Search Results (4,782)

Background/Objectives: Osteonecrosis of the femoral head (ONFH) is a progressive condition characterized by bone necrosis, impaired vascularization, and immune dysregulation, often resulting in femoral head collapse. Effective strategies to halt disease progression are limited. Extracellular vesicles (EVs), including exosomes and microvesicles, mediate intercellular communication and influence osteogenesis, angiogenesis, and immune responses. This review summarizes current evidence on EVs in ONFH and their translational potential. Methods: A structured narrative review of PubMed, Scopus, Web of Science, and Cochrane Central databases was conducted, including in vitro, preclinical, and clinical studies on EVs in ONFH. Data on EV sources, molecular cargo, signaling pathways, functional effects, and translational implications were qualitatively synthesized. No pooled statistical analysis was performed because the extracted data were heterogeneous. Bioinformatic analyses such as Gene Ontology, KEGG enrichment, and protein–protein interaction networks were also summarized. Results: In vitro, EVs from bone marrow mesenchymal stem cells, endothelial cells, and M2 macrophages modulate osteogenic differentiation, angiogenesis, and inflammation. Preclinical studies demonstrate that EV administration reduces femoral head necrosis, improves trabecular structure, and enhances neovascularization. Clinical studies have identified EV-associated molecules (SAA1, C4A, RPS8) linked to disease stage and the risk of femoral head collapse. Bioinformatic analyses connect EV cargo to pathways regulating bone formation, vascularization, immunity, and metabolism. Conclusions: EVs appear to play key roles in ONFH pathogenesis and may represent promising candidates for diagnostic and therapeutic applications. However, current clinical evidence remains limited and requires validation in larger studies. Nonetheless, heterogeneity and limited clinical data require standardized, longitudinal studies to validate their translational relevance. Full article

Munronia pinnata (Meliaceae), a medicinal plant used in Zhuang traditional medicine, is recognized as a rich source of structurally diverse limonoids. In our continuing investigation of bioactive constituents from Guangxi medicinal plants, four new prieurianin-type limonoids, munropins G–J (1–4), were isolated from their aerial parts. Their structures were determined through comprehensive spectroscopic analysis, including nuclear magnetic resonance and high-resolution mass spectrometry, and further supported by quantum chemical calculations for electronic circular dichroism and statistical probability analysis. Munropins G (1) and H (2) feature an unprecedented C-12 β-D-glucosylated α-methyl-2′-hydroxypentanoate side chain and a C-17 β-substituted furan ring, with 1 being the 7-O-acetyl derivative of 2. Munropins I (3) and J (4) possess a formyl group at C-11, a 3-methyl-2-hydroxypentanoate ester at C-12, and a C-17 γ-hydroxy-α,β-unsaturated γ-lactone unit (21-hydroxy for 3, 23-hydroxy for 4), each existing as an equilibrating mixture of C-21 epimers—a phenomenon observed for the first time within a prieurianin-type framework. The absolute configurations of 1 and 2 were established by quantum chemical electronic circular dichroism calculations, while those of 3 and 4 remain to be assigned. All compounds were evaluated for cytotoxicity against human lung (A549), liver (HepG2), breast (MCF-7), and colon (HCT116) cancer cell lines and for anti-inflammatory activity in lipopolysaccharide-induced RAW 264.7 murine macrophages, but none exhibited significant effects at a concentration of 80 μM. This study expands the chemical diversity of Munronia limonoids and provides new molecular scaffolds for future structure–activity relationship investigations and chemotaxonomic markers for the Meliaceae family. Full article

Titanium implants are widely used in orthopedic and dental fields but often face challenges such as insufficient osseointegration and peri-implant inflammation. While Strontium (Sr) possesses potent bioactive properties, achieving its controlled delivery at the implant-tissue interface remains technically challenging. To address this, we engineered a multidimensional composite coating by constructing a micro/nano-porous TiO₂ substrate via micro-arc oxidation (MAO), followed by polydopamine (PDA)-assisted Sr immobilization. This integrated architecture significantly enhanced surface hydrophilicity and facilitated high-content Sr loading with sustained release kinetics. Biological evaluations demonstrated that the PDA-mediated interface promoted superior initial adhesion and spreading of bone marrow mesenchymal stem cells (BMSCs), synergizing with released Sr²⁺ to markedly upregulate core osteogenic markers (Runx2, ALP). Crucially, the functionalized surface actively optimized the immune microenvironment by inducing M1-to-M2 macrophage polarization and comprehensively suppressing RANKL-induced osteoclastogenesis via the downregulation of TRAP and DC-STAMP. By integrating these pro-osteogenic, anti-inflammatory, and anti-resorptive capabilities, this tri-functional system effectively rebalances the bone remodeling microenvironment. Consequently, it provides a robust, universally applicable strategy for enhancing the therapeutic efficacy of next-generation orthopedic and dental implants. Full article

Alpha-Ketoglutarate (AKG), a central intermediate of the tricarboxylic acid cycle, is a crucial metabolic and signaling molecule that connects mitochondrial function with cellular homeostasis, immunological modulation, epigenetic remodeling, and lifespan. While mitochondrial AKG maintains energy metabolism, the nuclear AKG pool influences chromatin remodeling through DNA and histone modifications, which together control hypoxia responses and shape gene expression patterns. This dual role demonstrates AKG’s significance in mediating metabolic state, gene expression, and long-term cellular adaptability. AKG modulates immunological responses, reduces reactive oxygen species (ROS), promotes the polarization of anti-inflammatory macrophages, and suppresses nuclear factor kappa B (NF-κB) activation, thereby reducing chronic inflammatory processes. AKG restricts pro-inflammatory cytokine production, increases extracellular matrix synthesis, and reduces cartilage degradation in arthritic models, suggesting potential therapeutic benefits in autoimmune diseases and joint degeneration. Additionally, AKG affects lifespan in several model organisms, where supplementation enhances metabolic resilience, lowers age-related inflammation, modifies mTOR signaling, and preserves youthful epigenetic profiles. Additionally, because endogenous AKG levels decrease with age, oral supplementation of AKG, especially with calcium and arginine, has drawn attention to its potential benefits in longevity and metabolic health. Thus, AKG is versatile and has encouraging therapeutic promise for cancer, aging, and inflammatory illnesses. However, a lack of human clinical evidence prompts further research to determine ideal dosage, tissue selectivity, and long-term safety. The goal of this review is to critically examine the current mechanistic knowledge related to AKG biosynthesis and breakdown and its future implications in maintaining cellular homeostasis and controlling chronic inflammation. Full article

This study investigated the structural and anti-inflammatory properties of Zophobas morio lipids (ZMLs). The fatty acid (FAs) composition showed a higher proportion of unsaturated FAs, mainly consisting of oleic (30.30%) and linoleic acids (20.05%), than saturated FAs, including palmitic (24.80%) and stearic acids (12.96%). In addition, FT-IR and ¹H-NMR analyses confirmed that ZML possessed a typical triglyceride structure, with long-chain alkyl groups. Thermogravimetric analysis (TGA) indicated that ZML exhibited high thermal stability, with a degradation peak at 369 °C. Differential scanning calorimetry (DSC) displayed a thermal transition at −8 °C, corresponding to the crystallization of unsaturated FAs in ZML. ZML significantly inhibits lipopolysaccharide (LPS)-induced pro-inflammatory M1 macrophage polarization by suppressing nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, thereby attenuating the expression of inflammatory mediators. Additionally, ZML alleviated inflammatory oxidative stress by activating the nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant pathway. Notably, ZML not only induced M2 macrophage polarization in quiescent macrophages but also reprogrammed M1 macrophages toward the anti-inflammatory M2 phenotype. These findings suggest that ZML is a natural nutritional lipid source and a potential therapeutic agent for modulating inflammatory response. Full article

Cutaneous T-cell lymphoma (CTCL) comprises a heterogeneous group of extranodal non-Hodgkin lymphomas. With the publication of the fifth edition of the World Health Organization Classification of Hematolymphoid Tumors, the diagnostic framework for CTCL has shifted from primarily morphologic phenotypes toward an emphasis on molecular drivers. Current research suggests that malignant clones may arise from somatic mutations at the hematopoietic stem cell stage and may follow a continuous hematogenous dissemination model with bidirectional trafficking between the skin and systemic circulation. At the molecular level, genomic instability, often associated with somatic copy-number variations, may promote activation of the janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling pathway through gene-dosage effects. In parallel, chromatin remodeling linked to EZH2 overexpression and reduced special SATB1 expression may support a Th2-polarized program. This phenotype may contribute to epidermal barrier impairment via cytokines such as Interleukins-4 (IL-4) and IL-13, potentially creating conditions permissive for Staphylococcus aureus colonization. Microbial superantigens and exotoxins may further contribute to tumor progression and therapeutic resistance by reinforcing JAK/STAT signaling, particularly STAT3, and reducing CD8+ T-cell–mediated immune surveillance. In the dermis, reprogramming of cancer-associated fibroblasts and polarization of macrophages toward an M2 phenotype may collectively contribute to an immunosuppressive niche. Emerging biomarkers, including CD74, and acquired resistance mechanisms after anti-C-C chemokine receptor 4 therapy further extend the translational relevance of recent pathologic findings. Overall, CTCL evolution appears to be a systemic process shaped by interactions between tumor-intrinsic genetic alterations and the skin microenvironment. Full article

Alveolar echinococcosis (AE), caused by Echinococcus multilocularis larvae, is a severe zoonotic disease mimicking tumors, primarily affecting the liver with high mortality if untreated. Host immunity plays a pivotal role, shifting from Th1/Th17-mediated clearance to Th2/Treg-driven tolerance, enabling parasite survival. Liver macrophages, including Kupffer cells, polarize towards M2 phenotype under parasite antigens (e.g., phytic acid, exosomes), promoting immunosuppression, fibrosis, and T cell exhaustion via IL-10/TGF-β. This reshapes the tumor-like immune microenvironment with M2 macrophages recruiting Tregs, suppressing NK/DC functions, and fostering angiogenesis/fibrosis. Current treatment remains centered on surgery and benzimidazole therapy, both of which have notable limitations. Experimental immunomodulatory strategies, drug repurposing approaches, and targeted delivery systems may offer future therapeutic opportunities, but these concepts remain largely preclinical, unproven in AE, and require careful evaluation for safety and efficacy. Full article

Temporomandibular disorder (TMD) is recognized as a major public health problem, causing pain and physiological and psychosocial limitations. In this context, the present in vitro study investigated the synthesis of a hyaluronic acid (HA) hydrogel with hydrocortisone (Hyd), designed to enhance joint lubrication by reducing mechanical friction and delivering the anti-inflammatory drug. The hydrogels were prepared with 3% HA (30 mg/mL) and Hyd—0.125% (1.25 mg/mL), 0.250% (2.5 mg/mL), 0.500% (5 mg/mL), or 1% (10 mg/mL). Physicochemical analyses included Fourier transform infrared spectroscopy (FTIR), thermogravimetry (TGA), rheological tests (frequency, amplitude, and temperature ramp scans), and field emission scanning electron microscopy (FESEM), performed before and after sterilization and cycling. In addition, cytocompatibility was evaluated by protocol OECD 129 and confocal microscopy, as well as genotoxicity (OECD487) in mouse macrophages (RAW 264.7 strain) per 24 h of exposure. FTIR demonstrated the spectral signatures of the compounds with no covalent interactions between the drugs, as well thermal stability on TGA. Rheology demonstrated that Hyd protected the HA structure after autoclaving, maintaining viscoelastic properties. SEM confirmed homogeneous porous morphology. Biological assays showed cell viability > 70%, but with a dose-dependent increase in genotoxicity (4–17 micronuclei). Confocal analysis revealed increasing cytotoxicity at high Hyd concentrations, indicating a balance between biocompatibility and adverse effects at concentrations ≤ 0.5%. Among the tested formulations, the 3% HA + 0.250% Hyd hydrogel provided the best balance of viscoelastic stability, cytocompatibility, and low genotoxicity, supporting its potential as a dual-function intra-articular candidate for TMD therapy. Full article

While natural muds are widely used in traditional balneotherapy and dermatological applications, the cellular basis of their redox-related effects remains insufficiently defined. In this study, we evaluated the effects of a mineral-rich mud extract on L929 fibroblasts and RAW 264.7 macrophages. This study was designed as an initial in vitro exploratory investigation to evaluate the cellular responses induced by a complex mud-derived material containing multiple inorganic components under standardized extract conditions. The mud extract showed no overt cytotoxicity up to 1000 μg/mL under the tested conditions. Intracellular reactive oxygen species (ROS) levels remained near baseline across the measured time points, with limited cell type-dependent variation. In parallel, antioxidant-related responses were observed primarily in RAW 264.7 cells, including a transient early increase in superoxide dismutase (SOD)-associated activity and subsequent increases in catalase (CAT) and glutathione peroxidase (GPx) activities. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis further showed dose-dependent upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) transcripts, particularly in RAW 264.7 cells. Collectively, these findings suggest that the mud extract is associated with coordinated antioxidant-related responses under non-cytotoxic conditions. However, because the present study was conducted in two murine cell lines and relied partly on assay systems potentially susceptible to matrix effects, the results should be interpreted as supportive of redox-associated modulation rather than definitive proof of a therapeutic mechanism. Furthermore, these findings should be interpreted as preliminary evidence obtained from a standardized aqueous extract system and not as definitive proof of component-specific mechanisms or direct applicability. Full article

Interleukin (IL)-1β is a pro-inflammatory cytokine implicated in sterile inflammation and tumor development. Investigating the role of MAPKAP kinase 2 (MK2) in IL-1β processing, we found that Il1b mRNA and IL-1β protein levels were elevated in resting MK2-knockout (KO) macrophages and in the serum of MK2/3 double-KO mice. This was linked to activation of the non-canonical NF-κB pathway in the absence of MK2 or its activator, p38α. Rescue by MK2, its kinase-inactive mutant MK2K79R, or p38α suppressed this pathway and reduced Il1b expression. We also observed decreased basal protein levels of tumor suppressor p53 in MK2- or p38α-deficient cells. Mechanistically, p53 interacts with caspase-3, promoting cleavage of RelB, thereby inhibiting non-canonical NF-κB signaling and subsequent Il1b and TP53 expression. These findings explain elevated basal IL-1β levels in MK2-KO macrophages and uncover a new autoregulatory mechanism of TP53 expression. Additionally, they reveal a new mechanism that contributes to the long-discussed link between cancer and inflammation, wherein the tumor suppressor p53 inhibits cytokine production in parallel. Full article

Geopropolis, a complex natural product composed of propolis, wax, plant resins, and soil produced by Meliponine (stingless) bees, has traditionally been used for its therapeutic properties. Its chemically diverse composition and broad biological activities have recently attracted growing scientific interest. In this study, we characterized the physicochemical and immunomodulatory properties of a hydroalcoholic extract of geopropolis (HEG) from Melipona quadrifasciata (Mandaçaia). Physicochemical characteristics were determined by measuring moisture, ash, and wax content, and its bioactive constituents were identified by GC–MS. THP-1-derived macrophages were exposed to increasing HEG concentrations to assess cytotoxicity, and two sublethal doses were selected for immunomodulatory assays with or without LPS stimulation. Cytokine and chemokine secretion were quantified by CBA, and the expression of key immunoregulatory and angiogenic genes was evaluated by RT-qPCR. Chemical profiling revealed a high wax content and a predominance of di- and triterpenoids, largely derived from coniferous sources. In mccrophages stimulated with LPS, HEG at 31.25 and 62.50 µg/mL significantly reduced the secretion of pro-inflammatory mediators (IL-6, CCL2, CCL5, CXCL9, and CXCL10) while preserving cell viability. In unstimulated macrophages, HEG upregulated the expression of genes VEGFA and TGFB1 as well as the protein CXCL8, all of them associated with angiogenesis and tissue repair. These findings demonstrate that M. quadrifasciata geopropolis extract modulates macrophage activity, promoting a shift toward a reparative phenotype that integrates inflammatory resolution with pro-healing effects. These results underscore its pharmacological potential as a terpenoid-rich natural product with complementary anti-inflammatory and regenerative activities. Full article

Biological heterogeneity among different breast cancer (BC) subtypes results in markedly varying clinical outcomes. Identification and analysis of key gene biomarkers that are differentially regulated during radiation therapy (RT) may pose multiple clinical challenges for BC treatment. The purpose of the study is to identify and analyze the expression of key gene biomarkers and their networks that are differentially regulated after hypofractionated RT. Patients with BC (cT0-T2, N0, M0) were treated with hypofractionated whole breast RT 25 Gy in five fractions, 4 to 8 weeks before breast conservation surgery (BCS). Biopsy (pre-RT; n = 5) and surgical (post-RT; n = 14 or 15) BC tumor samples were used for NanoString targeted sequencing. We identified 165 and 244 differentially expressed genes (DEGs; p < 0.05) in BC tumor samples from BC patients post-RT using the nCounter BC360 and IO360 panels, respectively. Gene networks and pathway analysis revealed that RT increases the gene signature of tumor inflammation (TIS), cytotoxicity, and apoptosis, while downregulating the gene signatures of tumor cell proliferation, differentiation, and cell adhesion, and increases the claudin-low gene score. RT-induced mammary stemness and enhanced infiltration of stroma, mast, and macrophage cells in the BC tumor microenvironment (TME). Further, the nCounter IO360 (immuno-oncology) panel analysis validated the findings of BC360 and demonstrated that RT increased the myeloid inflammation signature and chemokine expression, modulated B, T, NK, and DC cell activities, and enhanced residual cancer burden (RCB) in BC tumors, thus creating an immunosuppressive TME. Collectively, RT sensitized BC tumors by increasing the gene signature of TIS, cytotoxicity, apoptosis, and mammary stemness. RT facilitated an immunosuppressive environment and increased RCB, suggesting that the therapeutic potential of RT is highly individualized for each patient based on their unique tumor biology, genetic makeup, and TME. Full article

N-Lactoyl-phenylalanine (Lac-Phe), identified in 2022 as an exercise-inducible signaling metabolite, is formed by carnosine dipeptidase 2 via conjugation of lactate and phenylalanine. Its circulating levels rise sharply after intense exercise in mice, humans, and racehorses, reflecting increased glycolytic flux. Beyond exercise, Lac-Phe also rises with feeding and metformin, positioning it as a potential integrator of energy intake, expenditure, and metabolic homeostasis. Centrally, Lac-Phe may contribute to appetite suppression by inhibiting hypothalamic orexigenic agouti-related protein neurons, primarily observed in obese rodent models, while sparing anorexigenic pro-opiomelanocortin neurons, thereby reducing food intake, promoting weight loss, and improving glucose tolerance in obese models without altering energy expenditure. Peripherally, it drives anti-inflammatory M2 macrophage polarization, ameliorating colitis and aiding recovery after spinal cord injury via NF-κB suppression and reactive oxygen species reduction. As a biomarker, Lac-Phe may offer advantages over lactate in reflecting mitochondrial dysfunction in conditions such as MELAS, sepsis, and NADH-reductive stress; however, these observations derive mainly from small-scale or exploratory studies and require prospective validation. Recent studies from 2024 to 2025 further reveal its partial and context-dependent role in mediating metformin’s effects, intensity- and sex-dependent responses, renal clearance via SLC17A1/3 transporters, and links to exercise-induced redox adaptations. The first human phase I trial (NCT06743009), launched in 2025, is assessing the metabolic effects of Lac-Phe in obesity. This Perspective summarizes Lac-Phe biosynthesis, physiological mechanisms, including its emerging but largely correlative connections to redox homeostasis, and therapeutic promise, underscoring its potential relevance for exercise-mimicking strategies in metabolic, inflammatory, and redox-related disorders. Full article

Head and neck squamous cell carcinoma (HNSCC) develops within a chronically inflamed and metabolically constrained tumor microenvironment that profoundly shapes innate immune function. Tumor-associated macrophages (TAMs) are abundant in HNSCC and display marked plasticity, yet predominantly acquire immunosuppressive states that promote tumor progression and therapeutic resistance. Traditional M1/M2 polarization models fail to capture this dynamic behavior. Emerging evidence instead identifies metabolic reprogramming as a central regulator of macrophage function in cancer. Hypoxia, nutrient limitation, extracellular acidification, and tumor-derived metabolites such as lactate and lipids rewire macrophage metabolism, directly influencing inflammatory signaling and immune suppression. This review integrates recent advances in immunometabolism to examine how metabolic adaptations govern macrophage innate functions in HNSCC and highlights therapeutic opportunities targeting macrophage metabolism to overcome immune resistance. Full article

The receptor for advanced glycation end-products (RAGE) is a lung-enriched pattern recognition receptor implicated in inflammatory responses. Its role in ferroptosis-mediated lung injury during viral infection, however, remains unclear. Here, we combined bioinformatics analysis with in vitro and in vivo experimental validation to investigate the RAGE–ferroptosis axis in influenza virus infection. Cross-analysis of RAGE- and ferroptosis-related genes identified overlapping candidates, suggesting functional crosstalk. Influenza-infected A549 cells exhibited ferroptotic cell death, characterized by Fe²⁺ accumulation, reactive oxygen species (ROS) elevation, and lipid peroxidation, which was markedly attenuated by the RAGE inhibitor FPS-ZM1. In A/PR/8/34 (H1N1)-infected female C57BL/6J mice, FPS-ZM1 treatment improved survival, reduced lung injury, restored redox balance, and modulated key ferroptosis regulators ACSL4, POR, and GPX4. Moreover, RAGE inhibition decreased M1 macrophage and neutrophil infiltration and reduced pro-inflammatory cytokines. Collectively, these findings reveal that RAGE activation drives ferroptosis and amplifies oxidative stress–associated lung injury, whereas RAGE inhibition mitigates tissue damage via the ACSL4/POR/GPX4 pathway and immunomodulation. This study identifies the RAGE–ferroptosis axis as a potential therapeutic target for severe pulmonary inflammation. Full article