mechanistic insights into TRAIL biology with current therapeutic advances, providing a comprehensive framework for understanding resistance and for designing rational TRAIL-based combination strategies. We summarized the structural and signaling features of TRAIL receptors, outlined the major determinants of TRAIL sensitivity, and evaluated predictive biomarkers that may guide patient selection. In addition, we examined next-generation TRAIL agonists and targeted delivery systems developed to enhance receptor clustering, pharmacokinetics, and tumor specificity. Together, these insights highlight the therapeutic promise of mechanistically informed TRAIL combinations. A deeper understanding of resistance pathways and biomarker-guided stratification will be essential for restoring apoptotic competence and improving clinical outcomes. Full article

Background/Objectives: Aryl hydrocarbon receptor (AHR) ligands are known to suppress antibody production. However, it remains unclear whether this suppression translates into altered antibody-mediated Fcγ receptor signaling in human cells. This study aimed to investigate the effects and mechanisms by which AHR ligands regulate antibody production and antibody-triggered responses in human peripheral blood mononuclear cells (PBMCs). Methods: PBMCs were isolated from blood obtained from anonymous healthy donors. PBMCs were stimulated with pokeweed mitogen (PWM) to induce IgG1 production or Strept-Biotin IgG1/IgG2 immune complexes to induce antibody-triggered signaling. Before any stimulation, cells were pretreated with vehicle (0.01% DMSO) or AHR ligands TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), ITE (2-(1H-indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester), or FICZ (6-formylindolo[3,2-b]carbazole), or the proligand I3C (indole-3-carbinol). Results: Our data revealed that PWM stimulation significantly increased IL6 and IL1B gene expression and PWM-induced IL-6 cytokine secretion, which was significantly suppressed by TCDD, ITE, FICZ, and I3C. However, only TCDD was able to suppress PWM-stimulated IgG1 antibody production. Transcriptomic analysis using I3C revealed upregulated AHR-responsive genes such as CYP1A1, CYP1B1, AHRR and TIPARP in PWM-stimulated human PBMCs. Notably, I3C downregulated genes TRAPPC9 and C1QTNF3, which play a role in NF-κB-associated inflammatory signaling. It also revealed potential sex differences in I3C-mediated gene modulation associated with B cell function, Ig expression, FcγR signaling, and inflammatory pathways. Lastly, IgG1 and IgG2 immune complex-stimulated IL-6 cytokine secretion was significantly suppressed by TCDD, whereas I3C showed modest, although not statistically significant, suppression. Conclusions: Overall, these findings demonstrate that AHR activation by TCDD suppressed antibody production and IgG-mediated immune signaling in human PBMCs. Full article

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate below 10%. Cancer-associated fibroblasts (CAFs) promote epithelial–mesenchymal transition (EMT) and metastasis, yet the specific CAF subtypes and molecular axes driving PDAC progression remain incompletely understood. Here, using multi-omics data from PDAC samples, we identified a malignant ductal subpopulation, termed Ductal-T0, characterized by the highest EMT activity and prominent acquisition of myofibroblastic CAF (myCAF)-like transcriptional programs. Computationally, we predicted that myCAF-secreted THBS2 and FN1 engage the ITGA3/ITGB1/SDC1/SDC4 receptor axes in Ductal-T0 cells, which could activate TNF, NF-κB, TGF-β, and PI3K-AKT-signaling pathways to promote EMT. Pseudotime trajectory and velocity analyses suggested that Ductal-T0 cells exhibited the highest propensity to acquire myCAF-like features among all ductal subpopulations. Survival analysis revealed that an increased proportion of Ductal-T0 cells and elevated abundance of THBS2-ITGA3/ITGB1 and THBS2-SDC1 ligand–receptor pairs were significantly associated with poor prognosis. Spatial transcriptomics further revealed that myCAFs and Ductal-T0 cells co-localized at the tumor margin, which may contribute to reduced immune cell presence via dense extracellular matrix (ECM) barrier formation—a computationally inferred model of EMT-associated immune exclusion and metastatic progression—and identify THBS2 as a promising candidate for future therapeutic investigation to disrupt CAF–tumor crosstalk in PDAC. Full article

Exercise generally elicits changes in bone and inflammatory biomarkers, but it is unclear if these changes are related. The purpose of this secondary analysis was to investigate associations between bone and inflammatory biomarkers before and after a single bout of high-intensity/impact exercise and post-exercise nutrition. In a repeated measures crossover design, 13 healthy, young adult females (age = 20.3 ± 2.3 y) performed high-intensity resistance and impact exercise followed by nutrient consumption (skim milk and an isoenergetic carbohydrate beverage). Venous blood was obtained pre-exercise, 15 min, 75 min, 24 h, and 48 h post-exercise. Serum bone biomarkers (cross-linked C-telopeptide of type I collagen [CTX], receptor activator of NF-κB ligand [RANKL], sclerostin [SOST], osteoprotegerin [OPG], total osteocalcin [OC]) and cytokines (interleukin [IL]-1β, IL-6, IL-10, and tumor necrosis factor-alpha [TNF-α]) were measured. Separate linear mixed regression models were performed for each bone biomarker. There were significant associations between bone and inflammatory biomarkers, including CTX with TNF-α (positive) and IL-10 (negative), OPG with TNF-α (negative) and IL-10 (positive), RANKL with IL-6 (positive) and SOST with TNF-α (negative) and IL-10 (positive). Thus, relationships exist between inflammatory and bone biomarkers in the context of an exercise and nutrition stimulus, which may have implications for optimizing exercise recovery strategies. 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

Objectives: Inflammatory bowel disease (IBD) is associated with extraintestinal comorbidities, and lung diseases are widespread manifestations. Respiratory bacterial insult is a common illness that results in acute lung injury (ALI) in critical patients. IBD concurrence with respiratory infection may further exacerbate lung injury. Tryptophan (Try), an essential amino acid, is processed by gut microbiota and produces aryl hydrocarbon receptor (AhR) ligands. These ligands can activate the AhR pathway that exerts anti-inflammatory properties and provides protection against mucosal barrier injury. This study investigated the effects of dietary Try on lipopolysaccharide (LPS)-stimulated ALI in mice with colitis induced by dextran sodium sulfate (DSS). Methods: Mice with colitis were allocated to four groups: (1) ND-Sal: normal diet + DSS + intratracheal saline injection; (2) ND-LPS: normal diet + DSS + intratracheal LPS injection; (3) TD-Sal: Try diet + DSS + intratracheal saline injection; (4) TD-LPS: Try diet + DSS + intratracheal LPS injection. Mice were sacrificed 24 h after the intratracheal injection. Results: Results showed that colitis resulted in a high disease activity index. Following induction of ALI in colitis mice, neutrophil populations and inflammatory cytokine levels in bronchoalveolar lavage fluid increased. Gene expression levels associated with toll-like receptor (TLR)4/nuclear factor (NF)-κB signaling were upregulated, and tight junction proteins decreased in the lungs. Dietary Try supplementation decreased circulating LPS levels, suppressed pulmonary TLR4/NF-κB signaling, upregulated AhR/interleukin-22 expression, attenuated oxidative stress and improved the capillary–epithelial barrier integrity in DSS-treated mice. Conclusions: These findings imply that Try may have potential therapeutic significance in bacterial-induced ALI in a colitis condition. Full article

Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, restores hyperglycemic conditions in patients with type 2 diabetes and has recently shown promising anti-inflammatory properties. In this study, we explored its potential to suppress osteoclast formation and bone loss triggered by lipopolysaccharide (LPS), an inflammatory agent. In animal models, the co-administration of liraglutide with LPS on the calvaria regions in mice markedly reduced osteoclast numbers and bone resorption areas relative to treatment with LPS alone. Furthermore, the expression levels of receptor activators of the NF-κB ligand (RANKL) and tumor necrosis factor (TNF)-α mRNA were notably lower in the group receiving liraglutide and LPS compared to treatment with LPS alone. Moreover, in vitro tests revealed that liraglutide has no direct inhibitory effect on RANKL-induced osteoclastogenesis and TNF-α-induced osteoclastogenesis. In addition, liraglutide had no direct inhibitory effect on LPS-stimulated RANKL expression in osteoblasts. Moreover, liraglutide effectively suppressed TNF-α mRNA expression in macrophages stimulated by LPS. These findings suggest that liraglutide prevents inflammatory bone destruction not by targeting osteoclast formation directly but by inhibiting the production of TNF-α within macrophages. Full article

The innate immune response is a critical defense mechanism by which vertebrates recognize and eliminate invading pathogens. Pattern recognition receptors (PRRs) detect pathogen-associated molecular patterns and activate downstream signaling pathways. NOD1, a classic PRR of the NLR family, recruits the adaptor protein RIPK2 to initiate antibacterial signaling. In this study, we cloned and characterized the NOD1 gene from snakehead (Channa argus). Briefly, the full-length NOD1 cDNA is 2829 bp encoding 943 amino acids, showing high homology with Perciformes. The qPCR analysis revealed widespread NOD1 gene expression in various tissues, with significant upregulation in the gill (p < 0.05) and spleen (p < 0.05) following bacterial infection. Overexpression of the NOD1 gene activated the NF-κB signaling pathway in a dose- and time-dependent manner, and specifically responded to the bacterial ligand iE-DAP but not to other tested ligands. Furthermore, NOD1 synergized with the downstream adaptor RIPK2 to enhance NF-κB activity, and direct protein interaction between NOD1 and RIPK2 was confirmed by co-immunoprecipitation. Taken together, these findings demonstrate that snakehead NOD1 plays a critical role in the host antimicrobial immune response. 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

The CD40–CD154 receptor-ligand axis is a core costimulatory regulator of antiviral immunity in mammals, but its functional role in teleosts remains largely unknown. Here, we identified the CD40 and CD154 homologs (MsCD40 and MsCD154) from largemouth bass (Micropterus salmoides), a globally farmed perciform teleost. Bioinformatic analysis confirmed that MsCD40 and MsCD154 harbor the conserved domain architectures of tumor necrosis factor receptor superfamily and TNF superfamily, respectively, with a teleost-specific phylogenetic clustering pattern. Both genes were ubiquitously expressed in immune-relevant tissues, and their transcription was dynamically regulated in response to viral hemorrhagic septicemia virus (VHSV) and largemouth bass virus (LMBV) challenge in vivo. Co-immunoprecipitation and immunofluorescence co-localization assays verified that MsCD40 and MsCD154 physically interact at the plasma membrane, forming a functional receptor-ligand complex. Functional assays showed that overexpression of either MsCD40 or MsCD154 significantly suppressed VHSV and LMBV infection in vitro. Furthermore, MsCD40 and MsCD154 overexpression dose-dependently activated nuclear factor-κB (NF-κB) reporter activity, and markedly upregulated the transcription of NF-κB downstream effector genes, including IL-8, NLRP3 and P105, under both VHSV and LMBV infection. Collectively, our findings demonstrate that the teleost CD40–CD154 costimulatory axis restricts both RNA and DNA viral infection in largemouth bass through NF-κB-mediated immune activation, which provides promising molecular targets for the development of broad-spectrum antiviral strategies in largemouth bass aquaculture. Full article

Excessive bone resorption by osteoclasts causes pathological bone loss in diseases such as osteoporosis. 7-Deacetoxy-7-oxogedunin (CG-1), a limonoid isolated from Carapa guianensis (Meliaceae), exhibits various biological activities. Here, we examined the anti-osteoclastogenic effect of CG-1 and its underlying mechanism in receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation of RAW264.7 cells. CG-1 inhibited the formation of tartrate-resistant acid phosphatase-positive multinucleated cells and decreased the expression of osteoclastogenesis-related genes. When CG-1 was added to the culture during the first 3 days of the 5-day-osteoclastogenesis period, the expression levels of the osteoclastogenesis-related genes (Nfatc1, Acp5, Src, Ctsk, and Mmp9) were decreased, as was observed when CG-1 was added continuously for 5 days. Furthermore, CG-1 lowered RANKL-induced Akt phosphorylation, which is similar to the results seen with the PI3K inhibitor, LY294002. Moreover, CG-1 and LY294002 suppressed the RANKL-induced expression of NFATc1, the master transcription factor for regulating terminal differentiation into osteoclasts. These results suggest that CG-1 attenuated RANKL-induced osteoclastogenesis by inhibiting the PI3K/Akt-NFATc1 axis during the early stage of osteoclast differentiation. Thus, CG-1 has the potential to suppress osteoclast-mediated bone resorption. Full article

Bone metastasis remains a major cause of morbidity in advanced cancer, driven not only by tumor–bone crosstalk but also by profound immune remodeling within the marrow. Myeloid-derived suppressor cells (MDSCs), including polymorphonuclear (PMN-MDSC) and monocytic (M-MDSC) subsets, are increasingly recognized as central effectors of this process, integrating inflammatory signals with metabolic and stromal cues to enforce immune suppression and support skeletal colonization. In this review, we synthesize current evidence that bone metastases transform the bone marrow into an “MDSC amplifier,” where vascular and endosteal niches, CXCL12-rich stromal compartments, hypoxia, and adipocyte-derived lipids collectively promote MDSC recruitment, persistence, and functional maturation. We discuss the dominant suppressive programs deployed by MDSCs in bone (e.g., arginase-1 activity, reactive oxygen/nitrogen species, and checkpoint ligand expression), and how these mechanisms converge to impair cytotoxic T-cell and NK-cell responses while fostering regulatory T-cell dominance. Importantly, because the marrow is a hematopoietic organ, bone lesions can also generate systemic consequences through myeloid spillover, providing a mechanistic basis for reduced responsiveness to immune checkpoint blockade in bone-dominant disease. We then evaluate pharmacologic strategies to target MDSCs in the context of bone metastasis, including approaches that block trafficking (e.g., CCR2/CXCR2 axes), deplete or reprogram suppressive myeloid states (e.g., STAT3-directed strategies, differentiation therapy), and disrupt bone-resorptive feedback loops (e.g., receptor activator of NF-κB ligand (RANKL) inhibition and bisphosphonates), emphasizing rational combinations and sequencing to limit marrow toxicity. Finally, we highlight emerging single-cell and spatial profiling tools that can resolve bone-specific heterogeneity in MDSCs and guide biomarker-driven, mechanism-informed therapeutic development. Full article

Osteoclast hyperactivity represents a central mechanism in pathological bone destruction, underscoring the importance of discovering novel anti-resorptive compounds. In this study, we present early-stage evidence that 8-Epixanthatin can inhibit osteoclast differentiation induced by receptor activator of nuclear factor kappa-B ligand (RANKL). 8-Epixanthatin exhibited no significant cytotoxicity at the concentrations used for osteoclast differentiation studies. The compound showed concentration-dependent reductions in TRAP-positive multinucleated osteoclasts, with an IC₅₀ value of 2.3 μM. Our mechanistic investigations revealed that 8-Epixanthatin interferes with RANKL-activated signaling networks, particularly nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) cascades. Collectively, these observations identify 8-Epixanthatin as a promising lead structure for anti-osteoclast drug discovery. Full article

Oncometabolites and hypoxia-regulated exosomes orchestrate hypoxia-inducible factor (HIF)–driven macrophage reprogramming across chronic cardiometabolic and oncologic conditions. In type 2 diabetes (T2D) and obesity, regional hypoxia in expanding white adipose tissue (WAT) reconfigures macrophage immunometabolism and chemokine signaling, recruits C-C chemokine receptor 2 (CCR2⁺) monocytes, and skews adipose-tissue macrophages toward M1-like programs that sustain low-grade inflammation and blunt the physiological M1-to-M2 transition during wound repair. In atherosclerotic plaques, lipid-core hypoxia stabilizes HIF-1α, amplifies nuclear factor kappa-light-chain-enhancer of activated B cells/reactive oxygen species (NF-κB/ROS) signaling, increases matrix metalloproteinase-2/-9 (MMP-2/-9) release, and reduces ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux, weakening the fibrous cap. In tumors, poorly perfused niches accumulate lactate and succinate, which act as paracrine cues. Lactate activates PKA/cAMP pathways and promotes immunosuppressive tumor-associated macrophages (TAMs), whereas succinate signals through succinate receptor 1 (SUCNR1) to reinforce HIF-1α–dependent transcription and M2-like programming. In parallel, hypoxia-regulated exosomes deliver microRNAs such as miR-301a-3p, which suppress phosphatase and tensin homolog (PTEN) and activate PI3Kγ, thereby augmenting immunosuppression and programmed death-ligand 1 (PD-L1) expression. Clinically, this hypoxia–oncometabolite–exosome triad links oxygen debt with macrophage state, plaque destabilization, impaired wound repair, and tumor immune escape. Translational entry points include selective HIF-2α inhibition, phosphoinositide 3-kinase gamma (PI3Kγ) blockade, SUCNR1 targeting, and exosome-based miRNA modulation, while a biomarker panel comprising HIF-1α, vascular endothelial growth factor A (VEGF-A), and MMP-9 offers a pragmatic readout of hypoxia burden, macrophage programming, and therapeutic response. We conducted a focused narrative review (PubMed, Scopus, Web of Science; English; 2003–2025), prioritizing mechanistic and translational studies on hypoxia–HIF, lactate/succinate, and hypoxia-regulated exosomes across T2D, atherosclerosis, and cancer. Full article