Search Results (3,143)

Treat-to-target management in inflammatory bowel disease (IBD) combines symptoms, fecal and serum biomarkers, endoscopy, histology, and cross-sectional imaging, but these measures frequently diverge. Discordance may reflect analytical variation, timing, disease location, phenotype, comorbidity, or partially non-overlapping biological processes. We performed a critical narrative review using a structured PubMed/MEDLINE search, supplemented by citation chaining and publisher searches. Guidelines, systematic reviews, diagnostic studies, cohorts, randomized trials, and selected mechanistic studies were prioritized. Fecal calprotectin (FC) and lactoferrin primarily reflect intestinal neutrophilic inflammation, whereas C-reactive protein (CRP) and related serum indices reflect a nonlocalizing systemic response. The fecal immunochemical test (FIT) detects gastrointestinal bleeding, and leucine-rich alpha-2 glycoprotein (LRG) remains promising but insufficiently standardized. We distinguish five biological biomarker domains—namely, fecal–neutrophil; serum–systemic; epithelial/barrier; restitution/resolution; and fibrosis/extracellular matrix (ECM) remodeling—from symptoms and clinical indices, pharmacologic measurements, and phenotype-directed reference assessments. Circulating barrier, repair, and matrix-turnover markers remain investigational. Reactive therapeutic drug monitoring (TDM) for anti-tumor necrosis factor (anti-TNF) agents has the most mature evidence. Vedolizumab and ustekinumab show exposure–response associations, but actionable thresholds are unvalidated, and clinical TDM is not established for newer biologics or oral small molecules. After objective confirmation of disease activity, the framework may support phenotype-directed therapeutic decisions but is not a validated algorithm. Clinically important disagreement should prompt assessment of sampling, assay, timing, infection, medication-related confounding, and pretest probability before phenotype-directed endoscopy, histology, imaging, or reactive TDM is selected. A single discordant result should neither trigger treatment escalation nor exclude active or structural disease. Full article

Cryopreserved mesenchymal stem cells (MSCs) are widely used as off-the-shelf therapeutics. However, conventional manufacturing workflows typically include a post-thaw 2D monolayer recovery step before 3D spheroid formation. This study evaluated whether immediate spheroid formation following thawing (Direct-3D) could replace the conventional 2D-to-3D workflow while maintaining or improving chondrogenic potential. Using passage 5 Wharton’s jelly MSCs (WJ-MSCs), spheroid morphology, early chondrogenic priming, differentiation, and extracellular matrix (ECM) formation were systematically compared between the two strategies. The Direct-3D group exhibited faster and more uniform spheroid compaction and significantly increased SOX9 expression as early as 3 h, indicating enhanced early priming. This response was accompanied by higher COL2A1 expression and an increased COL2A1/COL1A1 ratio during early differentiation while maintaining minimal collagen type X expression. These findings demonstrate that the post-thaw monolayer recovery step is not essential for producing high-quality chondrogenic spheroids from WJ-MSCs. By simplifying the manufacturing workflow while preserving—and potentially enhancing—early chondrogenic performance, the Direct-3D strategy represents a practical and scalable approach for WJ-MSC-based cartilage tissue engineering and cell therapy. Full article

Background/Objectives: Skin aging involves interconnected inflammatory, oxidative, hormonal, extracellular matrix (ECM), and cellular senescence-related mechanisms, supporting the need for multitarget approaches. This study aimed to evaluate the effects of a multicomponent natural product-based injectable formulation developed in Korean medicine practice, Dong-An Pharmacopuncture (DAP), on skin aging-related pathways. Methods: A network pharmacology approach was used to identify the active compounds, predicted molecular targets, and signaling pathways associated with DAP. Sixty-two active compounds from 11 constituent materials were screened, and 70 final targets were identified using STITCH-based prediction, intersection with GeneCards-derived skin aging-related targets, and quality filtering. Results: Herb-compound-target network analysis yielded 225 compound–target interactions across 292 edges. Protein-protein interaction analysis identified a highly connected network with 1,334 edges, and hub analysis converged on 10 core targets: TNF, IL6, ESR1, TP53, AKT1, PPARG, EGFR, PTGS2, CASP3, and PPARA. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses identified four major mechanistic axes: inflammatory and oxidative stress regulation, hormonal skin homeostasis, tissue repair and ECM remodeling, and cellular senescence-related regulation. Because DAP is administered by injection, a Good Laboratory Practice-compliant single-dose subcutaneous toxicity study was additionally conducted in Sprague–Dawley rats, which showed no mortality, abnormal clinical signs, or histopathological findings attributable to DAP at 1.0 mL/head. Conclusions: The findings in this study provide a systems-level framework for the predicted multitarget mechanisms of DAP in skin aging-related pathways and support the need for further experimental validation of its predicted mechanisms and repeated-dose safety. Full article

The increasing prevalence of dermatophytosis and biofilm-associated infections highlights the need for new therapeutic approaches. This study evaluated the potential of Lavandula luisieri essential oil against clinically relevant dermatophytes. The essential oil obtained by hydrodistillation was chemically characterized by gas chromatography–mass spectrometry (GC–MS). Antifungal activity was assessed through determination of minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC), while antibiofilm activity against Epidermophyton floccosum was evaluated by measuring biofilm biomass, extracellular matrix (ECM) deposition, and cell viability. An ex vivo model of Trichophyton rubrum-induced skin infection was used to assess efficacy under tissue-relevant conditions. The essential oil was mainly composed of oxygenated monoterpenes, with trans-α-necrodyl acetate (19.1%), lavandulyl acetate (13.6%), camphor (8.8%), 1,8-cineole (6.1%), and trans-α-necrodol (5.3%)as major constituents. The oil exhibited antifungal activity against all tested dermatophytes (MIC: 12.5–100 μg/mL), induced hyphal morphological alterations, significantly inhibited E. floccosum biofilm formation, particularly ECM deposition, and reduced fungal dissemination in the ex vivo skin model. These findings support the antidermatophytic and antibiofilm potential of L. stoechas subsp. luisieri essential oil, although further studies are required. Full article

Skin photoaging, primarily driven by UVA radiation, is characterized by the accumulation of senescent fibroblasts and the degradation of the extracellular matrix (ECM). While the roles of reactive oxygen species (ROS) and matrix metalloproteinases (MMPs) are well-documented, the regulatory impact of post-translational glycosylation in this process remains poorly understood. We established a UVA-induced photoaging model in human dermal fibroblasts (HDFs) and employed bulk mRNA-seq and high-throughput lectin microarrays to profile glycomic alterations. The functional role of the sialyltransferase ST6GAL1 was investigated through pharmacological inhibition of cellular sialylation (3Fax-Neu5Ac), siRNA-mediated knockdown, and gain-of-function overexpression. Mechanistic insights were gained via RAS-ERK pathway analysis and validated in a 3D reconstructed human full-thickness skin model (T-Skin™). Glycomic profiling revealed that UVA irradiation triggers a broad increase in α2,6-sialylation in HDFs. We identified ST6GAL1 as the primary enzymatic driver of this remodeling, with its expression upregulated in both photoaged HDFs and 3D skin models. Functional assays demonstrated that ST6GAL1 overexpression induces hallmark features of photoaging, including p16, MMP and γ-H2AX upregulation, G0/G1 cell cycle arrest and increased SA-β-gal activity. Conversely, pharmacological or genetic inhibition of ST6GAL1 effectively mitigated the photoaged phenotype. Mechanistically, ST6GAL1 regulates the expression of p16 via the activation of the RAS-ERK signaling cascade. Our study identifies ST6GAL1-mediated α2,6-sialylation as a novel functional hallmark of skin photoaging, highlighting the association of ST6GAL1 with the RAS-ERK-p16 axis as a potential regulator for targeting UVA-induced skin photoaging and dermal senescence. Full article

Background and Objective: Pancreatic ductal adenocarcinoma (PDAC) is characterized by dense extracellular matrix (ECM) with overexpression of extra domain B fibronectin (EDB-FN). Methods: Herein, we investigated novel albumin-binding peptide–drug conjugates, Mc-ZD2-SN38 and SSC-ZD2-SN38, which integrate the prolonged circulation properties of albumin with the active targeting capability of the ZD2 peptide toward EDB-FN. Covalent and noncovalent albumin-binding strategies extended the half-life by approximately 100-fold and 15-fold, respectively, compared with the non-albumin-binding peptide–drug conjugate (PDC) (ZD2-SN38). Results: Notably, ZD2-mediated targeting markedly reduced payload accumulation in major organs, resulting in an improved safety profile. In a BxPC-3 xenograft model, Mc-ZD2-SN38 and SSC-ZD2-SN38 demonstrated potent and sustained antitumor efficacy. Conclusions: These findings establish a long circulation and active targeting drug delivery strategy, providing an ideal framework for the development of PDCs with enhanced therapeutic indices. Full article

The plasminogen activator system (PAS), comprising urokinase-type plasminogen activator (uPA), tissue-type plasminogen activator (tPA), their receptors, and endogenous inhibitors, has been extensively investigated for its established roles in haemostasis, fibrinolysis, vascular remodelling and extracellular matrix (ECM) homeostasis. Increasing evidence indicates that the functions of the PAS extend well beyond the cardiovascular system and have important regulatory roles in neuronal plasticity, synaptic remodelling, neuroinflammation, and neurotrophic signalling. These processes are increasingly recognized as central contributors to the neurobiological adaptations underlying substance use disorders (SUDs). In this narrative review, we critically evaluate the current evidence regarding the involvement of the PAS in SUDs, with particular emphasis on the molecular and cellular mechanisms through which uPA and tPA influence addiction-related neuroplasticity. The available literature is predominantly derived from preclinical studies, while direct clinical evidence remains limited. Experimental findings support roles for uPA and tPA in modulating reward-related circuitry, behavioural sensitization, relapse-like behaviours, and neurotrophic signalling, including potential interactions with brain-derived neurotrophic factor (BDNF)-related pathways, although the relative contributions of plasmin-dependent and plasmin-independent pathways remain incompletely understood. We also discuss the potential involvement of the PAS in neuroinflammatory responses and synaptic remodelling, together with the challenges associated with translating these findings into clinically relevant biomarkers or therapeutic strategies. Finally, we identify important gaps in current knowledge, including the need for independent replication, mechanistic clarification, and well-designed human studies to establish the clinical relevance of PAS dysregulation in addiction. Collectively, the available evidence supports a modulatory role for the PAS in addiction-related neurobiology and provides a rationale for further translational investigation, while highlighting that PAS-directed therapeutic approaches remain experimental and require substantial preclinical and clinical validation. Full article

Demineralized bone matrix (DBM)-derived allografts retain extracellular matrix (ECM)-associated factors involved in bone repair, but biochemical protein recovery alone may not predict functional pathway activation. We evaluated the HEK-Blue™ TGF-β Reporter Assay as a targeted method for assessing Smad-dependent reporter activity in DBM-derived materials. ECM proteins were extracted from cortical demineralized bone granules (DBG) using guanidine hydrochloride (GuHCl) or urea and quantified after extraction, dialysis, and sterile filtration. Reporter cells were stimulated with extracted ECM proteins or directly with processed cortical and cancellous products, including DBG, wet heat-treated DBG formulated as Putty (PHT), and gamma-irradiated PHT (PGI). Non-pooled DBM sponge samples were also tested. Secreted embryonic alkaline phosphatase (SEAP) activity served as the functional reporter readout. Material-only no-cell controls assessed material-derived background. PrestoBlue™ readouts served as exploratory quality controls. The urea-derived extract yielded a higher apparent BCA-detectable protein concentration than the GuHCl-derived extract. Only the GuHCl-derived extract induced increasing SEAP activity at matched protein input. Direct stimulation showed reporter activation above the TNF-α pathway-negative cytokine control for cortical DBG, PHT, PGI, and cancellous DBG. DBM sponges also induced detectable SEAP activity. These findings support targeted functional screening of Smad-dependent TGF-β reporter activation in DBM-derived materials, but not total osteoinductivity assessment. Full article

A coordinated extracellular matrix (ECM) and cytoskeletal remodeling are critical drivers of hepatocellular carcinoma (HCC) progression, yet the upstream post-transcriptional mechanisms regulating these processes in spontaneous canine HCC remain poorly defined. Previously, we reported significantly downregulated miRNAs and enriched pathways from differentially expressed genes (DEGs) in canine HCC tissues. In the present study, we investigated putative post-transcriptional target interactions between the prioritized miRNAs and enriched ECM–cytoskeleton pathway-associated genes (n = 34). Integrative bioinformatic analysis prioritized ACTG1 and SDC1 as the key putative targets of cfa-miR-10a based on their concordant prediction by four target-prediction algorithms, high transcript abundance, and inverse correlations with cfa-miR-10a-5p. RNAhybrid and miRanda analyses supported favorable predicted interactions between cfa-miR-10a and the 3′UTRs of both transcripts, with RNAhybrid minimum free energy values ≤ −20 kcal/mol and miRanda scores ≥ 140. In the matched canine transcriptomic subset, cfa-miR-10a and its predicted targets showed inverse expression trends. Cross-species analysis using TCGA-LIHC datasets further demonstrated concordant dysregulation of ACTG1, SDC1 and hsa-miR-10a-5p in human HCC, despite their weak or non-concordant correlation with hsa-miR-10a-5p. Collectively, these exploratory findings identify a candidate cfa-miR-10a–ACTG1/SDC1 network associated with coordinated ECM and cytoskeletal transcriptomic alterations in canine HCC. While cross-species analysis supports the conservation of target gene dysregulation, the divergent miRNA-mRNA correlation patterns highlight potential species-specific post-transcriptional co-expression landscapes that warrant future functional validation. Full article

Tendinopathies represent a major clinical challenge. Vasculature, neuromuscular junctions, low cellularity, and slow extracellular matrix (ECM) turnover restrict endogenous repair and predispose injured tendons to fibrosis, mechanical weakness, and reinjury. Current therapeutic strategies including rehabilitation protocols, anti-inflammatory medications, platelet-rich plasma (PRP) injections, and surgical repair primarily address symptoms or structural deficits without correcting the underlying biological limitations of tendon healing. Cell-based therapies have emerged as a promising regenerative approach aimed at restoring tissue homeostasis through modulation of angiogenesis, collagen synthesis, immune responses, and tenogenic differentiation. Mesenchymal stem cells (MSCs), adipose-derived stem cells (ADSCs), tendon-derived stem cells (TDSCs), induced pluripotent stem cells (iPSCs), differentiated tenocytes, and extracellular vesicle (EV)-based products have demonstrated the ability to enhance vascularization, promote type I collagen remodeling, suppress excessive inflammation, and stimulate tenocyte lineage commitment. These effects are mediated through paracrine signaling, growth factor secretion, and activation of key pathways, including HIF-1α, TGF-β/SMAD, NF-κB, and PI3K/Akt signaling. Despite promising preclinical data, significant translational challenges remain, including limited cell survival at the injury site, variability in cell sources and dosing, immunogenicity, risk of misdifferentiation, and lack of standardization across clinical protocols. Emerging strategies such as genetic modification, hypoxic preconditioning, scaffold-based delivery systems, and extracellular vesicle engineering aim to enhance therapeutic efficacy and reproducibility. This review synthesizes current evidence on cell-based tendon repair, critically evaluates mechanistic insights, clinical trials, and translational barriers, and outlines future directions toward biologically informed regenerative therapies. Full article

Fibrosis emerges when normally self-limiting tissue repair fails to resolve and overlapping phases of injury, stromal activation, extracellular matrix (ECM) deposition and remodelling become sustained. MicroRNAs (miRNAs) shape this transition by coordinating signalling, cell-state and matrix programmes. Functionally, pro-fibrotic fibro-miRs amplify fibrogenic pathways, whereas anti-fibrotic miRNAs restrain fibroblast activation and ECM production; the miR-29 family is a principal member of the latter group. This review examines miR-29 family organisation, the regulation of miR-29b by transforming growth factor-β (TGF-β)/Smad and additional transcriptional and inflammatory inputs, and the molecular targets through which miR-29b controls collagen synthesis, processing and crosslinking. Direct canonical targets are distinguished from experimentally supported, predicted and indirect pathway components. Evidence is evaluated across fibroblasts and myofibroblasts, epithelial and endothelial cells, and pulmonary, hepatic, renal, cardiac, dermal and ocular fibrosis models. Therapeutic translation is considered in relation to miR-29b mimics and agomirs, local and tissue-targeted delivery, pharmacokinetics, dose control, off-target repression, immune activation and long-term safety. Overall, miR-29b remains a credible network-level anti-fibrotic candidate, but successful translation requires cell- and disease-specific target validation, selective delivery and preservation of physiological wound repair. Full article

In the current paper, pulmonary emphysema is hypothesized to emerge from a nonlinear breakdown of cooperation across two tightly coupled systems: the extracellular matrix (ECM) crosslink network and the cellular populations responsible for its maintenance. To formalize this concept, we construct a game-theoretic model that unifies the mechanical failure, inflammatory changes, and percolation-driven tissue collapse that are recognized features of the disease. At the ECM level, elastin and collagen crosslinks are modeled as players in an iterated Prisoner’s Dilemma, where cooperation corresponds to maintaining structural integrity, and defection corresponds to rupture under mechanical stress. At the cellular level, fibroblasts, macrophages, and neutrophils engage in a parallel strategic game in which repair reflects cooperative activity, and protease- or oxidant-producing phenotypes are indicative of defection. These parallel games are coupled through bidirectional payoff modulation, generating a dynamical system with bistability, tipping points, and runaway positive feedback. As the fraction of intact crosslinks falls below a critical percolation threshold, global network connectivity collapses and lung function drops precipitously. This framework explains the characteristic features of pulmonary emphysema, including spatial heterogeneity, abrupt acceleration, and irreversibility as emergent properties of coupled cooperation–defection dynamics, and identifies new leverage points for stabilizing cooperation and preventing catastrophic network failure in early disease. In support of this hypothesis, we present previously published studies from our laboratory involving measurements of elastin-specific desmosine crosslinks in human postmortem emphysematous lungs showing a marked increase in tissue crosslink density at the early stage of the disease, and accelerating loss of these crosslinks as airspace enlargement progresses, consistent with initial cooperation followed by defection. This conceptual framework is then applied to the poorly understood lung disease, Combined Pulmonary Fibrosis and Emphysema, to provide a potential mechanism for its pathogenesis. Full article

Abdominal aortic aneurysm (AAA) is a progressive and often asymptomatic vascular disease associated with high mortality after rupture, but reliable circulating biomarkers for noninvasive detection remain limited. We aimed to identify and validate plasma protein biomarkers for AAA using an integrated proteomics-based approach. Plasma samples from 22 patients with AAA and 22 healthy controls were analyzed through data-independent acquisition (DIA) mass spectrometry. Differentially expressed proteins were subjected to bioinformatic analyses, including Gene Ontology enrichment, Kyoto Encyclopedia of Genes and Genomes pathway analysis, protein–protein interaction, and weighted gene coexpression network analyses. Candidate biomarkers were selected on the basis of differential abundance, diagnostic performance, and biological relevance and subsequently validated by enzyme-linked immunosorbent assay in an independent cohort comprising 93 patients with AAA and 83 non-AAA controls. DIA proteomics identified 111 differentially abundant proteins, revealing enrichment of pathways related to mitochondrial respiration, oxidative stress, inflammation, extracellular matrix remodeling, and proteostasis. Among the candidates, plasma CHRDL1 levels were significantly reduced, whereas OGN and CCL18 levels were significantly elevated in patients with AAA; these findings were consistently confirmed in the validation cohort. A combined three-protein model demonstrated strong diagnostic performance, with an area under the receiver operating characteristic curve of 0.890. These findings identify CHRDL1, OGN, and CCL18 as promising plasma biomarkers for AAA detection and further highlight mitochondrial dysfunction, chronic inflammation, ECM remodeling, and dysregulated proteostasis as key molecular features of AAA. Full article

Background: The efficacy of chemotherapy in triple-negative breast cancer (TNBC) is limited by intrinsic resistance and the tumor microenvironment (TME). Accumulating evidence reveals a mechanistic connection between programmed death-ligand 1 (PD-L1) and c-x-c motif chemokine receptor 4 (CXCR4), which dominate stroma barriers, immune escape, and cancer metastasis. Earlier studies have shown that dual suppression of c-x-c motif ligand 12 (CXCL12)/CXCR4 and programmed cell death-1 (PD-1)/PD-L1 pathways regulates extracellular matrix (ECM) deposition, activation of cancer-associated fibroblasts (CAFs), and epithelial–mesenchymal transition (EMT) of pancreatic cancer cells. Methods: We combined BsNb PX4, a bispecific nanobody targeting PD-L1 and CXCR4, with paclitaxel or gemcitabine in multiple tumor cell lines and human peripheral blood mononuclear cell (hPBMC)-reconstituted xenograft mouse models. Antitumor activity was assessed by CCK-8, flow cytometry, and ELISA, and immune cell infiltration and TME remodeling were examined by immunofluorescence, immunohistochemistry, cytokine assays, and RNA-seq. Results: In MDA-MB-231 cells, BsNb PX4 synergistically enhanced paclitaxel-induced growth inhibition and apoptosis via G₂/M cycle arrest. This combinatorial strategy profoundly remodeled tumor immunity by expanding CD8⁺ T cells and depleting Foxp3⁺ CD4⁺ regulatory T cells (Tregs), while concurrently restoring T-cell cytotoxicity and skewing the cytokine balance toward an antitumor state, with elevated IFN-γ and reduced TGF-β1. Notably, compared with paclitaxel monotherapy, the combination significantly elevated intratumoral CD8⁺ T-cell infiltration, decreased Treg abundance, and exerted robust inhibitory effects on tumor growth and metastasis in humanized TNBC xenografts. Conclusions: These findings reveal that dual blockade of PD-L1 and CXCR4 acts synergistically with chemotherapy by triggering tumor cell apoptotic effects and reversing the immunosuppressive microenvironment, thereby emerging as a promising therapeutic strategy for TNBC. Full article

The extracellular matrix (ECM) in cancer differs from healthy tissue in structure, composition, and mechanical properties. Matricellular proteins (MCPs) play important roles in shaping ECM architecture during tissue remodeling. This narrative review, combined with a bioinformatics analysis, examines six major MCP families—Fasciclins, Tenascins, Thrombospondins, Small Leucine-Rich Proteoglycans, the SPARC family, and the CCN family—through a mechanobiological lens in bladder cancer. It summarizes current knowledge on the mechanical regulation of MCP expression, their effects on matrix stiffness, and their contributions to bladder cancer progression. Analyses of public datasets reveal that stromal cells are the predominant source of MCPs in the tumor microenvironment. Furthermore, mechanical upregulation and involvement in the formation of stiff ECM highlight MCPs as important players in a mechanotransduction feedback loop. While most MCPs exert pro-tumorigenic effects on bladder cancer cells, several display context-dependent or anti-tumorigenic activities. Existing studies have primarily focused on the isolated effects of MCPs on bladder cancer cell lines in two-dimensional systems or simple subcutaneous xenograft models. Both approaches fail to capture the context-dependent nature of MCPs and their involvement in ECM formation. These findings underscore the need for future studies to investigate the complex effects of MCPs on bladder cancer progression. Full article