Search Results (475)

This study characterized collagen remodeling in an electron-beam-sterilized porcine acellular dermal matrix (E-PADM) by evaluating host response kinetics during wound healing. E-PADM (n = 6 lots/time point) was implanted in an abdominal wall bridging defect in nonhuman primates (N = 24). Histological, immunohistochemical, and biochemical assessments were conducted. Pro-inflammatory tissue cytokines peaked 1 month post-implantation and subsided to baseline by 6 months. E-PADM-specific serum immunoglobulin G antibodies increased by 213-fold from baseline at 1 month, then decreased to <10-fold by 6–9 months. The mean percentage tissue area staining positively for matrix metalloproteinase-1 plateaued at 3 months (40.3 ± 16.9%), then subsided by 6 months (16.3 ± 11.1%); tissue inhibitor matrix metalloproteinase-1 content plateaued at 1 month (39.0 ± 14.3%), then subsided by 9 months (13.0 ± 8.8%). Mean E-PADM thickness (1.7 ± 0.2 mm pre-implant) increased at 3 months (2.9 ± 1.5 mm), then decreased by 9 months (1.9 ± 1.1; equivalent to pre-implant). Histology demonstrated mild inflammation between 1–3 months, then a peak in host tissue deposition, with ≈75%–100% E-PADM collagen turnover, and fibroblast infiltration and neovascularization between 3–6 months. Picrosirius red staining revealed that mature E-PADM collagen was replaced by host-associated neo-collagen by 6 months. E-PADM implantation induced wound healing, which drove dermal E-PADM collagen remodeling to native, functional fascia-like tissue at the implant site. Full article

Growth hormone (GH) signaling has been implicated in tumor progression and therapy resistance across multiple cancer types, yet its role in bladder cancer remains largely unexplored. In this study, we investigated the impact of GH and its receptor (GHR) on therapy resistance and disease progression in urothelial carcinoma (UC) through integrated transcriptomic and in vitro analyses. Transcriptomic profiling of The Cancer Genome Atlas bladder cancer cohort revealed that high tumoral GHR expression was associated with differential upregulation of genes involved in drug efflux, epithelial-to-mesenchymal transition (EMT), and extracellular matrix (ECM) remodeling. Notably, elevated GHR levels correlated with significantly reduced overall survival in patients with UC. In parallel, in vitro experiments demonstrated that GH promotes chemoresistance in UC cell lines via upregulation of ATP-binding cassette-containing (ABC) transporters and activation of EMT. GH also modulated ECM-remodeling-associated genes in a chemotherapy-dependent manner, including matrix metalloproteinases and tissue inhibitors of metalloproteinases. Importantly, these effects were abrogated by Pegvisomant, a GHR antagonist, indicating the functional relevance of GH/GHR signaling in the mediation of these phenotypes. Collectively, our findings support a mechanistic role for GH signaling in driving therapy resistance and tumor aggressiveness in bladder cancer and suggest GHR antagonism as a potential therapeutic strategy to improve treatment outcomes. Full article

The extracellular matrix (ECM) is a collagen-based scaffold that provides structural support and regulates nutrient transport and cell signaling. ECM homeostasis depends on a dynamic balance between synthesis and degradation, the latter being primarily mediated by matrix metalloproteinases (MMPs). These enzymes are secreted as pro-forms and require activation to degrade ECM components. Their activity is modulated by tissue inhibitors of metalloproteinases (TIMPs). Aging disrupts this balance, leading to the accumulation of oxidized, cross-linked, and denatured matrix proteins, thereby impairing ECM function. Bruch’s membrane, a penta-laminated ECM structure in the eye, plays a critical role in supporting photoreceptor and retinal pigment epithelium (RPE) health. Its age-related thickening and decreased permeability are associated with impaired nutrient delivery and waste removal, contributing to the pathogenesis of age-related macular degeneration (AMD). In AMD, MMP dysfunction is characterized by the reduced activation and sequestration of MMPs, which further limits matrix turnover. This narrative review explores the structural and functional changes in Bruch’s membrane with aging, the role of MMPs in ECM degradation, and the relevance of these processes to AMD pathophysiology, highlighting emerging regulatory mechanisms and potential therapeutic targets. Full article

Crohn’s disease (CD), characterized by chronic gastrointestinal inflammation, is complicated by intestinal stenosis resulting from dysregulated fibrogenesis and is marked by excessive extracellular matrix (ECM) deposition, fibroblast activation, and luminal obstruction. While biologics control inflammation, their failure to halt fibrosis underscores a critical therapeutic void. Emerging evidence highlights the multifactorial nature of stenosis-associated fibrosis, driven by profibrotic mediators and dysregulated crosstalk among immune, epithelial, and mesenchymal cells. Key pathways, including transforming growth factor (TGF-β), drosophila mothers against decapentaplegic protein (Smad) signaling, Wnt/β-catenin activation, epithelial–mesenchymal transition (EMT), and matrix metalloproteinase (MMP) and tissue inhibitors of metalloproteinase (TIMP)-mediated ECM remodeling, orchestrate fibrotic progression. Despite the current pharmacological, endoscopic, and surgical interventions for fibrostenotic CD, their palliative nature and inability to reverse fibrosis highlight an unmet need for disease-modifying therapies. This review synthesizes mechanistic insights, critiques therapeutic limitations with original perspectives, and proposes a translational roadmap prioritizing biomarker-driven stratification, combinatorial biologics, and mechanistically targeted antifibrotics. Full article

Background: Oral wound healing is a complex process influenced by extracellular matrix (ECM) remodeling and cellular migration. Hyaluronic acid (HA) and spermidine (SP) have shown regenerative potential, but their combined effects on oral tissues remain unexplored. This study aimed to characterize the effect of a gel composed of a mixture of HA and SP on the epithelial and connective compartments of oral tissue separately, evaluating (i) collagen turnover and cell migration on primary human gingival fibroblasts (HGFs) and (ii) epithelial integrity and cell proliferation on gingival organotypic cultures (OCs). Methods: HGFs were cultured, treated with HA-SP gel (1:0.5 HA-SP ratio) and evaluated for collagen types I and III (COL-I, COL-III), matrix metalloproteinase (MMP-1) protein and tissue inhibitor of MMP-1 (TIMP-1) levels secreted by the cells upon gel treatment, compared to CT. HGFs were also analyzed through a wound healing assay. Gingival samples were obtained to set OCs and were treated with different HA-SP formulations (HA 0.2%; 1:0.5 HA-SP ratio; 1:5 HA-SP ratio) to evaluate the beneficial addition of SP to HA for epithelial tissue. OC samples were formalin-fixed and paraffin-embedded and were stained with hematoxylin and eosin and immunostained for Ki-67 analysis. Results: In HGFs, the gel induced increased COL-III gene expression relative to that of COL-I after 48 h and stimulated cell migration, in turn favoring connective tissue remodeling and repair. In OCs, the gel preserved epithelial integrity up to 48 h, with the best effects observed with the 1:0.5 HA-SP ratio. After 72 h, epithelial detachment was more evident in HA formulations, suggesting that SP contributes to epithelial integrity. Conclusions: The HA-SP gel may support oral tissue healing by modulating ECM remodeling and maintaining epithelial integrity. The gel containing HA and SP at the 1:0.5 ratio may provide a promising solution for enhancing wound healing. Full article

Repairing and regenerating tissue barriers is a key challenge in regenerative medicine. Stem cells play a crucial role in restoring the structural and functional integrity of key epithelial barrier surfaces, including the skin and mucosa. This review analyzes the role of dental pulp stem cells (DPSCs) and their derivatives, including extracellular vesicles, conditioned medium, and intracellular factors, in accelerating skin wound healing. The key mechanisms include: (1) DPSCs regulating inflammatory microenvironments by promoting anti-inflammatory M2 macrophage polarization; (2) DPSCs activating vascular endothelial growth factor (VEGF) to drive angiogenesis; (3) DPSCs optimizing extracellular matrix (ECM) spatial structure through matrix metalloproteinase/tissue inhibitor of metalloproteinase (MMP/TIMP) balance; and (4) DPSCs enhancing transforming growth factor-β (TGF-β) secretion to accelerate granulation tissue formation. Collectively, these processes promote wound healing. In addition, we explored potential factors that accelerate wound healing in DPSCs, such as oxidative stress, mechanical stimulation, hypertension, electrical stimulation, and organoid modeling. In addition to demonstrating the great potential of DPSCs for skin repair, this review explores their translational prospects in mucosal regenerative medicine. It covers the oral cavity, esophagus, colon, and fallopian tube. Some studies have found that combining DPSCs and their derivatives with drugs can significantly enhance their biological effects. By integrating insights from skin and mucosal models, this review offers novel ideas and strategies for treating chronic wounds, inflammatory bowel disease, and mucosal injuries. It also lays the foundation for connecting basic research results with clinical practice. This represents a significant step forward in tackling these complex medical challenges and lays a solid scientific foundation for developing more targeted and efficient regenerative therapies. Full article

Background: Rheumatoid arthritis-related interstitial lung disease (RA-ILD) is a significant complication of RA which lacks effective treatments with high mortality. This study aimed to investigate the role of matrix metalloproteinase-7 (MMP-7) in mediating RA-ILD. Methods: Based on the database of RA-ILD patients, a bioinformatics analysis was performed. A protein–protein interaction (PPI) network focusing on MMP-7 was simulated. Pleural mesothelial cells (PMCs) were treated with RA-ILD patients’ serum or RA-ILD-related inflammatory factors, and the protein expressions of collagen-I and MMP-7 were examined. An arthritis model was established using complete Freund’s adjuvant (CFA). Changes in the weight and joints of mice were recorded, and lung tissues were evaluated by Masson staining and Sirius red stain techniques. MMP-7 inhibitor, MMP-7 siRNA and MMP shRNA lentivirus were used to inhibit MMP-7 and investigate changes in collagen-I and fibrosis in vivo and in vitro. Results: MMP-7 was found to be significantly expressed in RA-ILD lung tissue by bioinformatics analysis, and MMP-7 to maybe interact with collagen-I. In vitro experiments indicated cytokines IL-1β, IL-6 and TNF-α promoted MMP-7 and collagen-I expression in PMCs. Serum obtained from patients with RA-ILD also upregulated MMP-7 and collagen-I expression in PMCs. Inhibition of MMP-7 with MMP-7 siRNA or MMP inhibitor prevented collagen-I synthesis in PMCs. In vivo, CFA induced arthritis and subpleural lung inflammation in rats, but the MMP-7 inhibitor and MMP-7 siRNA attenuated CFA-induced lung inflammation and subpleural lung fibrosis. Conclusions: MMP-7 mediated subpleural lung inflammation as well as fibrosis in RA-ILD. It provided theoretical and experimental support for MMP-7 being a therapeutic target in RA-ILD. Full article

Antibody-mediated rejection (ABMR) remains a major cause of renal graft dysfunction and loss. The histological hallmark of antibody-mediated rejection is progressive tissue damage, in which extracellular matrix turnover plays an important role. This turnover is mainly regulated by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Recent studies suggest that MMP/TIMP imbalance may favor the progression of renal damage, inflammation, and fibrosis, but the utility of these molecules as a biomarker of antibody-mediated turnover has not been fully explored. We measured plasma MMP and TIMP levels by ELISA in 15 patients with antibody-mediated renal transplant rejection and 12 patients without rejection. There was a significant increase in MMP-1, MMP-2, and MMP-3 concentrations in the plasma of patients with rejection, directly correlating with the severity of different renal lesions. In contrast, TIMP-3 levels were elevated in patients without rejection, showing a negative correlation with the severity of histopathological lesions. The concentrations of these molecules demonstrated good diagnostic capacity for patients with rejection. Our results show that MMP-1, MMP-2, MMP-3, and TIMP-3 could be potential biomarkers of rejection. Full article

Bovine endometritis is a common endocrine and reproductive disorder in postpartum dairy cows, closely associated with elevated systemic oxidative stress. This disease can lead to delayed uterine involution, repeated breeding failure, and significant economic losses in the dairy industry. Studies suggest that oxidative stress may contribute to the pathological progression of endometritis by regulating ECM remodeling, but the specific molecular mechanisms remain unclear. ECM homeostasis relies on the coordinated action of matrix metalloproteinases (e.g., MMP2, MMP9) and collagen (e.g., type IV collagen, COL-IV), while the TGFβ1/Smad3 signaling pathway is implicated in ECM metabolic regulation. Therefore, elucidating the regulatory mechanisms of oxidative-stress-mediated TGFβ1/Smad3 signaling on ECM remodeling is crucial for understanding the pathogenesis of endometritis. This study investigates postpartum bovine uterine tissues, comparing inflammatory cytokines (IL-1β, IL-6, TNF-α) and oxidative-stress-related factors (GPx, SOD, CAT) between healthy and endometritis groups. Additionally, the differences in ECM-remodeling-associated proteins (MMP2, MMP9, COL-IV) and TGFβ1/Smad3 pathway activity are analyzed. To further validate the mechanisms, an oxidative stress model is established in vitro by treating bovine endometrial epithelial cells (bEECs) with 200 μM H₂O₂ for 4 h, followed by the valuation of the same indicators. Furthermore, gene silencing to downregulate Smad3 expression or inhibitor-mediated suppression of TGFβ1/Smad3 pathway activity is performed to observe their regulatory effects on MMP2, MMP9, and COL-IV. The results demonstrate that oxidative-stress-mediated endometritis significantly upregulates MMP2, MMP9, and the TGFβ1/Smad3 pathway activity, while suppressing COL-IV expression. Functional genetic experiments further reveal the dual regulatory role of the TGFβ1/Smad3 pathway in ECM remodeling: (1) pathway activation promotes MMP2/MMP9 expression, accelerating COL-IV degradation; (2) Smad3 positively regulates COL-IV synthesis. These findings provide a theoretical basis for targeting the TGFβ1/Smad3 pathway to mitigate the pathological progression of endometritis. Full article

Proteases play crucial roles in ovarian folliculogenesis, regulating several processes from primordial follicle activation to ovulation and corpus luteum formation. This review synthesizes the current knowledge on the diverse functions of proteases in ovarian physiology and pathology. We discuss the classification and regulation of proteases, highlighting their importance in extracellular matrix remodeling, cell signaling, and apoptosis during ovarian follicular development. We explore the roles of several proteases including matrix metalloproteinases, tissue inhibitors of metalloproteinases, the plasminogen activator system, and cathepsins, and their roles in the critical functions of ovarian biology including follicle dynamics and senescence. Furthermore, we address the involvement of proteases in ovarian pathologies, including cancer, polycystic ovary syndrome, and primary ovarian insufficiency. By integrating recent findings from clinical genomics and animal models, this review provides a comprehensive overview of protease functions in the ovary, emphasizing their potential use for therapeutic interventions in reproductive medicine. Full article

This study investigated the potential cosmetic properties of the ethyl acetate (EtOAc) fraction obtained from the roots of Astilboides tabularis (Hemsl.) Engl., focusing on skin-whitening, antiwrinkle, and moisturizing effects using cell-based assays and three-dimensional (3D) artificial skin models (Neoderm-ED and Neoderm-ME). The EtOAc fraction showed significant dose-dependent inhibitory activity against tyrosinase (TYR) (72.0% inhibition at 50 µg/mL), comparable to that of kojic acid. In α-melanocyte-stimulating hormone (α-MSH)-stimulated Neoderm-ME artificial skin containing melanocytes, the EtOAc fraction reduced melanin synthesis at concentrations of 50 and 75 µg/mL and decreased melanogenesis-related gene expression, including TYR, microphthalmia-associated transcription factor (MITF), tyrosinase-related protein-1 (TRP-1) and TRP-2. In the antiwrinkle assays, the EtOAc fraction effectively inhibited elastase activity (41.5% inhibition at 10 µg/mL), exceeding the efficacy of ursolic acid. In the Neoderm-ED artificial skin model, the EtOAc fraction reversed structural damage induced by particulate matter (PM10), restoring epidermal thickness and dermal density. This improvement was supported by the increased expression of skin barrier and antiwrinkle genes, including filaggrin, hyaluronic acid synthase-1 (HAS-1), HAS-2, aquaporin-3 (AQP-3), collagen type I alpha 1 chain (COL1A1), elastin, tissue inhibitor of metalloproteinases-1 (TIMP-1), and TIMP-2, as well as decreased expression of matrix metalloproteinases (MMP-1, MMP-3, and MMP-9). Our results indicate that the EtOAc fraction from A. tabularis root has considerable potential as a multifunctional cosmetic. Full article

Matrix metalloproteinases (MMPs) are key enzymes involved in the remodeling of the extracellular matrix (ECM) through the degradation of its components in a controlled endoproteolytic manner. Beyond ECM degradation, MMPs also target plasma membrane proteins implicated in signaling cascades and the progression of disease. Structurally, the catalytic function of MMPs is dependent on metal ions such as Zn²⁺. ECM remodeling by MMPs supports processes including tissue growth, morphogenesis, elongation, and adaptation to environmental changes occurring under both physiological and pathological conditions. These activities are subject to tight regulation by cellular MMP enzymes. While the current body of research has primarily centered on the functions of MMPs and their roles in cancer biology, knowledge of their involvement in vascular disease, endometriosis, fibrotic eye disease, epithelial cell differentiation, and the actions of MMP inhibitors remains comparatively sparse. This review explores the roles of MMPs in vascular disease and endometriosis, particularly as they relate to the ectopic growth of endometrial tissue. In addition, we summarize evidence regarding their contributions to disease mechanisms, with a focus on pathological progression. Due to their significant therapeutic promise in a variety of human diseases, advancing our understanding of MMP biology is likely to facilitate progress in clinical application and the development of novel interventions. This review also evaluates advances in the development and therapeutic potential of MMP inhibitors. Full article

Background/Objectives: Among other substrates, the a disintegrin and metalloproteinase with thrombospondin motifs 7 (ADAMTS7) protease degrades thrombospondin-5 (the cartilage oligomeric protein, COMP), thrombospondin-1 (TSP-1) and the tissue inhibitor of metalloproteinases-1 (TIMP-1) indicating a potential role of ADAMTS7 expression on coagulation cascade, tissue remodeling and wound healing. We analyzed the potential effect of direct oral anticoagulant (DOAC) treatment on ADAMTS7 promoter methylation and followed it over time to assess whether DOACs epigenetically modulate ADAMTS7 and induce pathways associated with coagulation or endothelium repair machinery. Methods: Eighty-four DOAC-treated atrial fibrillation (AF) patients followed-up from baseline (t0) to 7 days (t1, n = 70) and 28 days of treatment (t2, n = 62) and 19 non-AF controls were included in the study. Genomic DNA was extracted from blood at all timepoints and was bisulfite-converted prior to methylation analysis. ADAMTS7 promoter DNA methylation was analyzed with MIP-qMSP-PCR. Results: A total of 16 minor bleeding events occurred. The baseline percentage of ADAMTS7 methylation did not differ between AF patients and controls (15.8% vs. 16.1%, p = 0.908). In the patient cohort, DOAC therapy marginally decreased ADAMTS7 methylation from t0 to t2 (15.2% vs. 14.0%, p = 0.044). This ADAMTS7 demethylation from t0 to t2 was statistically significant only in patients experiencing bleeding (17.1%. vs. 13.4%, p = 0.010 in bleedings, 14.5% vs. 14.2%, p = 0.561 in non-bleedings). No other differences were observed. Conclusions: ADAMTS7 is demethylated during DOAC-related bleedings, a mechanism potentially leading to COMP degradation and thus thrombin-induced platelet aggregation, as well as the induction of endothelium repair through different ADAMTS7-dependent pathways. Full article

Background/Objectives: Early detection of pancreatic cancer can improve patient survival, and blood-based biomarkers to aid in this are a significant need. The goal of this study was to develop and evaluate the performance of a 4- to 6-plex biomarker signature for detection of early-stage pancreatic ductal adenocarcinoma (PDAC) that performs well in high-risk controls. Methods: Enzyme-linked immunosorbent assays were used to measure 10 previously identified serum protein biomarker candidates in Stage I and II PDAC cases (n = 128), high-risk controls (n = 465), and normal-risk controls (n = 30). Various combinations of biomarker candidates (models) were trained using machine learning and tested for robustness in differentiating cases from controls on the full cohort and in clinically relevant sub-types including those with diabetes, those ≥65 years of age, and low producers of carbohydrate antigen 19-9 (CA 19-9). Results: At 98% specificity, the top performing model, which was comprised of tissue inhibitor of metalloproteinase 1 (TIMP1), intracellular adhesion molecule 1 (ICAM1), thrombospondin 1 (THBS1), cathepsin D (CTSD), and CA 19-9, achieved 85% sensitivity in the full cohort and sensitivities of 91% in diabetics, 90% in ≥65 years of age, and 60% in low CA 19-9 producers. This model demonstrated significantly higher sensitivity in detecting PDAC in the full cohort and all sub-populations compared to CA 19-9 alone (p < 0.001). Conclusions: Our findings demonstrate the feasibility of a blood-based assay for detecting early-stage PDAC in high-risk individuals and key sub-populations, representing an important step towards improving diagnostic success for early-stage disease. Full article

Diagnosing tuberculosis (TB) in children presents significant challenges, necessitating the identification of reliable biomarkers for accurate diagnosis. In this study, we investigated plasma matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) as potential diagnostic markers. A prospective case–control study involved 167 children classified into confirmed TB, unconfirmed TB, and unlikely TB control groups. Plasma levels of MMPs (MMP 1, 2, 3, 7, 8, 9, 12, and 13) and TIMPs (TIMP 1, 2, 3, and 4) were measured using multiplex assays. Elevated baseline levels of MMP-1, MMP-2, MMP-7, MMP-9, TIMP-1, TIMP-2, TIMP-3, and TIMP-4 were observed in active TB cases compared to unlikely TB controls. Receiver operating characteristics (ROC) analysis identified MMP-1, MMP-2, MMP-9, and TIMP-1 as potential biomarkers with over 80% sensitivity and specificity. A three-MMP signature (MMP-1, MMP-2, and MMP-9) demonstrated 100% sensitivity and specificity. The findings suggest that a baseline MMP signature could serve as an accurate biomarker for diagnosing pediatric TB, enabling early intervention and effective management. Full article