Search Results (527)

CAR-T cell therapy has shown substantial efficacy in haematological malignancies, but its application to solid tumours remains limited by poor effector-cell infiltration, functional exhaustion, antigenic heterogeneity, and an immunosuppressive microenvironment. In this study, we develop a new spatiotemporal mathematical model of CAR-T therapy for solid tumours that integrates these resistance mechanisms within a single reaction–diffusion framework. The model is formulated as a system of partial differential equations describing functional and exhausted CAR-T cells, antigen-positive and antigen-low tumour subpopulations, and chemokine, immunosuppressive, and hypoxic fields. Steady-state analysis and finite-difference simulations showed that therapeutic outcome is governed by the interplay between CAR-T cell infiltration, exhaustion, and antigen escape. The model reproduces partial tumour regression followed by residual tumour persistence, therapy-driven enrichment of antigen-low cells, and reduced efficacy under stronger immunosuppressive and hypoxic conditions. In the combination therapy scenario considered here, repeated simulated CAR-T cell administration together with attenuation of the suppressive microenvironment improves tumour control. The proposed model provides a mechanistic basis for analysing resistance and for future optimisation studies of CAR-T therapy in solid tumours. Full article

Small extracellular vesicles (sEVs) derived from mesenchymal stem cells (MSCs) are emerging as potent acellular therapeutics; however, their rapid clearance hinders their clinical translation. To address this issue, 3D-bioprinted genipin-crosslinked gelatin (GECL) was engineered for human health. GECL hydrogels were functionalised with human umbilical cord MSC-derived sEVs (hUCMSC-sEVs) to create a bioactive wound-healing platform. These hydrogels demonstrated favourable physicochemical, mechanical, and biodegradable properties while providing an extracellular matrix (ECM)-mimetic environment conducive to tissue regeneration. MSCs were isolated from the umbilical cords, and their small extracellular vesicles (sEVs) were extracted and incorporated into gelatin-based hydrogels via 3D bioprinting. These sEV-loaded scaffolds were embedded in full-thickness wounds in mice, and healing was evaluated through macroscopic observation, histological analysis, collagen deposition, and angiogenesis assessment. Compared with the untreated controls, both the hydrogel-only (B) and sEV-loaded hydrogel (BE) groups significantly accelerated in vivo wound healing. Notably, the BE group achieved complete wound closure within 14 days, restoring the skin architecture, which closely resembled the native tissue with well-organised epidermal and dermal layers, optimal thickness, and skin appendages. Histological and ultrastructural assessments revealed an increased collagen type I deposition, a reduced α-smooth muscle actin (α-SMA) expression, and a robust neovascularisation. The TEM revealed tight junctions and active cellular infiltration, indicating scaffold integration and functional remodelling. Immunohistochemistry further revealed an upregulated CD31 expression with a balanced α-smooth muscle actin (α-SMA) expression, reflecting coordinated angiogenesis and myofibroblast regulation. These results highlight sEV-functionalised GECL hydrogels as robust and clinically translatable acellular therapeutic green products for accelerated wound closure and functional skin regeneration, advancing the fields of regenerative medicine and life expectancy. Full article

This study employed UPLC-MS/MS to determine the contents of major polyphenolic compounds and proanthocyanidins (PCs) in Kyoho grape seeds, optimized the extraction method and conditions for PCs using response surface methodology (RSM), and further evaluated the scavenging activities of PCs against 2,2-diphenyl-1-picrylhydrazyl (DPPH) and hydroxyl (•OH) radicals as well as their effects on growth, immunity, and oxidative stress in mice. Three hundred and sixty 3-week-old male mice (42.28 ± 0.31 g) were assigned to a single factor complete randomized trial design and fed with six different diets including 0 mg/kg vitamin E(VE) + 0 mg/kg PCs, 100 mg/kg VE, 25 mg/kg PCs + 75 mg/kg VE, 50 mg/kg PCs + 50 mg/kg VE, 75 mg/kg PCs + 25 mg/kg VE and 100 mg/kg PCs, respectively. The results demonstrated that PCs were identified as the predominant phenolic compounds, accounting for 29.6% of total phenolic substances in Kyoho grape seeds. Additionally, the ultrasound-assisted extraction method was superior to the shaker-assisted and low-temperature infiltration extraction methods, with optimal conditions of 60% ethanol concentration, material-to-liquid ratio of 1:20 g/mL, temperature of 30 °C, and extraction time of 50 min. Scanning electron microscopy (SEM) revealed that ultrasound treatment effectively disrupted the seed surface structure, facilitating PC release. In vitro, PCs exhibited significantly stronger DPPH and hydroxyl radical (•OH) scavenging activities than vitamin C (VC), Trolox, and gallic acid. Compared with the control group, mice fed diets containing PCs and VE showed higher superoxide dismutase (SOD) activity, glutathione peroxidase (GSH-PX) activity, and total antioxidant capacity (TAOC), Catalase (CAT), GPX and inflammation factor 10 (IL-10) genes levels in the serum and liver (p < 0.05), whereas the levels of immunoglobulin G (IgG), immunoglobulin A (IgA), immunoglobulin M (IgM), tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6), as well as the mRNA expression of IL-1β and TNF-α, showed the opposite trend (p < 0.05). In conclusion, the antioxidant capacity of PCs was stronger than that of VC and VE. The addition of PCs improved the antioxidant activity and immune function of mice. Full article

Background: Diabetic wounds represent a major clinical challenge due to persistent inflammation, oxidative stress, and impaired angiogenesis. Bone marrow mesenchymal stem cells (BMSCs) have strong regenerative potential, and their therapeutic effects and optimization strategies for diabetic wounds warrant further exploration. Objective: This study aimed to improve the therapeutic efficacy of BMSCs in diabetic wound healing via chrysin pretreatment, as well as to evaluate the healing capacity and molecular mechanisms of the derived chrysin-pretreated BMSC-conditioned medium (Chrysin-CM). Methods: BMSCs were pretreated with 1 μM chrysin for 48 h to generate Chrysin-CM. The therapeutic effects were evaluated in vitro by analyzing the proliferation, migration, and matrix synthesis of human umbilical vein endothelial cells (HUVECs) and human skin fibroblasts (HSFs) under high-glucose (HG) conditions. In vivo, a diabetic mouse model with full-thickness excisional wounds was established and treated topically with Chrysin-CM. Transcriptomic sequencing and immune infiltration analysis of wound tissues were performed on day 14 in order to investigate the underlying mechanisms. Results: Chrysin pretreatment significantly enhanced the functional activity of BMSCs, accompanied by increased proliferative capacity and accelerated cell cycle progression. In vitro, Chrysin-CM demonstrated superior efficacy, robustly protecting HUVECs and HSFs from HG-induced dysfunction. In vivo, Chrysin-CM significantly accelerated wound closure, re-epithelialization, and neovascularization compared to the control. Mechanistically, RNA sequencing (RNA-seq) revealed that Chrysin-CM induced multi-level remodeling, characterized by reduced inflammatory gene expression and immune cell infiltration, along with the upregulation of regenerative genes and alternative splicing events. Conclusions: Chrysin successfully improved the therapeutic efficacy of the BMSC secretome in wound healing. Chrysin-CM effectively accelerated diabetic wound healing by actively resolving chronic inflammation and promoting angiogenesis and structural remodeling, thus providing a potential strategy for stem cell-based cell-free treatment for chronic diabetic wounds. Full article

Static magnetic fields (SMFs) are underexplored as biophysical tools for transplant immunomodulation. This study investigated a 300 mT SMF as a non-pharmacological adjuvant to enhance graft survival in parathyroid xenotransplantation. Human parathyroid tissues were transplanted into Sprague-Dawley rats (n = 20) across four groups: control (G1), SMF-only (G2), transplantation-only (G3), and SMF-assisted transplantation (G4). Following 30-day continuous SMF exposure, functional and immunological assessments were performed. G4 achieved the highest systemic PTH recovery (p = 0.009) without altering intrinsic secretory capacity. Systemic cytokine profiling revealed significant IFN-gamma suppression in G4 (p = 0.0024), suggesting downregulation of Th1-mediated rejection pathways. While G2 showed pro-inflammatory increases (TNF-alpha, GM-CSF), G4 maintained baseline levels, confirming biocompatibility. IHC confirmed that SMF exposure sequestered lymphocytes to the graft periphery, preventing the diffuse infiltration observed in G3. In conclusion, continuous SMF exposure modulates the immune microenvironment by altering lymphocyte migration and IFN-gamma signaling. This biophysical strategy provides localized immunoprotection, potentially offering a drug-free alternative to systemic immunosuppression in endocrine tissue transplantation. Full article

Bcakground: Hepatocellular carcinoma (HCC) is a prevalent malignancy with limited therapeutic options. Drug repurposing offers an attractive strategy to accelerate anticancer discovery. The pleuromutilin class of antibiotics, including the human-approved agent lefamulin and the veterinary drug tiamulin, has shown preliminary anticancer potential, but its efficacy and mechanism in HCC remain unexplored. Methods: The anti-tumor effects of lefamulin and tiamulin were evaluated in HCC cell lines, patient-derived organoids, and a C57BL/6 mouse subcutaneous tumor model. Safety was assessed in a human normal hepatocyte cell line and by histopathological examination of major organs in treated mice. Mechanistic investigations were performed using RNA-sequencing, RT-qPCR, immunohistochemistry (IHC), filipin staining, pharmacological rescue assays, and shRNA-mediated gene silencing. Results: In this study, we found that both lefamulin and tiamulin markedly inhibited HCC cell proliferation in vitro and significantly suppressed tumor growth in vivo (lefamulin vs. control, p = 0.014; tiamulin vs. control, p = 0.021), without causing significant toxicity. RNA-sequencing analysis revealed consistent downregulation of the cholesterol transporter Abca1 (ATP-binding cassette transporter A1) and alterations in cell adhesion molecule pathways. Functional studies confirmed that treatment reduced ABCA1 protein levels, leading to intracellular cholesterol accumulation and aberrant distribution. Furthermore, treated tumors exhibited a significant increase in CD8⁺ T-cell infiltration, with CD4⁺ T cells and macrophage infiltration remained unchanged, indicating a specific modulation of the tumor immune microenvironment. Conclusions: These findings suggest that lefamulin and tiamulin are promising therapeutic candidates for HCC. Full article

Objective: To longitudinally investigate the effect of non-surgical periodontal therapy (NSPT) on the transcriptional and translational levels of Superoxide Dismutase (SOD) and Insulin Receptor Substrate type 2 (IRS2) in individuals with Type 2 Diabetes Mellitus (T2DM) and Periodontitis (P). Methods: This clinical study was registered at the Brazilian Clinical Trials Registry (ReBEC-RBR-5m3yxmb). Saliva, peripheral blood mononuclear cells (PBMCs), and gingival biopsies were collected from 156 individuals, distributed into five groups, each with at least 30 participants: T2DM_poorly_controlled+P, T2DM_well_controlled+P, T2DM_without_P, Periodontitis, and Control. Systemic levels of messenger RNA (mRNA) of Superoxide Dismutase 1 (SOD1) and IRS2 were measured using real-time polymerase chain reaction at baseline, 90, and 180 days after NSPT. SOD enzymatic activity in Saliva and IRS-2 immunohistochemistry in gingival biopsies were also assessed. Results: Higher SOD1 mRNA levels were observed in Control individuals at baseline. In contrast, higher IRS2 mRNA levels were detected in individuals with Periodontitis at baseline, followed by a significant reduction over time. A significant positive longitudinal correlation was identified between IRS2 and SOD1 gene expression in the groups without T2DM, indicating potential functional interaction between the molecules. Salivary SOD enzymatic activity was lower in individuals from the T2DM_poorly_Controlled+P and T2DM_well_Controlled+P groups. SOD concentration (U/g) normalized to the total protein content was higher in the saliva of individuals with Periodontitis. T2DM+P and Periodontitis groups showed extensive inflammatory infiltrate in the gingival biopsies, with predominant IRS-2 immunopositive cells in the T2DM+P groups, independently of the metabolic control. Conclusions: This study shows that non-surgical periodontal therapy (NSPT) is followed by longitudinal changes in IRS2 and SOD1 expression at the mRNA and protein levels in individuals with T2DM+P (poorly/well controlled) and periodontitis, reinforcing the clinical relevance of periodontal treatment in the systemic context of T2DM. Full article

Uranium mining generates complex multi-element contamination that affects interconnected ecosystem components, posing long-term ecological and sanitary risks; this review places these impacts in a broad environmental context and aims to synthesize current knowledge on the distribution, migration, and accumulation of uranium and associated heavy metals in water, soil, and plants. A structured analysis of international peer-reviewed literature was conducted, focusing on documented pathways of metal release from tailings and waste dumps, geochemical controls on mobility, and biological uptake by vegetation. The reviewed studies consistently show that tailings and disturbed ore-bearing strata act as persistent sources of uranium and heavy metals (e.g., Cd, Pb, Cr, Ni, Zn, Mn, As), which migrate through infiltration, acid mine drainage, and atmospheric dispersion, leading to elevated concentrations in surface and groundwater and long-term accumulation in soils. Soils function as the principal sink controlling metal bioavailability, while vegetation reflects the bioavailable fraction and exhibits pronounced species-specific accumulation patterns. These processes establish an active “soil–water–plant” transfer chain that facilitates entry of contaminants into food webs. The synthesis indicates that combined uranium and heavy metal contamination represents a sustained ecological and public health concern in uranium-mining regions and underscores the need for integrated monitoring of soils, waters, and vegetation, along with quantitative risk assessment and scientifically grounded remediation strategies. Full article

Surgical resection remains a cornerstone in the multidisciplinary management of central nervous system (CNS) tumors, particularly diffuse gliomas. Traditionally, the role of surgery has been evaluated primarily through quantitative metrics such as extent of resection and its association with survival outcomes. However, despite maximal and radiologically complete resections, recurrence remains nearly universal in malignant CNS tumors, suggesting that surgical cytoreduction alone does not fully account for post-surgical disease dynamics. Emerging biological and molecular evidence indicates that surgery represents not merely a technical intervention, but a biologically active event that profoundly reshapes tumor evolution and treatment response. In this review, we propose a conceptual framework that redefines surgery as a key biological driver in CNS tumor progression. We synthesize evidence demonstrating that surgical trauma induces inflammation, hypoxia, vascular remodeling, immune modulation, and extracellular matrix reorganization, collectively reprogramming the residual tumor microenvironment. These changes create selective pressures that favor the survival and expansion of adaptive tumor cell subpopulations, including invasive and stem-like phenotypes. From an evolutionary perspective, surgical resection functions as an acute selective bottleneck acting on heterogeneous tumor ecosystems, contributing to clonal selection and molecular divergence at recurrence. We further examine the dissociation between surgical (anatomical) margins and molecular (biological) margins, highlighting how biologically active tumor cells infiltrate beyond radiologically defined boundaries. This discrepancy provides a biological explanation for marginal and distant recurrences and challenges anatomy-based paradigms of surgical completeness. Importantly, we discuss how surgery-induced biological changes influence postoperative radiotherapy and systemic therapies, affecting radiosensitivity, target delineation, and therapeutic vulnerability. Finally, we outline future directions toward surgery-integrated precision neuro-oncology, emphasizing the potential of spatial profiling, liquid biopsy, advanced imaging, and artificial intelligence to capture perioperative tumor evolution. By reframing surgery as a biological inflection point rather than a neutral prelude to adjuvant treatment, this review advocates for a dynamic, biology-driven continuum of care aimed at anticipating tumor adaptation and improving long-term disease control in CNS tumors. Full article

Silicon carbide (SiC) and SiC fiber-reinforced SiC matrix composites (SiC/SiC) are receiving renewed attention for use in next-generation fusion reactors due to their ability to withstand extreme conditions, including high temperatures, neutron irradiation, and plasma interactions. General Atomics Electromagnetic Systems (GA-EMS) has demonstrated significant progress in scaling up the fabrication of SiC/SiC, achieving high mechanical uniformity and meeting dimensional requirements in components up to 12 feet in length. Key developments are discussed including scale-up of the chemical vapor infiltration (CVI) process from lab-scale to full sized parts, high-dose (100 dpa) irradiation testing, nuclear-grade ceramic joining technologies, and production-focused quality control with the collective aim to establish SiC/SiC as a reliable solution for structural and functional components in fusion systems. Beyond manufacturing, the paper addresses supply chain barriers, particularly the limited availability and high cost of nuclear-grade SiC fiber. GA-EMS is developing a novel SiC fiber production method based on a thermochemical cure step that is anticipated to reduce costs compared to traditional approaches. Additionally, advancements in engineered SiC materials, such as SiC foams and tungsten-graded SiC composites, are discussed as promising solutions for specific fusion reactor components. Full article

Background/Objectives: Epigenetic factors are increasingly recognized to contribute to the pathogenesis of intestinal diseases, yet the precise mechanisms through which these factors influence ulcerative colitis (UC) remain poorly understood. Methods: Transcriptome profiles pertaining to UC and genes associated with epigenetic factors (EFRGs) were retrieved from publicly accessible datasets. Candidate genes were ascertained through the intersection of differentially expressed genes (DEGs) and EFRGs. Key genes were screened through machine learning algorithms and validated via the Artificial Neural Network (ANN) model. Enrichment analysis and immune infiltration assays were conducted to elucidate the underlying mechanisms of these genes. The hub gene, CBX4 (Chromobox homolog 4), was validated through immunohistochemical analysis of both healthy controls and patients with UC, and the correlation was evaluated using UC-related clinical parameters. Additionally, CBX4 expression was knocked down in dextran sulphate sodium (DSS)-treated mice to examine its regulatory function. Unlike conventional broad-spectrum biomarker screens, this study specifically integrated epigenetic factor-related genes (EFRGs) with machine learning and experimental validation using both clinical samples and animal models. Results: SMARCB1, JAK2, CBX4, and PPARGC1A were identified as key genes, with SMARCB1, JAK2, and CBX4 being upregulated in the UC group, while PPARGC1A was significantly downregulated. The ANN model exhibited excellent diagnostic performance. Enrichment analysis revealed that the key genes were associated with pathways such as the “chemokine signaling pathway”. Immune cell infiltration analysis results revealed marked differences in the abundances of 13 immune cell types between the UC and control groups, and there were notable associations between immune cell infiltration and key genes. Notably, CBX4 expression was elevated in both DSS-treated mice and patients with UC, showing positive correlations with clinical indicators of UC. Further in vivo experiments revealed that silencing CBX4 alleviated DSS-induced colon damage and inflammation. Conclusions: This study identifies four EFRG-related key genes (SMARCB1, JAK2, CBX4, PPARGC1A) in UC, suggesting that CBX4 may play a significant role as an epigenetic regulator. CBX4 is upregulated in UC intestinal tissues, and its knockdown mitigates DSS-induced colitis. These findings provide critical theoretical support for developing targeted therapies for UC. Full article

Frankincense, a traditional Chinese medicinal resin with well-documented skin barrier-protective and anti-inflammatory properties, has elusive underlying mechanisms in psoriasis-like dermatitis. This study aimed to elucidate its therapeutic potential and molecular targets by investigating frankincense oil extract (FOE) and three key constituents (linalool, α-pinene and 1-octanol) in a classic imiquimod-induced murine psoriasis model, with clinical first-line topical drugs (calcipotriol, tapinarof and dithranol) used as positive controls. Phenotypically, FOE and its constituents significantly ameliorated core psoriasis symptoms (desquamation, erythema, epidermal thickening and splenomegaly) at an efficacy comparable to that of positive controls. FOE suppressed epidermal hyperproliferation and dermal inflammatory infiltration, attenuated the abnormally elevated epidermal expression of TRPV3, β-catenin and COX-2, and increased the expression of the barrier protein K10. Taken together, these findings suggest that FOE restores impaired epidermal barrier function by regulating TRPV3, β-catenin, COX-2 and K10 expression, providing a novel mechanistic basis for the clinical application of traditional frankincense in psoriasis and identifying promising targets for antipsoriatic-drug development. Full article

Glioblastoma (GBM) is a highly aggressive brain tumor with a complex tumor microenvironment (TME) that includes immune cell infiltration, notably macrophages. The role of macrophages in GBM progression is influenced by their polarization state, which can be either pro-inflammatory (M1) or immunosuppressive (M2). This study investigates the macrophage polarization in GBM, identifying key macrophage-related genes and their impact on tumor progression. Analysis of TCGA-GBM data revealed that macrophage infiltration correlates with poor prognosis, with 41 risk-associated genes identified. DSP dataset analysis highlighted 378 differentially expressed genes between CD68⁺ macrophages and GFAP⁺ controls, including immune-related genes like SPP1, CD74, and C3. Cross-validation with single-cell RNA-seq confirmed the expression of 9 key genes, with 7 genes being macrophage-specific. In vitro experiments using conditioned media from GBM cell lines demonstrated that GBM cells promote macrophage polarization towards an M2-like phenotype. Overexpression of CD74, CLEC7A, and IFI30 in macrophages further enhanced M2 polarization, which was associated with increased tumor-promoting functions, including enhanced invasion and reduced apoptosis in GBM cells. Together, these findings highlight the role of M2 macrophage polarization in promoting GBM progression and suggest that targeting macrophage polarization pathways may offer therapeutic potential. Full article

Clogging is the main mechanism that deteriorates the hydraulic functionality of permeable pavements, particularly in porous asphalt mixtures (PAM). This study evaluated the hydraulic impact of sediments from three peri-urban micro-watersheds in the Boyacá region of Colombia on the infiltration capacity of PAM. Road infrastructure and drainage conditions were analysed using orthophotos and field inspections to identify geomorphological factors that favour sediment transport toward the roadway. Annual erosion rates were estimated using the Universal Soil Loss Equation (USLE), and sediments were characterized both within the watersheds and at their outlet onto the road. Hydraulic performance was assessed through laboratory tests using a Falling Head Permeameter, complemented by field infiltration measurements with a Modified Cantabrian Infiltrometer (0.25 m²). Results showed erosion rates of up to 7.9 t/ha·year and infiltration losses above 90% under clogged conditions. A partial hydraulic recovery of around 40% was observed after maintenance, particularly when sediments exhibited a higher sand fraction. These findings demonstrate that combining USLE-based erosion modelling with controlled hydraulic testing provides a robust framework for evaluating clogging risks in peri-urban roads and offers new evidence on the hydraulic behaviour of PAM exposed to non-urban sediments in the design and maintenance of sustainable pavements. Full article

Background: Danhong injection (DHI), a standardized traditional Chinese medicine formulation, has shown clinical benefits in treating cerebrovascular diseases. Blood–brain barrier (BBB) disruption is a key pathological feature of ischemic stroke, but its modulation by DHI under hyperlipidemic conditions remains unclear. This study aimed to investigate the protective effects and mechanisms of DHI in cerebral ischemia/reperfusion injury (CI/RI) under hyperlipidemia, focusing on BBB integrity and the Wnt/β-catenin signaling pathway. Methods: Rats were divided into control, ischemic, hyperlipidemic, and treatment subgroups to evaluate DHI’s dose-dependent effects and pathway specificity using DKK1 inhibition. Assessments included neurological scores, TTC and Nissl staining, TEM, and molecular analyses (qRT-PCR/Western blot/immunofluorescence/immunohistochemistry). Results: DHI significantly improved neurological function, reduced cerebral infarct size, and alleviated cortical damage. DHI treatment upregulated the expression of tight junction proteins (Claudin-5, Occludin, ZO-1) and downregulated MMP-9 expression. Mechanistically, DHI promoted the nuclear translocation of β-catenin and increased the expression of Wnt3α, p-GSK-3β, and Cyclin D1, thereby activating the Wnt/β-catenin pathway. Additionally, DHI treatment increased the count of NeuN-positive neurons, suppressed astrocyte activation, and markedly reduced IgG infiltration in the ischemic cerebral cortex. These effects were reversed by DKK1. Conclusions: The results indicate that DHI protects BBB integrity and alleviates CI/RI in hyperlipidemic rats independently of direct lipid-lowering activity. Specifically, DHI activates the Wnt/β-catenin pathway by enhancing β-catenin nuclear translocation, which in turn mediates the upregulation of tight junction proteins and suppression of MMP-9, ultimately preserving BBB integrity. These findings support its therapeutic potential in ischemic stroke with comorbid hyperlipidemia. Full article