Search Results (14,811)

Lactic acid bacteria-fermented food materials are promising sources of functional ingredients, but the active components underlying their bioactivity often remain unclear. We localized the macrophage-stimulatory activity of a red pepper-based fermentate prepared with Lactiplantibacillus plantarum CJLP243. Compared with the unfermented matrix and a non-fermented matrix supplemented with freeze-dried CJLP243, the fermentate induced greater IL-6 and TNF-α production in J774A.1 macrophages. Activity was reproducibly concentrated in the pellet-derived lysate-insoluble fraction (PDIF) and remained in residual debris after solvent extraction. LTA-directed fractionation and analytical screening did not support lipoteichoic acid as the principal determinant. Lysozyme markedly reduced activity, whereas proteinase K had a partial effect, a pattern consistent with a lysozyme-sensitive, cell wall-associated structure or cell wall–matrix complex, within which peptidoglycan-associated material remains a plausible candidate; contributions from co-associated components cannot be excluded. Targeted metabolomics revealed fermentation-associated changes in pellet-associated amino acid pools, consistent with broader adaptation of amino acid and nitrogen metabolism during fermentation; their biochemical linkage to cell-wall precursor pathways provides metabolic support rather than direct structural evidence. These findings identify a reproducible, process-linked insoluble fraction with macrophage-stimulatory activity and provide a framework for developing and standardizing fermentation-derived functional food ingredients. Full article

Tissue repair and regeneration are highly coordinated multicellular processes that rely on the active resolution of inflammation rather than merely its passive cessation. Reciprocal orchestration among stromal, innate, and adaptive immune systems is key to maintaining or restoring tissue homeostasis from pathological perturbations. Macrophages serve as a central nexus of these responses, exhibiting dynamic functional plasticity that extends beyond dichotomous M1/M2 classification. This review explores the evolving, context-dependent roles of macrophages in restoring tissue homeostasis, with a particular focus on efferocytosis and subsequent metabolic rewiring as key drivers of inflammation resolution. Furthermore, we highlight the bi-directional crosstalk between macrophages and heterogeneous fibroblast populations. While these stromal-myeloid interactions are essential for transient matrix remodeling and physiological healing, their sustained activation under inflammatory conditions drives maladaptive repair and fibrotic remodeling. We discuss how the defects and dysregulation of these cellular circuits contribute to the pathogenesis of autoimmune disorders, as exemplified by recent findings in rheumatoid arthritis (RA), systemic sclerosis (SSc), and inflammatory bowel disease (IBD). Finally, we evaluate emerging “resolution therapies” that aim to harness endogenous tissue-reparative programs of macrophages therapeutically to treat autoimmune diseases, including the application of specialized pro-resolving mediators (SPMs) and macrophage reprogramming strategies. Full article

Glioblastoma (GBM) exhibits profound metabolic reprogramming, among which the balance between unsaturated and saturated fatty acids (UFA/SFA) emerges as a critical determinant of tumor behavior and treatment response. Recent studies have shown that fatty acid metabolic reprogramming is a key mechanism driving GBM progression. Abnormalities in fatty acid uptake, synthesis, desaturation, and oxidation collectively reshape the lipid composition of tumor cells, particularly by altering the unsaturated/saturated fatty acid ratio. Monounsaturated fatty acids mainly promote tumor cell proliferation and membrane biosynthesis, polyunsaturated fatty acids can induce lipid peroxidation and ferroptosis under specific stress conditions, whereas excessive saturated fatty acids can cause lipotoxicity when desaturation is limited. Key enzymes in fatty acid metabolism constitute a regulatory network and provide potential therapeutic targets for GBM. In addition, fatty acid metabolism can remodel the tumor immune microenvironment, especially by affecting the functional state of tumor-associated macrophages. Rather than targeting a single lipid species or isolated metabolic enzyme, therapeutic strategies that recalibrate the UFA/SFA ratio may provide a more integrated approach to restraining GBM progression and improving treatment sensitivity. Full article

A bioactive polysaccharide (CDP-D1) was isolated from the bulbs of Cistanche deserticola and purified by DEAE anion-exchange chromatography, yielding a purity of 95.5% and a recovery rate of 33.1%. It exhibits an irregular amorphous structure, with a porous and loose surface, and displays distinct shear-thinning behavior. Its molecular weight (MW) is 142.52 kDa, and its polydispersity index (Mw/Mn) is 1.77, confirming its heterogeneity. Gas chromatography–mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) analysis identified it as a heteropolysaccharide. Functional studies indicate that CDP-D1 mediates a protective effect against lipopolysaccharide (LPS)-induced inflammation in RAW264.7 macrophages. CDP-D1 restored LPS-induced decreases in cell viability to near-normal levels and suppressed pro-inflammatory signaling by downregulating TLR4 mRNA, key cytokines (IL-1, IL-6, TNF-α), and their cascade amplification. Metabolomic analysis (PLS-DA) validated the reliability of the model and identified 420 metabolites. LPS induced metabolic suppression, whereas CDP-D1 reversed this trend. Key pathways regulated by CDP-D1 include glutathione metabolism and amino acid/nucleoside/purine metabolism, partially restoring metabolic homeostasis. These findings provide preliminary evidence that CDP-D1 modulates inflammatory responses in LPS-stimulated macrophages, potentially through regulation of oxidative stress and metabolic reprogramming, and warrant further investigation into its molecular mechanism of action. Full article

Fungal infections remain a major global health challenge, underscoring the need to better understand host–pathogen interactions. Extracellular vesicles (EVs) released by fungal pathogens are emerging as key modulators of immune responses. Here, we investigated how EVs from Candida albicans and Aspergillus fumigatus influence macrophage activation, focusing on the integration of pattern recognition receptors (PRRs) and cytosolic sensing pathways. EVs were characterized by nanoparticle tracking analysis, zeta potential, and cryo-electron microscopy. Human THP-1-derived macrophages were stimulated with fungal EVs, and cytokine production, gene expression, and signaling pathway activation were assessed by ELISA, RT-qPCR, and Western blotting. C. albicans EVs induced a strong pro-inflammatory response, with increased production of IL-1β, IL-6, TNF, IL-8, and IFN-β after 24 h. In contrast, A. fumigatus EVs elicited a more limited response, characterized by IL-4 production and minimal pro-inflammatory cytokine induction. Both EV populations modulated PRR expression and activated the cGAS–STING–IRF3 axis; however, C. albicans EVs promoted coordinated activation of TLR4, TLR9, and Dectin-1–CARD9 signaling, whereas A. fumigatus EVs downregulated CARD9 and dampened inflammation. These findings demonstrate that fungal EVs differentially shape macrophage responses through species-specific integration of immune sensing pathways. Full article

This study investigated the repurposing potential of clomiphene citrate as a topical therapeutic candidate for tegumentary leishmaniasis (TL) and candidiasis. Comparative in silico analyses were performed to evaluate absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties in comparison with meglumine antimoniate and amphotericin B. In addition, molecular docking was conducted to investigate the interaction of clomiphene with Leishmania spp. arginase and the Sap5 protease of Candida albicans. Clomiphene exhibited a favorable physicochemical profile, characterized by high lipophilicity, moderate skin permeability, and predicted oral bioavailability and intestinal absorption superior to those of the reference drugs. Toxicological predictions also indicated a lower systemic toxicity profile compared with conventional therapies. Molecular docking revealed favorable binding energies and interactions with key residues within the active sites of both targets. Experimental assays demonstrated that clomiphene inhibited the early stages of C. albicans biofilm formation and exhibited potent leishmanicidal activity against L. amazonensis promastigotes, with a high selectivity index in macrophages. Together, these findings indicate that clomiphene citrate represents a promising candidate for further investigation as a potential therapeutic agent against tegumentary leishmaniasis and candidiasis. Full article

Tuberculosis (TB) and chronic obstructive pulmonary disease (COPD) remain global public health challenges, yet the mechanisms underlying their comorbidity remain poorly understood. COPD is associated with an increased risk of active TB, but the cellular and molecular basis of this association remains unclear. A growing body of evidence suggests that TB is not limited to an intramacrophage infection but is accompanied by a disruption of the local immune balance in lung tissue. This review analyzes the early interface of host–Mycobacterium tuberculosis (Mtb) interaction—from pattern recognition signaling pathways and metabolic reprogramming of macrophages to epithelial barrier responses and the delayed αβ T cell response. This review evaluates γδ T cells, particularly phosphoantigen (pAg)-reactive Vγ9Vδ2 cells, as a candidate early integrative component of the host response, positioned between macrophage infection, epithelial stress, mycobacterial antigens, and bacille Calmette–Guérin (BCG)-induced trained immunity. Available evidence suggests that COPD-associated immune alterations may impair mucociliary clearance, antimicrobial peptide production, phagocytosis, and innate T cell responses while favoring cytotoxic reactions, the IL-17A–G-CSF–neutrophil axis, and protease-mediated tissue damage; however, direct mechanistic evidence in patients with TB–COPD remains limited. It is important to note the differences in data obtained from studies in humans, primates, mice, and in vitro: the Vγ9Vδ2 system has no direct analog in laboratory mice, which represents a key limitation for preclinical studies. A key unresolved question remains the nature and functional consequences of γδ T cell changes in patients with coexisting COPD and TB infection. The answer to this question could inform new strategies for the prevention and treatment of TB in patients with COPD, including BCG revaccination, pAg-mediated immunomodulation, and the development of biomarkers to distinguish between protective and harmful early immune responses. Full article

Food scarcity is a major ecological challenge for cavefish; however, their coordinated physiological and molecular responses to prolonged starvation remain poorly understood. Here, we characterized the responses of Triplophysa rosa to 30, 60, and 90 days of food deprivation under controlled laboratory conditions by integrating growth measurements, histology, transcriptomics, quantitative reverse transcription PCR, and transmission electron microscopy. Starvation inhibited growth, reduced the condition factor and hepatosomatic index, and induced hepatocyte shrinkage, consistent with mobilization of hepatic energy reserves. Liver genes with declining temporal expression were enriched mainly in lipid biosynthesis, cholesterol metabolism, ribosomal function, and cell-cycle pathways, consistent with reduced biosynthetic activity. In the spleen, immune-related transcription increased during early starvation and declined at later stages, while the greater prominence of melano-macrophage centers was consistent with greater involvement of cellular clearance and tissue maintenance during prolonged starvation. Prolonged starvation also increased the expression of autophagy-related genes in the liver and spleen, and autophagy-related structures became more prominent in representative transmission electron microscopy images, consistent with increased involvement of intracellular recycling. Together, these findings reveal a coordinated temporal response involving metabolic adjustment, stage-dependent reorganization of splenic immune-related processes, and autophagy-associated cellular maintenance in T. rosa. This integrated approach improves our understanding of physiological maintenance during sustained nutrient limitation in cave-restricted fish. Full article

Mesothelioma is a rare, aggressive malignancy with poor prognosis. B7-H3 (CD276), an immune checkpoint molecule, and CD163-positive tumor-associated macrophages (TAMs) contribute to tumor progression and immune evasion. This study evaluated the prognostic impact of B7-H3 expression and CD163-positive TAM infiltration. This single-center retrospective study included 94 patients diagnosed with malignant mesothelioma between 2011 and 2024. B7-H3 expression was assessed using the H-score method and dichotomized at the cohort median. CD163-positive TAM density was quantified in hotspot high-power fields. Overall survival (OS) was analyzed using Kaplan–Meier, log-rank, and multivariable Cox regression analyses. Median OS was 10.15 months (IQR: 4.88–19.66). High B7-H3 expression was associated with shorter OS, whereas high CD163-positive TAM density was associated with longer OS. In multivariable analysis, B7-H3 expression, CD163 expression, tumor localization, recurrence status, and treatment status were independently associated with overall survival. Combined biomarker analysis showed the worst OS in the CD163-low/B7-H3-high group and the best OS in the CD163-high/B7-H3-low group. High B7-H3 expression was independently associated with shorter overall survival, whereas high CD163-positive TAM infiltration was associated with longer overall survival in this cohort. The combined B7-H3/CD163 profile may identify distinct prognostic subgroups and highlights the tumor immune microenvironment. Full article

Patients with autoimmune rheumatic diseases, particularly rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), experience excess cardiovascular risk that is not fully captured by conventional lipid measurements. In active RA, lower cholesterol may coexist with higher vascular risk, a pattern known as the lipid paradox. We propose that systemic inflammation can uncouple lipid concentration from lipoprotein function and organize the evidence along five mechanistic axes. Inflammatory cytokines, mainly interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), IL-1β, IL-17/IL-23 and type I interferons, remodel lipoprotein metabolism. High-density lipoproteins (HDL) lose protective functions and may become pro-inflammatory. Apolipoprotein-B particles are oxidized or otherwise modified, linking lipid metabolism to autoimmunity. Macrophage cholesterol imbalance and cholesterol crystals activate inflammasome pathways in experimental atherosclerosis, while immune-cell metabolic rewiring may amplify cytokine output; these mechanisms are treated as extrapolated when direct rheumatic-disease evidence is limited. The pathways converge on endothelial dysfunction and thrombo-inflammation. RA and SLE are the mechanistic anchors, whereas psoriatic disease, axial spondyloarthritis, systemic sclerosis, vasculitides and antiphospholipid syndrome are weighted by evidence category. Standard lipid panels may therefore underestimate risk in selected contexts, especially during active inflammatory disease. Full article

Oxidative stress and inflammation are the causes of many colonic diseases. Therefore, the aim of this study was to maximize the biological activity of hawthorn seed preparations aimed at modulating oxidative stress and the inflammatory response in the colon through selective fractionation and enrichment in compounds with antioxidant, anti-inflammatory, and cytotoxic potential. Fractionation of hawthorn seed extract (CE) was performed using C18 resin, and detailed phytochemical analysis was performed using ultra-performance liquid chromatography (UPLC-MS/MS). This work resulted in four fractions (F1-F4), with differential distribution of 28 identified polyphenolic compounds. Phenolic acids dominated in F1, flavan-3-ols in F2, and flavonols in F3 and F4. In terms of quantitative composition, the obtained fractions can be ranked in the order F1 > F2 > F3 > F4. In biological activity studies, the highest antioxidant activity in a chemical model was demonstrated for F2, which was also confirmed in a cellular model–colonocyte cells (CCD841CoN line) stimulated with H₂O₂. F2 also demonstrated the highest inhibition of ROS production by colonocytes and NO production by macrophages. High F2 activity was also demonstrated in studies of the proliferation, migration, and invasion of colon cancer cells. These findings underscore the validity of fractionation of hawthorn seed extract and its potential use in the prevention and treatment of colon diseases. Future studies should include in vivo models and estimation of the activity of the fraction truly bioavailable after digestion. Full article

Glioblastoma (GBM) is a highly aggressive malignant brain tumor accounting for 15% of all brain tumors and 50% of all gliomas. The exact cause of GBM is not fully understood but risk factors include age, genetic mutations, exposure to ionizing radiation, and certain genetic disorders. Symptoms of GBM include headaches, seizures, cognitive impairment, and weaknesses on one side of the body. Myeloid cells account for 30–50% of the tumor mass and are instrumental in shaping the complex tumor microenvironment (TME). Inflammation in the TME is an important driver of tumor growth and invasion; however, as the environment evolves, the immunosuppressive TME poses a significant hurdle as it hinders the immune-mediated killing of tumor cells. Our work utilizes neuroimmune organoids containing neurons, astrocytes, microglia, and vascular-like cells, to which we add patient-derived GBM cells and/or iPSC-derived macrophages to model the GBM TME. Model characterization was performed using single-cell RNA sequencing and supernatant proteomics to determine cell-specific changes during coculturing. Our findings are consistent with this 7-day coculture model recapitulating key aspects of GBM early tumor establishment and immune activation, with transcriptomic and secretome signatures suggestive of an emerging immune evasion phenotype. Full article

Beyond its canonical role as the principal inhibitory neurotransmitter in the central nervous system (CNS), peripheral GABAergic signaling has emerged as an important regulator of skin barrier immunity and tissue homeostasis. This review synthesizes current evidence on the expression, distribution, and function of both GABA-A and GABA-B receptors in keratinocytes, fibroblasts, melanocytes, sensory neurons, and cutaneous immune cells, including Langerhans cells, macrophages, mast cells, and T lymphocytes. Particular emphasis is placed on how GABAergic signaling regulates ion transport, calcium dynamics, epidermal differentiation, and immune homeostasis through coordinated interactions with ion channels within the broader cutaneous neuro-immuno-endocrine network. We further discuss evidence supporting the role of cutaneous GABAergic signaling in maintaining barrier integrity, modulating inflammatory responses, and contributing to skin–brain communication within the broader cutaneous neuro-immuno-endocrine network under physiological and pathological conditions. Finally, we summarize the therapeutic potential of targeting peripheral GABAergic pathways in atopic dermatitis, psoriasis, chronic pruritus, photoaging, and other stress-associated dermatoses, highlighting their promise as novel therapeutic strategies in precision dermatology. Full article

Spinal cord injury (SCI) often results in varying degrees of motor and sensory dysfunction with limited potential for recovery. Research into in vivo astrocyte-to-neuron reprogramming has led to promising results that, if translated to SCI, could offer substantial therapeutic benefit by replenishing lost populations of neurons for functional restoration. Previous studies have shown that AAV9-mediated delivery of NeuroD1 is capable of reprogramming astrocytes into neurons in vivo after chronic SCI in rats. Here we evaluate the dose-dependent functional and neuroprotective potential of the NeuroD1 gene therapy platform for acute and subacute SCI in rats. The Cre-dependent, DIO-based AAV9-NeuroD1 gene therapy platform was administered directly into the spinal cord of female Long-Evans rats after moderate, thoracic level 8/9 contusion SCI at one of two intervention timepoints: immediately after injury (acute) or 1 week post-contusion (subacute). The viruses were administered at a titer of 10¹¹ or 10¹³ GC/mL. We demonstrate that the AAV9-NeuroD1 reprogramming platform successfully, albeit variably, transduced spinal cells that persisted up to 6 weeks post-injury. However, histological analysis revealed substantial neuronal off-targeting, suggesting a lack of astrocyte-specific targeting from the AAV9 DIO-based delivery platform. Surprisingly, we also found titer- and intervention timing-dependent effects on motor function and tissue preservation—as demonstrated by 1–2 point decrease in BBB scoring and near 50% increase in peak lesion cavitation area—when AAV9-NeuroD1 was administered immediately after SCI. While did not find any effects of the AAV9-NeuroD1 platform on sensory function or neuroinflammatory cell density, a subset of NeuroD1 signal reflected phagocytic uptake by Iba1 and CD68-expressing microglia/macrophages. These results indicate that the NeuroD1 reprogramming platform can exacerbate injury-related functional deficits when administered in the acute stage of injury, but has neuroprotective benefit on tissue preservation when administered in the subacute stage of injury. Our study demonstrates that several factors must be considered, including viral titer and intervention timing, to assess the therapeutic potential of AAV9-NeuroD1-mediated reprogramming for SCI. Full article

Crohn’s disease (CD) is a chronic inflammatory bowel disease with a rising incidence and prevalence worldwide. It is associated with Mycobacterium avium subspecies paratuberculosis (MAP). Current CD treatment strategies are based on anti-inflammatory therapies, including anti-TNF-α drugs. These treatment options provide short-term benefits and are associated with numerous side effects in CD patients. Manuka honey is distinguished from other honey by its high content of methylglyoxal (MGO). MGO, a reactive metabolite, is also generated endogenously in macrophages during infection through glycolysis; however, the amount is insufficient to neutralize the ongoing infection and subsequent tissue damage. This study examined whether exogenous, low-dose MGO can modulate MAP-driven inflammatory and glycolysis- and lactate-associated markers in infected macrophages. THP-1 macrophages were infected with the CD-associated MAP strain and then treated with MGO doses at defined time intervals. We measured markers of M1-/M2-like phenotype polarization, monocarboxylate transporters, lactate export, antioxidant responses, cytokines, and selected glycolysis- and lactate-associated markers at both the mRNA and protein levels. MGO reduced M1 signaling markers CXCL10 (p < 0.05), TNF-α (p < 0.0001), IL-1β (p < 0.01), and IL-6 (p < 0.0001). Simultaneously, MGO promoted M2 shift, elevating CD206 by 1.20-fold and IL-10 by 7-fold. Low-dose MGO administration was associated with increases in Nrf-2 (1.4-fold), HO-1 (1.4-fold), and IL-1Ra (1.5-fold), while the pro-inflammatory cytokines decreased. Metabolically, MGO downregulated MCT4 (p < 0.01) and reduced lactate export by 30%. These changes were coupled with higher PHD2 (1.4-fold) and decreases in GLUT1 (0.9-fold), PKD1 (0.8-fold), and IL-1β, consistent with attenuated glycolysis- and lactate-associated inflammatory signaling. These results suggest that hormetic concentration of MGO mitigates MAP-induced inflammatory activation while altering glycolysis- and lactate-related signaling markers in infected macrophages. Most importantly, we unraveled the predicted molecular mechanism by which MGO suppresses inflammation and modulates oxidative damage. Full article