Search Results (366)

Peripheral edema is a pathological condition caused by abnormal fluid accumulation in the interstitial space due to elevated vascular permeability and inflammation. This study evaluated the therapeutic efficacy of Terminalia chebula fruit extract (TCE) in inflammation-induced peripheral edema and clarified its molecular mechanisms. Using hydrogen peroxide (H₂O₂)-stimulated human umbilical vein endothelial cells (HUVECs), TCE was tested for effects on cell viability, inflammatory gene expression, intracellular reactive oxygen species, endothelial barrier integrity, and vascular endothelial growth factor (VEGF)-induced migration. Its influence on nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) signaling was examined. In vivo, TCE was assessed in acetic acid-induced peritoneal vascular permeability and carrageenan-induced paw edema models, followed by histological analysis and serum tumor necrosis factor-α (TNF-α) measurement. TCE restored cell viability (76.2% to 94.8%), reduced TNF, IL6, and PTGS2 mRNA expression, and decreased reactive oxygen species by 27.2%. It enhanced barrier integrity, increased transendothelial electrical resistance, and inhibited VEGF-induced migration. TCE suppressed NF-κB and MAPK activation. In vivo, TCE reduced Evans blue extravasation by 41.6% and paw edema by 67.5%. Histology showed reduced dermal thickening and inflammatory infiltration, and serum TNF-α levels were lowered. TCE attenuates peripheral edema by preserving endothelial barrier function and suppressing inflammatory signaling, supporting its potential as a therapeutic agent for inflammation-associated vascular dysfunction and edema. Full article

Background: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, and progressive cognitive decline. Recent evidence has highlighted the role of blood–brain barrier (BBB) dysfunction in the early stages of AD pathology. Objective: We sought to explore the histological structure and physiological function of the blood–brain barrier, and to identify the shared pathological mechanisms between BBB disruption and Alzheimer’s disease progression. Methods: This narrative review was conducted through a comprehensive search of peer-reviewed literature from 1997 to 2024, using databases such as PubMed, Elsevier, Scopus, and Google Scholar. Results: Multiple histological and cellular components—including endothelial cells, pericytes, astrocytes, and tight junctions—contribute to BBB integrity. The breakdown of this barrier in AD is associated with chronic inflammation, oxidative stress, vascular injury, pericyte degeneration, astrocyte polarity loss, and dysfunction of nutrient transport systems like Glucose Transporter Type 1 (GLUT1). These alterations promote neuroinflammation, amyloid-β (Aβ) accumulation, and progressive neuronal damage. Conclusions: BBB dysfunction is not merely a consequence of AD but may act as an early and active driver of its pathogenesis. Understanding the mechanisms of BBB breakdown can lead to early diagnostic markers and novel therapeutic strategies aimed at preserving or restoring barrier integrity in Alzheimer’s disease. Full article

Lipid nanoparticles are a clinically validated platform for delivering nucleic acids, but performance is constrained by multiscale physiological barriers spanning circulation, vascular interfaces, extracellular matrices, cellular uptake, and intracellular trafficking. This review links composition–structure–function relationships for ionizable lipids, helper phospholipids, cholesterol, and PEG-lipids to systemic fate, endothelial access, endosomal escape, cytoplasmic stability, and nuclear transport. We outline strategies for tissue and cell targeting, including hepatocyte ligands, immune and tumor selectivity, and selective organ targeting through compositional tuning, together with approaches that modulate escape using pH-responsive chemistries or fusion-active peptides and polymers. We further examine immunomodulatory co-formulation, route and schedule effects on biodistribution and immune programming, and manufacturing and stability levers from microfluidic mixing to lyophilization. Across these themes, we weigh trade-offs between stealth and engagement, potency and tolerability, and potency and manufacturability, noting that only a small fraction of endosomes supports productive release and that protein corona variability and repeat dosing can reshape tropism and clearance. Convergence of standardized assays for true cytosolic delivery, biomarker-guided patient selection, and robust process controls will be required to extend LNP therapeutics beyond the liver while sustaining safety, access, and scale. Full article

Spontaneous intracerebral hemorrhage (ICH) is a devastating form of stroke, disproportionately affecting older adults and is associated with high rates of mortality, functional dependence, and long-term cognitive decline. Aging profoundly alters the structure and function of the cerebral vasculature, predisposing the brain to both covert hemorrhage and the development of cerebral microbleeds (CMBs), small, often subclinical lesions that share common pathophysiological mechanisms with ICH. These mechanisms include endothelial dysfunction, impaired cerebral autoregulation, blood–brain barrier breakdown, vascular senescence, and chronic inflammation. Systemic factors such as age-related insulin-like growth factor 1 (IGF-1) deficiency further exacerbate microvascular vulnerability. CMBs and ICH represent distinct yet interconnected manifestations along a continuum of hemorrhagic small vessel disease, with growing recognition of their contribution to vascular cognitive impairment and dementia (VCID). Despite their increasing burden, older adults remain underrepresented in clinical trials, and few therapeutic approaches specifically target aging-related mechanisms. This review synthesizes current knowledge on the cellular, molecular, and systemic drivers of ICH and CMBs in aging, highlights diagnostic and therapeutic challenges, and outlines opportunities for age-sensitive prevention and individualized care strategies. Full article

Traumatic brain injury (TBI) disrupts the blood–brain barrier (BBB), resulting in increased permeability, neuronal loss, and cognitive dysfunction. This study investigates the therapeutic potential of thyroid hormone (T4) to reduce BBB dysfunction following moderate fluid percussion injury. T4 injection (intraperitoneal) after TBI restores the levels of pericytes and endothelial cells vital for BBB integrity, reduces edema by downregulating AQP-4 gene expression, and enhances levels of the tight junction protein ZO-1. T4 counteracts the TBI-related increase in MMP-9 and TLR-4, significantly reducing BBB permeability. Furthermore, T4 enhances the neuroprotective functions of astrocytes by promoting the activity of A2 astrocytes. Additionally, T4 treatment increases DHA levels (important for membrane integrity and function), stimulates mitochondrial biogenesis, and leads to a notable improvement in spatial learning and memory retention. These findings suggest that T4 has significant potential to reduce vascular leakage and inflammation after TBI, thereby improving cognitive function and maintaining BBB integrity. Full article

Background: Endothelial cells (EC), crucial components of the vascular system, are adaptable cells that maintain homeostasis and respond to pathological events through structural and functional plasticity. Hepatocyte growth factor (HGF) is a multifunctional cytokine that has been demonstrated to have protective and disruptive influence on the blood barrier function. In endothelial biology, its role is also poorly characterized. The present study explores the impact of supraphysiological concentrations of HGF on mouse brain endothelial cells (MBECs), scrutinizing how it alters their integrity and morphology. Methods: Two groups of MBECs—control (CTR) and experimental (EXP)—were analyzed at two time points: early passage (p5) and late passage (p41). The EXP-groups (p5 and p41) were treated with HGF at a concentration of 4 µL/mL. Cellular morphology was assessed with brightfield microscopy; protein expression and localization of the tight junction marker (ZO-1) and the endothelial marker (Factor VII related antigen/von Willebrand factor, vWf) were analyzed using Western blotting, immunocytochemistry, and confocal microscopy. Intercellular barrier function was estimated via Transendothelial Electric Resistance (TEER) and Transendothelial Dextran Permeability (TEDP) assays. Results: Microscopical analysis demonstrated a change in the morphology of the MBECs from a longitudinal, spindle-like shape to a rounded, more spheroid, cobblestone-like morphology under high-dose HGF treatment. Western blotting revealed a progressive decrease of ZO-1 expression in the EXP-groups. The expression of vWf did not show significant differences. Qualitative immunocytochemical staining: vWf showed consistent expression across all groups. ZO-1 displayed a punctate, well-defined membrane and cytoplasmic localization pattern in the CTR-groups at p5 and p41. In contrast, the p5 EXP-group demonstrated a shift to a more diffuse cytoplasmic pattern. At p41, the EXP-group displayed a markedly reduced ZO-1 signal with no clear-cut membrane localization. Confocal analysis: ZO-1: punctate membrane-associated localization in CTR-groups at p5 and 41. The EXP-groups at p5 and p41 confirmed the diffuse cytoplasmic ZO-1 distribution. Phalloidin: well-organized actin cytoskeleton in CTR-groups, but rearrangement and stress fiber disorganization in the EXP-groups, especially at p41. The merged images confirmed reduced co-localization of ZO-1 with actin structures. Barrier function: TEER values dropped significantly in HGF-treated cells. TEDP to small and medium molecular weight dextran increased markedly under HGF treatment. Conclusions: Our data demonstrate that supraphysiological doses of HGF in an in vitro MBEC-barrier-like model disrupt TJ organization, leading to morphological changes and functional weakening of the MBEC-barrier-like structure, as shown by uncoupling between ZO-1/F-actin cytoskeleton, reduced TEER, and increased size-selective paracellular permeability (TEDP). Full article

Background/Objectives: The rapid progression of stroke often results in irreversible brain damage and poor outcomes when treatment is delayed. Prophylactic administration of FAD012 (3,5-dimethyl-4-hydroxycinnamic acid), a synthetic derivative of ferulic acid (FA), has demonstrated cerebroprotective effects in ischemic models through antioxidant and endothelial protective mechanisms. This study investigated the effects of FAD012 on cerebral infarction and blood–brain barrier (BBB) integrity using a photothrombotic stroke model in rats. Methods: Male Sprague Dawley rats received a single intraperitoneal injection of FAD012 or FA (100 or 300 mg/kg) 60 min prior to stroke induction. Under isoflurane anesthesia, the middle cerebral artery was exposed, and stroke was induced by intravenous administration of Rose Bengal followed by green laser irradiation. Cerebral blood flow (CBF) was monitored by laser Doppler flowmetry. BBB disruption was evaluated by Evans Blue extravasation and immunohistochemistry for tight junction (TJ) proteins. Results: Control rats exhibited extensive infarction, BBB disruption, and reduced expression of claudin-5, occludin, and ZO-1, along with fragmented collagen IV. In contrast, FAD012 (300 mg/kg) significantly attenuated CBF reduction, reduced infarct size, preserved BBB integrity, and maintained TJ protein expression, with greater efficacy than an equivalent dose of FA. FAD012 also preserved the expression and phosphorylation of endothelial nitric oxide synthase (eNOS), a key marker of vascular integrity. The CBF-preserving effect of FAD012 was completely abolished by N^G-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor. Conclusions: These findings suggest that FAD012 protects endothelial function, thereby contributing to the maintenance of CBF and BBB integrity, supporting its potential as a prophylactic therapeutic agent for ischemic stroke. Full article

Osteoarthritis involves complex interactions between articular joint tissues and the immune system, which is implicated in molecular trafficking via barrier-function modulating cytokines. The current study aims to test effects of an acute spike in TNF-α or TGF-β on vascular barrier function at multiple length scales, from the heart to tissue compartments of the knee, and cellular inhabitants of those respective compartments, in a spontaneous guinea pig model of osteoarthritis. First we quantified the intensity of a fluorescent-tagged 70 kDa tracer, similar in size to albumin, the most prevalent transporter protein in the blood, in tissue compartments of bone (periosteum, marrow space, compact bone, and epiphyseal bone) and cartilage (superficial cartilage, calcified cartilage, and the interface between, i.e., the epiphyseal line), as well as at sites of tendon attachment to bone (entheses). We then examined tracer presence and intensity in the respective pericellular and extracellular matrix zones of bone and cartilage. Acute exposure to TGF-β reduced barrier function (increased permeability) at nearest vascular interfaces in four of eight tissue compartments studied, compared to TNF-α where one of eight tissue compartments showed significant diminishment in barrier function. The increase in permeability associated with reduced barrier function was observed at both tissue compartment and cellular length scales. The observation of pericellular transport of the albumin-sized molecules to osteocytes contrasts with previous observations of barrier function in healthy, untreated animals and is indicative of increased molecular transport in pericellular regions of musculoskeletal tissues in cytokine-treated animals. Understanding age- and disease-related changes in molecular transport within musculoskeletal structures, such as the knee joint, is crucial for elucidating the etiology and pathogenesis of osteoarthritis. Full article

Glucagon-like peptide-1 (GLP-1) receptor agonists now serve as therapeutic agents for cardiovascular diseases (CVDs) beyond their original use for treating type 2 diabetes mellitus (T2DM). This review combines molecular mechanisms with clinical evidence to demonstrate how GLP-1 agonists help lower cardiovascular risk for conditions, including atherosclerosis, heart failure, stroke, and vascular dementia. These agents produce multiple beneficial effects, which include anti-inflammatory action along with anti-atherogenic effects, endothelial-protective benefits, and cardioprotective actions to minimize major adverse cardiovascular events (MACEs). GLP-1 agonists achieved substantial reductions in myocardial infarction, stroke, cardiovascular mortality, and heart failure events according to major cardiovascular outcome trials (CVOTs). Recent research, notably the pivotal SELECT trial, has confirmed their suitability for non-diabetic subjects with obesity and established CVD. New drug delivery methods and dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonists demonstrate potent efficacy, with tirzepatide showing significant MACE reduction in its own CVOT. However, significant challenges related to high cost, long-term safety uncertainties, and implementation barriers remain, requiring a balanced perspective. The review presents both mechanistic data and clinical evidence to demonstrate how GLP-1 agonists function as vital cardiovascular medications and outlines future research directions to address critical evidence gaps and maximize their therapeutic effectiveness. Full article

Vascular health relies on the proper function of endothelial cells, which regulate vascular tone, blood fluidity, and barrier integrity. Endothelial dysfunction, often aggravated by inadequate vitamin absorption, contributes to a spectrum of clinical disorders, including cardiovascular disease, cerebrovascular disease, peripheral artery disease, age-related macular degeneration, lymphedema, and chronic venous insufficiency. B-group vitamins (especially folate, or vitamin B9), along with vitamins B12, B6, C, D, and E, are essential in maintaining endothelial function, supporting DNA synthesis, regulating methylation, enhancing cellular repair, mitigating oxidative stress and inflammatory signaling, and curtailing vascular damage. Folate is noted for its central function in one-carbon metabolism and in converting homocysteine to methionine, thereby reducing vascular toxicity. We cover natural dietary sources of folate, synthetic folic acid, and the biologically active forms 5-methyl-(6S)-tetrahydrofolate (L-5-MTHF, L-methylfolate) and 5-formyl-(6S)-tetrahydrofolate (levoleucovorin). Therapeutic strategies to address vascular health and prevent hyperhomocysteinemia in order to preclude follow-on disorders include targeted vitamin supplementation, dietary improvements to ensure a sufficient intake of bioavailable nutrient forms, and, in certain clinical contexts, the use of active L-methylfolate or levoleucovorin (a drug product) to bypass metabolic conversion issues. These evidence-based interventions aim to restore endothelial homeostasis, slow disease progression, and improve patient outcomes across a variety of disorders linked to poor vascular health. Full article

Our study explored the role of serum 25-hydroxyvitamin D [25(OH)D] levels as an indicator of response to intravitreal anti–vascular endothelial growth factor (anti-VEGF) therapy in patients with diabetic macular edema (DME), highlighting functional and anatomical outcomes linked to systemic biomarker profiles. In a cohort of treatment-naive diabetic patients, vitamin D status was correlated with post-treatment changes in central macular thickness (CMT) and best-corrected visual acuity (BCVA), illustrating layered therapeutic responses among deficient, insufficient, and sufficient vitamin D groups. Functional gains, measured as improvements in decimal BCVA, and anatomical improvements, defined by CMT reduction via spectral-domain optical coherence tomography (SD-OCT), were primarily detected in patients with sufficient vitamin D levels. Remarkably, patients with serum 25(OH)D ≥ 30 ng/mL revealed complete dual-response rates, while those in the deficient group manifested partial therapeutic efficacy, supporting the immunoangiogenic modulatory role of vitamin D. Statistical associations exposed a tight linear connection between baseline and final visual acuity and a pronounced inverse relationship between CMT and final vision, suggesting that vitamin D may play a role in treatment-mediated structural recovery. These results may imply that low vitamin D levels lead to subclinical endothelial dysfunction and impaired retinal barrier repair, possibly through dysregulated anti–vascular endothelial growth factor (anti-VEGF) signaling, chronic inflammation, and oxidative stress. Our findings underscore the need for and importance of further research of vitamin D status as an adjunctive biomarker in the clinical approach of personalized DME and validates the potential of circulating vitamin D evaluation in therapeutic classification and predictive eye care. Full article

Claudin 5 (Cldn5) is a critical tight junction protein essential for maintaining paracellular barrier integrity across endothelial and epithelial cells in barrier-forming tissues, including the blood–brain barrier and blood–retinal barrier. Cldn5 plays a central role in regulating vascular permeability, immune responses, and tissue homeostasis. The complex distribution and organ-specific regulation of Cldn5 underscore its potential as a promising therapeutic target. This review comprehensively analyzes the role of Cldn5 in endothelial and epithelial barrier function, its regulation of vascular permeability, and the discrepancies in the literature regarding its expression, regulation, and function in both physiological and pathological conditions across multiple organ systems, including the retina, brain, lung, heart, gut, kidney, liver, skin, and peripheral nerves, while emphasizing its tissue-specific expression patterns. We discuss how both reduced and excessive expressions of Cldn5 can disrupt barrier integrity and contribute to the pathogenesis of ischemic retinopathies, neuroinflammation, cardiovascular injury, and other forms of barrier dysfunction. Furthermore, we explore the dual role of Cldn5 as both a biomarker and a therapeutic target, highlighting emerging strategies such as RNA silencing, pharmacological stabilizers, and transcriptional modulators in controlling barrier leakage in disease conditions. Full article

Zonula occludens-1 (ZO-1), encoded by the TJP1 gene, is a crucial scaffolding protein within tight junctions that maintains epithelial and endothelial barrier integrity. In addition to its structural role, ZO-1 participates in signal transduction pathways that influence various cellular processes such as proliferation, differentiation, and apoptosis. Increasing evidence suggests that tight junction proteins, including ZO-1, play important regulatory roles in tumor progression, particularly by modulating metastasis, cell polarity, and vascular remodeling. Ovarian cancer, the most lethal gynecologic malignancy, is characterized by rapid growth, peritoneal dissemination, and a strong reliance on tumor angiogenesis. However, the specific role of ZO-1 in regulating angiogenesis within ovarian cancer remains poorly defined. In this study, we used CRISPR-Cas9-mediated gene editing to generate TJP1 knockout (KO) ovarian cancer cell lines and investigated the impact of ZO-1 loss on the expression of angiogenesis-related genes. Transcriptomic and qRT-PCR analyses revealed upregulation of KLF5 and IL-8, both of which are well-established pro-angiogenic factors. Furthermore, functional assessment using a Matrigel™ tube formation assay demonstrated that conditioned media from ZO-1-deficient cells significantly enhanced endothelial tube formation. These findings indicate that ZO-1 loss promotes a pro-angiogenic tumor microenvironment, likely through modulation of key signaling molecules such as KLF5 and IL-8. Therefore, ZO-1 may serve as a potential suppressor of angiogenesis and a therapeutic target in ovarian cancer. Full article

Background: Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are critical conditions lacking effective pharmacologic therapies. Lipopolysaccharide (LPS), a bacterial endotoxin, is a well-established trigger of ALI. Emerging evidence suggests that heparin derivatives may attenuate lung injury, but their mechanisms remain unclear. Methods: This study evaluated the protective effects of 2-O, 3-O desulfated heparin (ODSH) in a murine model of LPS-induced ALI. Mice received LPS intratracheally with or without ODSH pre-treatment. Lung injury was assessed by bronchoalveolar lavage fluid (BALF) analysis, Evans blue dye albumin EBDA) extravasation, and histopathology. Results: ODSH treatment significantly reduced BALF protein concentration, inflammatory cell infiltration, and EBDA leakage. ODSH preserved endothelial barrier function in vitro, as evidenced by transendothelial electrical resistance (TER) measurements in human lung microvascular endothelial cell (HLMVEC) monolayers. Histological assessment (H&E staining) and myeloperoxidase (MPO) staining demonstrated reduced lung injury and neutrophil infiltration in the ODSH group. ODSH also downregulated pro-inflammatory mediators (NF-κB, IL-6, p38 MAPK) and upregulated the anti-inflammatory cytokine IL-10. Conclusions: ODSH mitigates LPS-induced ALI by reducing vascular permeability, neutrophilic inflammation, and pro-inflammatory signaling while enhancing IL-10 expression. These findings suggest ODSH may offer a novel therapeutic approach for treating ALI. Full article

Background/Objectives: Methamphetamine (METH), a potent psychostimulant, exerts harmful effects on the vascular system by promoting oxidative stress, inflammation, and endothelial injury. While its impact on the blood–brain barrier is well documented, its influence on the retinal microvasculature remains less understood. This study investigated the effects of METH on syndecan-1 expression and endothelial function in primary rat retinal microvascular endothelial cells (RRMECs) and isolated ophthalmic arteries. Methods: We assessed METH-induced changes in mRNA and protein expression levels of syndecan-1, matrix metalloproteinase (MMP)-2, and MMP-9. Endothelial function was evaluated using scratch migration assays and trans-endothelial electrical resistance (TEER) measurements. The mechanistic involvement of MMP-9 and trace amine-associated receptor 1 (TAAR-1), a known receptor for METH, was examined using selective pharmacological inhibitors. Results: METH exposure significantly decreased syndecan-1 expression and increased MMP-9 levels. These changes were accompanied by impaired endothelial migration and reduced TEER in RRMECs. Similar findings were confirmed in cultured ophthalmic arteries, reinforcing the translational relevance of our in vitro results. Inhibition of MMPs restored syndecan-1 expression and rescued endothelial function. Furthermore, TAAR-1 antagonism protected against syndecan-1 degradation, reduced MMP-9 upregulation, and improved endothelial migration and barrier resistance. Conclusions: Our findings suggest that METH induces loss of syndecan-1 and retinal vascular integrity by promoting TAAR-1–mediated MMP-9 upregulation. Targeting the TAAR-1/MMP-9 axis may offer a promising therapeutic strategy for preventing METH-induced microvascular damage in the retina. Full article