Search Results (54)

Polycystic kidney disease (PKD), the most common inherited kidney disorder, is characterized by progressive cyst growth and eventual organ failure. Although aberrant innate immune activation is a recognized contributor to PKD progression, the underlying molecular mechanisms remain incompletely defined. Here, we showed that Pkd1 deletion increased TLR2 and MyD88 mRNA expression in renal epithelial cells, indicating enhanced innate immune priming. In vivo, administration of Pam3CSK4 (PAM), a synthetic TLR2 agonist, preferentially amplified pro-inflammatory and pro-fibrotic responses in Pkd1^RC/RC mice compared with wild-type controls, despite inducing similar signaling responses in vitro. Acute PAM treatment for one week rapidly enhanced NF-κB activation in cyst-lining epithelial cells, increased renal inflammation and cell proliferation, and was associated with activation of mTOR signaling and upregulation of c-Myc and Wnt proteins. Sustained PAM treatment further accelerated cyst expansion and renal fibrosis in PKD mice. Importantly, the endogenous TLR2 ligands decorin and biglycan were markedly elevated in human PKD kidneys, supporting the translational relevance of enhanced TLR2 signaling in disease progression. Together, these findings suggest that TLR2 signaling is an important contributor to PKD progression and a potential therapeutic target. Full article

Proteoglycans are macromolecules consisting of a core protein and one or more glycosaminoglycan side chains. Proteoglycans synthesized by vascular endothelial cells modulate various functions such as anticoagulant activity and vascular permeability. We previously reported that some heavy metals interfere with proteoglycan expression, and that organic–inorganic hybrid molecules, such as metal complexes and organometallic compounds, serve as useful tools to analyze proteoglycan synthesis mechanisms. However, the effects of metal compounds lacking electrophilicity on proteoglycan synthesis remain unclear. Au₂₅(SG)₁₈, a nanoscale gold cluster consisting of a metal core protected by gold–glutathione complexes, exhibits extremely low intramolecular polarity. In this study, we investigated the effect of Au₂₅(SG)₁₈ on proteoglycan synthesis in vascular endothelial cells. Au₂₅(SG)₁₈ accumulated significantly in vascular endothelial cells at low cell density and suppressed the expression of perlecan, a major heparan sulfate proteoglycan in cells, by inactivating ADP-ribosylation factor 6 (Arf6). Additionally, Au₂₅(SG)₁₈ reduced the expression of biglycan, a small dermatan sulfate proteoglycan, in vascular endothelial cells at low cell density; however, the underlying mechanisms remain unclear. Overall, our findings suggest that organic–inorganic hybrid molecules regulate the activity of Arf6-mediated protein transport to the extracellular space and that perlecan is regulated through this mechanism, highlighting the importance of Arf6-mediated extracellular transport for maintaining vascular homeostasis. Full article

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent joint inflammation and progressive bone destruction. However, its complex pathogenesis remains poorly understood, and effective therapeutic targets are still lacking. Objective: This study aimed to identify key genes associated with RA and elucidate their biological significance by integrating bioinformatic analysis with experimental validation. Methods: Whole-transcriptome data from the anterior cingulate cortex (ACC) of Complete Freund’s Adjuvant (CFA)-induced inflammatory pain and control mice (GSE147216 dataset, GEO database) were collected from NCBI (National Center for Biotechnology Information). Differentially expressed genes (DEGs) were first identified. Subsequent analyses included Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, construction of a protein–protein interaction (PPI) network, and identification of hub genes using a Random Forest machine learning algorithm. Quantitative PCR (qPCR) was performed to validate gene expression levels. Results: A total of 76 DEGs were identified, including 64 upregulated and 12 downregulated genes. Among them, Fn1 (fibronectin 1), Bgn (biglycan), and Lum (lumican) were identified as hub genes. Functional enrichment analysis revealed inflammatory responses, extracellular matrix (ECM) remodeling, and the TGF-β signaling pathway. qPCR validation confirmed significant upregulation of Fn1, Bgn, and Lum mRNA in the CFA group. Conclusions: This study highlights the potential roles of Fn1, Bgn, and Lum in the central sensitization associated with inflammatory pain, offering insights relevant to RA. Full article

Proteoglycans and their fragments have potential as diagnostic or theragnostic biomarkers to identify diseases characterized by dysregulated extracellular matrix remodeling, such as juvenile idiopathic arthritis (JIA). Therefore, our study aimed to evaluate the diagnostic utility of plasma proteoglycan profiles, namely, aggrecan, decorin, and biglycan, released from osteoarticular structures into the blood of children with juvenile idiopathic arthritis. These profiles are potential biomarkers of tissue destruction and/or indicators of the efficacy of therapy with the biologic agent etanercept (ETA). This study was conducted on 263 blood samples collected from 25 healthy children and 34 children at various stages of juvenile idiopathic arthritis disease: immediately after diagnosis, following treatment with disease-modifying antirheumatic drugs (DMARD) (methotrexate, sulfasalazine, and prednisone), and during 3, 6, 12, 18, and 24 months of therapy with etanercept. Quantitative levels of aggrecan, biglycan, and decorin were measured using ELISA kits. In children with JIA, plasma aggrecan levels were elevated at diagnosis, decreased after ineffective DMARD therapy, and increased again at 24 months of etanercept treatment despite clinical improvement. By contrast, biglycan levels were similar to those in healthy controls but decreased during etanercept therapy. Decorin levels were initially high in untreated and DMARD-treated patients but returned to normal after 24 months of biologic treatment. After considering these findings and the ROC analysis, we conclude that decorin appears to be a promising biomarker for diagnosing and monitoring etanercept therapy in JIA, and biglycan is a useful biochemical marker for assessing the effectiveness of ETA treatment. Full article

Meester–Loeys syndrome (MLS) is an X-linked connective tissue disorder caused by pathogenic BGN variants. We describe a family carrying a novel missense variant. The index male, initially diagnosed with Ehlers–Danlos syndrome, had joint hypermobility, multiple visceral artery aneurysms, and recurrent musculoskeletal problems. A brother of the proband had an aortic root aneurysm. Female carriers had no or only minor manifestations. Studies of the aortic wall were consistent with a dysregulation of the TGF-β/SMAD pathway and assays with reporter vectors revealed reduced canonical Wnt and TGF-β activity in cell lines expressing mutant biglycan. However, patients’ dermal fibroblasts did not show consistent differences in the nuclear abundance of β-catenin or p-SMAD2/3 compared to cells from controls. This 3-generation family expands the genetic and phenotypic spectrum of MLS and underscores the importance of considering BGN testing in hypermobility syndromes to enable early surveillance and targeted management. Full article

Esophageal squamous cell carcinoma (ESCC) is associated with poor prognosis due to aggressive invasion and therapy resistance. Cancer-associated fibroblasts (CAFs) are key stromal components that promote tumor progression; however, their specific roles in ESCC remain unclear. Using a direct co-culture model of ESCC cell lines (TE-9, -10, and -15) and mesenchymal stem cells (MSCs) to generate CAF-like cells, we identified biglycan (BGN) as a significantly upregulated gene in CAF-like cells via cDNA microarray analysis. Public single-cell RNA sequencing data also demonstrated elevated BGN expression in CAF clusters. We confirmed that CAF-like cells exhibited elevated BGN expression and secretion at both the mRNA and protein levels. Recombinant human BGN enhanced ESCC cell proliferation and migration by activating Erk and NF-κB signaling pathways, effects abrogated by TLR4 blockade. Furthermore, BGN promoted CAF marker expression in MSCs, M2-like macrophage polarization, and enhanced proliferation and migration abilities in both cell types. Immunohistochemical analysis of 66 ESCC tissues revealed that high stromal BGN expression correlated with greater tumor invasion, lymphatic invasion, and shorter disease-free survival. These findings indicate that CAF-derived BGN promotes ESCC progression via TLR4-mediated signaling and modulates stromal cell behavior, highlighting its potential as a prognostic biomarker and therapeutic target. Full article

Tendon healing is limited by hypocellularity and low metabolic activity, resulting in poor regeneration. Mesenchymal stem cells (MSCs) offer potential for tendon repair, but reliable tenogenic differentiation protocols remain undefined. Photobiomodulation (PBM) has been proposed as an adjunct to assist differentiation, yet standardized parameters are lacking, particularly in 3D systems. This study evaluated the effects of PBM at 525 nm, 825 nm, and combined wavelengths, delivered at 5 J/cm² and 10 J/cm², on immortalized adipose-derived MSCs (iADMSCs) encapsulated in TrueGel3D hydrogels, with the goal of optimizing parameters to support tenogenic differentiation. Immortalized ADMSCs were characterized by immunofluorescence (CD44, CD90, and CD166) and encapsulated in hydrogels. Following a single PBM exposure, differentiation was induced with transforming growth factor-β1 and ascorbic acid for 3 days, followed by the addition of connective tissue growth factor for an additional 7 days. Morphology, membrane permeability, proliferation, and gene expression were assessed at days 1, 4, and 10. The cells adopted a spindle-shaped fibroblastic morphology, forming dense cellular networks throughout the hydrogel, although without alignment due to random RGD distribution. LDH release remained low across groups, confirming biocompatibility. Proliferation rates were not significantly different on day 1. By day 4, green and consecutive PBM at 10 J/cm² and day 10 green PBM at 5 J/cm² showed increased proliferation rates, respectively. PCR analysis showed co-expression of Scleraxis and Tenomodulin in all groups by day 10, confirming tenogenic differentiation. NIR and consecutive (10 J/cm²) PBM maintained Scleraxis expression over time, with NIR PBM enhancing Collagen I, III, Biglycan and Tenascin-C on day 1 and 4. However, consecutive PBM (10 J/cm²) maintained higher expression patterns more consistently compared to NIR on day 10. Thus, consecutive (525/825 nm) wavelengths at 10 J/cm² proved effective in enhancing tenogenic marker expression for a single-dose PBM protocol. Full article

Proteoglycans (PGs) are highly glycosylated proteins of great importance both structurally and for signalling in the extracellular matrix (ECM) as well as cell surfaces. In breast cancer (BC), they control the structure of tissue architecture, cellular communication pathways and tumour–stroma interactions, thus affecting adhesion, migration, angiogenesis, immune evasion, and metastasis. Their structural heterogeneity supports either subtype- or context-dependent functions. This review combines current studies of PGs in BC according to their classification into intracellular, cell-surface, pericellular, extracellular, and small leucine-rich PGs and a range of non-classical PGs. A literature-driven approach to focus on molecular mechanisms and clinical correlations will demonstrate how PGs respond with collagens, growth factors, cytokines, and proteolytic enzymes in order to modulate the ECM and affect therapy resistance. Indeed, PGs including syndecans, glypicans, perlecan, versican, biglycan and decorin showed the potential to be promoters or suppressors of cancer, with local effects on invasion, and have a significant modulating effect on BC subtypes or the prognosis and therapeutic response and may potentially serve as new biomarkers for stratification and liquid biopsy candidates. Furthermore, PGs appear to modulate the tumour immune landscape, are involved in the development of metastatic niches, and underlie signalling pathways like Wnt or TGFβ in a subtype-dependent manner, extending their translational prospects and therapeutic utility. PGs, taken together, seem to be major modulators of BC, with particular relevance for precision medicine. Full article

The extracellular matrix (ECM) is a complex noncellular network of (macro-)molecules that surrounds and supports diverse cells in tissues and organs. In cancer, ECM is a part of the tumor microenvironment (TME) that embeds its cellular components including cancer cells and the neighboring non-cancerous stromal cells such as fibroblasts, endothelial, and immune cells. Given the complexity of players and interactions that the ECM participates in and is exposed to in the TME, it does not come as a surprise that many of the processes that drive cancer progression take part precisely in the ECM compartment of the TME. Along with diverse glycoproteins and collagens, proteoglycans (PGs) are among the main components of the core ECM. PGs are composed of a protein core to which glycosaminoglycan chains are attached. Considering the structural diversity of these molecules and their ‘hybrid’ nature, it is not surprising that they are involved in a variety of processes that are vital for surrounding cells. Moreover, they are secreted by both cancer and stromal cells, contributing to the complexity of interactions in the TME. In prostate cancer, PGs have been shown to be involved in many steps of its progression; the most prominent examples include the seemingly tumor-promoting roles of versican, perlecan, and biglycan, and the tumor-suppressive roles of decorin and betaglycan. The role of syndecan 1 is a bit more complex; namely, the nature of its role is context dependent. In this narrative review article, the roles of PGs in prostate cancer progression and therapy resistance are discussed in more detail. Full article

Background: The skeletal muscle extracellular matrix (ECM) is critical for muscle force and the regulation of important physiological processes. A growing body of evidence demonstrates that in aging, altered ECM composition profoundly hinders the capacity for muscle adaptation in response to exercise training. We evaluated the pattern of ECM expression in response to exercise training between healthy young participants and patients with chronic obstructive pulmonary disease (COPD), to provide insight into how normal adaptive processes differ under conditions of chronic disease. Methods: Vastus lateralis muscle biopsies from 29 patients (mean ± SD FEV1: 43 ± 16% predicted) and 14 healthy subjects were analyzed before and after an interval exercise training program for myofiber distribution and size. A selection of ECM molecules was quantified using ELISA. Results: Compared to healthy participants, patients exhibited a lower capacity to increase myofiber type I distribution (by 4.7 ± 3.4 vs. 1.3 ± 2.2%) and mean fiber cross-sectional area (by 13.6 ± 3.2 vs. 9.1 ± 1.9%). Exercise training induced a diverse protein expression between the two cohorts in ECMs regulating tissue structure (collagens: up-regulated only in COPD), myogenesis (SPARC: up-regulated only in healthy), necroptosis (tenascin C: up-regulated only in COPD), adherence to muscle-cell precursors (Fibronectin: up-regulated only in healthy) and tissue integrity (biglycan: down-regulated only in COPD). Conclusions: Impaired ECM remodeling may underlie the reduced exercise training muscle adaptation observed in COPD patients. Full article

Myokines are secreted by muscle and play crucial roles in muscle repair and regeneration and also impact diverse physiological effects through crosstalk with other metabolic organs. However, aging is associated with a progressive decline in muscle mass, which in turn leads to reduced myokine secretion. This decline may contribute to the development of sarcopenia, leading to an increased risk of metabolic disorders such as type 2 diabetes. Accordingly, interest in identifying novel myokines and elucidating their biological functions is increasing. In this study, we explored the function of biglycan (BGN), a novel myokine, in aging-related metabolic tissues. BGN levels decreased in the muscle tissue and plasma of older adults and aged mice, whereas exercise intervention restored BGN expression in aged mice. BGN counteracted the expression of atrophy-related genes involved in muscle degradation and mitigated muscle mass loss by regulating AKT/mTOR signaling pathway. Notably, BGN decreased the expression of the senescence marker p21 and senescence-associated secretory phenotype (SASP)-related genes in hepatocytes. Additionally, BGN attenuated senescence-induced lipid accumulation and ROS generation. Our results suggest that BGN has beneficial effects against muscle atrophy and hepatocellular senescence, indicating its potential as a protective factor for age-related diseases. Full article

Tendon ruptures and tendinopathies represent a major part of musculoskeletal injuries. Due to the hypovascular and hypocellular nature of tendons, the natural healing capacity is slow and limited. Cell-free approaches for tendon injuries are being investigated as the next generation of therapeutic treatments. The aim of this study was to compare the proteomic profiles and biological activities of two different secretomes, obtained from New Zealand white rabbit adipose-tissue-derived mesenchymal stem cells (ADSCs) or a 3:1 mixed culture of ADSCs and rabbit tenocytes. The secretomes were analyzed by liquid chromatography–tandem mass spectrometry (LC–MS/MS) and their functional properties, such as gene expression, migration and angiogenesis, were investigated in vitro in rabbit tenocytes and in ovo using the chicken chorioallantoic membrane (CAM) assay after stimulation with secretomes or medium control. Both secretomes had a positive effect on angiogenesis and showed similar changes in relative gene expression levels associated with extracellular matrix (ECM) remodeling. Proteomic data showed that the two secretomes were clearly distinguishable, with 182 proteins significantly differentially expressed. The ADSC secretome was more effective in enhancing tenocyte migration under both healthy and inflammatory conditions. In the upregulated protein fraction of the mixed secretome, the tendon-related protein biglycan (BGN) and tenascin C (TNC) were increased. Based on our results, the mixed secretome shows great potential for promoting tendon healing as its composition is more effective in enhancing ECM-related processes and tendon development than the secretome of ADSCs. Full article

Introduction: Ischemic conditionings (ICon) were intensively investigated and several protective signaling pathways were identified. Previously, we have shown the role of matrix metalloproteinases (MMP) in myocardial ischemia/reperfusion injury (MIRI) and the cardioprotective role of biglycan (BGN), a small leucine-rich proteoglycan in vitro. Here, we hypothesized that cardiac MMP and BGN signaling are involved in the protective effects of ICon. Methods: A reverse target-microRNA prediction was performed by using the miRNAtarget™ 2.0 software to identify human microRNAs with a possible regulatory effect on MMP and BGN, such as on related genes. To validate the identified 1289 miRNAs in the predicted network, we compared them to two cardioprotective miRNA omics datasets derived from pig and rat models of MIRI in the presence of ICons. Results: Among the experimentally measured miRNAs, we found 100% sequence identity to human predicted regulatory miRNAs in the case of 37 porcine and 24 rat miRNAs. Upon further analysis, 42 miRNAs were identified as MIRI-associated miRNAs, from which 24 miRNAs were counter-regulated due to ICons. Conclusions: Our findings highlight 24 miRNAs that potentially regulate cardioprotective therapeutic targets associated with MMPs and BGN in a highly translatable porcine model of acute myocardial infarction. Full article

Radiation-induced heart disease (RIHD), a common side effect of chest irradiation, is a primary cause of mortality among patients surviving thoracic cancer. Thus, the development of novel, clinically applicable cardioprotective agents which can alleviate the harmful effects of irradiation on the heart is of great importance in the field of experimental oncocardiology. Biglycan and decorin are structurally related small leucine-rich proteoglycans which have been reported to exert cardioprotective properties in certain cardiovascular pathologies. Therefore, in the present study we aimed to examine if biglycan or decorin can reduce radiation-induced damage of cardiomyocytes. A single dose of 10 Gray irradiation was applied to induce radiation-induced cell damage in H9c2 cardiomyoblasts, followed by treatment with either biglycan or decorin at various concentrations. Measurement of cell viability revealed that both proteoglycans improved the survival of cardiac cells post-irradiation. The cardiocytoprotective effect of both biglycan and decorin involved the alleviation of radiation-induced proapoptotic mechanisms by retaining the progression of apoptotic membrane blebbing and lowering the number of apoptotic cell nuclei and DNA double-strand breaks. Our findings provide evidence that these natural proteoglycans may exert protection against radiation-induced damage of cardiac cells. Full article

Background: The etiopathogenesis of ACL rupture is not clarified. The aim of this study is to identify genomic regions and genetic variants relevant to anterior cruciate ligament injury susceptibility that could be involved in non-contact anterior cruciate ligament ruptures. Methods: A systematic review of the literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines with a PRISMA checklist and algorithm. A search of PubMed, MEDLINE, CINAHL, Cochrane, EMBASE, and Google Scholar databases was conducted using combinations of the terms “anterior cruciate ligament”, “ACL”, “rupture”, “genetics”, “single nucleotide polymorphisms”, and “SNP” since the inception of the databases until 2021. Results: Twenty-three studies were included. A total of 7724 patients were analyzed. In total, 3477 patients had ACL ruptures and 4247 patients were controls. Genetic variants in genes encoding for collagens, elastin, fibrillin, matrix metalloproteinases, proteoglycans, angiogenesis-associated signaling cascade proteins, growth differentiation factors, tissue inhibitors of metalloproteases, interleukins, and fibrinogen were analyzed. Conclusion: Findings regarding the association between genes encoding for collagen (COL3A1, COL1A1, and COL12A1), aggrecan (ACAN), decorin (DCN), matrix metalloproteinase (MMP3), interleukin 6 (IL-6), vascular endothelial growth factor A (VEGFA), biglycan (BGN), fibrinogen (FGB), and ACL injuries were found to be inconclusive. Additional evidence is required in order to establish substantial conclusions regarding the association between genetic variants and ACL rupture. Full article