Tissue Barriers最新文献

{"title":"Mutational signatures in blood-brain barrier: mechanisms, computational insights, and clinical applications in precision oncology.","authors":"Hare Krishna, Vinod Kumar Singh, Seema Awasthi, Ajay Kumar","doi":"10.1080/21688370.2026.2664236","DOIUrl":"https://doi.org/10.1080/21688370.2026.2664236","url":null,"abstract":"<p><p>The blood - brain barrier (BBB) plays a central role in maintaining central nervous system (CNS) homeostasis, and its disruption is a defining feature of malignant brain tumors such as glioblastoma. Emerging evidence indicates that BBB dysfunction not only alters the tumor microenvironment but also shapes the mutational processes that drive genomic instability in CNS malignancies. This review synthesizes current understanding of the biological mechanisms linking BBB breakdown with distinct mutational signatures, including those arising from oxidative stress, hypoxia-induced replication stress, lipid peroxidation, inflammation, and metabolic reprogramming. Advances in next-generation sequencing, coupled with computational tools such as non-negative matrix factorization, Bayesian modeling, and deep learning, have enabled precise extraction of these signatures and their integration with multi-omics data. Clinically, BBB-associated mutational signatures offer significant promise for therapeutic stratification, prediction of treatment response, and noninvasive monitoring through cerebrospinal fluid - derived circulating tumor DNA. Despite these advances, challenges persist due to limited tissue accessibility, low-yield CSF samples, incomplete mechanistic models, and the lack of CNS-specific analytical frameworks. A deeper understanding of BBB-driven mutational processes, supported by improved computational approaches and integrative datasets, holds potential to advance precision oncology in neuro-oncology.</p>","PeriodicalId":23469,"journal":{"name":"Tissue Barriers","volume":" ","pages":"2664236"},"PeriodicalIF":4.0,"publicationDate":"2026-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147821400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated transcriptomic and functional characterization of Claudin-1 reveals its oncogenic and immunomodulatory roles in pancreatic ductal adenocarcinoma.","authors":"Anju Surendranath, Yogain Taank, Saira Hamid, Tharini Karthikeyan, Ikhlak Ahmed, Imadeldin Elfaki, Rashid Mir, Rakesh Kumar, Sameer Mirza, Mayank Singh, Shahab Uddin, Ammira S Al-Shabeeb Akil, Muzafar A Macha, Punita Dhawan, Ajaz A Bhat","doi":"10.1080/21688370.2026.2648150","DOIUrl":"10.1080/21688370.2026.2648150","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) remains among the deadliest malignancies, driven by its invasive nature and lack of effective biomarkers. Disruption of the epithelial barrier, mediated by tight junction components, is a critical yet underexplored contributor to PDAC progression. Claudins, integral regulators of tight junction integrity, display altered expression across cancers, but their prognostic and immunomodulatory roles in PDAC remain unclear. We performed an integrative analysis of 177 RNA-Seq datasets from TCGA and GTEx to characterize Claudin family alterations in PDAC. Differential expression, copy number variation, methylation, and co-expression networks were analyzed alongside clinical and survival data. Prognostic significance was assessed using Kaplan - Meier and Cox regression analyses, while immune cell infiltration was examined using deconvolution algorithms. Functional validation of Claudin-1 was conducted in Capan-1 cells using CRISPR/Cas9 knockout, followed by proliferation, wound-healing, and Western blot assays. Ten Claudin genes were significantly dysregulated, with Claudin-1 and Claudin-4 frequently amplified and associated with advanced stage and poor survival. High Claudin-1 expression correlated with reduced immune infiltration, indicating an immune-excluded phenotype characterized by immune cells retained in the tumor stroma but largely absent from the tumor parenchyma. Claudin-1 knockout markedly inhibited proliferation, migration, and EMT, evidenced by downregulation of Snail and Slug and restoration of E-cadherin expression. This integrative transcriptomic and functional study identifies Claudin-1 as a key driver of PDAC aggressiveness and immune modulation. These findings establish Claudin-1 as a promising prognostic biomarker and therapeutic target for restoring epithelial integrity and counteracting immune evasion in pancreatic cancer.</p>","PeriodicalId":23469,"journal":{"name":"Tissue Barriers","volume":" ","pages":"2648150"},"PeriodicalIF":4.0,"publicationDate":"2026-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147677217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Occludin deficiency is associated with developmental impairment, locomotor dysfunction, and social deficiencies.","authors":"Silvia Torices, Nikolai Fattakhov, Oandy Naranjo, Destiny Daniels, Sierra Simon, Leah Daire, Luisa Mendoza, Marta Kopanska, Michal Toborek","doi":"10.1080/21688370.2026.2647450","DOIUrl":"https://doi.org/10.1080/21688370.2026.2647450","url":null,"abstract":"<p><p>Neurodevelopmental and psychiatric disorders, such as attention deficit hyperactivity disorder or autism spectrum disorder, have been intricately linked to structural impairments and compromised permeability of the blood-brain barrier (BBB). Occludin (ocln) is a tight junction (TJ) protein known for its role in maintaining BBB integrity. In the present manuscript, we report unexpected connection between ocln deficiency and behavioral alterations resembling neurodevelopmental and psychiatric disorders. Adolescent, occludin-deficient (ocln^-/-) mice displayed an abnormal growth and neurological phenotype along with deterioration of motor functions as compared to wild-type controls. Moreover, adult ocln^-/- mice exhibited increased hyperactivity, social difficulties, and attention deficits compared to control mice. Among the brain structures, the hippocampus appeared to be most susceptible to ocln deficiency as it exhibited higher expression levels of ocln than both the frontal cortex and striatum. Overall, the observed behavioral alteration patterns in ocln^-/- mice indicated pronounced neurological motor dysfunction and behavioral changes that parallel those seen in attention deficit hyperactivity disorder and autism spectrum disorder. These findings are important for better understanding the role of ocln in neurodevelopmental and psychiatric disorders.</p>","PeriodicalId":23469,"journal":{"name":"Tissue Barriers","volume":" ","pages":"2647450"},"PeriodicalIF":4.0,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147504880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction.","authors":"","doi":"10.1080/21688370.2026.2634592","DOIUrl":"https://doi.org/10.1080/21688370.2026.2634592","url":null,"abstract":"","PeriodicalId":23469,"journal":{"name":"Tissue Barriers","volume":" ","pages":"2634592"},"PeriodicalIF":4.0,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147391043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The gatekeepers breached: claudin dysregulation in psychiatric disorders.","authors":"Tarek Ziad Arabi, Wael Alkattan, Belal Nedal Sabbah, Abderrahman Ouban","doi":"10.1080/21688370.2026.2616111","DOIUrl":"https://doi.org/10.1080/21688370.2026.2616111","url":null,"abstract":"<p><p>Psychiatric disorders such as depression, bipolar disorder, schizophrenia, and autism spectrum disorder are increasingly understood not only as disruptions in brain chemistry or circuitry but also as disorders of neural microenvironments and barriers. This review explores the critical role of claudins, transmembrane proteins that form tight junctions, in maintaining the integrity of the blood - brain barrier (BBB) and other brain structures. Claudin-5, prominently expressed in the BBB, and claudin-11, essential for myelin integrity, emerge as central players in psychiatric pathophysiology. Evidence from human postmortem studies, serum biomarkers, and animal models indicates that claudin-5 is downregulated in key brain regions in depression, bipolar disorder, and schizophrenia, contributing to BBB permeability and facilitating neuroinflammation. Similarly, claudin-11 deficits in schizophrenia suggest impaired myelination and disrupted neural connectivity. In autism and ADHD, altered tight junction protein profiles imply more subtle or context-dependent barrier dysfunction. Mechanistically, claudin dysregulation permits peripheral inflammatory mediators and immune molecules to access brain tissue, triggering neuroinflammation, oxidative stress, and synaptic dysfunction. Additionally, loss of myelin barrier function may impair signal timing and synchronization. These findings support a unifying hypothesis: that barrier dysfunction, mediated by claudin disruption, underlies diverse psychiatric symptoms by destabilizing the brain's protected environment. Recognizing the role of claudins in mental illness opens avenues for novel biomarker development and therapeutic strategies aimed at restoring barrier integrity, offering a new perspective on the intersection of neurobiology and psychiatry.</p>","PeriodicalId":23469,"journal":{"name":"Tissue Barriers","volume":" ","pages":"2616111"},"PeriodicalIF":4.0,"publicationDate":"2026-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145998960","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Permeation of small extracellular vesicles across a human blood-brain barrier transwell model remains below particle detection limits, even under oxygen/glucose deprived conditions.","authors":"Adrián Klepe, Sonja Damberger, Ana Špilak, Andreas Brachner, Winfried Neuhaus","doi":"10.1080/21688370.2025.2610016","DOIUrl":"https://doi.org/10.1080/21688370.2025.2610016","url":null,"abstract":"<p><p>Ischemic stroke disrupts blood-brain barrier (BBB) integrity and alters small extracellular vesicle (sEV) signaling, yet the mechanisms underlying sEV transport across compromised barriers remain poorly understood. This study investigated BBB-sEV interactions under normal and stroke-mimicking oxygen/glucose deprivation (OGD) conditions using an <i>in vitro</i> human BBB co-culture model consisting of brain capillary endothelial (BCECs, hCMEC/D3) and astrocytoma cells (1321N1). Model characterization revealed that co-culture with 1321N1 cells enhanced BBB vulnerability to OGD compared to hCMEC/D3 mono-culture. OGD exposure (5 h and 24 h) progressively decreased transendothelial electrical resistance (TEER) and increased FITC-dextran 4 (FD4) permeability, with more severe impairment in co-cultures (e.g. TEER - after 5 h: 0.85-fold, after 24 h: 0.55-fold for co-culture related to mono-culture). Following 19 h oxygen and glucose restoration ('recovery') after 5 h OGD, barrier integrity loss was halted but not reversed. Transcriptomic analysis revealed adaptive cellular responses including upregulated glucose transporter 1 (GLUT1) and vascular endothelial growth factor (VEGF), alongside temporal changes in tight junction protein expression (CLDN5, CDLN6). sEV secretion kinetics in apical and basolateral compartments demonstrated that both cell types released particles in response to OGD in a time-dependent manner, with co-cultures showing enhanced secretion compared to mono-cultures. sEV uptake and permeation studies using eight cancer cell line-derived sEVs revealed cell-origin dependent internalization patterns by BCECs, with the highest uptake for HEK293T and SH-SY5Y sEVs. These internalized sEVs were predominantly targeted to lysosomes. Despite severe barrier disruption due to OGD transcellular permeation of single sEV particles was not detectable.</p>","PeriodicalId":23469,"journal":{"name":"Tissue Barriers","volume":" ","pages":"2610016"},"PeriodicalIF":4.0,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145935324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The oral mucosal barrier: a dynamic gateway in oral and systemic health.","authors":"Yuan Xin, Hu Lei","doi":"10.1080/21688370.2025.2610035","DOIUrl":"https://doi.org/10.1080/21688370.2025.2610035","url":null,"abstract":"<p><p>The oral mucosal barrier, the primary entry point for essential substances (water, food, air), is crucial for oral and systemic health. Comprising a salivary gel layer, commensal microbiota, stratified epithelia, underlying connective tissues, and immunocompetent cells, this complex interface orchestrates selective defense against pathogens and physical and chemical factors while facilitating the absorption of nutrient and bioactive compound. Disruption of this barrier is associated with oral pathologies (e.g. periodontitis) and systemic dysfunction, including cardiovascular, neurodegenerative, and metabolic diseases, underscoring its significance as a key determinant of systemic health. Although the etiology is multifactorial, the precise mechanisms linking oral mucosal barrier disruption to distant organ dysfunction remain incompletely characterized. Consequently, elucidating the underlying molecular networks and cross-organ communication pathways is imperative for oral and systemic health maintenance, as well as development of novel therapeutic strategies target oral and systemic diseases. This review synthesizes recent advances in understanding the molecular architecture of the oral mucosal barrier, explores its local and systemic regulatory networks, and evaluates emerging innovations in barrier-targeted precision medicine approaches.</p>","PeriodicalId":23469,"journal":{"name":"Tissue Barriers","volume":" ","pages":"2610035"},"PeriodicalIF":4.0,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145906882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antagonists of the N-cadherin/Fibroblast growth factor receptor tyrosine kinase complex.","authors":"Orest W Blaschuk","doi":"10.1080/21688370.2025.2532160","DOIUrl":"10.1080/21688370.2025.2532160","url":null,"abstract":"<p><p>This review describes similarities between the biological actions of cell adhesion molecule antagonists and pan-growth factor receptor tyrosine kinase (GF-RTK) antagonists. In particular, the biological consequences of the interaction between the cell adhesion molecule, neural (N)-cadherin (CDH2) and the fibroblast GF-RTK (FGF-RTK) are discussed. Intercellular adhesion mediated by N-cadherin stimulates FGF-RTK activity triggering intracellular signaling pathways (<i>e.g</i>. PI3/Akt/mTOR pathway) that regulate various morphogenetic processes (<i>e.g</i>. apoptosis). Antagonists of either N-cadherin or GF-RTKs modulate these processes. N-cadherin antagonists can be regarded as a previously unappreciated class of FGF-RTK inhibitors. These antagonists, similar to GF-RTK antagonists should be capable of serving as therapeutics for treating a variety of fibrotic diseases and cancers.</p>","PeriodicalId":23469,"journal":{"name":"Tissue Barriers","volume":" ","pages":"2532160"},"PeriodicalIF":4.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12959212/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144609712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Claudins in ovarian cancer: emerging biomarkers and therapeutic targets.","authors":"Lubna Therachiyil, Ajaz A Bhat, Shahab Uddin","doi":"10.1080/21688370.2025.2539026","DOIUrl":"10.1080/21688370.2025.2539026","url":null,"abstract":"<p><p>Tight junctions (TJ) comprise protein complexes that help with the movement of ions and molecules through the paracellular pathway, thus maintaining both epithelial and endothelial integrity. The TJ proteins are diverse and include claudins, occludins, tricellulins, cingulins, and junctional adhesion molecules (JAM). Claudins are transmembrane proteins that serve as critical components of TJs in epithelial and endothelial cells. The human genome comprises 23 claudin genes, with 27 transmembrane domains recognized in mammals. Ovarian cancer (OC) is the most lethal form of all gynecologic malignancies worldwide, characterized by poor prognosis and a recurrence rate of up to 75%. In OC, several claudins are overexpressed relative to normal ovarian tissue. These elevated expression observed among OC subtypes indicates their potential utility as diagnostic biomarkers. Claudins represent potential targets for innovative therapeutic strategies. Though their exact involvement in OC is still not well understood, they are believed to be crucial for cancer invasion and therapy resistance. Recent studies show that claudins are involved in the EMT pathway and ERK, enlightening the effect of claudins in drug resistance. Clostridium perfringens enterotoxin (CPE) demonstrates potential as a therapy targeting claudins, specifically claudin-3 and -4, which serve as receptors for this toxin. Despite these advancements, challenges remain in comprehensively understanding claudin functions and in the development of effective claudin-targeted therapies. This review consolidates existing knowledge regarding claudins in OC, focusing on their expression patterns, biological functions, diagnostic and prognostic significance, and therapeutic implications. A thorough understanding of claudins in OC establishes a basis for enhancing diagnostic, predictive, and therapeutic approaches, which may result in improved therapy outcomes.</p>","PeriodicalId":23469,"journal":{"name":"Tissue Barriers","volume":" ","pages":"2539026"},"PeriodicalIF":4.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12959229/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144849207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Concordance of claudin-18.2 expression in biopsy, resection, and recurrent specimens: implications for zolbetuximab therapy in pancreatic ductal adenocarcinoma.","authors":"Daisuke Kyuno, Kazuhiko Yanazume, Akira C Saito, Yusuke Ono, Tatsuya Ito, Masafumi Imamura, Makoto Osanai","doi":"10.1080/21688370.2025.2535047","DOIUrl":"10.1080/21688370.2025.2535047","url":null,"abstract":"<p><p>Claudin-18.2 is a promising therapeutic target for gastrointestinal cancer. However, its expression pattern in pancreatic ductal adenocarcinoma, especially the concordance between biopsy and resection specimens, is unknown. This study aimed to evaluate the consistency of claudin-18.2 positivity across different specimen types using the clinically validated antibody clone 43-14A employed in ongoing zolbetuximab trials. Immunohistochemical analysis for claudin-18 was conducted on 211 resected pancreatic cancer tissues, 133 matched preoperative biopsy samples, and 60 samples from recurrent lesions. The concordance between the biopsy and resection specimens was 92.5% using a 75% staining threshold. However, this high concordance likely reflects the large proportion of claudin-18.2-negative cases, as the biopsy sensitivity for detecting claudin-18.2-positive tumors was only 54.6%. This raises concerns about underdiagnosis and suggests that biopsy alone may miss patients eligible for zolbetuximab therapy. Receiver operating characteristic analysis showed that lowering the threshold to 20% in biopsy samples improved the sensitivity to 100%. However, patients meeting this threshold would still not qualify for therapy under the current trial criteria, highlighting a potential clinical dilemma. Claudin-18.2 expression was generally preserved in recurrent lesions (83.3% concordance with primary tumors), although reductions were noted in local recurrence and liver metastasis. These findings suggest that although biopsy-based assessments may be a practical initial tool, they should be interpreted with caution. Confirmatory studies on resection specimens using the same clinical trial protocol may be necessary to ensure the accurate identification of patients eligible for claudin-18.2-targeted therapy.</p>","PeriodicalId":23469,"journal":{"name":"Tissue Barriers","volume":" ","pages":"2535047"},"PeriodicalIF":4.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12959202/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144691684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}