Search Results (57)

Background/Objectives: Ankylosing spondylitis (AS) is a severe chronic inflammatory rheumatic disease involving the spine, sacroiliacs, and peripheral joints. A lack of therapeutic response leads to severe sequelae. Currently, new markers are being tested to identify patients with poor outcomes. Tenascin C (TNC) is involved in triggering some relevant mechanisms of inflammation. Today, it remains unclear whether TNC levels might be useful as a biomarker of persistent activity. The aim of this study was to evaluate in AS whether serum levels of tenascin C are associated with persistent disease activity despite treatment. Methods: We included AS patients who had been treated with conventional synthetic disease-modifying antirheumatic drugs (cs-DMARDS) or anti-TNF agents for at least three months in a cross-sectional study. Response was assessed with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI); scores ≥ 4 indicate persistent disease activity, while scores < 4 indicate inactive disease. Serum TNC levels, C-reactive protein (CRP) levels, and Erythrocyte Sedimentation Rate (ESR) were determined through the ELISA technique, nephelometry, and the Westergren method, respectively. Results: We evaluated 58 patients with AS (62.1% men); of them, 33 (56.9%) had persistent active disease (BASDAI ≥ 4) despite treatment and 25 (43.1%) had inactive disease (BASDAI < 4). The median TNC level was 18.6 ng/mL. BASDAI correlated with TNC levels (rho: 0.528, p < 0.001), CRP (0.352, p = 0.007), and ESR (0.342, p = 0.009). Patients with persistently active AS had higher serum TNC levels than those with inactive AS (35.2 vs. 6 ng/mL, p < 0.001). No differences in TNC level were found in patients treated with cs-DMARDS vs. anti-TNF agents. The ROC curve for serum tenascin C in active AS patients had an area under the curve = 0.78 (CI 95%: 0.65–0.91) with optimal serum tenascin C cutoff (>13.85 ng/mL). Sensitivity for detecting active AS was higher with TNC compared to ESR and CRP. Conclusions: We suggest that an elevated TNC level may be a useful biomarker of persistent disease activity despite treatment in AS; further studies should investigate the role of TNC levels in predicting the progression of the disease. Full article

Background: The treatment and management of atrial fibrillation poses substantial complexity. A delicate balance in the trade-off between the minimising risk of stroke without increasing the risk of bleeding through anticoagulant optimisations. Natural compounds are often associated with low-toxicity effects, and their effects on atrial fibrillation have yet to be fully understood. Whilst deep learning (a subtype of machine learning that uses multiple layers of artificial neural networks) methods may be useful for drug compound interaction and discovery analysis, graphical processing units (GPUs) are expensive and often required for deep learning. Furthermore, in limited-resource settings, such as low- and middle-income countries, such technology may not be easily available. Objectives: This study aims to discover the presence of any new therapeutic candidates from a large set of natural compounds that may support the future treatment and management of atrial fibrillation anywhere using a low-cost technique. The objective is to develop a deep learning approach under a low-resource setting where suitable high-performance NVIDIA graphics processing units (GPUs) are not available and to apply to atrial fibrillation as a case study. Methods: The primary training dataset is the MINER-DTI dataset from the BIOSNAP collection. It includes 13,741 DTI pairs from DrugBank, 4510 drug compounds, and 2181 protein targets. Deep cross-modal attention modelling was developed and applied. The Database of Useful Decoys (DUD-E) was used to fine-tune the model using contrastive learning. This application and evaluation of the model were performed on the natural compound NPASS 2018 dataset as well as a dataset curated by a clinical pharmacist and a clinical scientist. Results: the new model showed good performance when compared to existing state-of-the-art approaches under low-resource settings in both the validation set (PR AUC: 0.8118 vs. 0.7154) and test set (PR AUC: 0.8134 vs. 0.7206). Tenascin-C (TNC; NPC306696) and deferoxamine (NPC262615) were identified as strong natural compound interactors of the arrhythmogenic targets ADRB1 and HCN1, respectively. A strong natural compound interactor of the bleeding-related target Factor X was also identified as sequoiaflavone (NPC194593). Conclusions: This study presented a new high-performing model under low-resource settings that identified new natural therapeutic candidates for pharmacological cardioversion and anticoagulation. Full article

Background: Proteins with different functions, such as Hepatocyte growth factor activator inhibitor type 1 (HAI-1), Stathmin 1 (STMN-1), and Tenascin C (TN-C), whose activity has been observed in various types of cancers, inspired our study in bladder cancer (BC) patients. The aim of the study was to evaluate selected parameters and their combinations in the diagnosis of BC. The study took into account the degree of invasiveness and malignancy of BC. Based on the analysis of the Receiver Operating Characteristic Curve (ROC), the diagnostic value of single parameters and their combinations as potential indicators of BC was assessed. Patients and Methods: The research material consisted of urine samples from patients with BC, and urine samples from a control group without urological diseases. The concentrations of the examined parameters were measured using an immunoenzymatic method. Results: Statistically significant higher concentrations of HAI-1 (p ≤ 0.001), STMN-1 (≤0.001) and TN-C (0.002) were found in the patients with BC compared to the control group. Strong relationships were shown between these parameters. ROC analyses showed that the best single parameter for detecting BC is STMN-1, and in the combination of HAI-1+STMN-1. The highest diagnostic value was obtained for the combination of HAI-1+STMN-1 in the patients with high malignancy (sensitivity 82%, specificity 91%). Conclusions: Preliminary studies of parameters have shown their utility as potential markers in BC, especially of STMN-1 and combinations HAI-1+STMN-1. However, to learn more about the contribution of these parameters to the progression of bladder cancer, it would be appropriate to continue the studies. 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

To better understand adult neurogenesis, the biomolecular specificity of the subgranular zone should be investigated in comparison to other layers of the hippocampus. Adult neurogenesis occurs at a reduced rate in adulthood compared to the period of development, but it can be increased with exposure to an enriched environment (EE). This can be used to investigate the regulatory role of molecules present in the extracellular matrix, such as tenascin C (TnC). This study, using Synchrotron radiation Fourier Transform Infrared spectroscopy (SR-FTIR), shows that the differences between the hippocampal layers in adolescence are maintained as subtle and significant in adulthood. The main difference in FTIR spectra was observed for nucleic acid and carbohydrate and for the comparison of the subgranular zone (SGZ) with hippocampal CA3. Moreover, we have detected changes in the protein and nucleic acid content of the SGZ that accompany the process of neurogenesis under the influence of an enriched environment. The latter effects are, however, lacking in mice with a gene ablation for tenascin C. Overall, these results show that observed discrete biomolecular differences in hippocampal layers follow the rate of neurogenesis that is enhanced by EE and dependent on TnC. Full article

Background/Objectives: Types I, V, and XI collagen gene variants have been reported to associate with measurements of knee joint laxity and/or absolute knee ligament length changes. Type XII collagen and tenascin C are also ligament structural proteins whose expression is regulated by mechanical loading. This study investigated whether COL12A1 and TNC variants are associated with knee laxity and/or ligament length changes. Methods: Genu recurvatum, anterior–posterior tibial translation, external–internal tibial rotation, and ligament length changes were measured in 128 healthy participants. They were genotyped for COL12A1 (rs970547) and TNC (rs1061494, rs2104772, rs1138545). Results: Both the COL12A1 AA and TNC rs1061494 TT genotypes were associated with decreased external (p = 0.007, p = 0.010) and internal (p = 0.025, p = 0.002) rotation, as well as slack (p = 0.033, p = 0.014), in the dominant leg. Both genotypes, together with sex, weight, and/or COL1A1 genotypes, explained 26% and 32% of the variance in external and internal rotation, respectively. The TNC genotype, sex, and BMI explained 23% of the variance in slack. The COL12A1 AA and the TNC rs1061494 TT genotypes were associated with smaller changes in the MCL (aMCL: COL12A1 p = 0.009, TNC p = 0.045; iMCL: COL12A1 p = 0.004, TNC p = 0.043; pMCL: COL12A1 p = 0.003, TNC p = 0.067; aDMCL: COL12A1 p = 0.007, TNC p = 0.020; pDMCL: COL12A1 p = 0.007, TNC p = 0.023) and/or LCL (COL12A1 p = 0.652, TNC p = 0.049) lengths within the dominant knee. The TNC rs1061494 CC genotype was associated with larger changes in the non-dominant anterior (p = 0.021) and posterior (p < 0.001) ACL bundle lengths. Conclusions: These findings suggest that COL12A1 and TNC variants are associated with internal–external tibial rotation and knee ligament length changes in healthy individuals. Full article

Objective: Liver fibrosis, a hallmark of chronic liver diseases, is characterized by excessive extracellular matrix (ECM) deposition and scar tissue formation. Current antifibrotic nanomedicines face significant limitations, including poor penetration into fibrotic tissue, rapid clearance, and suboptimal therapeutic efficacy. The dense fibrotic ECM acts as a major physiological barrier, necessitating the development of a targeted delivery strategy to achieve effective therapeutic outcomes. Methods: We designed a liposomal delivery system functionalized with the GBI-10 aptamer and encapsulating obeticholic acid (OCA lips@Apt) to enhance selective delivery to fibrotic liver tissue while minimizing systemic toxicity. Results: Both in vitro and in vivo studies demonstrated that the aptamer-modified OCA liposomes effectively treated hepatic fibrosis through dual mechanisms: modulation of abnormal bile acid metabolism and attenuation of inflammation. The targeted delivery system leveraged the overexpression of Tenascin-C (TnC), a key ECM component in fibrotic tissues, for precise localization and enhanced endocytosis via the exposed cationic liposome surface. Conclusions: The OCA lips@Apt nanodrug demonstrated superior therapeutic efficacy with minimal off-target effects, offering a promising strategy to overcome critical barriers in liver fibrosis treatment. By precisely targeting the fibrotic ECM and modulating key pathological pathways, this TnC-guided liposomal delivery system provides a significant advancement in antifibrotic nanomedicine. Full article

Background/Objectives: Tendon structure is predominantly composed of the extracellular matrix (ECM), and genetic variants in non-collagenous ECM components may influence susceptibility to tendinopathy. We investigated the potential influence of single nucleotide polymorphisms (SNPs) in fibrillin-2 (FBN2), tenascin-C (TNC), and matrix metalloproteinase-3 (MMP3) on the tendon regeneration failure phenotype and impact on the susceptibility to tendinopathy in Brazilian high-performance athletes. Methods: This case–control study was conducted with 397 high-performance athletes from different sports modalities (197 tendinopathy cases and 200 controls), and they were analyzed by validated TaqMan^TM SNP genotyping assays of the SNPs FBN2 (rs331079), TNC (rs2104772), and MMP3 (rs591058). Results: Out of the 197 tendinopathy cases, 63% suffered from chronic tendon pain and 22% experienced more than three episodes of disease manifestation. The TNC-rs2104772-A allele was significantly associated with tendinopathy (OR: 1.4; 95% CI: 1.1–1.8), while athletes carrying the MMP3-rs591058-T allele were linked to an increased risk of more episodes of disease manifestation (OR: 1.7; 95% CI: 1.1–2.8). The TNC-MMP3 tendon regeneration failure phenotype (TNC-A/MMP3-T) was associated with an increased risk of tendinopathy (OR: 1.4; 95% CI: 1.1–2.0) and episodes of disease manifestation (OR: 2.0; 95% CI: 1.2–3.5). Athletes with tendinopathy who had the TNC-A/MMP3-T interaction were more prone to experiencing more than three disease exacerbations (OR: 4.3; 95% CI: 1.8–10.5) compared to TNC-A/TNC-C. Conclusions: This study suggests that rs2104772 and rs591058 SNPs could be involved in the tendon regeneration failure phenotype and may influence the molecular mechanism related to the regulation of the tendon ECM during training workload. Full article

In humans, tenascin-C (TN-C) expression has been detected in more aggressive neoplasms of the central nervous system, such as gliomas and meningiomas. No study has analyzed the immune expression of TN-C in canine meningioma. The current study aimed to investigate the immunohistochemical distribution of TN-C in different grades of canine meningiomas. Twenty-one cases of canine meningioma (12 grade I, 6 grade II, and 3 grade III) were analyzed. All samples were examined by immunohistochemistry with the following antibodies: TN-C, epithelial membrane antigen (EMA), Ki-67, pan-cytokeratin (Pan CK), and vimentin. The histopathological diagnosis of meningioma was reinforced with the positive labeling of vimentin (moderate to strong) and EMA (mild to moderate) in neoplastic cells in most cases, independently of its grade or subtype. The immunoreactivity of TN-C was irregular: mild in grade I, moderate in grade II, and moderate to severe in grade III neoplasms. Usually, immune positivity was observed in the stroma and perivascular space in all subtypes. In addition, the concentric whorls of neoplastic cells were labeled positive in some psammomatous and transitional meningiomas. The reaction to TN-C was more significant in grade II and III tumors. The immunohistochemical findings of the current study suggest that TN-C can act as a stromal marker, mainly in grade II or III meningiomas. Full article

The lung is a major dose-limiting organ for radiation therapy (RT) for cancer in the thoracic region, and the clarification of radiation-induced lung damage (RILD) is important. However, there have been few reports containing a detailed comparison of radiographic images with the pathological findings of radiation pneumonitis (RP)/radiation fibrosis (RF). We recently reported the upregulated expression of tenascin-C (TNC), an inflammation-associated extracellular matrix molecule, in surgically resected lung tissue, and elevated serum levels were elevated in a RILD patient. Therefore, we have developed a novel mouse model of partial lung irradiation and studied it with special attention paid to the computed tomography (CT) images and immunohistological findings. The right lungs of mice (BALB/c) were irradiated locally at 30 Gy/1fr, and the following two groups were created. In Group 1, sequential CT was performed to confirm the time-dependent changes in RILD. In Group 2, the CT images and histopathological findings of the lung were compared. RP findings were detected histologically at 16 weeks after irradiation; they were also observed on the CT images from 20 weeks. The immunostaining of TNC was observed before the appearance of RP on the CT images. The findings suggest that TNC could be an inflammatory marker preceding lung fibrosis. Full article

Background: We tested whether gene polymorphisms for angiotensin-converting enzyme (ACE, rs1799752) and tenascin-C (TNC, rs2104772) are associated with variability in fatigue resistance and metabolic strain during static lumbar exercise through interactions with chronic nonspecific lower back pain and habitual physical exercise levels (PA). Methods: Forty-eight patients and matched controls performed an isometric endurance test for lumbar extensors. Metabolic strain to longissimus muscle (oxygen saturation, lactate) and cardiovascular system (muscle hemoglobin, blood pressure) and holding time were monitored. Subjects were genotyped for rs1799752 (II, ID, DD) and rs2104772 (AA, AT, TT). Associations of variance with group, genotype, and PA were analyzed under a 5% false discovery rate. Results: The holding time was lower in patients than in controls (150.9 vs. 188.6 s). This difference was associated with both genotypes, as patients with DD-rs1799752-genotype (p = 0.007) and TT-rs2104772-genotype (p = 0.041) showed lower fatigue resistance. Muscle deoxygenation during exercise varied in positive association with the rs2104772-genotype and PA (p = 0.010, η2 = 0.236). Mean arterial blood pressure (p = 0.028, η2 = 0.108) and recovery of hemoglobin concentration (p = 0.003, η2 = 0.907) demonstrated complex group x rs2104772 interactions. Conclusions: Polymorphisms rs1799752 and rs2104772 influence back pain-related variability in lumbar fatigue resistance. rs2104772 was linked to cardiovascular strain during isometric exercise and recovery via muscle perfusion. Full article

Neuronal plasticity is a crucial mechanism for an adapting nervous system to change. It is shown to be regulated by perineuronal nets (PNNs), the condensed forms of the extracellular matrix (ECM) around neuronal bodies. By assessing the changes in the number, intensity, and structure of PNNs, the ultrastructure of the PNN mesh, and the expression of inhibitory and excitatory synaptic inputs on these neurons, we aimed to clarify the role of an ECM glycoprotein, tenascin-C (TnC), in the dorsal hippocampus. To enhance neuronal plasticity, TnC-deficient (TnC-/-) and wild-type (TnC+/+) young adult male mice were reared in an enriched environment (EE) for 8 weeks. Deletion of TnC in TnC-/- mice showed an ultrastructural reduction of the PNN mesh and an increased inhibitory input in the dentate gyrus (DG), and an increase in the number of PNNs with a rise in the inhibitory input in the CA2 region. EE induced an increased inhibitory input in the CA2, CA3, and DG regions; in DG, the change was also followed by an increased intensity of PNNs. No changes in PNNs or synaptic expression were found in the CA1 region. We conclude that the DG and CA2 regions emerged as focal points of alterations in PNNs and synaptogenesis with EE as mediated by TnC. Full article

One of the extracellular matrix proteins, tenascin-C (TN-C), is known to be upregulated in age-related inflammatory diseases such as cancer and cardiovascular diseases. Expression of this molecule is frequently detected, especially in the macrophage-rich areas of atherosclerotic lesions; however, the role of TN-C in mechanisms underlying the progression of atherosclerosis remains obscure. Previously, we found a hidden bioactive sequence termed TNIIIA2 in the TN-C molecule and reported that the exposure of this sequence would be carried out through limited digestion of TN-C by inflammatory proteases. Thus, we hypothesized that some pro-atherosclerotic phenotypes might be elicited from macrophages when they were stimulated by TNIIIA2. In this study, TNIIIA2 showed the ability to accelerate intracellular lipid accumulation in macrophages. In this experimental condition, an elevation of phagocytic activity was observed, accompanied by a decrease in the expression of transporters responsible for lipid efflux. All these observations were mediated through the induction of excessive β1-integrin activation, which is a characteristic property of the TNIIIA2 sequence. Finally, we demonstrated that the injection of a drug that targets TNIIIA2’s bioactivity could rescue mice from atherosclerotic plaque expansion. From these observations, it was shown that TN-C works as a pro-atherosclerotic molecule through an internal TNIIIA2 sequence. The possible advantages of clinical strategies targeting TNIIIA2 are also indicated. Full article

Tenascin-C (TNC) is a complex glycoprotein of the extracellular matrix (ECM) involved in a plethora of (patho-)physiological processes, such as oncogenesis and inflammation. Since chemokines play an essential role in both disease processes, we have investigated here the binding of TNC to some of the key chemokines, namely CCL2, CCL26, CXCL8, CXCL10, and CXCL12. Thereby, a differential chemokine-TNC binding pattern was observed, with CCL26 exhibiting the highest and CCL2 the lowest affinity for TNC. Heparan sulfate (HS), another member of the ECM, proved to be a similarly high-affinity ligand of TNC, with a Kd value of 730 nM. Chemokines use glycosa-minoglycans such as HS as co-receptors to induce immune cell migration. Therefore, we assumed an influence of TNC on immune cell chemotaxis due to co-localization within the ECM. CCL26- and CCL2-induced mobilization experiments of eosinophils and monocytes, respectively, were thus performed in the presence and the absence of TNC. Pre-incubation of the immune cells with TNC resulted in a 3.5-fold increase of CCL26-induced eosinophil chemotaxis, whereas a 1.3-fold de-crease in chemotaxis was observed when monocytes were pre-incubated with CCL2. As both chemokines have similar HS binding but different TNC binding affinities, we speculate that TNC acts as an attenuator in monocyte and as an amplifier in eosinophil mobilization by impeding CCL2 from binding to HS on the one hand, and by reinforcing CCL26 to bind to HS on the other hand. Full article

Adverse ventricular remodeling after myocardial infarction (MI) is progressive ventricular dilatation associated with heart failure for weeks or months and is currently regarded as the most critical sequela of MI. It is explained by inadequate tissue repair due to dysregulated inflammation during the acute stage; however, its pathophysiology remains unclear. Tenascin-C (TNC), an original member of the matricellular protein family, is highly up-regulated in the acute stage after MI, and a high peak in its serum level predicts an increased risk of adverse ventricular remodeling in the chronic stage. Experimental TNC-deficient or -overexpressing mouse models have suggested the diverse functions of TNC, particularly its pro-inflammatory effects on macrophages. The present study investigated the roles of TNC during human myocardial repair. We initially categorized the healing process into four phases: inflammatory, granulation, fibrogenic, and scar phases. We then immunohistochemically examined human autopsy samples at the different stages after MI and performed detailed mapping of TNC in human myocardial repair with a focus on lymphangiogenesis, the role of which has recently been attracting increasing attention as a mechanism to resolve inflammation. The direct effects of TNC on human lymphatic endothelial cells were also assessed by RNA sequencing. The results obtained support the potential roles of TNC in the regulation of macrophages, sprouting angiogenesis, the recruitment of myofibroblasts, and the early formation of collagen fibrils during the inflammatory phase to the early granulation phase of human MI. Lymphangiogenesis was observed after the expression of TNC was down-regulated. In vitro results revealed that TNC modestly down-regulated genes related to nuclear division, cell division, and cell migration in lymphatic endothelial cells, suggesting its inhibitory effects on lymphatic endothelial cells. The present results indicate that TNC induces prolonged over-inflammation by suppressing lymphangiogenesis, which may be one of the mechanisms underlying adverse post-infarct remodeling. Full article