Search Results (386)

Osteoarthritis (OA) is a chronic, debilitating degenerative joint disease whose prevalence is rising markedly with the rapid aging of the global population. In this study, we investigated the chondroprotective efficacy of NP-2007, an enzymatically hydrolyzed low-molecular-weight collagen from Cervi cornu, using IL-1β-stimulated SW1353 human chondrocyte cells and a medial meniscal transection (MMT)-induced OA rat model. In SW1353 cells, NP-2007 considerably suppressed the expression of inflammatory mediators (iNOS, COX-2) and cytokines (TNF-α, IL-6) without cytotoxicity. Crucially, it restored matrix homeostasis by downregulating catabolic enzymes (MMP-3, MMP-13, and ADAMTS-5) and upregulating anabolic markers (COL2A1, aggrecan), a process associated with the modulation of the Wnt/β-catenin and phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathways and the recovery of the master chondrogenic factor SOX9. These in vitro findings were consistent with the in vivo results from the MMT model, where oral administration of NP-2007 (50 and 200 mg/kg) for 8 weeks effectively preserved articular cartilage structure and proteoglycan content while markedly reducing serum levels of catabolic biomarkers, including MMP-13 and COMP. Collectively, our findings demonstrate that NP-2007 exerts potent chondroprotective effects by modulating the balance between cartilage degradation and synthesis, suggesting its potential as a therapeutic candidate for the management of OA. Full article

Background/Objectives: Therapeutic plasma exchange (TPE) is an extracorporeal treatment used in thrombotic microangiopathies (TMAs) and various autoimmune and neurological disorders. However, data regarding its use during early pregnancy remain limited. This study aimed to evaluate maternal laboratory response and perinatal outcomes in pregnant women who underwent TPE before 26 weeks of gestation. Methods: This retrospective case series included 10 pregnant women diagnosed before 26 weeks of gestation who underwent TPE between 2010 and 2023. Clinical and laboratory parameters before and after TPE were compared. Results: Indications for TPE included HELLP syndrome (n = 4), thrombotic thrombocytopenic purpura (n = 3), presumed atypical haemolytic uremic syndrome (n = 1), neuromyelitis optica (n = 1), and Guillain–Barré syndrome (n = 1). The mean gestational age at diagnosis was 22.1 ± 3.1 weeks, and the mean gestational age at delivery was 27.1 ± 6.9 weeks. Five fetuses (50%) died and five (50%) survived to discharge. In patients with TMAs, TPE was associated with significant decreases in LDH, INR, APTT, ALT, AST, and total bilirubin levels, along with a significant increase in platelet count and ADAMTS13 activity (p < 0.01). No maternal complications occurred in neurological cases, all of which resulted in term deliveries with healthy neonates. Conclusions: In this uncontrolled case series, TPE was associated with rapid maternal clinical and laboratory improvement in selected pregnant women with TMAs, although a causal effect cannot be established from these data. However, perinatal outcomes were primarily determined by gestational age at delivery: all fetal losses occurred before 26 weeks, whereas all infants survived when delivery occurred after 26 weeks. Larger studies are needed to confirm these findings. Full article

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by persistent low-grade inflammation and progressive cartilage destruction. Macrophage-driven inflammatory responses contribute to extracellular matrix (ECM) degradation and accelerate disease progression. Here, we investigated the therapeutic potential of a DHA-derived lipid mediator mixture (LM), generated via soybean lipoxygenase and composed of 17S-hydroxydocosahexaenoic acid, resolvin D5, and protectin DX (3:47:50), in regulating macrophage–chondrocyte crosstalk and OA progression. LM significantly reduced IL-6, IL-1β, and TNF-α production in lipopolysaccharide-induced THP-1 macrophages. Conditioned medium from LM-treated macrophages attenuated ECM degradation in primary chondrocytes by suppressing MMP13 and ADAMTS5 while restoring COL2A1 and ACAN expression, indicating that LM may indirectly protects ECM by modulating the inflammatory microenvironment. In parallel, LM directly protected chondrocytes against IL-1β-induced inflammatory and catabolic responses, and restored ECM homeostasis. Mechanistically, LM significantly increased SIRT1 expression and deacetylation activity, as demonstrated by reduced NF-κB p65 acetylation. Both pharmacological inhibition by EX527 and siRNA-mediated SIRT1 knockdown abolished the protective effects of LM on ECM preservation. In vivo, LM oral administration alleviated cartilage destruction, improved joint structure and suppressed OA progression in a monosodium iodoacetate-induced OA model. Notably, micro-CT studies have demonstrated that LM significantly improved subchondral bone architecture, as evidenced by increased bone volume fraction and improved trabecular parameters. Histological analyses confirmed that LM attenuated inflammation and maintained cartilage integrity. Consistently, immunohistochemical findings showed reduced MMP13 expression, restoration of collagen II and aggrecan, and upregulation of SIRT1 in the LM-treated group compared to OA rats. Collectively, these findings suggest that LM mitigates OA progression by reducing inflammation, preserving ECM homeostasis, and attenuating subchondral bone deterioration. Full article

Osteoarthritis (OA) is a highly prevalent joint disorder traditionally considered a consequence of mechanical cartilage wear; however, it is now recognized as a complex, multifactorial disease driven by interconnected molecular and cellular mechanisms. This narrative review synthesizes current knowledge on key pathogenic pathways underlying OA progression, with a focus on inflammatory signaling, subchondral bone remodeling, and dysregulation of mineral metabolism. Chronic low-grade inflammation promotes catabolic responses in chondrocytes and contributes to cartilage degradation. In addition, obesity influences OA pathogenesis through both biomechanical loading and adipokine-mediated inflammatory mechanisms. Alterations in the receptor activator of nuclear factor kappa-B/receptor activator of nuclear factor kappa-B ligand/osteoprotegerin (RANK/RANKL/OPG) axis disrupt bone homeostasis and promote pathological subchondral remodeling, while imbalances in inorganic phosphate metabolism contribute to crystal deposition and further joint damage. These processes interact synergistically, driving disease progression. Current therapeutic strategies remain largely symptomatic and do not adequately target underlying molecular drivers. A deeper understanding of these mechanisms may facilitate the development of disease-modifying therapies. Full article

Background: Yes-associated protein 1 (YAP1), a key effector of the Hippo signaling pathway and mechanosensitive transcriptional coactivator, plays a complex role in osteoarthritis (OA) and cartilage regeneration. While YAP1 is essential for tissue homeostasis, its dysregulation has been implicated in both inflammatory and degenerative joint pathologies. However, its precise function remains ambiguous. Methods: We silenced YAP1 with small interfering RNA (siYAP1) in two human-cell-based models relevant to OA pathogenesis and cartilage repair: (1) IL-1β (10 ng/mL)-stimulated articular chondrocytes in monolayer and pellet cultures, and (2) TGF-β1 (10 ng/mL)-induced chondrogenesis in MSC pellet cultures. Outcome measures comprised YAP1 nuclear localization; inflammatory/catabolic markers in chondrocytes (IL6, IL8, ADAMTS5, MMP13); and, in MSC pellets, chondrogenic or hypertrophic markers (COL2A1, ACAN, RUNX2, MMP13, COL10A1) together with glycosaminoglycan (GAG) deposition. Statistical significance was assessed using an ANOVA or Friedman test with post hoc correction (Tukey or Dunn’s test, respectively); p < 0.05 was considered significant. Results: In human chondrocytes, siYAP1 reduced IL-1β-induced nuclear YAP1 localization and suppressed pro-inflammatory mediators IL6 and IL8, indicating an anti-inflammatory effect. YAP1 silencing also downregulated ADAMTS5 expression in 2D monolayers but not in 3D pellet cultures, suggesting reduced regulatory influence in the three-dimensional environment. Notably, MMP13 expression was paradoxically increased following YAP1 knockdown, underscoring the complexity of YAP1’s role in catabolic regulation. In MSC chondrogenesis, siYAP1 enhanced TGF-β1-induced chondrogenesis by increasing COL2A1 and ACAN expression and promoting GAG deposition on day 21. Additionally, it reduced hypertrophic markers RUNX2 and MMP13 on day 7, though COL10A1 remained elevated compared to negative siRNA, indicating only partial suppression of hypertrophic differentiation. Nuclear YAP1 levels were increased by day 21 despite reduced mRNA, suggesting post-transcriptional regulation or enhanced nuclear translocation. Conclusions: These findings demonstrate that YAP1 knockdown exerts context-specific anti-inflammatory and pro-chondrogenic effects while partially mitigating hypertrophy. However, divergent outcomes, namely elevated MMP13 in chondrocytes and upregulated COL10A1 in MSCs, indicate that YAP1 silencing does not uniformly suppress inflammation or hypertrophy. YAP1 represents a potential therapeutic target for OA, but its modulation requires careful consideration of cellular context, siRNA delivery method, and timing to optimize outcomes for cartilage repair and joint preservation. Full article

This review aims to provide a comprehensive and integrative evaluation of the therapeutic potential of curcumin in arthritis, focusing on its molecular mechanisms, preclinical evidence, and clinical applications. A systematic literature search was conducted across major databases, and a total of 165 studies were included in this review. Curcumin exerts multi-target effects on key pathogenic pathways involved in arthritis. At the molecular level, it inhibits inflammatory signaling pathways, particularly NF-κB, and reduces the production of pro-inflammatory mediators, including TNF-α, IL-1β, IL-6, COX-2, and PGE2. In parallel, curcumin modulates oxidative stress by enhancing antioxidant defenses, including superoxide dismutase (SOD) and glutathione (GSH), while reducing lipid peroxidation. It also regulates cell death pathways, including apoptosis, autophagy, and emerging mechanisms such as pyroptosis and ferroptosis, and preserves cartilage integrity by inhibiting matrix metalloproteinases and ADAMTS while promoting extracellular matrix components. Preclinical studies consistently demonstrate anti-inflammatory, antioxidant, and chondroprotective effects across in vitro and animal models. Clinical evidence, particularly in osteoarthritis, indicates improvements in pain and functional outcomes, with some studies suggesting efficacy comparable to nonsteroidal anti-inflammatory drugs. However, this evidence remains limited and should be interpreted with caution. However, variability in formulations and limited bioavailability remain key challenges influencing clinical outcomes. Overall, curcumin represents a promising multi-target therapeutic agent for arthritis. Further large-scale, well-designed randomized controlled trials using standardized and bioavailable formulations are required to confirm its efficacy and optimize its clinical application. Full article

Background/Objectives: Keratoconus is a corneal disorder that causes thinning and bulging of the cornea, resulting in astigmatism and other refractive errors. Mechanical effects and environmental factors are known to exacerbate the disease, and genetic predisposition plays a significant role in its development. Methods: This study investigated the presence of genetic variants in 32 keratoconus patients. We used a next-generation sequencing-based method, and variant interpretation was performed according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Variants were prioritized based on multiple criteria, including population frequency data from the Genome Aggregation Database (gnomAD) (minor allele frequency < 1%), variant type and predicted functional effect, gene–disease association, inheritance pattern, phenotypic relevance, and in silico prediction tools. Results: Thirteen variants were identified in 11 patients (34.3%). Two patients carried variants in two different genes, raising the possibility of oligogenic contributions. Ten variants (76.9%) were novel. The variants were detected in 12 genes, namely ADAMTS18, BEST1, CHST6, COL17A1, CYP1B1, KRT3, PAX6, SLC4A11, TACSTD2, UBIAD1, VSX1, and ZNF469. No association was observed between detected variants and patient age. Conclusions: Our findings demonstrate a substantial proportion of novel variants and support the genetic heterogeneity of keratoconus, while also raising the possibility of oligogenic contributions in a subset of patients. Full article

Osteoarthritis (OA) remains an alarming therapeutic challenge, as conventional intra-articular interventions primarily address symptomatic relief without halting progressive cartilage and bone degeneration. In this study, we investigated the disease-modifying potential of Cyclo(His-Pro) (CHP) in a monosodium iodoacetate (MIA)-induced OA rat model. Intra-articular CHP yielded significant clinical improvements, reducing joint edema and reversing OA-induced mechanical and thermal hypersensitivity, as evidenced by lifting behavior, rotarod performance, and hot plate tests. Beyond analgesia, micro-computed tomography (micro-CT) analysis showed that CHP preserved subchondral bone architecture, restoring trabecular volume and thickness and reducing serum C-terminal telopeptide of type II collagen (CTX-2), indicative of suppressed cartilage degradation. At the molecular level, CHP reprogrammed the joint microenvironment by suppressing Cox2, Adamts5, Mmp13, Mmp1, Mmp2, and Timp2 expression and decreasing systemic prostaglandin E2 (PGE₂) levels. Moreover, CHP showed efficacy comparable to Conjuran, a polynucleotide-based mechanical supportive agent, while additionally targeting COX-2/PGE₂-driven inflammatory cascades and cartilage catabolic pathways. Collectively, these findings indicate that intra-articular CHP confers combined analgesic, chondroprotective, and osteoprotective effects, supporting its potential as a promising disease-modifying osteoarthritis drug candidate. Full article

Upshaw–Schulman syndrome (USS) is a rare inherited autosomal recessive thrombotic microangiopathy affecting less than 1/1,000,000 individuals. It is a congenital form of thrombotic thrombocytopenic purpura (TTP) caused by ADAMTS13 protease deficiency because of mutations in the ADAMTS13 gene. USS is characterized by the formation of platelet thrombi in the microcirculation, accompanied by hemolytic anemia, thrombocytopenia, and clinical and laboratory signs of renal and neurological failure. The aim of this study was to describe the ADAMTS13 gene mutation spectrum in the Russian population. We analyzed the ADAMTS13 gene in 45 unrelated patients with TTP of unknown origin. DNA was extracted from blood cells using the phenol-chlorophorm method, and all exons of the gene were investigated using Sanger sequencing. In 15 out of 45 patients, we identified 20 different variants associated with USS, including two frameshift, two variants affecting the splice site, one nonsense and fifteen missense mutations. Eight out of those mutations were previously undescribed. Tree variants were revealed more than once: p.Arg1060Trp (7 patients), p.Glu1326ArgfsTer6 (7 patients) and p.Cys1067SerfsTer30 (3 patients). Variants (p.Arg1060Trp) and p.Glu1326ArgfsTer6 prevailed in the global population; however, p.Cys1067SerfsTer30 was not previously described in the European population. Our results expand the existing knowledge of the molecular basis of USS and may contribute to improved genetic diagnostics in Russia. Full article

Background/Objectives: Traditional breast cancer prognostic tools relying on clinical staging often miss molecular heterogeneity, leading to divergent patient outcomes. Extracellular matrix (ECM) remodeling, driven by the Matrix Metalloproteinase (MMP), ADAM, and ADAMTS enzyme families, is critical to tumor progression. This study evaluates whether integrating ECM protease transcript abundance with standard clinical variables improves survival prediction accuracy and personalized risk stratification. Methods: Clinical and transcriptomic data from The Cancer Genome Atlas (TCGA) breast cancer cohort were analyzed. We integrated the protein-coding transcripts per million (pTPM) of top-ranked protease genes with standard clinical covariates (age, ordinal stage). Cox Proportional Hazards (CoxPH), penalized Cox (CoxNet), Random Survival Forest (RSF), and Gradient Boosting Survival (GBS) models were evaluated under a stratified 70/30 train–test split, followed by five-fold cross-validation. The locked final RSF model was then externally tested in METABRIC without retraining or risk-cutoff optimization. Results: Univariate screening identified ADAM15, MMP15, and ADAMTSL1 as global risk factors, whereas ADAMTS8 and MMP7 were protective. Prognostic signals were subtype-dependent. Integrated multivariable models outperformed transcript-only approaches in internal testing. The integrative RSF achieved the highest held-out discrimination (C-index = 0.797), outperforming a clinical-only Cox baseline trained on age and stage alone (C-index = 0.742, 95% CI 0.636–0.826). In METABRIC, the external C-index was 0.581 (95% CI 0.562–0.598), with significant survival separation across training-defined risk groups (log-rank p < 0.0001). Conclusions: ECM protease transcript profiles provide complementary prognostic information in TCGA-BRCA and show partial transportability to METABRIC. However, the modest external C-index indicates limited individual-level discrimination across platforms, so these candidate markers should be interpreted as hypothesis-generating and require further validation before clinical implementation. Full article

Background: ADAMTS13 is a protein that cleaves large multimers of von Willebrand factor, thereby limiting platelet aggregation and adhesion and regulating thrombogenesis. Research findings suggest a possible association between low ADAMTS13 levels and an increased risk of cardiovascular events, and its activity may be influenced by polymorphic variants of the ADAMTS13 gene. Methods: The study group included 259 patients diagnosed with coronary artery disease (CAD) and 238 control blood donors. Genotyping of ADAMTS13 polymorphisms (rs2301612, rs2073932, and rs2285489) was performed using TaqMan PCR. Results: ADAMTS13 gene polymorphisms showed no association with CAD risk or patient survival at 5- or 10-year follow-up. However, higher HDL cholesterol levels were observed in carriers of the G alleles (rs2301612 and rs2073932) and the T allele (rs2285489). Additionally, the rs2285489 and rs2301612 polymorphisms were associated with certain proatherogenic lipid indices. In silico analysis indicated that all studied polymorphisms influenced gene expression in certain vascular tissues or blood. Conclusions: ADAMTS13 gene polymorphisms may affect gene expression in specific tissues; however, this effect does not appear sufficient to meaningfully influence CAD onset or patient survival. A significant association between the analyzed polymorphisms and HDL levels or some proatherogenic lipid indices was observed; however, the underlying mechanism requires further investigation. Full article

Background: Intervertebral disc degeneration (IVDD) is driven by the interplay between inflammatory signaling, extracellular matrix (ECM) degradation, and impaired cellular adaptation. Although several nutraceutical compounds have been reported to exert protective effects in IVDD-related models, their multitarget mechanisms within integrated molecular networks remain incompletely characterized. Methods: An in silico framework integrating molecular docking with network-based analyses was employed to evaluate resveratrol, quercetin, melatonin, curcumin, and baicalein against a predefined panel of IVDD-associated targets, within an exploratory in silico framework. Binding affinities and interaction profiles were assessed using molecular docking, followed by protein–protein interaction (PPI) network construction, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and hub gene identification. Results: Docking analyses revealed binding energies ranging from −4.59 to −13.25 kcal/mol, with curcumin and quercetin showing plausible docking poses across a subset of selected targets under the applied protocol. Network analysis showed a highly interconnected structure centered on key inflammatory regulators, including NFKB1, IL6, TNF, IL1B, STAT3, and NLRP3, together with ECM-associated components such as ACAN, COL2A1, SOX9, MMP13, and ADAMTS5. Enrichment analyses further suggested significant associations with inflammatory signaling pathways, cytokine regulation, and ECM organization. Conclusions: These findings are compatible with a distributed, multitarget interaction pattern of nutraceutical compounds within IVDD-associated molecular networks. By integrating molecular docking with network-based analyses, this study offers a system-level framework for interpreting previously reported effects within a disease-specific context. Docking-derived interaction patterns should be interpreted as qualitative and exploratory observations, as docking scores represent model-dependent estimates and do not establish comparable pharmacological effects across heterogeneous targets. The results should be considered hypothesis-generating and require experimental validation. Full article

Maternal infection (MI) can increase the risk of neurodevelopmental and behavioural changes. This study examined MI-induced changes in motor coordination through the inflammatory-pathway-mediated epigenetic status of Reln. On gestational day (GD) 10, rats were assigned as (i) Control (Ctrl); (ii) Cronobacter sakazakii (CS) infection on GD-10 through recto-vaginal colonization; (iii) Negative Control (NC) [infected with C. sakazakii and treated with dimethyl sulfoxide (DMSO) 1 h before and 24 h after infection]; and (iv) C. sakazakii-infected rats treated with matrix metalloproteinase inhibitor (MMPI), 1 h before and 24 h after infection (CS + MMPI). Offspring were subjected to footprint analysis and the ladder rung walking test, which revealed that MI caused significant deficits in motor coordination. In addition, MI activated complement components—a disintegrin and metalloproteinase with thrombospondin motifs-1 (ADAMTS-1, C5a)—as well as proinflammatory cytokines such as interleukin-6 (IL-6) and matrix metalloproteinases (MMP-2, MMP-3, and MMP-9). Furthermore, the levels of DNA methyltransferase 3 alpha (DNMT3A), methyl-CpG-binding protein 2 (MeCP2), and histone H3 lysine 4 trimethylation (H3K4me3) were elevated in the CS and NC groups. Concurrently, the level of Reln promoter methylation increased; as a result, mRNA and protein, as well as postsynaptic density protein-95 (PSD-95), levels were decreased. Overall, the findings suggest that MI altered MMP-2/3/9 activity, H3K4me3, and the methylation of Reln, thereby affecting reelin, synaptic protein expression, and motor coordination in an experimental meningitis rat model. Full article

Ovarian function relies on a network of well-coordinated molecular mechanisms that regulate follicular development, oocyte maturation, ovulation, and corpus luteum function. When these processes are disrupted, infertility can result. Extracellular matrix (ECM) remodeling represents a central regulatory component in these processes and is essential for follicle rupture and oocyte release. This mechanism involves metalloproteinases (MMPs), mainly MMP-2 and MMP-9, which degrade the ECM and allow the necessary structural changes. Other ECM-modulating proteases, such as ADAM and ADAMTS families, also contribute to this process. Their activity is tightly regulated by tissue inhibitors of metalloproteinases (TIMPs), ensuring that tissue remodeling occurs in a controlled manner. Disruption of the balance between MMPs and TIMPs increases the risk of infertility-related conditions such as polycystic ovary syndrome (PCOS), endometriosis, luteinizing hormone (LH) deficiency syndrome, and ovarian aging. In addition to the ECM, other factors, including intracellular signaling pathways, oxidative stress (OS), and mitochondrial function, contribute to ovarian physiology and directly affect oocyte quality and viability. This narrative review focuses on the molecular mechanisms governing ovarian function, with particular emphasis on the remodeling of the ECM by MMPs during ovulation, and examines how their disorders contribute to infertility. A deeper understanding of these mechanisms may lead to the identification of new therapeutic targets and the improvement of assisted reproduction outcomes. Full article

Temporomandibular joint osteoarthritis (TMJOA) is a degenerative maxillofacial disorder marked by progressive cartilage degradation and subchondral bone resorption, severely compromising patients’ quality of life. Intra-articular injection (IA), a standard route for conservative therapy, offers clinical advantages in safety and efficacy; however, outcomes remain limited due to short drug retention, poor tissue penetration, and variable agent efficacy, necessitating repeated administration. To overcome these limitations, fisetin-loaded poly (lactic-co-glycolic acid) nanoparticles (FST-PNP) were developed as a localized drug delivery system (DDS) for TMJOA treatment. Physicochemical analyses showed FST-PNP had uniform spherical morphology, excellent dispersibility, stability, high encapsulation efficiency, and substantial drug loading capacity. An in vitro study demonstrated more sustained and stable release from FST-PNP than free fisetin. The in vivo IA administration of FST-PNP preserved mandibular condylar osteochondral structures in TMJOA models. Notably, FST-PNP suppressed the expression of metalloproteinase-13 and a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS5) as catabolic enzymes and downregulated p16 and p21 as senescence markers, indicating synergistic anti-inflammatory and anti-senescent effects. These findings highlight FST-PNP as a DDS integrating controlled-release with multifaceted therapeutic actions, providing a promising strategy for IA therapy of TMJOA. Full article