Search Results (8,767)

Diabetic wounds are a common and severe complication of diabetes mellitus, characterized by delayed healing due to persistent inflammation, impaired angiogenesis, and cellular dysfunction. Conventional therapeutic approaches remain limited in efficacy. In recent years, exosomes have attracted considerable attention in wound healing and regenerative medicine because of their crucial role in intercellular communication and tissue repair. However, rapid clearance of exosomes in vivo greatly limits their therapeutic efficacy. To address this critical limitation, we engineered a decellularized extracellular matrix (dECM)-based hydrogel system functionalized with exosomes derived from skin-derived precursor cells (SKPs). This biomimetic scaffold was designed to serve as a local exosome-delivery platform at the wound site, with the aim of improving exosome utilization and augmenting their regenerative effects. Comprehensive in vitro characterization demonstrated that the exosome-loaded composite hydrogels exhibited robust pro-angiogenic activity, as evidenced by enhanced endothelial cell proliferation, migration, and tube formation. Moreover, the hydrogels displayed significant antibacterial effects against wound-relevant pathogens and potent reactive oxygen species (ROS)-scavenging capacity, thereby mitigating oxidative damage. Notably, the composite hydrogels also promoted the phenotypic polarization of macrophages toward the pro-regenerative M2 phenotype. In parallel, in vivo studies using a streptozotocin-induced diabetic rat wound model confirmed that treatment with the composite hydrogels significantly accelerated wound closure rates compared to control groups. Histological and immunohistochemical analyses revealed enhanced angiogenesis, as evidenced by increased CD31-positive microvessel density, as well as improved collagen deposition, re-epithelialization, and an attenuated local inflammatory microenvironment characterized by reduced pro-inflammatory cytokine expression and elevated M2 macrophage infiltration. Collectively, the SKPs exosome-loaded dECM based composite hydrogels developed in this study represent a potential therapeutic strategy for the treatment of diabetic wounds. Full article

Decellularized extracellular matrix (dECM) scaffolds derived from xenogeneic tissues represent promising biomaterials for tissue engineering. In this study, dECM scaffolds were developed and characterized from four ovine tissues—skin, tunica vaginalis, fascia lata, and pericardium—using a detergent-based decellularization protocol to evaluate decellularization efficiency and extracellular matrix (ECM) preservation. Decellularization was performed using a sequential detergent-based protocol with sodium dodecyl sulfate and Triton X-100. Decellularization efficacy and matrix preservation were evaluated through gross examination, histological analysis, scanning electron microscopy (SEM), and residual DNA quantification. Gross inspection revealed increased translucency and reduced pigmentation in decellularized tissues compared with native counterparts, indicating effective cellular removal while maintaining overall tissue architecture. Histological assessment confirmed the complete absence of nuclear and cytoplasmic material, alongside preservation of collagen-rich extracellular matrix organization. SEM analysis demonstrated well-maintained ultrastructural features, including aligned collagen fibers and porous ECM architecture, with complete removal of epithelial and stromal cellular elements. Quantitative analysis revealed approximately 94% reduction in residual DNA content across all decellularized tissues compared with native controls. This study demonstrated that the employed detergent-based protocol reliably produces structurally preserved, acellular scaffolds from multiple ovine tissues. The resulting biomaterials exhibit structural characteristics that support their potential use in tissue engineering applications, pending further functional validation. Full article

Zearalenone (ZEA) is a mycotoxin widely present in cereals, feeds, and foods, posing a persistent threat to human and animal health. Hepatic fibrosis is a pathological process characterized by excessive extracellular matrix (ECM) deposition. Chronic liver injury caused by sustained oxidative stress can initiate the development of early hepatic fibrosis. However, whether liver injury induced by ZEA can trigger hepatic stellate cell (HSC) activation and promote early profibrotic responses remains unclear. The aim of this study was to assess whether ZEA-induced liver injury promotes HSC activation and early profibrotic responses. To address this, we established a BALB/c mouse exposure model and used the murine HSC line (JS-1) for in vitro validation. The results showed that ZEA exposure caused structural damage in hepatic tissue and produced an incomplete bridging pattern of collagen thickening suggestive of an early profibrotic tendency. ZEA shaped a proinflammatory microenvironment by activating the IκBα/NF-κB axis and induced the TGF-β1/Smad2/3 pathway, accompanied by Smad7 suppression, thereby promoting HSC activation and the expression of fibrosis-related genes. ZEA also altered autophagy-related markers in liver tissue and JS-1 cells. Pharmacological inhibition with chloroquine partially attenuated ZEA-induced upregulation of α-SMA and collagen I/III, suggesting that autophagy-related processes may be involved in ZEA-associated HSC activation and early ECM deposition. In summary, ZEA promotes HSC activation and early profibrotic changes in the liver and is associated with inflammatory activation, TGF-β1/Smad signaling, and altered autophagy-related activity. These findings provide a basis for further investigation into the mechanisms underlying ZEA-induced early profibrotic remodeling in the liver. Full article

Keloids and hypertrophic scars are fibroproliferative disorders of wound healing characterized by excessive extracellular matrix deposition, constant inflammation, and high recurrence rates despite appropriate management. Conventional therapies, including surgical excision, corticosteroid injections, laser therapy, and radiation, can provide temporary relief. However, treatment failure remains common, specifically in refractory keloids. Recent findings suggest these outcomes cannot be fully explained by technical or mechanical factors alone, and pathological scarring may reflect underlying immune and neuroimmune dysfunction. Current evidence shows prolonged activation of pro-inflammatory and pro-fibrotic cytokine pathways like IL-6, TNF-α, TGF-β, and IL-17 drives sustain fibroblast activation and disrupts normal wound healing and remodeling. Additionally, the skin functions as an integrated neuro-endocrine-immune organ, allowing bidirectional communication between cutaneous nerves, immune cells, and stromal tissue. Neurogenic inflammation is mediated by neuropeptides, mast cell activation, and stress-induced hypothalamic–pituitary–adrenal axis dysregulation, which further amplifies inflammation within scar tissue. Psychiatric comorbidities like depression, anxiety, and chronic psychological stress serve as a positive feedback mechanism and are increasingly recognized as biologically active contributors to immune dysregulation. This review highlights critical gaps in current management strategies and emphasizes the need for biologically informed, multidisciplinary approaches to improve long-term outcomes for keloid and hypertrophic scar management. Full article

Chondrosarcoma (CHS), the second most common primary malignant cartilage tumor, is largely resistant to conventional therapies, making surgical resection the standard treatment. Proton therapy offers a physical advantage through the Bragg peak, enabling targeted irradiation while sparing surrounding tissues. However, differential biological responses between malignant and normal cartilage cells remain poorly understood. In this study, CHS SW1353 cells and normal chondrocytes (MC615) were exposed to proton irradiation. Biological responses were assessed via clonogenic survival, cell viability, apoptosis (caspase 3/7), micronucleus formation, cell cycle profiling, and oxidative stress markers. Proteomic changes were analyzed using mass spectrometry and bioinformatics. CHS cells exhibited higher radioresistance (D₁₀ = 6.45 Gy) than normal chondrocytes (D₁₀ = 5.08 Gy), oxidative stress adaptation, G1 arrest and proteomic plasticity, whereas normal chondrocytes displayed increased oxidative stress, extracellular matrix fragility and impaired integrin signaling. Notably, the tumor-specific increased levels of Tyrosine-protein kinase Fyn and Yes1-associated transcriptional regulator (YAP1) signaling suggest molecular drivers of radioresistance. Overall, proton irradiation elicits distinct biological and proteomic responses in malignant versus normal cartilage cells. These findings highlight potential radiosensitization targets, including Fyn/Src and YAP1/Hippo pathways, while underscoring the need to optimize proton therapy to enhance tumor control while minimizing damage to healthy cartilage. Full article

Cardiac fibrosis is a central determinant of heart failure progression and arises from pathological remodeling characterized by fibroblast activation, myofibroblast differentiation, and excessive extracellular matrix deposition. In contrast, physiological remodeling permits adaptive cardiac growth without net fibrosis. Pregnancy represents an underexplored physiological model of reversible cardiac remodeling. In response to hemodynamic load, the maternal heart undergoes hypertrophic growth that resolves postpartum, constituting a natural paradigm of fibrosis-resistant cardiac adaptation. Pregnancy and lactation are accompanied by profound endocrine and immune reprogramming of maternal tissues. We propose that this hormonal milieu orchestrates coordinated crosstalk among endothelial cells, fibroblasts, and immune cell populations to suppress profibrotic pathways and preserve extracellular matrix homeostasis. Candidate regulators include estrogen, progesterone, prolactin family peptides, relaxin, oxytocin, and components of the renin–angiotensin–aldosterone system. During the postpartum and lactational period, prolactin and oxytocin may further promote reverse remodeling. These hormones likely act by modulating local cytokine and growth factor networks that otherwise drive fibroblast activation. By focusing on non-myocyte cardiac cells and extracellular matrix dynamics, this review positions pregnancy as a translational model to uncover endogenous anti-fibrotic mechanisms and identify novel therapeutic strategies for cardiac fibrosis. Full article

Endothelial dysfunction (ED) arises in multiple pathologies, and its severity correlates with disease progression. Common ED biomarkers could provide prognostic value for associated complications. This study aims to identify shared ED biomarkers and assess their prognostic significance. Endothelial cells in culture (human microvascular endothelial cells, HMEC-1) were exposed to sera from patients in five disease groups (n = 20 patients/group)—liver cirrhosis with portal hypertension, idiopathic pulmonary arterial hypertension, placental disorders such as intrauterine growth restriction, coronary artery disease with acute myocardial infarction, and chronic kidney disease—or matched controls, in the absence/presence of anti-inflammatory (apixaban) and antioxidant (EUK134) compounds. We explored changes in: VCAM-1, ICAM-1, eNOS, VWF, extracellular matrix thrombogenicity, and reactive oxygen species (ROS). In serum samples, proteomics and metabolomics analyses (including lipids, amino acids, and polar metabolites) were performed through an extraction protocol to identify common ED biomarkers. Expression of VCAM-1, ICAM-1, VWF, platelet adhesion, and ROS increased in most groups versus controls (p < 0.05). Both drugs decreased all biomarker levels except eNOS (n = 6 for in vitro experiments). For serum ED biomarkers, 18 metabolites and 24 proteins showed AUC-ROC and hit rates >77.5%, and six metabolites were associated with event-free survival. These diseases share ED driven by systemic inflammatory, oxidative, and metabolic stress, are partially reversible in vitro, and are linked to biomarkers associated with clinical outcomes. Overall, ED emerges as a modifiable pathological axis with potential prognostic value. Full article

Nanogrooves provide instructive cues to cells in culture. Several nanofabrication techniques have been developed to create biomimetic substrates, advancing our understanding of cell adhesion. Their integration into nervous system models highlights the critical role of the extracellular matrix (ECM) in developing functional tissue constructs for in vitro platforms such as Brain-on-Chip (BoC) and Nervous System-on-Chip (NoC). This study presents a nanofabrication approach that integrates photolithography and microtransfer molding (μTM) to pattern nanogrooves using photocurable polymer NOA81 onto microelectrode array (MEA) plates. The resulting nanogrooves exhibited a pattern periodicity of 976 nm and a ridge width of 232 nm, as confirmed by scanning electron microscopy and atomic force microscopy. We assessed the biocompatibility and functional impact of these modified substrates using human induced pluripotent stem cell (hiPSC)-derived neuronal cultures. Neurons cultured on nanogroove-modified MEAs exhibited aligned neural processes due to the anisotropic surface features and expressed vivid spiking behavior and higher burst frequency compared to randomly cultured neuronal networks. In conclusion, the proposed fabrication technique integrates nanogrooves with commercial MEAs using a combination of microtransfer molding and photolithography, resulting in modified culture substrates that enhance spike activity and network organization, aiding in the development of more in vivo-like neural models. Full article

Lower-grade gliomas (LGGs) often follow a relatively protracted clinical course; however, a substantial proportion eventually undergo malignant transformation to high-grade, treatment-refractory disease. This process has traditionally been interpreted in the context of stepwise histopathologic progression and recurrent genetic alterations. Increasing evidence, however, suggests that malignant transformation is more accurately understood as an evolutionary process shaped by the interplay among epigenetic constraints, cell-state plasticity, and selective pressures. In this review, we examine current evidence supporting a model in which early LGGs, particularly isocitrate dehydrogenase (IDH)-mutant tumors, are initially maintained in relatively restricted cellular states by metabolically imposed epigenetic programs, but progressively escape these constraints under the cumulative influence of therapy, hypoxia, immune remodeling, and genomic instability. We summarize recent advances demonstrating that progression from lower-grade to high-grade disease is accompanied by cell-state transitions characterized by altered lineage identity, acquisition of stem-like features, increased proliferative capacity, and adaptation to cellular stress. We further discuss how these transitions are reinforced by microenvironmental evolution, including vascular remodeling, extracellular matrix reorganization, and changes in immune composition, thereby creating conditions that favor clonal expansion, invasion, and therapeutic resistance. Particular attention is given to longitudinal, single-cell, and spatially resolved studies, which collectively indicate that malignant transformation is not a discrete event but a continuous process of evolutionary selection and phenotypic reprogramming. Finally, we discuss the translational implications of this framework for early risk stratification, biomarker development, and mechanism-based therapeutic intervention. By reframing malignant transformation in LGGs as a process of cell-state escape under persistent selective pressure, this review aims to provide an integrated view of glioma progression and to highlight new opportunities for precision monitoring and treatment. Full article

The cardiac extracellular matrix (ECM) is a dynamic, mechanically active network continuously shaped and interpreted by cardiomyocytes, fibroblasts, and macrophages. Interdependent mechanosensing, force transmission, and ECM remodeling functions create multicellular feedback loops that control tissue stiffness, alignment, maturation, and fibrotic remodeling. Together, these biomechanical processes create reciprocal signaling pathways in which cellular behavior modifies the ECM while the ECM’s mechanics concurrently shape cellular phenotype and function. This review explores cell–ECM mechanoreciprocity, a physiologic framework that unifies cell-sensing mechanotransduction, mechano-electrical coupling, and ECM-based biochemical signaling with cell-driven ECM remodeling. We propose three interconnected feedback loops that integrate biochemical and mechanical cues across cell types: load amplification, structural alignment, and immune regulation. We discuss how advanced two- and three-dimensional engineered cardiac systems incorporating tunable and dynamic mechanical cues can be used to model these interactions. We address the limitations of existing experimental platforms and the need for better models to fully recapitulate in vivo complexities. Understanding and recreating these reciprocal mechanical interactions will provide essential frameworks for disease modeling and therapeutic development while reducing reliance on in vivo studies. Full article

Background: Intervertebral disc degeneration (IVDD) is driven by the interplay between inflammatory signaling, extracellular matrix (ECM) degradation, and impaired cellular adaptation. Although several nutraceutical compounds have been reported to exert protective effects in IVDD-related models, their multitarget mechanisms within integrated molecular networks remain incompletely characterized. Methods: An in silico framework integrating molecular docking with network-based analyses was employed to evaluate resveratrol, quercetin, melatonin, curcumin, and baicalein against a predefined panel of IVDD-associated targets, within an exploratory in silico framework. Binding affinities and interaction profiles were assessed using molecular docking, followed by protein–protein interaction (PPI) network construction, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and hub gene identification. Results: Docking analyses revealed binding energies ranging from −4.59 to −13.25 kcal/mol, with curcumin and quercetin showing plausible docking poses across a subset of selected targets under the applied protocol. Network analysis showed a highly interconnected structure centered on key inflammatory regulators, including NFKB1, IL6, TNF, IL1B, STAT3, and NLRP3, together with ECM-associated components such as ACAN, COL2A1, SOX9, MMP13, and ADAMTS5. Enrichment analyses further suggested significant associations with inflammatory signaling pathways, cytokine regulation, and ECM organization. Conclusions: These findings are compatible with a distributed, multitarget interaction pattern of nutraceutical compounds within IVDD-associated molecular networks. By integrating molecular docking with network-based analyses, this study offers a system-level framework for interpreting previously reported effects within a disease-specific context. Docking-derived interaction patterns should be interpreted as qualitative and exploratory observations, as docking scores represent model-dependent estimates and do not establish comparable pharmacological effects across heterogeneous targets. The results should be considered hypothesis-generating and require experimental validation. Full article

Background/Objectives: Zebrafish fin regeneration serves as a classic model for investigating vertebrate tissue regeneration, yet the core regulatory networks and their crosstalk with the immune microenvironment remain incompletely characterized. This study aimed to identify hub genes, and elucidate the underlying molecular mechanisms and immune microenvironment dynamics during zebrafish fin regeneration. Methods: We integrated multiple bulk RNA-seq datasets of zebrafish fin regeneration from the GEO database, followed by data standardization with batch effect removal. Hub genes were screened via differential expression analysis, weighted gene co-expression network analysis (WGCNA), and predictive models constructed with 13 classic machine learning algorithms. Functional enrichment, time-ordered gene co-expression network (TO-GCN) method, immune infiltration analyses and RT-qPCR validation were further performed. Results: We identified upregulated differentially expressed genes, regeneration-correlated gene modules and their overlapping genes, including 82 candidate genes and 10 hub genes enriched in cytoskeleton remodeling, extracellular matrix organization, and focal adhesion. Temporal analysis uncovered hierarchical gene regulation and functional switching during regeneration. Hub gene expression was significantly correlated with the infiltration of B cells, M1/M2 macrophages and CD8+ T cells, revealing a stage-specific immune microenvironment. RT-qPCR validation showed high consistency with the multi-omics data. Conclusions: This study provides potential gene targets for understanding zebrafish fin regeneration, and offers a valuable reference for investigating the crosstalk between regulatory networks and the immune microenvironment in vertebrate tissue regeneration. Full article

Chalcones, a subclass of flavonoid-derived phenolic compounds, have demonstrated promising anthelmintic activity against parasitic nematodes. This study aimed to obtain insights into the biological effects a cis/trans mixture of chalcone and its geometric isomer, trans-chalcone, using RNA sequencing in the model organism Caenorhabditis elegans. Fourth-stage larvae (L4) were exposed to cis/trans-chalcone or trans-chalcone for 3 h, and total RNA was extracted for high-throughput sequencing. Transcriptomic analysis revealed that exposure to cis/trans-chalcone and trans-chalcone induced pronounced modulation of genes involved in lipid metabolism and repression of collagen and structural genes, potentially leading to defective extracellular matrix maintenance, thereby suggesting these combined effects as potential mechanisms underlying their anthelmintic activity. Also, metabolic and stress response pathways, with several genes implicated in detoxification and cellular defense, were markedly upregulated. These findings provide new insights into the molecular mechanisms affected by chalcones, advancing our understanding of their anthelmintic potential and supporting future drug development efforts. Full article

Hyaluronic acid (HA), a major extracellular matrix component, is used therapeutically to aid healing and deliver drugs to injury sites. Burns create serious clinical and aesthetic problems needing fast skin repair to prevent complications. This study compared 1.8% pharmaceutical-grade HA with panthenol-containing gel (PCG) in deep-burn healing in rats against spontaneous healing. HA slightly accelerated wound closure from day 3 compared to PCG; both induced granulation by day 7 and epithelialization by day 28. HA caused early collagen drop (day 3), later matched PCG levels with abnormal distribution, and both exceeded control by day 28. HA normalized systemic leukocyte counts by day 14 while strongly increasing local leukocyte infiltration in the wound area. HA dual immune effect depends on source and properties; further research is required for clinical use in wound healing. Full article

Background: Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, and although PD-1/PD-L1 immune checkpoint blockade has improved outcomes in some patients, therapeutic responses remain heterogeneous. Tumor-intrinsic heterogeneity within malignant epithelial populations is increasingly recognized as a critical determinant of disease progression and therapy response. Methods: Here, we constructed a comprehensive single-cell atlas of NSCLC by integrating 650,461 cells from 216 tumor and normal samples. Tumor-derived epithelial cells were reclustered to identify transcriptionally distinct subpopulations. Pseudotime analysis, functional experiments, and in vivo validation using a humanized xenograft model were performed to investigate the role of COL3A1. Results: Reclustering of tumor-derived epithelial cells revealed 25 transcriptionally distinct subpopulations. Among these, a high-risk cluster exhibited coordinated activation of epithelial–mesenchymal transition (EMT) and angiogenesis programs and was associated with poor patient survival. Within this aggressive subpopulation, Collagen type III alpha 1 (COL3A1) emerged as a tumor-intrinsic gene associated with extracellular matrix remodeling and angiogenic signaling. Pseudotime analysis indicated that COL3A1⁺ cells represent a late-stage, poorly differentiated malignant state. Functional experiments demonstrated that COL3A1 knockdown impaired NSCLC cell proliferation, migration, and invasion. Virtual knockout further suggested that COL3A1 may be associated with transcriptional programs involved in PD-L1 upstream signaling pathways, indicating a potential indirect link between tumor-intrinsic states and immune regulatory networks. Consistently, in vivo silencing of COL3A1 enhanced the antitumor efficacy of PD-L1 blockade. Conclusions: Collectively, our study identifies COL3A1 as a tumor-intrinsic gene enriched in malignant epithelial cells with mesenchymal features and a potential therapeutic target. These findings provide a rationale for exploring combinatorial strategies integrating tumor-intrinsic pathway inhibition with immune checkpoint blockade in NSCLC. Full article