Search Results (8,775)

Endometriosis is a chronic inflammatory disease in which transforming growth factor-beta (TGF-β) has been implicated in immune dysregulation, extracellular matrix remodeling, and fibrosis. Data on baseline secretion of TGF-β isoforms by systemic immune cells remain limited. This pilot study quantified unstimulated secretion of TGF-β1, TGF-β2, and TGF-β3 by peripheral blood mononuclear cell (PBMC) cultures from women with and without endometriosis and explored stage-related patterns. In this prospective case–control study, PBMCs from 50 women with surgically confirmed endometriosis and 30 controls were cultured for 24 h without exogenous stimulation. Supernatant concentrations were measured using a multiplex bead-based immunoassay (Bio-Plex, Bio-Rad) and expressed as pg/mL; between-group and stage-related differences were assessed using non-parametric tests. Median 24 h secretion was similar between groups (TGF-β1: 103,816 vs. 114,700 pg/mL, p = 0.25; TGF-β2: 3735 vs. 3732 pg/mL, p = 0.32; TGF-β3: 3280 vs. 3284 pg/mL, p = 0.70). Within the endometriosis cohort, TGF-β2 was significantly higher in moderate/advanced disease (rASRM stages III–IV) than in minimal/mild disease (stages I–II), whereas TGF-β1 and TGF-β3 did not reach statistical significance for a stage-dependent pattern in this pilot cohort (p = 0.42 and p = 0.41, respectively; Kruskal–Wallis), and a type II error cannot be excluded given the small sample size per rASRM (revised American Society of Reproductive Medicine)stage (n = 11–14). These findings suggest that TGF-β dysregulation is compartmentalized to the peritoneal environment rather than systemically imprinted in circulating immune cells. The stage-dependent elevation of TGF-β2 supports its role in progressive fibrogenesis and as a candidate severity biomarker, warranting confirmation in larger, stimulus-augmented studies. Full article

Gingival recession is commonly linked to alveolar bone dehiscence, inflammatory burden, traumatic brushing, or excessive orthodontic forces. However, recession is also observed in some patients despite apparently mild or “biologically acceptable” loading, particularly in thin periodontal phenotypes. Here, we propose the Gingival Creep Failure Theory, a hypothesis-driven conceptual framework in which gingival soft tissues undergo time-dependent viscoelastic deformation (creep) under sustained or repetitive tensile microstrain. Over time, accumulated deformation and microstructural fatigue may reduce recoil capacity and shift the gingival margin apically once tissue-level tolerance is exceeded. Gingival connective tissue is modeled as a fiber-reinforced, fluid-rich viscoelastic composite whose response depends on collagen architecture, cross-linking, proteoglycan-mediated hydration, and vascular support. In thin phenotypes characterized by reduced connective tissue volume and altered extracellular matrix (ECM) organization, creep progression is hypothesized to accelerate, lowering the threshold at which fatigue-related microdamage translates into clinically detectable marginal migration. Evidence from collagenous connective tissue biomechanics supports the plausibility that sub-failure sustained or cyclic loading can produce cumulative deformation and incomplete recovery; however, direct creep–fatigue data for human gingiva remain limited, underscoring the need for targeted validation studies. This hypothesis integrates soft tissue mechanics with periodontal phenotype biology and orthodontic loading patterns and proposes creep and microstructural fatigue as plausible time-dependent contributors to gingival recession in susceptible phenotypes. Because direct in vivo gingival strain and creep–fatigue measurements remain limited, the model should be interpreted as hypothesis-generating and in need of targeted clinical and experimental validation. Full article

A high-fat, high-cholesterol diet (HFHCD) has a lipotoxic effect on the heart. It not only leads to the development of atherosclerosis but also influences the extracellular matrix within the heart. The aim of the study was to investigate the effect of HFHCD on matrix metalloproteinases MMP-2, MMP-9, MMP-13, and MMP-14 expression in both the cardiac tissue and plasma of ApoE (-/-) mice and on mRNA expression of c-Jun and TGF-β in the cardiac tissue of both ApoE (-/-) mice and wild-type C57BL/6J mice. The study was carried out on two groups of ApoE (-/-) mice: (1) mice from 10 weeks of age that were kept on a HFHCD (n = 10) for the following 14 weeks; (2) control mice (NFD, n = 10) that were kept on a standard, normal-fat diet for the same time as the HFHCD. Additionally, 10 wild-type (WT) mice on a standard, normal-fat diet were also included in the study for mRNA analysis of c-Jun and TGF-β. Atherosclerotic plaque, intima, and media dimensions were assessed in the aortas of the ApoE (-/-) mice by histopathology. Concentrations of MMP-2, MMP-9, MMP-13, and MMP-14 were assessed by ELISA both in cardiac tissue and in the plasma of the ApoE (-/-) HFHCD and ApoE (-/-) NFD mice, while the mRNA expression of c-Jun and TGF-β was assessed by RT-PCR in both the ApoE (-/-) and WT groups. The results demonstrate a significantly increased MMP-9 concentration in the cardiac tissue of the HFHCD mice compared to the NFD mice (2.83 ng/mL vs. 1.91 ng/mL, p = 0.006), and a moderate correlation between the cardiac and plasmatic MMP-9 in ApoE (-/-) mice (r = 0.492, p = 0.0398). Moreover, although the mRNA expression of c-Jun and TGF-β did not differ between NFD and HFHCD ApoE (-/-) mice, the c-Jun expression was significantly elevated in the WT group compared with both ApoE (-/-) groups. The study demonstrated that a high-fat, high-cholesterol diet increases MMP-9 concentration in cardiac tissue, which might reflect its influence on the extracellular matrix within the heart. Full article

Ovarian cancer is the most lethal gynaecological cancer, largely because it is often diagnosed late and shows strong tumour heterogeneity, therapy resistance, and rapid metastatic spread. A key driver of this aggressive behaviour is the tumour’s ability to reshape its surrounding microenvironment to support invasion, angiogenesis, and escape from treatment. Cathepsin L (CTSL), a lysosomal cysteine protease, has emerged as an important mediator of these processes and is gaining attention as both a prognostic marker and a potential therapeutic target. This review examines the diverse roles of CTSL in ovarian cancer progression, focusing on how its expression, localisation, and extracellular release are altered within the hypoxic and acidic conditions typical of the tumour microenvironment. It also outlines emerging therapeutic strategies aimed at targeting CTSL, including selective inhibitors, multi-cathepsin approaches, CTSL-activated prodrugs and antibody-drug conjugate linkers, and nanomedicine systems designed for tumour-specific delivery. Overall, the evidence highlights CTSL as a central regulator of invasion, angiogenesis, and relapse in ovarian cancer, underscoring its potential as a target for new therapies in aggressive disease. Full article

Since MDCK cells are inherently tumorigenic, their safety in vaccine production has long been a concern; thus, establishing a screening method for low-tumorigenic cells is of great significance for influenza vaccine development. This study successfully obtained a low-tumorigenic MDCK cell line through monoclonal screening and systematically evaluated its potential as a cellular substrate for influenza vaccines using male nude mice (BALB/c nu/nu, 4–7 weeks old) for tumorigenicity assessment. Comprehensive analysis of the biological characteristics of the screened cells—including growth curves and transcriptomic features—showed that the cell line exhibits stable growth and consistent traits. Transcriptomic comparison was performed between two defined biological states: parental MDCK cells (SQ group) and the low-tumorigenic clone MDCK-20B9 (SH group). Transcriptomic analysis revealed good dispersion among samples and an overall consistent gene expression distribution. Differential expression analysis identified a total of 2198 differentially expressed genes, including 902 upregulated and 1296 downregulated genes. GO functional enrichment analysis indicated that these genes are mainly involved in biological processes such as acute-phase response, retinol metabolism, mitotic chromosome condensation, and cell migration; are enriched in cellular components such as kinetochores and the extracellular matrix; and are associated with molecular functions including calcium ion binding and the Wnt signaling pathway. KEGG pathway analysis further revealed that the differentially expressed genes are significantly enriched in key pathways such as cancer pathways, cell cycle, and cell adhesion molecules. The expression trends of five key differentially expressed genes were validated by RT-qPCR. In summary, this study successfully screened a stable and consistent low-tumorigenic MDCK cell line, providing a theoretical basis and practical foundation for its use as a cellular substrate in influenza vaccine development. Full article

Solution electrospinning (SES) and melt electrowriting (MEW) are complementary fiber-based fabrication platforms extensively investigated in tissue engineering. SES generates fibers typically ranging from the nanometer to the low-micrometer scale, producing fibrous networks that mimic the native extracellular matrix (ECM) and support key cellular functions. MEW, by contrast, operates solvent-free and enables precise, layer-by-layer deposition of microfibers with well-controlled geometry, conferring the mechanical integrity and open-pore architecture that SES constructs inherently lack. Despite growing interest, the body of peer-reviewed literature reporting original hybrid SES–MEW fabrication and biological outcome data remains limited, with no comprehensive cross-tissue synthesis available to date. This narrative review examines the current state of SES–MEW hybrid strategies across five tissue engineering targets selected for their clinical relevance: skin, vascular grafts, bone, cartilage, cardiac valves, and skeletal muscle. For each application, the architectural rationale, the fabrication approach, and the in vitro and in vivo biological outcomes are discussed in an integrated manner, with attention to how the spatial organization of nano- and microfibers translates into tissue-specific functional responses. A comparative analysis across tissue types highlights both the versatility of hybrid constructs and their persistent limitations, including suture retention values that remain below clinically accepted thresholds in vascular applications, incomplete cellular infiltration through dense nanofibrous layers, and the absence of validated, reproducible scale-up protocols compatible with clinical-grade manufacturing. The review concludes by identifying the most critical open questions in the field, encompassing process standardization, regulatory classification, and the emerging role of machine learning in closed-loop MEW process optimization. This work aims to provide an evidence-based perspective on the current state of hybrid SES–MEW scaffold engineering and the key translational gaps limiting clinical application. Full article

Regenerative medicine aims to restore the structure and function for improved tissue health; reduced tissue health can arise from causes such as aging, which results in the ongoing degradation of the extracellular matrix (ECM) of the skin. Replacement of a single biological component is not sufficient for an esthetic treatment to be described as regenerative; it is the relative amounts, ratios, types and organization of stimulated components that are important in a treatment’s regenerative potential. Regenerative aesthetics aims to recapture the youthful structure and function of tissue by exploiting the body’s own systems. Poly-L-lactic acid (PLLA-SCA; Sculptra^®), an injectable, biodegradable, non-permanent biostimulator, induces a combination of mechanotransductional/mechanical stimulation and foreign body reaction response and promotes ECM remodeling via the production of collagen through the upregulation of cytokines interleukin-1b and CXCL6, elastin, proteoglycans and multiadhesive glycoproteins. In addition, PLLA-SCA stimulates adipocyte rejuvenation/adipogenesis and increases the thickness of the dermis and adipose layers. Hence, PLLA-SCA stimulates endogenous pathways, and the array of biostimulatory effects should not be considered individually but as interlinked with the overall goal of improvement in skin health. These effects manifest clinically as long-term improvements in the mechanical properties of the skin, the restoration of volume and elasticity, improvements in skin quality and thickness, and dermal remodeling. Full article

Human neutrophil elastase (HNE) is a central mediator of neutrophil-driven inflammation. Yet, despite decades of research and drug development, therapies targeting HNE have not consistently translated into clear clinical benefits. We suggest that this translational gap partly arises from how HNE has traditionally been conceptualized, as a single enzyme to inhibit. In biological systems, however, HNE operates within a complex and tightly regulated network of proteases and inflammatory mediators. This network is spatially compartmentalized and strongly influenced by local redox conditions, making HNE activity highly context-dependent. From a systems perspective, HNE acts as an amplifier of inflammation. Its extracellular activity connects several pathological processes, including activation of innate immunity, extracellular matrix degradation, disruption of epithelial and endothelial barriers, and the transition toward chronic inflammation. In this review, we integrate insights from enzymology, systems biology, and clinical research to reassess the development of HNE inhibitors, ranging from endogenous antiproteases to more recent reversible synthetic compounds. Despite their chemical and pharmacological diversity, many of these strategies have encountered similar limitations. We therefore argue that future therapeutic approaches should move beyond the inhibition of HNE as an isolated target and instead aim to modulate the broader protease network, with particular attention to drug–target kinetics and precise delivery to disease-relevant microenvironments. Full article

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