Search Results (6,413)

Aspartame is a widely used artificial sweetener, but its possible relationship with rheumatoid arthritis (RA) remains insufficiently understood. This study aimed to explore, rather than prove, potential molecular links between aspartame-related targets and RA-associated gene networks. Three public RA transcriptomic datasets (GSE55235, GSE55457, and GSE77298) from the Gene Expression Omnibus (GEO) database were integrated as discovery/training data. Because these datasets included different tissue origins, batch correction was used to reduce dataset-level technical variation, whereas tissue-origin-related biological variation was not assumed to be fully removable. After differential expression analysis, RA-associated differentially expressed genes (DEGs) were identified. The single-cell dataset GSE200815 was used for cell annotation and cellular expression visualization; because its comparator group consists of psoriatic arthritis (PsA) samples rather than healthy controls, single-cell results were interpreted as RA-vs-PsA observations and were not treated as disease-versus-healthy-control evidence. Potential targets of aspartame were retrieved from ChEMBL, SwissTargetPrediction, and the Similarity Ensemble Approach (SEA), and were intersected with RA-related DEGs to construct an aspartame-gene-RA regulatory network. Diagnostic models were developed using 113 machine-learning algorithm combinations to determine an optimal multigene model and its core genes. HLA-DRB1 was selected for exploratory scTenifoldKnk-based virtual knockout mainly because it was included in the optimal model and has a well-established role in RA immunogenetics; the single-cell analysis was used only to describe cellular distribution in the RA/PsA dataset. Molecular docking was then used to evaluate the possible interaction between aspartame and HLA-DRB1. Forty-four intersected genes linked the predicted aspartame targets with RA DEGs. The random forest plus partial least-squares generalized linear model (RF + plsRglm) identified 16 core genes. Network-level interpretation indicated that these genes were distributed across immune/antigen-processing, inflammatory-signaling, protease/extracellular-matrix-remodeling, adhesion, metabolic, and proliferation-related modules; therefore, HLA-DRB1 was treated as a prioritized immune-module candidate rather than as the sole driver of the network. Following virtual knockout of HLA-DRB1, affected genes were enriched in extracellular matrix organization, extracellular structure organization, extracellular matrix, collagen trimer, extracellular matrix structural constituent, and collagen binding. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways included integrin signaling, focal adhesion, proteoglycans in cancer, cytoskeleton in muscle, and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling. Molecular docking showed a minimum binding energy of −6.7 kcal/mol, which was more negative than the preset stability criterion of −5.0 kcal/mol, and the docking pose suggested contacts around ARG-146. This integrative analysis suggests a hypothesis-generating association between aspartame-related predicted targets and RA-relevant molecular networks involving HLA-DRB1 and other core genes. The findings do not establish causality and require experimental, epidemiological, biophysical, and tissue-stratified validation before any causal or clinical inference can be made. Full article

Research in the last two decades has well established galectin-3 (Gal3), a member of the lectin family, as a clinical biomarker and mediator of cardiovascular as well as other diseases. Gal3 contributes to progression of diseases by promoting pathological components, including inflammation, fibrosis, cell death or proliferation, and metabolic remodeling, and hence forms an ideal therapeutic target. Notably, nearly all Gal3 inhibitors that are currently under intensive pre-clinical and clinical testing target carbohydrate recognition/binding domain (CRD) of Gal3 molecules. Whereas the role of Gal3 in cardiovascular disease (CVD) has been well established, research on Gal3 in cancer or immunology has been leading the frontiers in this discipline. Therefore, it is important to have an integrated understanding on the biology and pathophysiology of Gal3 in a spectrum of pathological conditions. This review describes current findings from studies on diverse disease conditions and examines the role of Gal3 in the pathogenesis of diseases focusing on its transcription, post-translational modifications, intracellular dynamics, extracellular exporting, and interactions with a variety of signaling molecules. By bridging findings from different disciplines on the role of Gal3 in diseased settings, we explore the diverse anti-Gal3 strategies in addition to inhibition of CRD binding and highlight the significance of interventions targeting the transcription and post-translational modifications of Gal3, as well as intracellular actions of Gal3. At the end of this review, we provide perspectives for future research and therapeutic implications in CVD. Full article

Craniosynostosis is a congenital bone developmental condition characterized by the premature ossification of calvarial sutures, leading to restricted skull expansion and potential neurological complications. Although little is known about the signaling that governs this accelerated fusion, our research group has previously identified a stiffness-dependent upregulation of osteogenic genes in cells derived from fused sutures, highlighting the role of mechanotransduction in disease progression. Building on these findings, the present study describes the development of a unique patient-derived three-dimensional (3D) tissue-engineering (TE) model of non-syndromic craniosynostosis (NS-CS) to investigate how extracellular matrix (ECM) composition and biochemical cues regulate ossification timing and patterns. Cells isolated from clinically relevant tissues, surgically obtained from patent and prematurely fused calvarial sutures of pediatric NS-CS patients, were characterized and cultured under both two-dimensional (2D) and 3D suture-mimicking conditions. Comparative analysis revealed differences in cellular responsiveness between cells isolated from fused and patent sutures across the different experimental conditions, with cells from fused sutures consistently exhibiting higher expression of osteogenic markers. Notably, the elevated expression of osteogenic and chondrogenic markers suggested the possible involvement of endochondral-like ossification mechanisms during the pathological process of suture fusion. This patient-derived model was designed to recapitulate biophysical and biochemical features of the extracellular matrix of healthy and pathological sutures, serving as a tool for future research, helping us to understand the underlying mechanisms behind the pathophysiology of craniosynostosis. Full article

Postoperative wound complications remain a major cause of morbidity, prolonged hospitalization, increased healthcare costs, and reduced quality of life. While traditional wound dressings functioned primarily as passive barriers against contamination and exudate, advances in wound biology have transformed surgical wound management. Tissue repair is now recognized as a dynamic immunometabolic process involving coordinated interactions among immune cells, stromal populations, extracellular matrix remodeling, mechanotransduction, mitochondrial function, redox balance, microbial ecology, and bioelectrical signaling. Consequently, modern wound dressings are increasingly designed as bioactive systems capable of actively modulating the wound microenvironment. Recent developments in biomaterials science, immunoengineering, nanotechnology, extracellular vesicle biology, bioelectronics, and artificial intelligence have enabled the creation of advanced wound platforms, including stimuli-responsive hydrogels, immunomodulatory biomaterials, nanozyme-based dressings, conductive scaffolds, oxygen-generating matrices, extracellular vesicle-loaded systems, and biosensor-integrated interfaces. Therapeutic strategies are progressively shifting from antimicrobial-focused approaches toward immune-regenerative modulation targeting chronic inflammation, mitochondrial dysfunction, ferroptosis, cellular senescence, and impaired mechanobiological signaling. This review examines emerging surgical wound dressings from mechanistic, translational, and biomaterial perspectives, highlighting current innovations, translational challenges, and future directions. Collectively, these technologies may enable intelligent therapeutic systems capable of sensing and directing tissue regeneration in real time. Full article

Oral mucosal repair is a redox-regulated process that may be impaired by diabetes, chronic inflammation, infection, and chemotherapy- or radiotherapy-induced oral mucositis. Reactive oxygen species (ROS) support host defense, epithelial migration, angiogenesis, extracellular matrix remodeling, and adaptive repair when their production is transient and compartmentalized. In contrast, persistent ROS promote lipid, protein, and DNA oxidation, mitochondrial dysfunction, and extracellular matrix damage. Photobiomodulation (PBM) is increasingly used to support oral tissue repair, but its effects should be interpreted as dose- and context-dependent redox modulation rather than as simple antioxidant activity. This narrative review synthesizes oxidative stress biomarkers and redox-sensitive pathways relevant to oral mucosal repair and PBM, including oxidant–antioxidant balance, lipid and protein oxidation, oxidative DNA damage, antioxidant defense, thiol/disulfide homeostasis, mitochondrial and NADPH oxidase-derived ROS, Nrf2/HO-1, NF-κB, HIF-1α/VEGF, MAPK/ERK, PI3K/Akt, and MMP/TIMP signaling. The review emphasizes the distinction between transient mitochondrial ROS/nitric oxide signaling and sustained NADPH oxidase-driven oxi-inflammatory stress. It proposes a practical redox-guided framework for biomarker selection, PBM response interpretation, and future study design, while noting that this framework remains conceptual and is not yet a validated clinical decision algorithm. Full article

Thrombospondin-2 (TSP-2) is an extracellular matrix glycoprotein involved in angiogenesis, vascular remodeling, cell adhesion, and tissue repair. Its expression is induced by pathological stimuli, including mechanotransduction, hypoxia, and TGF-β signaling, and has been associated with several cardiovascular diseases (CVDs), such as heart failure, coronary artery disease, abdominal aortic aneurysm, and hypertension. Elevated circulating TSP-2 levels, particularly in combination with NT-proBNP, as well as alterations in THBS2 and its regulatory non-coding RNAs, have been linked to disease severity and adverse cardiovascular outcomes. This review summarizes current evidence on the role of TSP-2 in cardiovascular pathophysiology and its involvement in cardiovascular homeostasis. Although accumulating data suggest that TSP-2 may have diagnostic, prognostic, and therapeutic relevance, its clinical utility as a biomarker or therapeutic target has not yet been established. Further large-scale studies and standardized assessment methods are required to validate its potential and support future clinical translation. Full article

Carotid body tumors (CBTs) exhibit pronounced clinical heterogeneity, particularly in fibrotic progression, yet the underlying cellular mechanisms remain poorly defined. Here, we performed single-cell RNA sequencing on 64,944 cells from three fibrotic CBT (FCBT) and three non-fibrotic CBT (nFCBT) specimens to construct a high-resolution cellular atlas of CBT fibrosis. Integrated analyses revealed that FCBTs are distinguished by a FOXP2+ chief cell subpopulation exhibiting a metabolic shift toward mitochondrial respiration and enhanced MIF signaling, which may facilitate macrophage recruitment. Endothelial cells expanded in FCBTs and acquired pro-angiogenic signatures driven by macrophage-derived CXCL signaling. Notably, CXCL14+ fibroblasts emerged as the principal effectors of extracellular matrix deposition, with lineage inference suggesting their origin from smooth muscle cells. Immune cells, including T/NK and mast cells, further modulated the fibrotic niche through cytokine interactions. This study provides the first comprehensive single-cell dissection of CBT fibrosis, identifies FOXP2+ chief cells as initiators of stromal remodeling, and highlights CXCL14+ fibroblasts as key matrix-producing effectors. These findings nominate FOXP2 and CXCL14 as potential therapeutic targets for mitigating fibrosis in CBT patients. Full article

There is no proven therapy for Long COVID, a post-acute condition characterized by persistent symptoms following SARS-CoV-2 infection. Extracellular vesicles (EVs) are emerging as mediators of disease pathogenesis through their molecular cargo. We investigated whether EV glycosylation is altered in Long COVID plasma and whether these vesicles can be selectively targeted using a glycan-binding affinity resin. Large (100–500 nm) and small (40–200 nm) EVs were isolated from post-acute COVID-19 plasma and analyzed by nanoparticle flow cytometry to assess surface glycosylation. Small EV capture assays were performed using Galanthus nivalis agglutinin (GNA) affinity resin. Plasma miRNA profiles before and after GNA treatment were evaluated using NanoString nCounter analysis, and potential downstream pathway effects were computationally inferred using validated miRNA–mRNA interactions and PROGENy. Mannose-positive large EVs were significantly increased in Long COVID compared to recovered controls (p < 0.05). GNA-mediated small EV capture correlated with mannose-positive EV abundance (r = 0.341, p < 0.05), and seven miRNAs were significantly reduced following treatment. Computational pathway analysis suggested modulation of key signaling pathways, including JAK-STAT, Estrogen, VEGF, and PI3K. These findings suggest a glycan-associated EV signature in Long COVID and support further investigation of lectin-based capture as a potential strategy to target vesicle-associated molecular cargo. Full article

Lactate was traditionally considered a metabolic by-product of anaerobic glycolysis, mainly associated with tissue hypoxia and muscle fatigue. However, increasing evidence has redefined lactate as a multifunctional metabolic intermediate and signaling molecule involved in exercise-induced systemic adaptations. During physical activity, circulating lactate levels rise markedly when skeletal muscle production exceeds systemic clearance, allowing lactate to act as an exercise-responsive metabolite, or exerkine, and as a mediator of cardiometabolic adaptation. In the cardiovascular system, lactate serves not only as an efficient substrate for myocardial energy production but also as a regulator of vascular tone, endothelial function, angiogenesis, inflammation, and cardiac remodeling. These effects occur through receptor-dependent and receptor-independent mechanisms, including activation of hydroxycarboxylic acid receptor 1 (HCAR1/GPR81), modulation of intracellular redox balance, and histone or non-histone protein lactylation. This review summarizes current evidence on lactate in cardiovascular physiology and disease, focusing on myocardial lactate metabolism, HCAR1/GPR81 signaling, protein lactylation, extracellular vesicle communication, gut microbiota interactions, and therapeutic implications in heart failure, atherosclerosis, and diabetic cardiomyopathy. Although lactate is also produced under resting, postprandial, and pathological conditions, exercise is characterized by the amplitude and kinetics of lactatemia, coordinated hormonal and hemodynamic responses, and transient high-concentration signaling. These features support exercise-derived lactate as a context-dependent cardiovascular exerkine. Full article

Toll-like receptors (TLRs) are essential components of the innate immune system that enable host cells to sense microbial and endogenous danger signals and to initiate inflammatory and antimicrobial responses. Activation of TLRs triggers complex intracellular signaling networks that culminate in the induction of pro-inflammatory cytokines, type I interferons, and co-stimulatory molecules. In addition to the well-characterized nuclear factor κB (NF-κB) and interferon regulatory factor (IRF) pathways, mitogen-activated protein kinases (MAPKs) play a critical modulatory role in TLR signaling. MAPK/ERK kinase (MEK) inhibitors were originally developed for the treatment of cancer and are widely used in clinical oncology. Accumulating evidence indicates that pharmacological inhibition of MEK/extracellular signal regulated kinase (ERK) signaling profoundly affects immune cell function and TLR-driven responses. Depending on timing, dose, and disease context, MEK inhibition can attenuate excessive inflammation but may also interfere with protective host defense mechanisms. This duality highlights the context-dependent role of MEK/ERK signaling in infection and inflammation. In this review, I summarize current knowledge on the integration of MEK/ERK signaling into TLR-mediated innate immune responses and discuss the immunological consequences of MEK inhibition in infectious and inflammatory settings. By synthesizing mechanistic and translational studies, I aim to provide a framework for understanding MEK inhibitors as immune modulators rather than as broadly acting anti-inflammatory agents. Full article

This research paper focused on the synthesis of 1-[2-hydroxy-3-(phenylcarbamoyloxy)propyl]-4-(R¹, R²-substituted phenyl)piperazin-1-ium chlorides (I)–(III), containing R¹, R² = H, Cl and/or OCH₃, and the evaluation of some of their physicochemical parameters. The in vitro biological investigation of these N-arylpiperazine (NAP) derivatives consisted in assessing their impact on purinergic P2X7-associated signaling, that is, the evaluation of antioxidant, anti-inflammatory and immunomodulatory characteristics. The ultraviolet type C (UVC) irradiation (λ = 254 nm, 0.954 kJ/m²) induced a pronounced stress response in human leukocytes without marked cytotoxicity while maintaining high cell viability (≥90%), as evidenced by increased interleukin (IL)-1β production (94%), elevated IL-1β mRNA expression, enhanced lipid peroxidation (66%), and increased intracellular adenosine 5′-triphosphate (ATP; 97%), respectively. Under basal conditions, these lipophilic NAPs, defined with logarithmic values of retention (capacity) factors corresponding to 100% water in isocratic elution RP-HPLC, i.e., k_w descriptors (varying from 2.3829 to 4.3689), and isocratic chromatographic hydrophobicity index (φ₀) parameters (ranging from 0.7578 to 0.8842), reduced IL-1β production (by 26–63%) and enhanced superoxide dismutase (SOD) activity (up to 64%) without inducing oxidative damage. Under UVC-induced stress, all evaluated compounds decreased lipid peroxidation (up to 45%) and significantly increased antioxidant enzyme activities, including SOD (up to 223%) as well as catalase (up to 145%). The observed effects were associated with changes in intracellular ATP levels and redox-related parameters. In the experiments described in this paper, intracellular ATP was measured so that no direct conclusions could be drawn regarding the extracellular ATP-dependent activation of purinergic receptors, including P2X7. Overall, the results demonstrated that variations within the structure of these NAPs significantly affected compounds’ biological activity, highlighting their potential for further optimization as cytoprotective and anti-inflammatory agents. Full article

Renal cell carcinoma (RCC) is a biologically heterogeneous malignancy characterized by variable clinical behavior and diverse molecular phenotypes. Although immune checkpoint inhibitors and targeted therapies have transformed the treatment landscape of advanced RCC, clinically validated biomarkers capable of improving risk stratification, therapeutic-decision making and disease monitoring remain lacking. Kidney injury molecule-1 (KIM-1), also known as hepatitis A virus cellular receptor-1 (HAVCR1) or T-cell immunoglobulin and mucin domain-containing protein-1 (TIM-1), has emerged as a biologically compelling investigational biomarker e because of its close relationship to proximal tubular epithelial injury and renal carcinogenesis. KIM-1 is a transmembrane glycoprotein minimally expressed in normal kidney tissue but markedly upregulated in dedifferentiated proximal tubular epithelial cells following injury, and in clear cell RCC, where its extracellular domain can be shed into plasma and urine. Beyond its role as a marker of tubular injury, KIM-1 participates in immune regulation, phagocytosis, inflammatory signaling and tissue remodeling, supporting its potential relevance to tumor biology. Clinical studies have demonstrated associations between elevated circulating KIM-1 levels and RCC diagnosis, recurrence risk, and survival outcomes, particularly in localized and postoperative disease settings. KIM-1 has additionally been investigated as a therapeutic target through antibody–drug conjugate approaches. Despite promising translational data, important limitations yet remain. Current evidence is predominantly prognostic rather than predictive, and substantial analytical and biological challenges continue to limit implementation. Assay standardization, clinically meaningful cutoffs, specimen selection, timing of sampling, and confounding by chronic kidney disease or nonmalignant renal injury remain incompletely resolved. Furthermore, evidence supporting incremental value beyond established clinicopathologic models remains limited. This review critically evaluates the biological rationale, analytical considerations and clinical evidence supporting KIM-1 in RCC. Particular emphasis is placed on distinguishing prognostic, predictive, pharmacodynamic, and therapeutic applications, as well as defining the evidentiary gaps that must be addressed before clinical implementation. Current evidence is derived predominantly from retrospective and exploratory analyses, and important limitations remain regarding assay standardization, biological specificity, chronic kidney disease-related confounding, and prospective validation. The review concludes with a summary of the evolving landscape of KIM-1-directed biomarker strategies in RCC, which may ultimately contribute to improved biologic risk stratification and biomarker-driven clinical investigation in RCC. Full article

Adipose tissue remodeling is a dynamic process essential for metabolic homeostasis, enabling tissue expansion, extracellular matrix (ECM) turnover, angiogenesis, and coordinated immune adaptation. In obesity, however, maladaptive remodeling characterized by fibrosis, chronic low-grade inflammation, and hypoxia disrupts adipose plasticity and promotes systemic insulin resistance. Central to these processes is the tightly regulated homeostasis between proteases and their inhibitors, in which the serine protease inhibitor (serpin) superfamily represents an important yet underappreciated regulatory axis. Beyond their classical roles in coagulation and fibrinolysis, serpins regulate ECM remodeling, macrophage recruitment and polarization, cytokine signaling, angiogenic responses, adipokine activity, and insulin sensitivity, thereby orchestrating immune–metabolic crosstalk within adipose depots. Emerging evidence indicates that individual serpins exert distinct and context-dependent effects, with some promoting fibrosis, inflammation, and metabolic dysfunction, whereas others preserve adipose tissue homeostasis and metabolic function. This review synthesizes current knowledge on the structural and functional diversity of the serpin superfamily and examines their mechanistic roles in adipose tissue remodeling during obesity, with particular emphasis on how adipose-associated serpins regulate adipose tissue homeostasis, depot-specific remodeling, and immune–metabolic crosstalk. The review further discusses the experimental and translational applications of emerging single-cell and spatial transcriptomics, multi-omics, and computational approaches that may advance the understanding of serpin biology, improve the investigation of human adipose tissue, and accelerate the identification of clinically relevant serpin-related biomarkers and therapeutic targets for obesity and related metabolic disorders. By positioning serpins as key regulators of adipose tissue remodeling and immune–metabolic integration, this review highlights protease–antiprotease balance as a central determinant of metabolic health and identifies serpins as promising biomarkers and therapeutic targets for obesity and related metabolic disorders. Full article

Background: Eggshell membrane peptides (ESMPs) are natural bioactive compounds with reported chondroprotective properties. However, their regulatory effects on canine chondrocytes remain unclear. This study investigated ESMP in an interleukin-1β (IL-1β)-induced inflammatory model of canine chondrocytes. Methods: Chondrocytes were assigned to control (Cont), IL-1β, and ESMP + IL-1β groups. Cell viability was assessed using the Cell Counting Kit-8 (CCK-8) assay. NF-κB p65 nuclear translocation was evaluated by immunofluorescence staining. Real-time quantitative PCR (RT-qPCR) and Western blotting (WB) were used to measure mRNA and protein expression levels, respectively. Results: ESMP inhibited IL-1β-induced NF-κB p65 nuclear translocation and reduced the IL-1β-induced increases in interleukin-6 (IL-6), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and matrix metalloproteinase-13 (MMP-13) at both mRNA and protein levels. ESMP also decreased IL-6, nitric oxide (NO), and prostaglandin E₂ (PGE₂) levels in culture supernatants. ESMP reversed the IL-1β-induced reduction in type II collagen α1 chain (COL2A1) and aggrecan (ACAN) expression at both transcriptional and protein levels. Conclusions: ESMP attenuates IL-1β-induced inflammatory responses and extracellular matrix degradation in canine chondrocytes, potentially associated with suppression of NF-κB p65 nuclear translocation. This supports its potential application in promoting joint health in dogs. Full article

Background: Solriamfetol, a dopamine and norepinephrine reuptake inhibitor widely used in narcolepsy management, has not been thoroughly investigated for its anti-fibrotic and anti-inflammatory properties. Herein, we investigated its potential therapeutic applications and underlying mechanisms in both cellular and murine models of pulmonary fibrosis. Methods: To induce fibrosis, C57BL/6 male mice (six-week-old) were administered bleomycin via the intratracheal route. These animals subsequently received solriamfetol orally once per day at dosages of 3 or 10 mg/kg. Histological and immunohistochemical techniques were employed to evaluate inflammatory cell infiltration, collagen accumulation, and α-smooth muscle actin (α-SMA) expression in bronchoalveolar lavage samples and lung tissue sections. Cytokine levels were measured by ELISA, and gene/protein expression of pro-fibrotic markers, A_2A/A_2B adenosine receptors (ARs), adenylate cyclases (ACs), Epac, K_Ca3.1, and adenosine deaminase (ADA) were assessed via quantitative PCR and Western blot. Electrophysiological recordings evaluated K_Ca3.1 channel activity. Purified ADA and normal human lung fibroblasts (NHLFs) were treated with solriamfetol to assess effects on ADA activity and levels of cAMP and adenosine, respectively. Results: Solriamfetol significantly reduced inflammatory cell infiltration, collagen accumulation, and α-SMA expression in fibrotic lungs. Solriamfetol restored downregulated A_2AAR, A_2BAR, ACs, and Epac, while suppressing ADA expression and activity, resulting in elevated extracellular adenosine and intracellular cAMP. The intervention potentiated Epac signaling and inhibited fibroblast activation. Solriamfetol inhibited the K_Ca3.1 current in fibroblasts and reduced K_Ca3.1 protein expression levels in TGFβ-treated fibroblasts and lung tissues from bleomycin-challenged mice. Notably, these effects were abolished by A_2AAR or A_2BAR antagonists, implying that they occur through AR-mediated pathways. Conclusions: Solriamfetol inhibits ADA and reinforces adenosine–cAMP signaling, suppressing pathological fibroblast activation. These findings suggest its therapeutic utility as a novel anti-fibrotic compound for various fibrotic diseases, including pulmonary fibrosis. Full article