Search Results (917)

Background/Objectives: Biodegradable magnesium (Mg)-based biomaterials release Mg²⁺ ions during degradation and may promote vascular-related regeneration. However, their effects on lymphatic endothelial cells (LECs) and lymphangiogenesis remain unclear. This study investigated whether magnesium powder-derived ionic extracts could enhance lymphangiogenesis-related behaviors of LECs in vitro. Methods: Mg powder extracts were prepared and diluted for in vitro treatment. After viability screening, Mg (1:10), Mg (1:100), and Mg (1:1000) were selected for further analysis. LEC proliferation, migration, and tube formation were assessed, together with intracellular reactive oxygen species (ROS) levels and the expression of VEGFA, VEGFC, and VEGFR3. Results: Mg (1:10) and Mg (1:100) showed good cytocompatibility and significantly promoted LEC proliferation, migration, and tube formation compared with the control and Mg (1:1000) groups. These effects were accompanied by reduced intracellular ROS levels and increased expression of VEGFA, VEGFC, and VEGFR3. Conclusions: Magnesium powder-derived ionic extracts enhance lymphangiogenesis-related responses of LECs in vitro, particularly at the 1:10 and 1:100 dilutions. These findings support the potential of Mg-based biodegradable biomaterials for lymphatic tissue regeneration. Full article

Background: Early vascular aging (EVA) is a common complication of type 2 diabetes mellitus. Early identification is crucial in middle-aged individuals with T2DM, as vascular stiffness can occur gradually for years before cardiovascular disease. However, EVA is rarely considered in routine care. Adropin is a vasoprotective peptide that may counter-regulate endothelin-1 (ET-1). Therefore, this study aims to examine the association between circulating adropin, ET-1, oxLDL, MMP-2, VEGFA, and EVA. Methods: This observational study included 300 adults aged 25–55 years (150 T2DM; 150 age/sex-matched controls). ePWV was calculated from age and mean blood pressure. EVA was classified using a residual-based, age-specific ePWV threshold derived from controls. Associations were tested using correlation and logistic regression. ROC and decision curve analyses were performed to evaluate diagnostic performance and clinical utility. Results: EVA prevalence was 38.6% overall, occurring in 7.3% of controls and increasing across T2DM with good and poor glycemic control (56.1% and 80.95%, respectively, p < 0.001). Compared with normal vascular aging, EVA showed lower adropin and higher ET-1, oxLDL and MMP-2, with lower VEGFA (all p < 0.05). In fully adjusted models, adropin (OR 0.991 per pg/mL; p < 0.001) and ET-1 (OR 1.017 per pg/mL, p = 0.005) remained independently associated with EVA. A combined adropin + ET-1 predictor improved discrimination (AUC 0.901, 95% CI 0.868–0.934), at a predicted-probability cutoff of 0.607, 78.7% sensitivity and 87.0% specificity. Conclusions: In middle-aged T2DM, EVA was associated with lower adropin and higher ET-1 in T2DM. These findings support an association between these biomarkers and the EVA phenotype. Full article

Chronic inflammation contributes to bladder cancer (BC) development and progression through dysregulated cytokine signaling and tumor–immune interactions. This case–control study investigated associations between IL6 rs1800795, TNF rs1800629, CCL2 rs1024611, and VEGFA rs699947 polymorphisms, circulating cytokine levels, clinicopathological characteristics, and autonomic nervous system balance assessed by heart rate variability (HRV) in 73 BC patients and 88 controls. Genotyping was performed using PCR–RFLP, serum cytokine levels were measured by ELISA, and associations were evaluated using logistic, linear regression, and survival analyses. No significant associations with BC risk were observed for IL6, TNF, or VEGFA variants. However, the CCL2 rs1024611 GG genotype was associated with increased BC risk (recessive model: OR = 5.82, p = 0.026). Stratified analyses showed a lower frequency of the IL6 rs1800795 C allele and TNF rs1800629 GA genotype in high-grade and muscle-invasive tumors, suggesting potential associations with reduced tumor aggressiveness. No polymorphism was associated with serum cytokine levels or disease-free survival. In BC patients, the TNF rs1800629 A allele was associated with higher parasympathetic-related HRV indices and lower sympathetic parameters, whereas no such associations were observed in controls. These findings indicate that genetic variation within inflammatory pathways may contribute to BC susceptibility and tumor phenotype and may also modulate neuroimmune interactions. Full article

Repairing maxillofacial bone defects remains a major clinical challenge due to inadequate vascularisation and poor integration with host tissue. While bioactive scaffolds have shown promise in supporting osteogenesis and angiogenesis, achieving robust and synchronised dual regenerative outcomes is still elusive. This study presents a multifunctional, cell-free magnetic hydrogel platform designed to biomimetically coordinate osteogenic and angiogenic processes for effective maxillofacial bone regeneration. The composite poly(vinyl alcohol)-vaterite (PVA-Vat) hydrogel scaffold incorporates tuneable magnetic nanoparticles (MNPs) composed of single-domain superparamagnetic iron oxide (Fe₃O₄). By harnessing magneto-mechanical cues to orchestrate bilateral communication between human bone mesenchymal stem cells and endothelial cells, this platform provides a deeper mechanistic understanding of coupled tissue regeneration and delivers superior dual-regenerative performance for maxillofacial bone repair. Under magnetic stimulation, a coculture system demonstrated strong osteogenesis-angiogenesis coupling mediated by reciprocal VEGFA-BMP2 signalling. This reciprocal crosstalk was evidenced by a synergistic amplification of VEGFA and BMP2 expression in coculture compared to monocultures, where MNP-stimulated osteoprogenitors secreted VEGFA to drive endothelial capillary-like network formation, while endothelial cells reciprocally enhanced endogenous BMP2 levels to accelerate osteoblastic mineralisation. These findings establish MNP-integrated hydrogels as a cell-free, multifunctional platform capable of synchronising dual regenerative pathways, offering a biomimetic strategy to overcome vascularisation and integration barriers in maxillofacial bone repair. Full article

Background: Wound healing remains a major clinical challenge, often impaired by persistent inflammation, oxidative stress, and abnormal extracellular matrix remodeling. Electrospun nanofibers (NFs) have emerged as promising wound dressing platforms due to their biomimetic structure and capacity to incorporate multiple bioactive compounds (ACs) with synergistic therapeutic effects. Objectives: This study aimed to biologically assess novel chitosan/poly(vinyl alcohol) (CH/PVA) NFs functionalized with natural active compounds (L-arginine—ARG, allantoin—ALA, royal jelly—RJ, and curcumin—CUR) as multifunctional systems for wound healing and tissue remodeling. Methods: The nanofibrous systems performed the in vitro evaluation of antioxidant activity (DPPH, ABTS, FRAP, PRAP), anti-inflammatory potential (protein denaturation test), hemocompatibility, and cytocompatibility using dermal fibroblasts. In vivo healing performance was evaluated in an excisional wound model using macroscopic wound contraction analysis, histopathology, and immunohistochemical staining (MMP-9, CD31, VEGF-A, α-SMA). Results: The bioactive-enriched CH/PVA NFs exhibited strong antioxidant and anti-inflammatory activity, excellent hemocompatibility (hemolysis < 5%), and excellent cytocompatibility, with promoting fibroblast proliferation. In vivo experiments revealed that the treated groups exhibited accelerated wound closure, improved re-epithelialization, increased angiogenesis, and showed more efficient tissue remodeling compared to the controls, as validated by histological and immunohistochemical studies. Conclusions: The findings indicate that bioactive-enriched CH/PVA NFs serve as effective, biocompatible, and multifunctional matrices for wound healing, hence endorsing their potential for further translational advancement in skin regeneration applications. Full article

Background/Objectives: Vascular inflammation and impaired endothelial regeneration contribute to chronic degenerative disorders, including ocular neovascularization and retinal degeneration. Nutritional bioactives that modulate molecular pathways governing angiogenesis and tissue remodeling represent promising adjunct strategies for vascular health. This study investigated whether cocoa powder (CP) regulates hypoxia-driven molecular signaling and attenuates vascular inflammation and degeneration. Methods: The vascular-modulatory effects of CP were examined in human umbilical vein endothelial cells (HUVECs) and in murine models of alkali-induced corneal neovascularization and N-methyl-N-nitrosourea (MNU)-induced retinal degeneration. Hypoxia-inducible factor-1α (HIF-1α) signaling and downstream angiogenic targets were assessed by Western blotting and quantitative PCR. Endothelial migration, tube formation, and transwell assays were performed to evaluate angiogenic responses. In vivo, oral CP (50 or 200 mg/kg) was administered, and vascular growth, inflammatory and remodeling markers, and retinal structural integrity were analyzed by histology, immunofluorescence, and protein expression. Results: At non-cytotoxic concentrations (0.1–1.0 μg/mL), CP suppressed hypoxia-induced HIF-1α protein stabilization without altering HIF-1α mRNA levels and reduced expression of VEGFA, EPO, and GLUT1. CP significantly inhibited VEGF-A-induced endothelial migration, network formation, and chemotactic invasion. In alkali-injured corneas, CP reduced the neovascularized area and downregulated VEGF, MMP2, MMP9, α-smooth muscle actin, and Ninj1, indicating attenuation of vascular inflammation and fibrotic remodeling. In the MNU model, CP preserved outer nuclear layer thickness, reduced glial activation (GFAP), maintained rhodopsin expression, and decreased MMP9 induction. Conclusions: CP functions as a nutritional modulator of hypoxia-responsive and inflammatory pathways, suppressing pathological angiogenesis while supporting structural preservation in degenerative vascular conditions. These findings highlight the translational potential of dietary polyphenol-rich interventions in regulating vascular inflammation and regeneration. 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

Uveal melanoma (UM) lacks minimally invasive and reproducible biomarkers to support clinical risk stratification, motivating the need for molecular profiling of aqueous humor (AH) as an alternative to fine-needle tumor aspiration (FNAB). This study aimed to generate a calibrated AH protein concentration map to identify tumor-associated signals present at clinically measurable levels and assess their associations with established molecular and clinical features. AH samples from 70 UM eyes were analyzed using next-generation sequencing-based proximity extension assays (PEAs), and leftover AH from 27 samples was further assessed using qPCR-based PEA to obtain reference concentration values. Regression models derived from overlapping proteins enabled extrapolation of calibrated pg/mL-level concentrations across the full cohort. Twenty-three proteins had median modeled concentrations above 5 pg/mL and were examined for clinical relevance and translational feasibility. Several proteins, including CXCL8, CXCL10, VEGFA, HGF, PDCD1, FLT1, FLT3LG, and CCL2, showed progressive increases from GEP1/PRAME− to GEP2/PRAME+ tumors and from AJCC Stage I/II to Stage III/IV, with Stage IV tumors demonstrating significant elevations in CXCL8, VEGFA, and PDCD1. Pathway analysis revealed activation of inflammatory and tumor microenvironment pathways, and upstream regulator analysis identified VEGFA and CCL2 as potential drivers. These findings demonstrate that calibrated AH proteomic profiling can identify clinically measurable protein changes associated with UM risk and stage, supporting its potential utility for biomarker development. Full article

Neovascular age-related macular degeneration (nAMD) remains a major cause of visual morbidity worldwide, although its contribution to blindness in developed healthcare systems has declined in the era of anti-VEGF therapy. Although randomized clinical trials have consistently demonstrated meaningful visual gains under structured retreatment protocols, real-world outcomes frequently decline over time due to undertreatment, limited durability, and persistent disease activity. Recent therapeutic advances have shifted the focus from maximizing short-term efficacy to engineering sustained disease control. Faricimab, a bispecific antibody targeting both VEGF-A and angiopoietin-2, introduces dual-pathway vascular modulation, while high-dose aflibercept (8 mg) enhances VEGF suppression through pharmacokinetic intensification. This perspective critically examines the biological rationale, clinical evidence, real-world implications, and strategic positioning of these agents, proposing a durability-centered framework for next-generation management of nAMD. Full article

The accurate prediction of motor progression in Parkinson’s disease (PD) remains a major clinical challenge that limits personalized treatment planning and efficient clinical trial design. In this study, we developed and validated a machine-learning framework integrating a targeted panel of plasma proteins measured by Olink proximity extension assays with clinical variables to stratify patients according to their progression risk. We analyzed baseline plasma samples from 211 early-stage PD patients enrolled in the Parkinson’s Progression Markers Initiative (PPMI) cohort using four targeted Olink panels, from which 28 circulating proteins were retained after quality-control filtering. Patients were classified as rapid or slow progressors based on their annualized change in MDS-UPDRS Part III scores. Among the algorithms tested, Random Forest achieved the highest discriminative performance with an area under the receiver operating characteristic curve (AUC) of 0.751 (95% CI: 0.684–0.811), which exceeded that of clinical predictors alone (AUC 0.666). The integration of targeted proteomic and clinical features further improved model performance (AUC 0.773; p = 0.009). Nested cross-validation confirmed minimal optimistic bias (AUC 0.743). To enhance clinical interpretability, we applied SHapley Additive exPlanations (SHAP) analysis, which identified interleukin-6 (IL-6), brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor A (VEGF-A) as the most influential predictors. SHAP feature rankings were highly stable across cross-validation folds (mean Spearman ρ = 0.91). The robustness of these findings was confirmed through sensitivity analyses using extreme quartile comparisons (AUC 0.823), treatment-naïve subgroup analysis (AUC 0.738), and a clinically anchored outcome definition based on the minimal clinically important difference (AUC 0.739). A decision curve analysis demonstrated a net clinical benefit across threshold probabilities of 0.25–0.70. Our results establish targeted plasma protein profiling combined with interpretable machine learning as a promising tool for PD motor progression risk stratification, with potential applications in individualized patient counseling regarding motor prognosis and the selection of candidates for disease-modifying trials. Full article

Background: The aim of our study was to evaluate the association of angiopoietin 2 (ANGPT2) rs2442598 and vascular endothelial growth factor A (VEGFA) rs2010963 with diabetic nephropathy (DN) in Slovenian subjects with type 2 diabetes mellitus (T2DM). Angiopoietin–endothelial tyrosine kinase receptor (Ang-Tie2) and VEGF-A signaling regulate glomerular endothelial stability and permeability and may contribute to DN susceptibility. Methods: We conducted a case–control study including 897 unrelated Slovenian subjects with T2DM (344 DN cases; 553 long-standing T2DM controls without DN). ANGPT2 rs2442598 and VEGFA rs2010963 were genotyped using TaqMan assays. Genetic associations were analysed using co-dominant, additive, dominant, and recessive genetic models with logistic regression adjusted for waist circumference, systolic blood pressure, fasting glucose, and triglycerides. Results: ANGPT2 rs2442598 was significantly associated with DN, with increased risk in carriers of the C allele, including a significant additive per allele effect (OR 1.39, 95% CI 1.10–1.74) and a dominant model effect (OR 1.47, 95% CI 1.11–1.96). In contrast, VEGFA rs2010963 showed no evidence of association across genetic models. Conclusions: In Slovenian patients with T2DM, ANGPT2 rs2442598 is associated with DN, whereas VEGFA rs2010963 is not. This association suggests that ANGPT2 genetic variation may influence DN risk and supports further functional work to define the biological effects of rs2442598. Full article

Modeling immune cell recruitment within a wound-relevant microenvironment remains challenging. Here, we developed a novel skin-derived extracellular matrix (ECM) hydrogel model to study monocyte (THP-1) entry and phenotypic changes within a dermal fibroblast-populated (NHDF) matrix. The main novelty of this study is that it compares the effects of fibroblast-derived soluble signals and active monocyte infiltration in a 3D biomimetic model. Signaling by fibroblast-secreted soluble factors enhanced a pro-angiogenic secretome (e.g., >3-fold upregulation of VEGFA at day 1) and promoted endothelial tube formation (increasing network junctions to 1.16 ± 0.16 vs. 0.93 ± 0.23 in monoculture). In contrast, this paracrine signaling did not induce the matrix-driven pro-fibrotic response in hydrogels. Crucially, physical immune infiltration restricted monocyte penetration (mean depth of 8.92 ± 2.27 μm vs. 121.1 ± 15.9 μm in monoculture at day 5), reduced hydrogel-induced myofibroblast activation (decreasing α-SMA+ cells from 79.1% to 54.3% upon initial contact), and was associated with slower collagen loss during the early phase. (retaining a high-density collagen ratio of 3.46 ± 0.33 vs. 2.02 ± 0.29 in monoculture at day 1). These observations were accompanied by a shift toward a matrix-stabilizing profile, including increased TIMP expression and reduced pro-fibrotic markers. (ACTA2 and COL1A1). By including active immune infiltration (which was absent in previous tSVF models), we capture the transition from inflammation to the proliferation stage. Although the later stages of extensive ECM remodeling appear suppressed here, they may occur as repair progresses. Overall, our findings highlight that the immune cell is a key regulatory component for coordinating matrix preservation and vascular support. Importantly, this model replicates the early phases of wound healing, a stage where the monocyte–fibroblast secretome supports endothelial network formation. We established this innovative 3D ECM hydrogel system as a practical and physiologically relevant platform to investigate immune–matrix–stromal crosstalk. Full article

Background/Objectives: Radiolabeled bevacizumab-based immuno-PET tracers enable a non-invasive quantification of VEGF-A expression in gynecologic malignancies. While the previously reported [⁵²Mn]Mn-DOTAGA-bevacizumab demonstrated selective VEGF-A-targeted uptake in a KB-3-1 cervix carcinoma mouse model, further improvements in chelator stability and tumor-to-background contrast remain desirable. The recently developed BPPA chelator exhibits exceptionally high Mn(II) complex stability and favorable radiolabeling characteristics. This study aimed to characterize the in vivo biodistribution of [⁵²Mn]Mn-BPPA-bevacizumab, and to compare the tumor-to-background ratios of [⁵²Mn]Mn-BPPA-bevacizumab with the previously published values of [⁵²Mn]Mn-DOTAGA-bevacizumab in VEGF-A-expressing cervix carcinoma. Methods: Female KB-3-1 tumor-bearing CB17 SCID mice underwent PET/MRI imaging following intravenous administration of [⁵²Mn]Mn-BPPA-bevacizumab. SUV_mean values were measured in various organs and in the subcutaneously injected tumor, and tumor-to-organ ratios were calculated at various time points up to 10 days post-injection. Results: [⁵²Mn]Mn-BPPA-bevacizumab demonstrated sustained tumor uptake, with tumor SUVmean values increasing from approximately 1.0 at 4 h to peak values of approximately 2.4–2.5 at 72 h post-injection. Tumor-to-background ratios increased progressively over time and were significantly higher for [⁵²Mn]Mn-BPPA-bevacizumab compared with previously reported [52Mn]Mn-DOTAGA-bevacizumab, particularly for tumor-to-blood, tumor-to-liver and tumor-to-lung ratios at later imaging time points (p < 0.0001). Conclusions: The novel [⁵²Mn]Mn-BPPA-bevacizumab tracer exhibits satisfactory in vitro and in vivo stability for PET imaging, high VEGF-A-specific tumor uptake, and markedly improved tumor-to-background ratios compared to the previously published DOTAGA-based probe. These results position [⁵²Mn]Mn-BPPA-bevacizumab as a highly promising next-generation immuno-PET agent for imaging VEGF-A-expressing gynecologic malignancies and for guiding anti-angiogenic therapies. Full article

Renal cell carcinomas (RCCs) driven by TFE3 rearrangement or TFEB alteration (MiT-RCC) account for up to 40% of pediatric RCCs but are rare in adults. MiT-RCC includes fusion-driven tumors with TFE3 or TFEB rearrangements (translocation RCC, tRCC) and TFEB-amplified RCC. Morphologic heterogeneity and historical exclusion from trials have limited evidence-based management. We reviewed the literature through January 2026 to summarize molecular biology, pathology, clinical behavior, and systemic therapy. MiT-RCC comprises biologically distinct entities: TFEB-rearranged tumors are often indolent in younger patients, whereas TFEB-amplified RCC, frequently co-amplifying VEGFA, behaves aggressively in older adults. In TFE3-rearranged RCC, fusion partner influences prognosis. Paradoxically, ASPSCR1::TFE3 fusions have the poorest natural history, yet fusion-annotated cohorts suggest these tumors may derive particular benefit from immune checkpoint inhibitor (ICI) plus VEGF receptor tyrosine kinase inhibitor (VEGFR-TKI) combinations. Diagnostic advances including GPNMB immunohistochemistry, TRIM63 RNA in situ hybridization, and sequencing-based fusion panels improve detection of cryptic alterations. First-line ICI + VEGFR-TKI combinations are increasingly favored for metastatic tRCC in eligible patients, while optimal management of TFEB-amplified RCC remains uncertain. Full article

Glioblastoma (GBM) is a universally fatal cancer for which the standard of care has remained largely unchanged for the last 20 years. Recent work has demonstrated that most therapeutic trials for GBM fail due to complex mechanisms of immunosuppression mediated by both the innate and adaptive immune systems. Various metabolic alterations in the tumor microenvironment help maintain this local and systemic immunosuppression, of which the axis of hypoxia-driven tryptophan degradation has garnered substantial attention over the last decade. This paper synthesizes a much-needed elucidation of the immunometabolic reshaping of glioma, myeloid, endothelial, and lymphoid cell lineages induced by hypoxia. The current paper critically evaluates the role of IDO1/TDO2-mediated breakdown of tryptophan and the consequent accumulation of kynurenine, a metabolite that triggers GCN2- and AHR-mediated CD8+ T-cell exhaustion and supports regulatory T-cell differentiation and expansion. Furthermore, we propose a synthesis of mechanistic evidence that establishes a role for the Trp-GCN2-ATF4-VEGFA axis in hypoxia-induced immunosuppression, supporting that pro-tumoral metabolic dysregulation is directly linked to angiogenesis. In GBM, hypoxia and tryptophan–kynurenine pathway dysregulation operate as an integrated metabolic circuit that drives widespread immunosuppression. These mechanisms can be captured by a metabolic signature shared across nearly every cell type in the GBM microenvironment. Drawing on recent spatial transcriptomic, metabolomic, and pharmacologic studies, we outline how this metabolic axis shapes disease biology and how it can be targeted to restore effective antitumor immunity. Full article