Tissue Barriers最新文献

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.

Vocal fold organoids recapitulate critical structural and functional features of native vocal fold mucosa, providing a physiologically relevant model for investigating vocal fold biology and disease mechanisms. However, conventional histological processing of these organoids remains technically demanding, often resulting in substantial sample loss, inadequate visualization during embedding and difficult retrieval the blocks from Eppendorf tubes. To address these issues, we established a comprehensive protocol that integrates direct eosin pre-staining, agarose pre-embedding and fine-needle-assisted retrieval of agarose-embedded blocks. This optimized workflow increases processing efficiency, enables enhanced visual monitoring and better preserves cytoarchitectural integrity. Consequently, sectioning is facilitated, and both hematoxylin and eosin (HE) staining and immunofluorescence (IF) exhibit superior quality and reproducibility, producing highly consistent morphological details and robust signal resolution. The proposed method provides a standardized and reliable platform for high-resolution histological and IF examination of epithelial organoids, thereby extending its utility in vocal fold research and related organoid applications.

Diabetic neuropathy (DN) is a multifaceted and progressive complication of diabetes mellitus, characterized by functional and structural damage to peripheral, autonomic, and sensory nerves. Despite its high prevalence and debilitating consequences, current therapeutic approaches remain largely symptomatic, with limited disease-modifying strategies available. The pathogenesis of DN is driven by a complex network of molecular, cellular, and enzymatic interactions, primarily instigated by chronic hyperglycemia. This review unravels the intricate molecular and cellular crosstalk underlying DN, emphasizing the roles of specific cellular and enzymatic mediators in disease progression. Key cellular players, including neurons, Schwann cells, satellite glial cells, macrophages, and bone marrow-derived cells, orchestrate and respond to pathogenic stimuli, contributing to neuroinflammation, demyelination, and axonal degeneration. Chronic hyperglycemia activates several enzymatic pathways that exacerbate oxidative stress, mitochondrial dysfunction, and vascular impairment. Among the pivotal enzymes involved is aldose reductase, which drives the polyol pathway and sorbitol accumulation; diacylglycerol (DAG)-mediated protein kinase C (PKC), linked to vascular dysfunction; poly(ADP-ribose) polymerase (PARP), which amplifies DNA damage responses; and endogenous antioxidants, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase, whose dysregulation further fuels oxidative injury. Additionally, growth factors (e.g. NGF, IGF-1, and VEGF), along with metabolic regulators (like AMPK), play pivotal roles in maintaining neuronal growth, survival, and function by modulating cellular energy homeostasis, oxidative balance, and inflammatory responses. By examining these interconnected molecular mechanisms, this review highlights potential therapeutic targets and proposes future directions for mechanism-based interventions aimed at halting or reversing the progression of diabetic neuropathy.

Glomerular podocytes, specialized epithelial cells, are central to the filtration function of vertebrate kidneys. Through their interdigitating foot processes, podocytes provide epithelial coverage to capillaries. They maintain selective filtration by allowing water, ions, and small solutes to filter while retaining proteins and larger molecules in the blood. The slit diaphragm (SD), a specialized junction between podocyte foot processes, along with glomerular basement membrane (GBM) and fenestrated endothelium, serves as a glomerular filtration barrier (GFB). Injury to GFB, such as loss of SD integrity and foot process effacement, compromises permselectivity and results in proteinuria. The SD consists of junctional proteins (nephrin, Neph1), adaptors (podocin, CD2AP), and channels (e.g. TRPC6), which assemble into a molecular sieve and a dynamic signaling hub. Monogenic mutations and resultant structural defects in SD components perturb podocyte filtration function, leading to proteinuria, nephrotic syndrome, and focal segmental glomerulosclerosis. This review summarizes structural and functional insights into SD architecture and emphasizes advances from biochemical, biophysical, and high-resolution imaging approaches. We particularly discuss the role of intrinsically disordered regions in mediating oligomerization and protein - protein networks within the SD. Emerging Cryo-EM studies further provide new perspectives on the stoichiometry of Nephrin - Neph1 complexes and their implications for SD ultrastructure. Finally, we outline unresolved questions regarding SD composition, assembly, and signaling, proposing how integrative structural biology may illuminate mechanisms underlying proteinuric kidney diseases.

Despite its widespread application in the treatment of cancer and autoimmune diseases, methotrexate (MTX) is associated with several adverse effects. Selenium nanoparticles (SeNPs) have antioxidant and anti-inflammatory effects. This study aimed to investigate the ameliorating effects of SeNPs against MTX-induced gastric fundus damage and the possible underlying mechanisms. Rats were randomly allocated into five groups: control group, SeNPs group, MTX group, and two SeNPs administered groups either prophylactic or concomitant. Physical and macroscopic evaluations were performed. Gastric fundus specimens were collected for biochemical and histological changes. The Methotrexate group showed a significant decrease in weight gain, food intake, and gastric total antioxidant capacity (TAC). Also, there was a disruption of the gastric epithelial barrier indicated by the significant decrease in occludin, E-cadherin gastric levels, and zonula occludens-1 (ZO-1) immune-expression, together with mucous barrier alteration indicated by a significant decrease in Periodic acid-Schiff (PAS) stain mean area fraction. While gastric malondialdehyde (MDA), toll-like receptors 4 (TLR4), and Myeloid differentiation primary response 88 (MYD88) levels, the nuclear factor kappa B (NF-κB) and cleaved caspase 3 immune-expression were significantly increased. Furthermore, histological assessment revealed mucosal ulceration, vascular congestion, and inflammatory cellular infiltration with a significant increase in mast cells. Surprisingly, SeNPs administration attenuated oxidative stress, apoptosis, and TLR4/NF-κB signaling. Moreover, a significant increase in occludin, E-cadherin, and ZO-1 and a significant decrease in mast cell number were noticed with SeNPs administration together with histological structure preservation. Notably, the prophylactic treatment with SeNPs caused more improvement than its concomitant administration.

Blood-brain barrier (BBB) dysfunction is an early event observed in Alzheimer's disease (AD). Two characteristics of AD brain and brain vasculature contribute to BBB dysfunction: the accumulation of aggregated amyloid-β protein (Aβ) and an increase in oxidative stress. This work uses a BBB model of primary human brain microvascular endothelial cells to investigate the individual and synergistic influence of both pathogenic Aβ oligomers and oxidative stress on BBB transendothelial electrical resistance (TEER), an indicator of barrier integrity. Results indicate that nontoxic, physiological concentrations of Aβ oligomers reduce TEER, while Aβ monomer remains inert. Moreover, introducing mild oxidative stress, which alone does not influence monolayer integrity, exacerbates the effect of Aβ oligomers on TEER within this BBB model. These findings advance the understanding of BBB dysfunction in AD and point toward therapeutic strategies targeting this early event that contributes to a currently irreversible disease.

Blood-tissue barriers (BTBs) are highly specialized, selectively permeable surfaces that separate the circulatory system from delicate tissues and organs. Critical examples include the blood-brain barrier (BBB), blood-retinal barrier (BRB), blood-testis barrier (BTB), and other organ-specific barriers, including the alveolar-capillary interface in the lungs and the glomerular filtration barrier in the kidneys. These barriers regulate the bidirectional transport of nutrients, gases, and waste while restricting pathogens, toxins, and immune cells to maintain physiological balance. Nevertheless, viruses have evolved multiple strategies to circumvent or compromise these barriers, facilitating viral entry, evading immune surveillance, and establishing infection within protected compartments. Neurotropic viruses, including the West Nile virus and Japanese encephalitis virus, impair the blood-brain barrier by disrupting tight junction proteins and cytokine storms. In contrast, respiratory viruses such as influenza and SARS-CoV-2 affect the lung barrier, resulting in alveolar injury and systemic inflammation. Other viruses, such as the Zika virus, affect the BTB and placental barriers, presenting significant risks to fetal development and reproductive health. Such breaches facilitate viral spread, exacerbate tissue damage, and complicate therapeutic interventions. This review provides a comprehensive overview of blood-tissue barrier architecture, function, and mechanisms of viral disruption, highlighting their dual role in protection and susceptibility during viral infections. By elucidating interactions between viruses and blood-tissue barriers, this work highlights emerging research directions to mitigate viral pathogenesis and enhance treatment efficacy for barrier-associated diseases.