Search Results (2,302)

Acute or chronic rotator cuff tears are major causes of shoulder dysfunction, motivating the development of scaffolds with tailored thickness and mechanics for supraspinatus tendon regeneration. This study aimed to investigate the effect of bilayer poly(butylene adipate-co-terephthalate) (PBAT) scaffold thickness on the tenogenic differentiation of rat adipose mesenchymal stem cells (r-AdMSCs) and supraspinatus tendon regeneration. Aligned fibers with a diameter of approximately 476 nm were deposited onto randomly oriented layers at different times (4 h; 4S, 6 h; 6S, 8 h; 8S), and scaffolds with increasing thicknesses from 441 µm (4S) to 1132 µm (8S) were produced. Mechanical testing showed comparable tensile strength for 4S and 6S (≈1.9–2.0 MPa) and modulus (5.5–7.3 MPa), while 8S exhibited markedly reduced stiffness (0.5 MPa) and hyper elastic deformation. Mechanical performance across degradation conditions remained strongly thickness-dependent: thinner scaffolds retained integrity and strengthened, with modulus increases during hydrolytic and enzymatic degradation, whereas thicker matrices showed limited remodeling and instability. Rat-AdMSCs’ were cultured on the scaffolds for 21 days. Cell-free and cell-laden mechanical responses further reflected thickness effects: cell-free samples stiffened due to media-induced passive matrix tightening, whereas cell-laden scaffolds showed extracellular matrix (ECM)-driven reinforcement, most prominently in 4S, which reached 2.1 MPa tensile strength with improved elasticity and balanced deformation. The 4S scaffold exhibited the highest tensile strength and significantly increased collagen-1 (col1), tenomodulin (tnmd) and scleraxis (scx) expression compared with the other groups. In conclusion, among all groups, 4S scaffolds demonstrated the most favorable mechanical and biological performance, suggesting that scaffold thickness plays a critical role in regulating tendon regeneration and will become even more suitable when matured in bioreactors. Full article

Adipose tissue remodeling is a dynamic process essential for metabolic homeostasis, enabling tissue expansion, extracellular matrix (ECM) turnover, angiogenesis, and coordinated immune adaptation. In obesity, however, maladaptive remodeling characterized by fibrosis, chronic low-grade inflammation, and hypoxia disrupts adipose plasticity and promotes systemic insulin resistance. Central to these processes is the tightly regulated homeostasis between proteases and their inhibitors, in which the serine protease inhibitor (serpin) superfamily represents an important yet underappreciated regulatory axis. Beyond their classical roles in coagulation and fibrinolysis, serpins regulate ECM remodeling, macrophage recruitment and polarization, cytokine signaling, angiogenic responses, adipokine activity, and insulin sensitivity, thereby orchestrating immune–metabolic crosstalk within adipose depots. Emerging evidence indicates that individual serpins exert distinct and context-dependent effects, with some promoting fibrosis, inflammation, and metabolic dysfunction, whereas others preserve adipose tissue homeostasis and metabolic function. This review synthesizes current knowledge on the structural and functional diversity of the serpin superfamily and examines their mechanistic roles in adipose tissue remodeling during obesity, with particular emphasis on how adipose-associated serpins regulate adipose tissue homeostasis, depot-specific remodeling, and immune–metabolic crosstalk. The review further discusses the experimental and translational applications of emerging single-cell and spatial transcriptomics, multi-omics, and computational approaches that may advance the understanding of serpin biology, improve the investigation of human adipose tissue, and accelerate the identification of clinically relevant serpin-related biomarkers and therapeutic targets for obesity and related metabolic disorders. By positioning serpins as key regulators of adipose tissue remodeling and immune–metabolic integration, this review highlights protease–antiprotease balance as a central determinant of metabolic health and identifies serpins as promising biomarkers and therapeutic targets for obesity and related metabolic disorders. Full article

Background: Chronic enteropathy associated with the SLCO2A1 gene (CEAS) is a rare disease characterized by multiple small intestinal ulcers whose pathogenesis remains poorly understood. This study aimed to characterize the proteomic and phosphoproteomic profiles of CEAS and to identify molecular pathways involved in its pathogenesis. Methods: Quantitative proteomics and phosphoproteomics were performed on intestinal mucosal tissues from patients with CEAS (n = 3), Crohn’s disease (CD, n = 3), and healthy controls (n = 3). Differentially expressed proteins (DEPs) and differentially phosphorylated proteins (DPPs) were analyzed using functional enrichment, gene set enrichment analysis (GSEA), protein–protein interaction (PPI) networks, and integrative analysis. Results: A total of 900 DEPs were identified in CEAS and 277 in CD relative to controls, including 717 CEAS-specific proteins. CEAS-specific alterations were strongly enriched in focal adhesion and extracellular matrix-related pathways, whereas shared proteins between CEAS and CD were primarily associated with epithelial barrier function, including tight junction and adherens junction pathways. GSEA revealed that CEAS was characterized by upregulation of tissue remodeling and focal adhesion pathways, accompanied by suppression of digestive and metabolic processes, while CD exhibited prominent adaptive immune activation. PPI network analysis identified POSTN, CDH1, TLN1, and VIM as candidate hub proteins; however, none retained significance after FDR correction, whereas brush-border components (CDHR2, MUC3A, MUC13, ALPI) and actin cytoskeletal regulators remained the most statistically robust alterations. Integrated analysis further highlighted focal adhesion-related proteins with coordinated expression and phosphorylation changes. Conclusions: This exploratory study provides the first integrative proteomic and phosphoproteomic characterization of CEAS, suggesting that impairment of the intestinal brush border and mucosal barrier, together with actin cytoskeletal reorganization, may distinguish CEAS from immune-dominant CD. These findings are hypothesis-generating and require validation in larger cohorts. Full article

Arrhythmogenic cardiomyopathy (ACM/ARVC) is an inherited myocardial disease characterized by progressive fibro-fatty replacement, ventricular arrhythmias, and an increased risk of sudden cardiac death. In addition to mutations in desmosomal genes, growing evidence suggests that microRNAs (miRNAs) actively contribute to disease pathogenesis by regulating key processes such as fibrosis, cell adhesion, and cardiac remodeling. This systematic review analyzed the main miRNAs identified in studies of human cardiac tissue and animal models of ARVC. Materials and Methods: Studies based on human myocardial tissue analysis (including autopsy and biopsy samples) and animal models of arrhythmogenic cardiomyopathy were included, using RNA sequencing, small RNA sequencing, miRNA arrays, and RT-qPCR. Studies on circulating miRNAs and narrative reviews were excluded. miRNAs were analyzed in relation to their functional pathways and their role in disease pathogenesis. Results: The synthesis of studies on human and animal cardiac tissue reveals a consistent miRNA signature associated with arrhythmogenic cardiomyopathy. MiR-21-5p and miR-29b-3p are associated with fibrosis and extracellular matrix remodeling, whereas miR-133a-b and miR-130a are linked to cardiomyocyte integrity loss and desmosomal dysfunction. A second group of miRNAs, including miR-217-5p, miR-708-5p, and miR-135b, regulates key pathways such as Wnt/β-catenin and Hippo signaling, contributing to structural remodeling and loss of cellular identity. Furthermore, downregulation of miR-499-5p is associated with mitochondrial dysfunction and cellular vulnerability, while the miR-142-3p, miR-182-5p, and miR-183-5p clusters contribute to differential molecular signatures compared with other cardiomyopathies. Overall, miRNAs converge on three main pathogenic axes: myocardial fibrosis, desmosomal impairment, and remodeling of cellular signaling pathways. Conclusions: The available evidence indicates that arrhythmogenic cardiomyopathy is regulated by a coordinated network of miRNAs that actively drives myocardial damage progression. These miRNAs represent not only biomarkers but also functional mediators of disease, suggesting potential diagnostic and therapeutic applications based on tissue-specific molecular signatures, including in post-mortem settings. Full article

Usnic acid (UA), a prominent lichen secondary metabolite, exhibits a unique dual therapeutic profile in dermatology, though its clinical translation is limited by systemic hepatotoxicity and poor solubility. This review comprehensively evaluates the topical efficacy, molecular mechanisms, and advanced formulation strategies of UA enantiomers and UA-rich extracts. A literature search across PubMed, Scopus, and Google Scholar identified 36 original publications focusing on anti-melanoma activity, photoprotection, and tissue regeneration. In vitro studies demonstrate that UA induces apoptosis in resistant melanoma cell lines (A375, HTB-140) via extrinsic/intrinsic pathways, with (−)-UA effectively overcoming doxorubicin resistance. Conversely, in non-cancerous models, low concentrations of UA accelerate wound and burn healing by upregulating vascular endothelial growth factor (VEGF), stimulating fibroblast proliferation, and optimizing extracellular matrix remodeling while preventing hypertrophic scarring. To mitigate skin sensitization and systemic risks, advanced drug delivery systems—including liposomes, nanoemulsions, chitosan nanogels, and electrospun scaffolds—have been developed, significantly enhancing skin permeability and localized dermal retention. Ultimately, the development of bio-functionalized smart dressings and targeted nano-formulations represents the most viable path toward unlocking the full clinical potential of UA in modern dermatological and oncological care. Full article

Cellular senescence is a state of stable cell cycle arrest triggered by various internal and external stressors. It represents an important tumor-suppressive mechanism that effectively prevents the proliferation of damaged cells. During tumor initiation and progression, cellular senescence plays a dual and paradoxical role. On one hand, it induces cell cycle arrest to inhibit the development of tumors in potentially malignant cells. On the other hand, it can promote tumor progression through the senescence-associated secretory phenotype (SASP), which enhances inflammation and extracellular matrix remodeling. This review outlines the definition and key characteristics of cellular senescence and analyzes different senescence-inducing stimuli along with their underlying molecular mechanisms. It further discusses the molecular basis for the maintenance of stable senescence, mechanisms to escape growth arrest, and how these cells contribute to tumor recurrence through dedifferentiation and acquisition of stemness properties. Additionally, the dual regulatory role of SASP in tumor progression is examined. In terms of cancer therapy, with a deeper understanding of the mechanisms of senescent cells, treatment strategies are gradually shifting from single senescence-inducing approaches to more comprehensive combinatorial strategies. Meanwhile, the integration of single-cell omics technologies with artificial intelligence and machine learning offers new prospects for personalized therapy. Full article

Background/Objectives Lysyl oxidase-like 2 (LOXL2), a member of the lysyl oxidase family of amine oxidases involved in collagen cross-linking, has emerged as a key mediator of pathological extracellular matrix remodeling and tissue fibrosis. Dysregulated LOXL2 activity has been implicated in various fibrotic diseases; however, its role in fibrosis-driven chronic kidney injury, particularly in the context of calcineurin inhibitor-induced kidney toxicity, remains incompletely defined. Methods To investigate the contribution of LOXL2 inhibitor to cyclosporine A (CsA)-induced nephropathy, a well-established model of progressive tubulointerstitial fibrosis, male CD-1 mice were administered either saline or CsA (15 mg/kg/day, intraperitoneally) for 8 weeks. After 4 weeks of CsA exposure, CsA-treated mice were further divided into two groups and received either vehicle or a LOXL2 inhibitor (10 mg/kg/day, oral gavage) for an additional 4 weeks. Kidney function, albuminuria, histological fibrosis, inflammatory cell infiltration, and profibrotic gene expression were assessed. Results In a murine model of CsA-induced nephropathy, pharmacological inhibition of LOXL2 markedly improved kidney outcomes. LOXL2 inhibition significantly reduced albuminuria and ameliorated kidney dysfunction. In parallel, tubulointerstitial fibrosis was substantially attenuated, accompanied by reduced myofibroblast activation and extracellular matrix accumulation. These protective effects were associated with downregulation of profibrotic and inflammatory mediators and inhibition of TGF-β-related downstream signaling pathways activated by CsA. Conclusions The present preclinical findings suggest that Compound #765-mediated LOXL2 inhibition may offer a potential therapeutic benefit in CsA-induced fibrosis, though further validation is warranted. Full article

Extracellular vesicles (EVs), particularly small extracellular vesicles (sEVs), are lipid bilayer-delimited particles involved in intercellular communication through the transfer of proteins, lipids, and nucleic acids; many products and studies in aesthetic medicine refer to these preparations as exosomes, although endosomal origin is not always demonstrated. This review examines current evidence on the mechanisms, clinical effectiveness, safety, therapeutic applications, and regulatory challenges of EV- and sEV-based interventions, complemented by an exploratory qualitative assessment of physicians’ perceptions regarding clinical implementation. A narrative review of studies indexed in Scopus and PubMed was conducted with emphasis on skin rejuvenation, hair restoration, wound healing, pigmentation disorders, and inflammatory dermatoses, and responses from 12 aesthetic physicians in Colombia were analyzed qualitatively. Available evidence suggests that EVs/sEVs may promote extracellular matrix remodeling, angiogenesis, immunomodulation, and tissue repair, with potential benefits across several aesthetic and regenerative indications. However, the literature remains heterogeneous and limited by variability in biologic sources, isolation and administration protocols, insufficient high-quality clinical trials, and unresolved regulatory issues. Reports of adverse reactions linked to unapproved products marketed as exosome-based formulations further highlight the need for stronger oversight. EVs, particularly sEVs, often referred to as exosomes in the aesthetic literature, remain a promising therapeutic platform, but safe clinical integration requires rigorous validation, technical standardization, and robust regulatory frameworks. Full article

Vein graft restenosis is a leading cause of long-term failure after coronary artery bypass grafting (CABG), driven by maladaptive vascular smooth muscle cell (VSMC) responses to arterialization-induced inflammation. The key molecular mediators of this pathological remodeling, however, remain incompletely defined. Here, we integrated multi-omics analyses of human and canine vein graft specimens with in vitro functional assays to identify tenascin-C (TNC)—a matricellular extracellular matrix protein—as a critical regulator of VSMC dysfunction. TNC was specifically enriched in a synthetic, pro-inflammatory VSMC subpopulation. Pro-inflammatory stimuli potently induced TNC expression, which was functionally linked to VSMC phenotypic modulation, hyperproliferation, and enhanced migration. Mechanistically, TNC acts upstream of NF-κB signaling; siRNA-mediated TNC knockdown significantly reduced nuclear p65 protein levels and attenuated inflammatory responses. Our integrated computational and experimental data suggest that TNC, NF-κB, and TNF-α function within a sequential pro-inflammatory signaling cascade that sustains vascular inflammation and promotes neointimal hyperplasia. These findings reposition TNC from a passive structural component to an active driver of vascular pathology and highlight the TNC–NF-κB axis as a candidate target for therapeutic intervention to improve vein graft patency. Full article

This study evaluated the structural, electronic, pharmacokinetic, and receptor-binding properties of three bisphosphonate derivatives, alendronate, risedronate, and zoledronate, to investigate their therapeutic relevance in osteoporosis and breast cancer. Density Functional Theory (DFT) calculations at the B3LYP/6-31G(d,p) level showed that risedronate exhibited the highest kinetic stability (ΔE = 6.7468 eV), whereas zoledronate displayed greater chemical reactivity (ΔE = 2.9669 eV) and the strongest nonlinear optical response (β = 1.20 × 10⁻³⁰ esu). ADMET analysis indicated acceptable safety profiles for all compounds, although high polarity and low lipophilicity may limit oral bioavailability. Molecular docking against 11 breast cancer- and bone metabolism-related targets revealed favorable binding affinities, particularly for zoledronate and risedronate. Zoledronate showed strong interactions with ESR2, VEGFR/KDR, GGPS1, and FPPS, whereas risedronate exhibited notable affinity for BRCA2 and MMP9. Bioinformatics analyses identified significant dysregulation of GGPS1, FDPS, TNFSF11, ESR1, MMP9, and BRCA2 in breast cancer tissues, while survival analysis linked elevated FDPS, MMP9, and BRCA2 expression to poor prognosis. Network analyses highlighted pathways related to mevalonate metabolism, hormone signaling, angiogenesis, extracellular matrix remodeling, and the RANK/RANKL/OPG axis. These findings support the potential repurposing of bisphosphonates, particularly zoledronate, for breast cancer-associated bone disease. Full article

Regenerative medicine integrates interdisciplinary approaches towards restoring the function of diseased organs. This study examined alterations that occurred in the liver under a high-fat diet (HFD) with the development of obesity and fatty liver, and changes in metabolic homeostasis and glucose levels, in mice. HFD nutrition causes hyperglycemia, leading to the formation and accumulation of advanced glycation end-products (AGEs) promoting protein post-translational modifications (PTMs) and introducing crosslinking in the extracellular matrix (ECM). Using histological and gene expression analyses, we detected an increase in adiposity, as well as in ECM protein deposition in the liver. Further, decellularization of the liver yielded the isolated ECM organ scaffold, allowing us to analyze the chemical modification in proteins by various imaging methods combined with spectroscopy. The measurements of intrinsic protein fluorescence are consistent with increased AGE-associated levels. SEM allows for the visualization of ECM fiber thickening as a result of protein crosslinking. Using cathodoluminescence, a label-free imaging method, we confirmed the protein modifications. The combination of innovative technologies highlights the ECM structural alterations associated with impaired glucose regulation and liver adiposity. These findings provide novel views on liver-scaffold ECM structure under metabolic diseases that will play a significant role in accelerating the understanding of effective regenerative therapies. Full article

Background/Objectives: Liposarcoma is a heterogeneous soft tissue sarcoma in which anthracycline-based chemotherapy, including doxorubicin, remains a cornerstone of treatment for advanced disease. However, variable and often limited therapeutic responses highlight the need for improved understanding of disease-associated transcriptional adaptation under chemotherapeutic stress. In this study, a bioinformatics-driven transcriptomic analysis was performed to characterize gene expression alterations associated with doxorubicin treatment in liposarcoma using publicly available data from the Gene Expression Omnibus (GSE12972). Results: Differential expression analysis identified 365 significantly altered genes, including 164 upregulated and 201 downregulated transcripts in treated samples compared with untreated controls. Functional interpretation using Ingenuity Pathway Analysis identified transforming growth factor beta 1 (TGFB1), tumor necrosis factor (TNF), and SMARCA4 as prominent predicted upstream regulators associated with transcriptional programs related to extracellular matrix remodeling, inflammatory and immune modulation, epithelial-to-mesenchymal transition-like states, and chromatin-mediated transcriptional plasticity. Enriched canonical pathways included Liposarcoma tumor microenvironment-associated signaling and fibrosis-related pathways, reflecting stromal activation and immune-related transcriptional changes. Notably, fibroblast growth factor 1 (FGF1) emerged as a supportive regulatory node linked to survival- and anti-apoptotic gene expression patterns. Conclusions: Collectively, these findings provide a disease-oriented, cross-subtype systems-level view of the transcriptional changes associated with doxorubicin treatment in liposarcoma. This work is intended as a hypothesis-generating framework that may inform future functional studies and integrative approaches aimed at understanding therapeutic response and disease progression. Full article

Protease-activated receptor 1 (PAR1), a G protein-coupled receptor, plays a central role in coordinating multiple phases of cutaneous wound healing, including hemostasis, cell proliferation, migration, and extracellular matrix remodeling. Despite its therapeutic potential, PAR1-selective positive allosteric modulators (PAMs) remain limited. Here, we characterized the wound healing efficacy of gestodene, a third-generation progestin previously identified as a selective PAM of PAR1. Gestodene exhibited no intrinsic agonist activity but selectively potentiated PAR1-activating peptide (PAR1-AP)-induced calcium signaling without affecting PAR2 or PAR4 responses. Consistently, gestodene induced a concentration-dependent leftward shift in the PAR1-AP dose–response curve. Notably, gestodene enhanced PAR1-dependent cell proliferation, migration, and ERK1/2 activation, effects abolished by PAR1 knockout or pharmacological inhibition with vorapaxar in human keratinocytes (HaCaT) and dermal fibroblasts (HDF). Gestodene also potentiated the expression of wound healing-associated genes, including matrix metalloproteinases (MMP-1, -2, -3, -10), fibronectin, and type I collagen (COL1A1). In a murine wound model, topical administration of gestodene accelerated wound closure, achieving complete re-epithelialization by Day 8 and significantly enhancing collagen deposition, effects reversed by vorapaxar. Collectively, these findings demonstrate that gestodene accelerates cutaneous wound healing through PAR1-selective positive allosteric modulation and supports its potential as a drug repositioning candidate for wound repair. Full article

Cancer remains one of the most formidable health challenges worldwide. Extensive research has shown that tumor progression is not driven solely by malignant cells but is profoundly shaped by the tumor microenvironment (TME), which influences cancer initiation, immune evasion, and metastatic spread. Consequently, the TME has become an increasingly compelling therapeutic target. Nanotechnology has transformed cancer diagnostics and therapy, with metallic nanoparticles (mNPs) gaining particular attention due to their distinctive physicochemical properties and broad therapeutic potential. However, their interactions within the TME remain insufficiently understood, particularly with the non-cancerous cellular components, such as Cancer-Associated Fibroblasts (CAFs), Tumor-Associated Macrophages (TAMs), Dendritic Cells (DCs), Natural Killer (NK) cells, and T cells. Most existing reviews emphasize nanoparticle interactions with non-cellular TME components, such as the extracellular matrix, while far less attention has been given to their effects on cellular constituents (a gap this work specifically addresses). Although several molecular pathways through which mNPs modulate TME-resident cells have been identified, these likely represent only a small portion of the underlying mechanisms explored in this review. Progress in the field is further hindered by the limited availability of physiologically relevant experimental models; current in vitro and in vivo systems often fail to capture the complexity and dynamic heterogeneity of the TME. These limitations highlight the urgent need for more comprehensive and mechanistically grounded studies to validate the TME as a viable therapeutic target for nanoparticle-based cancer interventions. In particular, deeper insights into how mNPs influence immune regulation, stromal remodeling, and metabolic reprogramming within the TME will be essential for unlocking their full therapeutic potential in oncology. Full article

Age-related deterioration of the dermal extracellular matrix is driven primarily by fibroblast dysfunction, leading to loss of collagen integrity, elasticity, and structural support. In aesthetic dermatology, injectable and biostimulatory interventions increasingly target qualitative dermal remodelling, with collagen reorganisation widely adopted as a histological endpoint. Picrosirius red (PSR) staining under polarised light remains the most frequently used method for visualising collagen architecture; however, its birefringence colour patterns are often misinterpreted as proxies for collagen subtype shifts, particularly between types I and III. This conceptual review examines the methodological basis of such interpretations. We summarise the biological roles of major dermal collagens and compare current histochemical, immunohistochemical, ultrastructural and molecular methods for collagen assessment. We propose an interpretative framework that separates architectural collagen remodelling from molecular collagen synthesis and addresses the temporal dissociation between early fibre reorganisation and later subtype-specific expression as a plausible explanation for between-study discrepancies. Practical guidance is provided to support responsible interpretation and reporting of PSR-based collagen analyses. PSR is best regarded as a complementary tool for assessing collagen architecture rather than a definitive method for collagen subtype identification. Full article