Search Results (8,800)

Hyaluronan (HA) is a ubiquitous extracellular matrix (ECM) component that is gaining significant attention for its diverse roles in cell signalling and disease. The biological functions of HA are dependent on its molecular weight (M_w): low M_w polysaccharide chains drive stimulatory processes such as inflammation and angiogenesis, whereas high M_w HA is stabilising and anti-inflammatory. Growing evidence indicates that HA is integral to brain function. The composition of HA in the brain is regulated by the balance of enzymatic synthesis and degradation, mediated by different isoforms of hyaluronan synthase (HAS) and hyaluronidase (HYAL) respectively. Fluctuating expression of the genes encoding the HAS and HYAL enzymes has been implicated in neuropathology and ageing, with some studies providing evidence towards epigenetic regulation of these genes. The regulatory environment of the brain confers a unique balance of enhanced protection alongside the requirement for maximum flexibility. This scoping review focuses on summarising current knowledge regarding epigenetic regulation of HAS and HYAL genes in neural contexts, as well as identifying gaps in knowledge against which future research can be directed. Understanding how these genes are regulated, particularly through epigenetic mechanisms, provides insight into how HA is regulated in the brain, facilitating understanding regarding its function in brain health and disease. Full article

Dynamic knowledge representation in curved manifolds conventionally relies on integer-order Markovian sequence encoders, intrinsically yielding exponential memory decay. This paradigm fails to model the anomalous diffusion and heavy-tailed historical dependencies inherent in complex evolutionary networks and dense physical environments. This manuscript proposes the Fractional–Temporal Lorentz Graph Convolutional Network (FTL-GCN), formalizing temporal evolution as a continuous fractional geometric flow explicitly defined on the tangent bundle of the Lorentz manifold. Analytical derivations demonstrate that the discrete Grünwald–Letnikov memory kernel establishes a non-exponential, power-law lower bound for historical state retention, preventing topological manifold collapse over extended temporal horizons. Empirical evaluations demonstrate that FTL-GCN achieves competitive forecasting accuracy against the latest 2025–2026 state-of-the-art discrete models within specific temporal windows, while uniquely mitigating predictive degradation by up to 52% in long-horizon dependency stress tests and maintaining sub-millisecond latency for physical control. The architecture is subsequently deployed within an in silico biophysical simulation for autonomous micro–nano robotic navigation in the Tumor Microenvironment (TME). By establishing a physical-mathematical structural analogy—mapping the empirical fractional viscoelasticity of the extracellular matrix to the cognitive network’s fractional derivative order—FTL-GCN sustains continuous-space navigation policies in dense anomalous environments where standard integer-order models experience mechanical slip. Full article

Skin aging is driven by both intrinsic and extrinsic factors, including ultraviolet (UV) radiation and environmental stressors. Tumor necrosis factor-alpha (TNF-α) is a key pro-aging cytokine that promotes reactive oxygen species (ROS) production, leading to collagen degradation and inflammatory responses in skin cells. In this study, we investigated the protective effects of Prunus persica flower extract and its major constituents (1–4) against TNF-α–induced oxidative and inflammatory responses in human dermal fibroblasts (HDFs) and human epidermal keratinocytes (HEKs). In HDFs, the extract and isolated compounds significantly suppressed TNF-α–induced ROS generation and matrix metalloproteinase-1 (MMP-1) secretion while enhancing collagen synthesis. Notably, mandelamide (4) markedly reduced MMP-1 secretion (from 7.53 ± 0.28 to 2.97 ± 0.12, p < 0.001) and restored collagen levels (from 3.3 ± 0.03 to 19.1 ± 0.58, p < 0.001). In HEKs, mandelamide attenuated the production of inflammatory mediators under TNF-α stimulation and further suppressed MMP expression while restoring the mRNA expression of hyaluronan synthase genes under TNF-α/ interferon-γ (IFN-γ) co-stimulation. Importantly, mandelamide exhibited selective activity under inflammatory conditions without affecting basal cellular states. Collectively, these findings demonstrate that mandelamide is a key bioactive constituent of Prunus persica (P. persica) flowers and exerts protective effects against inflammation-associated skin aging through the modulation of oxidative stress and extracellular matrix homeostasis. Full article

Mulibrey nanism is a rare autosomal recessive multisystem disorder caused by biallelic loss of function variants in TRIM37 encoding a peroxisomal E3 ubiquitin ligase. Initially described in Finland, where it remains most prevalent due to a founder mutation, the condition is now recognized worldwide and is characterized by severe prenatal-onset growth failure, distinctive craniofacial features, radiological abnormalities, ocular findings, and hepatopathy. Although its clinical spectrum extends far beyond these core manifestations, the major determinant of morbidity and mortality is progressive cardiovascular disease, including constrictive pericarditis and restrictive cardiomyopathy. Additional features include metabolic dysfunction such as insulin resistance and type 2 diabetes, gonadal insufficiency, skeletal abnormalities including fibrous dysplasia, and an increased risk of benign and malignant tumours. The clinical course evolves across the lifespan from early growth and developmental abnormalities to progressive multisystem disease in adolescence and adulthood. Recent advances have expanded understanding of TRIM37 function, linking it to mTORC1 TFEB signalling autophagy, centrosome integrity, extracellular matrix regulation, and immune cell function, providing mechanistic insights into tumour predisposition, skeletal pathology, and immune dysregulation. Management remains supportive and requires multidisciplinary care with emphasis on early recognition and treatment of cardiac disease, metabolic complications, and malignancy risk. Prognosis is variable but improves with early diagnosis and appropriate surveillance. This review summarises the clinical spectrum molecular mechanisms and current management of Mulibrey nanism and highlights priorities for future research. Full article

Gelatin–alginate composite hydrogels are some of the most prevalent bioinks used for extrusion-based three-dimensional (3D) bioprinting because of their combined bioactivity and ability to ionically crosslink. Ionically crosslinked gelatin–alginate constructs containing human bone marrow–derived mesenchymal stem cells (hBM-MSCs) were characterised over time under standardised in vitro conditions to assess physicochemical properties and resultant cell behaviour. Water uptake and degradation were quantified over time in phosphate-buffered saline (PBS) and collagenase type II media for up to 21 days. Cell viability and metabolic activity were quantified, and osteogenic gene expression (RUNX2, COL1A1, OCN) was assessed. Raman spectroscopy and compressive mechanical characterisation were performed. Collagen and glycosaminoglycan-related peaks were observed from extracellular matrix (ECM)-associated components, with an increased presence of protein-associated signatures later in culture. Hydrogels displayed nonlinear elastic behaviour with increased stress after longer incubation times, suggesting no degradation of mechanical integrity over the duration of the study. Hydrogels experienced rapid hydration followed by decreased swelling over time, with a maximum swelling ratio at 24 h. Degradation rates significantly increased over longer incubation times (p < 0.001) and in collagenase media compared to PBS (p < 0.001). Observed differences were likely due to both ion-exchange-mediated network disassembly and the dissolution of gelatin components. Cell metabolic activity decreased under osteogenic culture conditions, while changes in osteogenic marker expression were sequential, suggesting a transition from proliferation to early osteogenic commitment in this 3D system. This work provides both physicochemical and biological characterisation of a commonly utilised gelatin–alginate bioink system, to provide future optimisations within the field of extrusion-based bone tissue engineering, a reproducible baseline for future optimisation of bioink systems in extrusion-based bone tissue engineering. Full article

Introduction: With age and injury, the infiltration of fat in the paraspinal muscles can cause degeneration, disorganizing the structural integrity of the connective tissue and causing lower back pain (LBP). Human umbilical cord tissue allografts (UCTAs) have a collagen-rich matrix with various extracellular matrix (ECM) components that can replace damaged connective tissue. The objective of this paper is to analyze the preliminary findings from an observational repository on UCTAs for the supplementation of degenerated tissue in thoracic and lumbar paraspinal muscles refractory to standard conservative methods through patient-reported scales. Materials and Methods: A total of 117 patients from an observational repository were identified with paraspinal muscle degeneration. Patients received one to three applications of UCTAs; outcomes were tracked using the Numeric Pain Rating Scale (NPRS), the Western Ontario and McMaster University Arthritis Index (WOMAC), and the Quality-of-Life Scale (QOLS). Results: All groups showed positive improvement in the NPRS and WOMAC scales. Multi-application groups revealed statistically significant differences in the analyses. No adverse events or complications were reported. Discussion: Limitations included a lack of a control group, non-standardized application protocol, and the increase in recall and response bias due to using patient-reported measures. Conclusion: This pilot investigation presents the preliminary effectiveness necessary in hypothesis generation for continued research through randomized controlled trials to validate efficacy, establish optimal dosage protocols, and compare UCTAs to other conservative interventions. Full article

Background: Quiescent cancer cells (QCCs) evade conventional therapies and contribute to minimal residual disease (MRD) and relapse, yet the signaling pathways governing their survival remain poorly understood. Methods: Here, we performed integrative proteomic and phosphoproteomic profiling of triple-negative breast cancer (TNBC) cells transitioning between proliferation and serum removal-induced quiescence, followed by re-stimulation. Results: We identified dynamic remodeling of both proteome and phosphoproteome, with quiescent cells showing downregulation of mitotic drivers and upregulation of extracellular matrix components. Notably, phosphorylation of CK2 substrates was increased during quiescence, and CK2 inhibition using CX-4945 impaired cell survival under nutrient and genotoxic stress, disrupted autophagy, microtubule dynamics, and protein synthesis. Phospho-enrichment and functional assays identified death-associated protein kinase 3 (DAPK3) as a CK2-regulated effector mediating stress-induced apoptosis. In silico analysis confirms a link between high CK2 expression and poor chemotherapy response in basal breast cancer. Conclusions: These findings establish CK2 as a critical survival kinase in QCCs and a potential therapeutic target for MRD eradication in breast cancer. Full article

Copy number variations (CNVs) are a major source of structural genomic diversity that influence adaptation, reproduction, and production traits in livestock. The Black Bengal goat, an economically important Indian breed known for its high fecundity, superior skin quality, and resilience to humid tropical climates, was studied to uncover its structural genomic landscape. We performed whole-genome CNV analysis using high-depth (10×) sequencing data from eight individuals. A total of 31,816 copy number variants (CNVs) were identified, predominantly duplications, with an average length of approximately 45 kb. These CNVs were combined into 8910 copy number variation regions (CNVRs) covering approximately 0.15 Gb (about 5.3% of the autosomal genome). CNVR hotspots were mainly located on chromosomes 1. Gene annotation showed that regions overlapping with CNVs and CNVRs contained over 1987 protein-coding genes that are involved in pathways related to immunity, reproduction, metabolism, and extracellular matrix (ECM) organization. The presence of copy number variations involving genes such as GDF9 and BMPR1B on chromosome 7 & 6, respectively, are important because it indicates that the breed has a high reproductive capacity due to dosage-sensitive duplications. Changes in the extracellular matrix and increased dermal strength have been linked to duplications of genes such as COL6A1, LAMC2, LAMB3, FMN1, and CLDN1. This helps explain the superior hide quality of the breed. This research offers a comprehensive map of CNVs and CNVRs within the genome of the Black Bengal goat. It demonstrates how these duplications lead to structural changes that enhance both reproductive performance and skin resilience. These findings provide a valuable genomic resource for future marker-assisted selection, comparative genomics, and conservation breeding programs aimed at preserving indigenous goat populations. Full article

Background: Modern oncology views immune system dysfunction as a key factor in carcinogenesis. The induction of immunogenic cell death (ICD), a form of regulated cell death capable of activating adaptive immunity, represents a promising therapeutic strategy. Damage-associated molecular patterns (DAMPs) play a central role in this process. This review aims to summarize current knowledge of DAMPs, their release mechanisms during ICD, their classification, and their prognostic and therapeutic significance in antitumor immunity. Methods: We systematically reviewed and synthesized literature published in Pubmed and Google Scholar on ICD and DAMPs, focusing on distinct forms of DAMPs which were categorized based on recognition mechanisms (five classes) and cellular origin (extracellular, mitochondrial, nuclear, and cytosolic). Key molecules, their receptors, downstream signaling pathways, and clinical associations were analyzed. Results: The spatiotemporally coordinated release of the pattern of DAMPs promotes dendritic cell maturation, antigen presentation, activation of cytotoxic T lymphocytes, and elimination of tumor cells. DAMPs can exhibit a dual role: they are able to induce sterile inflammation essential for antitumor immunity, but may also contribute to metastasis and chronic inflammation. Among all DAMPs, high-mobility group box 1 (HMGB1, a nuclear DAMP) and calreticulin (CRT, a cytosolic protein) demonstrate the greatest prognostic value. Other DAMPs (e.g., extracellular matrix components, uric acid) act as signal amplifiers during various forms of cell death. Conclusions: Understanding the spatiotemporal dynamics of DAMP release is critical for activating immune responses against malignant cells. Monitoring DAMPs may improve patient stratification, predict therapeutic responses, and enable personalized immunotherapeutic strategies. Further investigation of ICD mechanisms and DAMP release represents a fundamental basis for developing novel anticancer therapies. Full article

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease marked by excessive extracellular matrix (ECM) deposition. Current FDA-approved therapies, such as pirfenidone and nintedanib, offer limited efficacy in halting disease progression. Lysyl oxidase-like 2 (LOXL2) is a key enzyme involved in ECM remodeling and fibrosis. This study investigates Compound #765, a novel indolizine derivative, as a potential LOXL2 inhibitor for IPF treatment. Methods: Compound #765 was synthesized and characterized using spectroscopic methods. Its inhibitory effect on LOXL2 activity was evaluated using LOXL2 enzymatic assays, in vitro fibrosis models with human lung fibroblasts, and in vivo models of pulmonary fibrosis, including bleomycin-treated and TGF-β1-overexpressing transgenic mice. In silico docking studies predicted the binding affinity of Compound #765 to LOXL2. Results: Compound #765 targeted LOXL2 activity and reduced collagen production in lung fibroblasts. In both bleomycin-induced pulmonary fibrosis and TGF-β1-overexpressing murine models, Compound #765 significantly alleviated fibrosis, as indicated by reduced collagen accumulation and inflammatory cell infiltration. The in silico docking studies predicted favorable binding affinity to LOXL2, which was confirmed through in vitro experiments. Importantly, Compound #765 suppressed fibrosis-associated markers in fibroblasts derived from IPF patients, suggesting translational potential. Conclusions: These results demonstrate that Compound #765 functions as a LOXL2 inhibitor with significant anti-fibrotic effects in vitro and in vivo, offering a promising therapeutic approach for IPF and other fibrotic lung diseases. Full article

Objective: Gastric cancer (GC) is characterized by molecular heterogeneity, yet current classifications are largely based on cross-sectional molecular profiles and do not account for the temporal order of mutation accumulation. This study aimed to reconstruct somatic mutation trajectories to identify prognostically distinct subtypes and to examine transcriptomic and microenvironmental features associated with these inferred trajectories. Methods: We applied the Subtype and Stage Inference (SuStaIn) algorithm to TCGA-STAD somatic mutation data to infer the temporal sequence of mutation accumulation. Stage-correlated gene expression analysis was performed to identify genes whose expression levels changed with evolutionary stage. The tumor microenvironment (TME) was characterized using EcoTyper and single-cell RNA sequencing deconvolution, while drug sensitivity was estimated through transcriptome-based IC₅₀ prediction. The clinical relevance of the inferred trajectories was further evaluated in three independent external transcriptomic cohorts. Results: We identified two distinct evolutionary trajectories: the Accelerated Path (AP, 65%) and the Gradual Path (GP, 35%). In the AP, TP53 mutations were positioned at an earlier evolutionary stage (Stage 3) compared to the GP (Stage 8). AP patients had significantly worse overall survival (Hazard Ratio = 1.437, p = 0.044, adjusted for clinical stage and molecular subtypes). The AP was associated with stage-correlated downregulation of the sodium channel gene SCN4A (ρ = −0.36, p < 0.001) and an increase in a squamous-associated gene expression score, while the GP showed stage-correlated expression changes in the mitochondrial gene SDHD (ρ = −0.35, p < 0.001). The AP was further characterized by higher inferred abundance of extracellular matrix CAFs (eCAFs) and lower inferred immune cell scores, whereas the GP was associated with higher inferred signatures of activated B cells and effector memory T cells. Computational drug sensitivity modeling predicted a negative correlation between AP stage and IC₅₀ values for 5-Fluorouracil and Docetaxel. Conclusions: Two distinct mutational ordering patterns identified by SuStaIn are associated with divergent transcriptomic features, TME compositions, and clinical outcomes in gastric cancer. The AP subtype is characterized by early TP53 mutations, SCN4A downregulation, and a stromal-enriched microenvironment, while the GP subtype is associated with later TP53 mutations, SDHD-correlated expression, and higher inferred immune cell scores. The reproducibility of these associations was confirmed in independent cohorts. The computational drug sensitivity predictions and the proposed mechanistic links between gene expression patterns and clinical outcomes should be viewed as hypothesis-generating findings that require prospective and functional validation. Full article

The modulation of the tumour microenvironment represents a pivotal step in tumorigenesis and metastasis and results from direct and paracrine cellular interactions. The innate immune Toll-like receptor 4 (TLR4) controls immune and inflammatory signalling in the tumour microenvironment. A growing body of evidence shows that TLR4 activation in cancer, immune and stromal cells upregulate gelatinase expression and activity, linking innate immune responses to extracellular matrix (ECM) remodelling. Gelatinases, or matrix metalloproteinases (MMP2) and (MMP9) play a pivotal role in tumour matrix degradation, thereby facilitating invasion, angiogenesis and metastasis. Interestingly, although TLR4 signalling in cancer cells and tumour-associated macrophages leads to different activation outputs, they can both induce gelatinases through NF-κB, MAPK, and Akt pathways. Evidence from clinical tumour tissues, co-culture models, in vivo and in vitro studies supports the crucial interplay between TLR4 signalling and gelatinases production in tumour growth and metastasis. An in-depth understanding of this crosstalk may reveal new therapeutic opportunities in targeted strategies. Full article

Background/Objectives: Phillygenin (PHI), a natural lignan derived from Forsythia suspensa, has garnered attention for its potential to alleviate chronic diseases, including chronic colitis, pulmonary fibrosis, and diabetes. Chronic kidney disease (CKD) poses a global health challenge, characterized by high morbidity and mortality rates and associated with a spectrum of secondary complications. In this study, we aim to investigate the therapeutic effectiveness of PHI on CKD and also identify molecular signals by using a unilateral ureteral obstruction (UUO) mouse model and in vitro experiments. Methods: C57BL/6 mice were administered PHI at 50 mg/kg/day to assess its therapeutic effectiveness. In vitro, lipopolysaccharide (LPS) and adenosine triphosphate (ATP) were used to induce pyroptosis, also known as pyroptosis, in renal proximal tubular cells (NRK52E). Results: After PHI treatment for 14 consecutive days, the collagen deposition and extracellular matrix (ECM) accumulation, the expression of oxidative stress response proteins (catalase, superoxide dismutase 2, NADPH oxidase 4, and thioredoxin reductase 1), pro-inflammatory markers (TNF-α and Cyclooxygenase-2(COX-2), and infiltration of neutrophils and macrophages were significantly ameliorated in the UUO mice. Interestingly, the pyroptosis-related proteins (NLRP3/Caspase-1/GSDMD/IL-1β) and cell apoptotic death were also conspicuously relieved after treatment with PHI. Furthermore, PHI administration significantly attenuated the ATP/LPS-induced NF-κB/NLRP3/Caspase-1/GSDMD pyroptosis signal pathway in NRK52E cells. Conclusions: These results demonstrate, for the first time, that PHI treatment ameliorates inflammation and the related pyroptosis via inhibitory regulation of the NF-κB/NLRP3/Caspase-1/GSDMD axis, leading to attenuated renal fibrosis and progressive CKD in UUO mice and in vitro. Our findings suggest that PHI could be a nutraceutical candidate for attenuating CKD progression. Full article

Tendinopathy involves a dysregulated inflammatory microenvironment in which cytokines, growth factors (GF) and extracellular matrix components interact dynamically. Platelet-rich plasma (PRP) is widely used as a regenerative therapy, but its mechanisms of action in inflamed tendon remain unclear. This study evaluated whether platelet-rich gel supernatant (PRGS) reprograms the inflammatory–anabolic mediator network in an equine in vitro tendon explant system stimulated with lipopolysaccharide (LPS). Tendon explants were cultured under six experimental conditions, including non-stimulated control, LPS-stimulated control, and LPS combined with 25% or 50% PRGS or platelet-poor gel supernatant (PPGS). Cytokines, GF, and hyaluronic acid (HA) were quantified at 1 h and 48 h and analyzed using linear mixed-effects models, mediator ratios, correlation networks, and principal component analysis. PRGS contained higher concentrations of PDGF-BB (2044 pg/mL, 95% CI 1382–2706) and IL-1ra (1196 pg/mL, 95% CI 424–1967) compared with PPGS. In LPS-stimulated explants, PRGS significantly increased IL-1ra and PDGF-BB, while IL-1β and HA exhibited significant time-dependent changes (F = 8.675 and F = 10.752, respectively). The PDGF-BB:HA ratio remained consistently higher in PRGS-treated groups (F = 46.100, p < 0.001). Multivariate analysis showed that the first two principal components explained 62% of the total variance and revealed coordinated shifts in mediator organization over time. These findings indicate that PRGS does not simply suppress inflammation but actively reprograms the tendon microenvironment toward a regulatory and reparative phenotype within this experimental system. Full article

The production of cultivated meat relies on in vitro animal cell growth and requires the use of scaffolds that structurally resemble key features of the extracellular matrix (ECM), providing mechanical support and biochemical cues for cell adhesion, proliferation, and differentiation. Electrospinning has emerged as a promising technique for manufacturing three-dimensional edible scaffolds because it is robust, versatile, and capable of producing nanofibers with a high surface area-to-volume ratio, tunable porosity, and ECM-like fibrous architectures. Natural biopolymers are promising candidates for the fabrication of electrospun scaffolds, combining biocompatibility, biodegradability, and processing compatibility with food-grade requirements. However, the absence of fully food-grade electrospinning systems, coupled with limited scalable green-processing strategies, remains a critical barrier to industrial translation. In this context, this review presents recent advances in the food-grade electrospinning of natural biopolymers focused on cultivated meat production. Furthermore, scientific gaps in the development of fully edible scaffolds are discussed, along with the need for alternatives to animal-derived materials and synthetic carrier polymers, considering sustainability, consumer acceptance, and the translation from laboratory-scale studies to industrial systems. Finally, this review outlines a strategic roadmap to accelerate the transition from proof-of-concept studies toward scalable, regulatory-compliant, and industrially viable electrospinning technologies for cultivated meat production. Full article