Search Results (2,179)

Background: Idiopathic pulmonary fibrosis (IPF) is an incurable disease with limited therapeutic options and a poor prognosis. Current standard therapies are characterized by drugs or surgical strategies with limited effects, as they are either not curative or their use is restricted to a specific subset of the population. The aim of this scoping review is to evaluate the drugs currently under investigation in Phase II and Phase III trials and provide an overview of the mechanisms of new therapeutic strategies for IPF. Methods: The search strategy was conducted in accordance with PRISMA guidelines and included studies conducted on adults with IPF retrieved from the registered ClinicalTrials.gov database up to 31 December 2025. Results: Nineteen studies were included. The clinical trials investigate key signaling pathways and molecular targets, including MAPK, RhoA/ROCK, PDE4B/cAMP, Wnt/β-catenin, Hedgehog/SMO, IL-11/STAT3, and LPA/autotaxin, as well as extracellular receptors and mediators such as CSF1R, TBXA2R, and WISP1. Conclusions: Ongoing clinical research in IPF reflects a broad diversification of molecular targets; however, translational success remains limited. Current evidence suggests that biological complexity, pathway redundancy, and systemic constraints significantly restrict the clinical impact of single-target strategies. Future progress will likely depend on improved patient stratification, combination approaches, and biomarker-guided trial design rather than isolated pathway modulation. Full article

Hair follicle (HF) stem cells are multipotent adult stem cells that play a key role in the hair follicle cycle. However, it remains poorly understood how the outer root sheath (ORS)—specifically, the stem cells in the bulge region of the hair follicle—promotes skin repair. This study aims to investigate the role of bulge stem cells in tissue growth and repair and to determine whether the ORS of transplanted hair follicles can facilitate skin repair. We further seek to elucidate the mechanisms by which bulge stem cells contribute to hair follicle development, regeneration, and skin wound healing. In this study, hair follicle samples were obtained from neonatal mice using microdissection. Hair follicle morphology was assessed by Sirius red staining, H&E staining, and transmission electron microscopy. Immunofluorescence staining was used to detect changes in CD34 and SOX9 protein expression. Additionally, microdissection-based hair follicle transplantation and Western blotting were employed to investigate protein activation and inhibition in the Wnt/β-catenin signaling pathway. The results show that the hair follicle bulge, inner root sheath, and dermal papilla all increase in size as hair follicles grow, with each structure growing relatively rapidly on day 7. Treatment with Teplinovivint effectively inhibits the expression of Wnt/β-catenin signaling pathway-related proteins and hair follicle stem cell markers. Damaged hair follicle tissues cultured in vitro are capable of self-repair. At the transplantation site, the skin gradually closes as the outer root sheath wound heals. In contrast, the central region of the outer root sheath becomes progressively filled with numerous dividing cells and extracellular matrix. The inner portion of the outer root sheath is densely populated with cells, and the markers CD34 and SOX9 are also widely distributed. This indicates that activation of the Wnt/β-catenin signaling pathway enhances the proliferation and differentiation of hair follicle stem cells, thereby promoting hair follicle growth, repair of damaged follicles, and healing of skin wounds. Furthermore, this study demonstrates the feasibility of using transplanted outer root sheath (ORS) to repair skin wounds—specifically, the potential to achieve large-scale hair regeneration from a limited number of hair follicle stem cells—providing a new approach for the clinical treatment of skin injury disorders. Nevertheless, achieving long-term, stable, and scalable clinical translation of ORS stem cells for hair follicle regeneration remains a major challenge. Full article

The zig-zag eel (Mastacembelus armatus) exhibits sexual dimorphism in growth patterns. Identifying the genes involved in sex differentiation is a crucial step toward achieving single-sex breeding and serves as a vital foundation for elucidating the XY sex determination mechanism in M. armatus. This study measured the morphological characteristics of male and female M. armatus and found that males were significantly superior to females in body weight and nearly all morphological indices. Subsequently, whole-transcriptome sequencing was performed on the gonads of adult males and females, identifying 11,714 DEmRNAs, 3442 DElncRNAs, 416 DEcircRNAs, and 620 DEmiRNAs, including male sex differentiation genes such as Sox30, Tbx1, Sox9, and Gata4, and female sex differentiation genes like Sox3, Foxl2, and Wnt4a. Functional enrichment analysis identified pathways associated with sex differentiation, including the TGF-beta signaling pathway, the steroid hormone biosynthesis, the Hippo signaling pathway, and the Wnt signaling pathway, etc. A ceRNA network was constructed based on differentially expressed mRNAs and ncRNAs, revealing that the sex differentiation-related genes Sox3, Sox9, Sox30, Tbx1, and Wt1 are regulated by one or multiple pairs of lncRNA/circRNA-miRNA pairs. The study results will provide molecular targets for research on sex-controlled breeding in M. armatus and lay an important theoretical foundation for clarifying its sex differentiation mechanisms. Full article

Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) dysfunction is increasingly recognized as a key contributor to a broad spectrum of human diseases beyond classical cystic fibrosis (CF). CFTR is a cAMP-regulated chloride and bicarbonate ion channel expressed in both epithelial and non-epithelial tissues, where it regulates ion homeostasis, mucosal hydration, and cellular signaling. Both inherited CFTR mutations and acquired dysfunction resulting from environmental or inflammatory factors can disrupt these physiological processes and drive disease progression. Current evidence linking CFTR dysregulation to respiratory diseases, such as cystic fibrosis, chronic obstructive pulmonary disease (COPD), asthma, and HIV-associated airway disease, as well as cardiovascular, renal, neurological diseases, and cancer, is comprehensively discussed. Mechanistically, impaired CFTR function promotes oxidative stress, chronic inflammation, epithelial barrier dysfunction, altered mucociliary clearance, and dysregulation of signaling pathways, including NF-κB, TGF-β, PI3K/Akt, MAPK, and Wnt/β-catenin. In the context of HIV infection and cigarette smoke exposure, CFTR suppression is mediated in part by TGF-β signaling and miRNA-dependent mechanisms, resulting in compromised airway defense and increased susceptibility to pulmonary complications. Recent studies further demonstrate that CFTR dysregulation alters the expression of genes involved in fibrosis, inflammation, angiogenesis, and epithelial–mesenchymal transition (EMT). Notably, CFTR may act as either a tumor suppressor or a context-dependent oncogene, depending on tissue type and signaling milieu, highlighting its complex role in cancer biology. Advances in CFTR-targeted therapies, including potentiators, correctors, gene therapy, and combination approaches, have markedly improved outcomes in CF and may offer therapeutic potential for diseases associated with acquired CFTR dysfunction. We summarize the systemic consequences of CFTR dysregulation and the need for further mechanistic and translational research to clarify its role across diverse human diseases. Full article

Renal cell carcinoma (RCC) remains a major challenge in modern oncological urology, owing to its high heterogeneity, latent clinical course, and intrinsic resistance to chemotherapy and radiotherapy. In recent decades, the paradigm of carcinogenesis research has shifted from a primary focus on protein-coding genes alone to a broader investigation of the non-coding part of the transcriptome. Within this framework, long non-coding RNAs (lncRNAs) have emerged as fundamental regulators of cellular homeostasis. Accumulating evidence indicates that lncRNAs are not merely ‘transcriptional noise’ but components of intricate regulatory networks governing epigenetic, transcriptional, and post-transcriptional processes. Here, we present a comprehensive systematic review of the current literature addressing the role of lncRNA in the molecular pathogenesis of RCC. We discuss the roles of these molecules in key oncogenic signaling pathways, including PI3K/AKT/mTOR, Wnt/β-catenin, and Notch, and their contributions to tumor metabolic plasticity. The paper summarizes data on the link between lncRNAs and novel forms of regulated cell death—ferroptosis, cuproptosis, and disulphidosis. Particular attention is paid to their role in mediating resistance to tyrosine kinase inhibitors and their potential utility as highly specific biomarkers. Collectively, this review provides an updated perspective on the contribution of lncRNAs to RCC pathogenesis and outlines strategic directions for future research to support the development of more precise approaches in personalized oncology. Full article

Ductal carcinoma in situ (DCIS) is a non-invasive precursor to invasive breast cancer. DCIS incidence continues to rise, yet its clinical management remains constrained by the absence of reliable biomarkers that can adequately distinguish indolent lesions from those with high invasive potential, to circumvent over- or under-treatment. Black women with DCIS are significantly more likely to progress to invasive breast cancer, are disproportionately diagnosed with high-grade, hormone receptor-negative lesions, and experience elevated risk of recurrence and mortality relative to White women with DCIS. These disparities persist despite comparable access to screening and treatment, suggesting underlying biological and tissue microenvironmental factors. This review synthesizes emerging evidence implicating early molecular and systemic changes that may be driving the disparity in DCIS progression. We highlight racial distinctions in interconnected pathways involving Wnt/β-catenin signaling, metabolic and nutritional dysregulation, immune microenvironment remodeling, and cellular tolerance of genomic instability. We further discuss how epigenetic alterations, obesity-associated inflammation, and immune dysregulation may arise during the pre-invasive stage that intersect with social and environmental exposures to influence racial differences in lesion fate. We spotlight candidate biomarkers disproportionately associated with aggressive disease in Black women—including KIFC1, a mediator of centrosome clustering and genomic instability tolerance, and ACKR1/DARC, a regulator of chemokine gradients and immune trafficking—as potential drivers of progression-permissive states. This review advances an integrated, equity-informed framework for DCIS progression that links early tumor evolution to coordinated alterations in genomic instability, immune regulation, metabolic signaling, and stress-adaptive pathways. Importantly, we propose that DCIS progression is governed not by isolated molecular alterations but by coordinated programs that enable survival under genomic and immunologic stress. Current clinical risk assays, which primarily capture tumor-intrinsic proliferation and hormone signaling, do not fully resolve these pathways and may therefore incompletely reflect biologically meaningful racial disparities. This synthesis underscores the need for pathway-level, microenvironment-informed, and population-representative approaches to DCIS risk stratification. Advancing such frameworks will be essential for identifying actionable biomarkers, refining early intervention strategies, and ultimately reducing racial disparities in breast cancer outcomes. Full article

Background: Hepatocellular carcinoma (HCC) develops predominantly from chronic liver injury, with diet representing a clinically actionable yet mechanistically complex modulator of hepatic carcinogenesis. Despite advances in immunotherapy, long-term survival remains poor, underscoring the need for complementary preventive and adjunctive strategies. Methods: We conducted a narrative review of epidemiological, experimental, and clinical literature on dietary patterns, polyphenols, and non-polyphenol nutraceuticals for HCC prevention and management, with a focus on underlying molecular and cellular mechanisms. Results: Dietary polyphenols and selected nutraceuticals exert pleiotropic effects on signaling pathways implicated in HCC, including NF-κB, STAT3, TGF-β/SMAD, PI3K/AKT, and Wnt/β-catenin, while modulating hepatic stellate cell activation, immune cell polarization, and microbiome-derived metabolites. Preclinical studies suggest that some compounds may enhance antitumor immunity and sensitize tumors to systemic therapies; however, clinical translation is constrained by limited bioavailability, pharmacokinetic variability, formulation heterogeneity, and a lack of high-quality trials. Conclusions: This review highlights the potential of dietary patterns and nutraceuticals in HCC prevention and as adjunctive therapies. It outlines key translational priorities, including etiologic stratification, biomarker-driven trial design, and rigorous safety evaluation. Full article

Demyelinating diseases are characterized by loss of myelin and impaired neuronal function. Differentiation of oligodendrocyte progenitor cells (OPCs) and neural stem and progenitor cells is regulated by intracellular kinase signaling pathways. PI3K/Akt/mTOR and Wnt/GSK-3β signaling are involved in oligodendrocyte maturation and neurogenesis, and pharmacological modulation of these pathways affects myelin formation and neuronal differentiation. Small-molecule compounds targeting these pathways influence protein synthesis, lipid production, and β-catenin-dependent transcription. Activation of Akt and mTOR is associated with increased myelin-related protein expression, whereas inhibition of mTOR reduces oligodendrocyte differentiation. In contrast, inhibition of GSK-3β affects β-catenin stability and is associated with oligodendrocyte differentiation. These pathways also affect proliferation and differentiation of neural stem and progenitor cells. However, effects observed in experimental demyelination models have not been established as direct evidence of remyelination in patients. In addition, pharmacological agents act on multiple cell populations in the central nervous system (CNS), which complicates interpretation of their effects on specific cell types. This review examines pharmacological targeting of PI3K/Akt/mTOR and Wnt/GSK-3β signaling and describes intracellular mechanisms involved in oligodendrocyte and neuronal differentiation, with consideration of therapeutic application in demyelinating diseases. Full article

Spondyloarthritis represents a group of chronic immune-mediated rheumatic diseases that manifest as peripheral or axial musculoskeletal involvement. In axial spondyloarthritis (axSpA), the milestones of structural damage are represented by inflammation, followed by erosions in the sacroiliac joints (SIJ) and new bone formation. The purpose of this narrative review is to address the unmet needs regarding targeted risk stratification of disease progression in axSpA. While studies concerning predictive biomarkers have been conducted, their use in clinical practice has not yet been validated. Analysis of disease progression in patients recently diagnosed with non-radiographic axSpA, with fulfillment of the Assessment of Spondyloarthritis International Society criteria, determined a mean time of structural changes progression of 2.4 years. While factors such as human leukocyte antigen (HLA)-B27 and C-reactive protein are useful in classifying patients into risk categories regarding radiographic progression, novel biomarkers are needed in clinical practice to further facilitate treatment strategy selection. Choosing biomarkers to analyze the potential of both spinal and SIJ radiographic progression is useful in monitoring patients and reducing the burden of disease. Fetuin-A, sclerostin, and autoantibodies against Cluster of Differentiation 74 (anti-CD74) were associated with SIJ changes in various studies. Regarding spinal structural damage, adipokines, particularly leptin and visfatin, have been extensively studied and have shown promising results. Dickkopf-1, a regulator of the Wnt signaling pathway, vascular endothelial growth factor, and matrix metalloproteinase-3 have also presented associations with worsening modified Stoke Ankylosing Spondylitis Spine Score. The potential of each biomarker may be heightened by their use in prediction models with the purpose of implementation in clinical practice, particularly in improving patient outcomes and tailoring treatment strategies for individuals with spinal structural damage. Full article

Disease-modifying therapies (DMT)s) for relapsing-remitting multiple sclerosis (RRMS) act through distinct immunological mechanisms, yet the within-patient molecular response programs associated with these therapies remain incompletely defined. Here, we reanalyzed publicly available peripheral blood mononuclear cell (PBMC) miRNA microarray data (GSE230064) using a longitudinal, robustness-focused framework to compare therapy-associated miRNA response patterns following cladribine versus ocrelizumab treatment. Baseline (t0) and 6-month post-treatment (t1) samples were paired within individuals and technical replicates consolidated prior to analysis, yielding a final paired cohort of four cladribine-treated and six ocrelizumab-treated patients. Within each treatment arm, we quantified per-patient Δ-miRNA (t1 − t0) values and prioritized therapy-associated response features using a multi-evidence framework integrating effect direction, magnitude, directional consistency across individuals, and leave-one-out sensitivity. Cladribine treatment was associated with a highly coordinated, directionally concordant upregulation of five miRNAs including hsa-miR-27a-3p, hsa-miR-27b-3p, hsa-miR-503-5p, hsa-miR-148a-3p, and hsa-miR-26a-5p, all exhibiting 100% directional stability across patients and mean Δ-expression values ranging from +0.77 to +1.38. These miRNAs target pathways relevant to MS pathophysiology, including Th17/Treg balance, Wnt-β-catenin signaling, macrophage polarization, and epigenetic immune regulation. In contrast, ocrelizumab elicited a more selective response pattern, with five miRNAs including hsa-miR-100-5p, hsa-miR-410-3p, hsa-miR-432-5p, hsa-miR-296-5p, and hsa-miR-485-3p showing moderate directional stability (83%) and greater inter-individual heterogeneity, consistent with the more targeted mechanism of CD20+ B-cell depletion. Notably, the two treatment-associated signatures were non-overlapping, with hsa-miR-27b-3p representing the only miRNA shared with prior cross-sectional analyses of this dataset. The identified ocrelizumab-associated miRNAs implicate pathways including mTOR/IGF1R signaling, NF-κB regulation, RNA editing, and mitochondrial biogenesis, several of which are dysregulated in progressive MS. Together, these findings demonstrate that cladribine and ocrelizumab induce distinct, treatment-specific miRNA response architectures that reflect their divergent immunological mechanisms. This work establishes a stability-aware analytic template for extracting reproducible longitudinal miRNA signals from small paired RRMS cohorts and provides a ranked set of biologically plausible candidate miRNAs for prospective validation and mechanistic investigation. Full article

Glioblastoma is the most aggressive form of brain tumor resulting in low overall patient survival rates of 12–15 months post diagnosis. Several factors contribute to the complexity of the tumor, including tumor heterogeneity, blood–brain barrier complications, genetic defects, cancer stem cell generation, and immune evasion. These factors can result in the progression of glioblastoma and are controlled by signaling pathways. Some of the signaling pathways involved in glioblastoma progression include ERK, NF-κB, Wnt, and PI3K/AKT/mTOR. Our and others’ previous studies have found that TIM-3 and TGF-β signaling is altered in glioblastoma patients and may contribute to cancer progression. Immune promoting pathways such as STING have also been studied in glioblastoma to enhance anti-tumor immunity; however the interconnecting roles of these pathways are not well described. This review highlights the role of these three key cancer-related pathways in glioblastoma and their mechanistic link. Better understanding these links may result in improved treatment targets or disease progression biomarkers. Full article

Matrix metalloproteinases (MMPs) are zinc-dependent proteolytic enzymes involved in extracellular matrix remodelling in oral and dental tissues, including the periodontal ligament, alveolar bone, dentin, dental pulp, and periapical tissues. This narrative review summarises selected evidence on the role of MMPs and tissue inhibitors of metalloproteinases (TIMPs) in orthodontic tooth movement, dental trauma and root resorption, restorative adhesive dentistry, and pulp/periapical disease. Particular attention is given to signalling pathways that regulate MMP/TIMP activity, including nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), Wnt/β-catenin, and transforming growth factor beta (TGF-β)/Smad-related mechanisms. The review also discusses the biomarker potential and translational status of MMP-targeted strategies. Across clinical contexts, MMP activity contributes to both matrix degradation and tissue repair, and its biological effect depends on local stimuli, TIMP-mediated regulation, pathway crosstalk, and the stage of disease or treatment. Full article

Background and Objectives: Early progression (PFS < 90 days) in NSCLC patients undergoing ICI treatment constitutes a significant clinical challenge. Although predictive biomarkers have been extensively investigated, specific transcriptomic and immune microenvironment characteristics contributing to early progression remain inadequately characterized. Materials and Methods: We analyzed RNA-seq data from 27 NSCLC patients receiving anti-PD-1/PD-L1 therapy (GSE135222). Patients were categorized as Early Progression (PFS < 90 days; n = 17) or Clinical Benefit (PFS ≥ 90 days; n = 10). GSEA was performed with Hallmark and C7 ImmuneSigDB gene sets. Immune cell deconvolution was performed using EPIC. An 87-gene immunosuppressive risk score was derived from TGF-β, WNT/β-catenin, and EMT pathway leading-edge genes. Results: GSEA identified 17 significantly enriched Hallmark pathways in early progressors, predominantly immunosuppressive (TGF-β, WNT/β-catenin) and oncogenic (MYC targets, E2F targets, G2M checkpoint) programs. C7 ImmuneSigDB analysis revealed 131 enriched immune signatures including CD8 T cell dysfunction, Treg activation, and M2 macrophage polarization. An 87-gene immunosuppressive risk score demonstrated a significant negative correlation with PFS (Spearman ρ = −0.516, p = 0.006) and a trend toward poorer survival outcomes (HR = 2.12, p = 0.093). Conclusions: In NSCLC patients receiving ICI, early disease progression is marked by simultaneous activation of TGF-β/WNT-mediated immunosuppressive pathways, oncogenic signaling, and CD8 T cell dysfunction. The 87-gene immunosuppressive risk score demonstrates a statistically significant negative correlation with PFS (Spearman ρ = −0.516, p = 0.006); however, given the small sample size (n = 27) and absence of external validation, these findings should be interpreted as exploratory and hypothesis-generating, warranting prospective validation in independent cohorts. Full article

Ocular surface inflammation is a major disruptor of corneal epithelial homeostasis and a key driver of limbal stem cell deficiency (LSCD). Limbal stem cells (LSCs), residing within the specialized limbal niche, maintain corneal transparency through continuous epithelial renewal and by preventing conjunctival encroachment onto the corneal surface. Chronic or severe inflammatory insults—stemming from systemic autoimmune disorders, ocular surface diseases, infections, trauma, or environmental stressors—can damage both LSCs and their microenvironment, ultimately leading to limbal insufficiency. This review synthesizes current insights into the mechanisms by which inflammation impairs LSC survival, including cytokine-mediated cytotoxicity, oxidative stress, immune cell infiltration, and disruption of essential signaling pathways such as Wnt, Notch, and BMP. The distinction between LSC depletion and LSC dysfunction is highlighted, as residual stem cells may persist even in clinically advanced disease and can regenerate the corneal surface once the inflammatory milieu is corrected. Clinical manifestations, staging systems, and diagnostic markers—including p63α, ABCG2, and additional emerging molecular indicators—are summarized to support accurate assessment of LSCD severity. Current therapeutic strategies, ranging from anti-inflammatory medical management to surgical approaches such as SLET, CLET, and allogeneic transplantation, are reviewed alongside evolving regenerative and cell-based therapies. By integrating mechanistic understanding with clinical implications, this review underscores the critical interplay between inflammation and limbal niche failure and emphasizes the importance of early recognition and targeted intervention to preserve or restore LSC function. Full article

Background: Diffuse Large B-cell Lymphoma (DLBCL) is a biologically heterogeneous subtype of non-Hodgkin’s lymphoma (NHL), accounting for 30–40% of cases worldwide. Despite the incorporation of rituximab into standard chemo-immunotherapy regimen, approximately one-third of patients present with relapsed or refractory disease, implicating the need for improved prognostic markers and therapeutic targets. Gene expression profiling successfully classified DLBCL into Germinal Center B-cell-like (GCB) and non-GCB subtypes, which differ in genetic alterations, response to therapy, and clinical outcome. While intrinsic tumor biology has been extensively studied, the contribution of the tumor microenvironment (TME) to disease progression and therapeutic resistance still remains incompletely understood. Methods: In this study, we investigated the mutational landscape of stromal-related genes in DLBCL and evaluated their impact on gene expression, downstream signaling pathways, and tumor progression. Results: A total of 176 DLBCL patients were screened, of which 113 were enrolled based on availability of complete clinical data. The cohort demonstrated male predominance (male:female ratio: 2.1:1), advanced disease stage in 72.6% of patients, and elevated serum lactate dehydrogenase levels in 57.5%. Based on immunohistochemistry, 43.4% cases were classified as GCB-DLBCL and 56.6% as non-GCB DLBCL. Although the International Prognostic Index (IPI) retained prognostic significance for event-free survival (EFS) and overall survival (OS), considerable heterogeneity was observed within similar risk groups. Whole-exome sequencing (WES) uncovered recurrent somatic mutations in key oncogenic and epigenetic regulators, including TNFAIP3, NFIB, NOTCH1, TSC2, EZH2, EP300, KMT2D, and B2M, with subtype-specific distribution. Pathway enrichment analysis implicated role of Notch, Wnt, mTOR, JAK-STAT, TGF-β, and antigen-presentation pathways. Comprehensive WES analysis identified multiple novel mutations in genes associated with the stromal/extracellular matrix with distinct patterns in GCB and non-GCB DLBCL, accompanied by concordant alterations in gene expression profiles, suggesting functional relevance within the TME. Functional validation through primary cell culture demonstrated significantly elevated Th2 (IL-4, IL-6, IL-10) and Th17 (IL-17) cytokines in co-cultures containing both neoplastic cells and stromal components, underscoring the role of TME in DLBCL progression. Conclusions: Taken together, this study provides novel insights into stromal mutational signatures and cytokine-mediated tumor–stroma interactions, offering potential prognostic biomarkers and therapeutic targets for the improved management of DLBCL. Full article