Tissue Barriers最新文献

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.

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 in vitro 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.

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.

Epithelial to mesenchymal transition (EMT) has been widely implicated in diverse cellular processes such as development, would healing, as well as in cancer metastasis and therapy resistance. Exosomes are nanosized vesicles that carry cellular products and are known to mediate cell-cell communication. We describe here how a systems biology approach relying on simple experimental data in combination with in silico tools and mathematical modeling can be used to understand complex biological phenomenon such as EMT.

Diabetic foot ulcer (DFU) is a chronic and predominantly microvascular and neuropathic complication in more severe or chronic cases of diabetes mellitus. It is characterized by chronic nonhealing wounds, vascular impairment, and delayed healing process, leading to severe complications, limb amputations, and increased mortality. With an annual incidence rate of approximately 2%, DFU poses a significant global healthcare and economic burden. Despite its prevalence, current treatment options remain limited, necessitating the urgent need for a deeper understanding of the underlying molecular pathways or mechanisms to develop effective therapeutic strategies. Present work is emphasized on molecular mechanisms involved in pathogenesis of DFU and current and emerging therapeutic interventions for the treatment of DFU. Due to its high prevalence, multifaceted pathophysiology, and significant healthcare and economic burden, a thorough understanding of molecular pathways underlying DFU is essential to develop precise therapeutic interventions to improve clinical outcome and reduce the healthcare burden associated with DFU. Several therapeutic interventions have been utilized, like modulators of key signaling pathways (Wnt/β-catenin, PI3K/Akt/mTOR, JAK/STAT, and Notch), repurposed pharmacological agents (e.g. metformin, colchicine, deferoxamine, and lithium carbonate), and advanced local treatments such as bioactive hydrogels and next-generation dressings. Furthermore, regenerative approaches like gene therapy, stem cell transplantation, therapeutic peptides, and 3D-bioprinted adipose tissue constructs provide a promising strategy for restoring tissue integrity and promoting healing.

Neuroinfectious diseases such as meningitis, encephalitis, and myelitis continue to be a significant health issue especially in low- and middle-income nations where the timely identification and successful treatment are mostly not yet available. There is also the complicating factor of the restrictive nature of the blood-brain barrier (BBB) which greatly limits the passage of antimicrobial and anti-inflammatory agents through into the central nervous system. Exosomes which are nano-sized extracellular vesicles released by a vast variety of cells have been proposed as a promising solution to overcome this barrier because of their natural biocompatibility, low immunogenicity and capacity to enter the BBB by receptor-mediated, adsorptive-mediated and carrier-mediated processes. This review critically discusses the structural and functional dynamics of the BBB in infection, the recent discoveries in the exosome trafficking pathways, and the diagnostic and therapeutic role of exosomes in infection, including infections related to HIV-associated neurocognitive disorders, tuberculous meningitis, cryptococcal meningitis, neurotoxoplasmosis. Special consideration will be given to engineered exosomes and how they could be used to improve targeted delivery of drugs, decrease systemic toxicity and offer minimally invasive biomarkers platforms to detect disease earlier. He/she points possible solutions to CNS infections by combining mechanistic understanding with newly acquired pre-clinical and clinical results, this review emphasizes the increasing promise of exosome-based nanomedicine as a transformational technology.

Nanoparticle (NP)-based technologies are transforming the management of central nervous system (CNS) disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and brain cancer (BC), glioblastoma, by surpassing the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB). This review integrates NP approaches, comprising organic (e.g. liposomes, polymeric NPs), inorganic (e.g. gold, iron oxide), carbon-based, and hybrid systems, to overcome disease-specific barriers. In AD, superparamagnetic iron oxide NPs (SPIONs) and gold NPs (AuNPs) improve amyloid-beta plaque and tau protein detection, while liposomes precisely deliver anti-amyloid drugs. For PD, dopamine-loaded liposomes and cerium oxide NPs reinstate dopaminergic function and decrease oxidative stress, with improved motor outcomes. In MS, PEGylated liposomes and PLGA NPs regulate autoimmune responses, inducing remyelination and attenuating neuroinflammation. For BC, dendrimers and magnetic NPs facilitate targeted chemotherapy delivery across the BBB/BBTB, improving glioblastoma treatment outcomes. We compare NP types critically based on physicochemical characteristics, efficacy, toxicity, and clinical translation potential, highlighting gaps in long-term safety and scalability. Challenges like NP toxicity and regulatory complexities are discussed, suggesting biocompatible designs and standardized FDA/EMA pathways. By consolidating diagnostic and therapeutic innovations, this review outlines a roadmap for NP-based precision medicine, paving the way for clinical translation and better patient outcomes in CNS disorders and brain cancer.

The placenta possesses several structural and immunological barriers against viral infections, the SARS-CoV-2 detection in placental tissues has raised concerns regarding possible alternative viral entry mechanisms beyond the canonical ACE2/TMPRSS2-mediated pathway. In this context, the present study evaluated the immunohistochemical expression patterns of ADAM17, Cathepsin L, Clathrin, ACE-2, Furin, NRP-1, and TMPRSS2-molecules involved in SARS-CoV-2 placental entry pathways - as well as the detection of viral RNA by RT-qPCR in paraffin-embedded samples. The study included 75 paraffin-embedded placental samples (decidua and villi) collected after spontaneous placental delivery at birth from patients who tested positive for COVID-19 (COVID-19 Group), and 19 paraffin-embedded control placental samples collected prior to the COVID-19 pandemic (NON-COVID-19 Group). A statistically significant reduction in NRP-1 expression was observed in the COVID-19 group decidua (p < 0.001), including in RT-qPCR - positive samples (p = 0.001), regardless of comorbidities or underlying conditions. A statistically significant reduction in Clathrin expression was also found in the decidual samples of the COVID-19 group and in RT-qPCR - positive samples (p = 0.05and 0.013, respectively), while Cathepsin L expression was significantly increased in the placental villi of the COVID-19 group (p < 0.001) and in RT-qPCR - positive samples (p = 0.005). These findings may contribute to a better understanding of the mechanisms underlying SARS-CoV-2 interaction with the placenta, possibly through auxiliary and/or endocytic entry pathways, and may support future investigations into the impact of these alterations in the context of maternal SARS-CoV-2 infection.

Bacopaside I (BM4), a saponin found in Bacopa monnieri, has nootropic, neuroprotective, and anti-depressant properties. Neuroprotective entities generally are impermeable across the brain membrane, and this hassle can be resolved by using drug-encapsulated polymeric nanoparticles (NPs). Epileptic seizures are linked to the increased expression of fractalkine, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors, and mammalian target of rapamycin (mTOR) dysregulation. This study investigated the effect of BM4 encapsulated poly(lactic-co-glycolic acid) (PLGA)-polyethylene glycol (PEG)-nanoparticles (BM4NP) in comprehending seizure and its ability to protect brain tissues from kainic acid (KA)-induced excitotoxicity associated neuroinflammation, oxidative stress, and over-expression of seizure markers. The optimal size (87.31 ± 9.2 nm) and zeta potential (-18.8 ± 4.7 mV) of BM4NP resulted in efficient drug loading and release kinetics. Our data demonstrated that BM4NP reduced KA-induced brain tissue damage, by restoring normal nuclear outline and strengthening brain membrane integrity. BM4NP also suppressed the over-expression of fractalkine, AMPA receptors, and mTORC1 signaling and increased antioxidant levels, suggesting it as a therapeutic agent to contain seizures.

Intestinal tight junction disruption initiates progression of related diseases including inflammatory bowel disease (IBD) with no FDA-approved drug for tight junction recovery. To demonstrate the effect of pharmacological activation of the cannabinoid/lysophosphatidylinositol-sensing G-protein coupled receptor 55 (GPR55) by its specific synthetic agonist O1602 on intestinal barrier function, tight junction-dependent permeability, and its underlying mechanisms. We show that O1602 treatment increased transepithelial electrical resistance (TER) across intestinal epithelial-like T84 cell monolayers and suppressed 4-kDa FITC-dextran permeability. Neither CB1 inhibitor nor CB2 inhibitor has affected TER increases in response to O1602 treatment. O1602 was ineffective in enhancing intestinal barrier integrity in T84 monolayers treated with GPR55 antagonist or in GPR55 KD T84 monolayers, indicating that GPR55 agonism promotes intestinal barrier function and inhibits tight junction-dependent leak pathway permeability. In fact, O1602 treatment also prevented TNF-α-induced intestinal barrier disruption in IFN-γ-primed T84 and Caco-2BBe monolayers. The effect of O1602 treatment on enhancing TER across T84 cell monolayers was abolished by pre-treatment with inhibitors of PLC, CaMKKβ, AMPK, SIRT-1, ERK, PKA, β-arrestin, and mTOR. In addition, O1602 failed to promote TER increases in SIRT-1 KO T84 monolayers. Our data from western blot analysis, SIRT-1 activity assay, and immunofluorescence staining of tight junction proteins, coherently recapitulates that GPR55 agonism induces intestinal tight junction assembly via PLC/[Ca²⁺]_i/CaMKKβ/AMPK/SIRT-1/ERK-dependent mechanism. Hence, we furnish the first line of evidence supporting that GPR55 is the regulator of tight junction in intestinal epithelial monolayers and may serve as a novel class of therapeutic target for tight junction disruption-associated diseases.