Search Results (161)

V-agents are exceedingly toxic oily substances, among which phosphonothiolates VX and VR have been extensively studied. Nevertheless, V-agents encompass a large family of nerve agents with diverse structures, including the phosphonate esters of alkyl acetoacetates or 2-alkoxycarbonyl-1-methylvinyl cycloalkyl methylphosphonates. These agents exist in two geometric isomers, and their properties remain largely unknown. Due to continuous concerns about chemical terrorism and safety, it is necessary to study their properties in order to develop effective countermeasures. Here, we applied computational tools to predict their ADME profile, chemical properties, and structure-related toxicity. These agents exhibited optimal drug-like properties, and it was predicted that they can penetrate the skin, acting as percutaneous hazards, and further penetrate the gastrointestinal tract and the blood–brain barrier. Certain CYP450 enzymes could differentially recognize the E- and Z-isomers, and this may explain the observation that E-isomers are significantly more toxic than their Z-counterparts. Analyses of the E- and Z-isomer stabilities also offered evidence for the reported lability of the Z-isomers. In conclusion, this study provides the first detailed in silico description of these V-agents, requiring future targeted experimental validation. Full article

The oral microbiota represents a complex and dynamic microbial ecosystem that plays a critical role in preserving both oral and systemic homeostasis. Emerging evidence suggests that alterations in oral microbial milieu (dysbiosis) may contribute to the pathogenesis of neurodegenerative disorders, especially Alzheimer’s disease (AD), through the oral–brain axis. This review synthesizes current evidence on the pathways linking oral microbiota to cognitive decline, integrating microbial, immunological, and vascular perspectives. Oral pathogens may access the central nervous system via hematogenous dissemination or neural routes, including the trigeminal nerve, while simultaneously promoting systemic inflammation, immune activation, and blood–brain barrier disruption. These processes converge on key neurodegenerative mechanisms, including chronic neuroinflammation, amyloid-β accumulation, and tau pathology. In parallel, alterations in oral microbial composition have been linked to disease severity, supporting a potential role of dysbiosis in both initiation and progression of cognitive impairment. Diet emerges as a critical modifiable determinant of oral microbial ecology. Diets rich in refined sugars may promote dysbiosis and inflammatory signaling, whereas (poly)phenols, probiotics, and prebiotics may support microbial eubiosis and exert neuroprotective effects through modulation of host–microbe interactions. Although current evidence remains largely observational and mechanistic, the diet–oral microbiota–brain axis represents a promising target for preventive and therapeutic strategies aimed at mitigating cognitive decline and promoting healthy aging. Future longitudinal and interventional studies are required to establish causality and translate these insights into clinical practice. Full article

Disorders of the central nervous system (CNS) are intricate and often resistant conditions that create a significant global impact, affecting millions of individuals each year. The blood–brain barrier (BBB) acts as a protective mechanism for the brain against external substances, but it also prevents most therapeutic agents from entering the CNS, leading to inadequate drug absorption and reduced effectiveness after diagnosis. Nasal drug delivery has emerged as a viable approach to bypass the BBB, facilitating direct access to the brain through the olfactory and trigeminal nerve routes. Although considerable research focuses on innovative nasal formulations with proven clinical promise, a critical gap persists: a systematic framework that bridges laboratory breakthroughs with clinical implementation. This review addresses this unmet need by integrating recent basic research advances with practical clinical requirements. We summarize nasal transport pathways, targeted design strategies, formulation optimization, and device engineering. Crucially, we propose a structured clinical evaluation framework built upon five essential pillars: targeting precision, pharmacokinetic performance, multi-organ safety profiling, device–drug clinical compatibility, and anatomical translation from animal models to humans. By mapping current research capabilities against clinical readiness criteria, this framework identifies translational bottlenecks and provides actionable guidance to accelerate the bench-to-bedside transition of intranasal drug delivery systems for CNS disorders. Full article

Vascular dementia (VaD) represents a spectrum of neurodegenerative disorders driven by chronic or acute cerebral hypoperfusion, converging on the structural collapse of the neurovascular unit (NVU). While vascular mechanics and neuroinflammation have been extensively characterized, the extracellular matrix (ECM) remains an under-appreciated driver of this pathology. Far from being a passive scaffold, the ECM serves as a dynamic regulator of brain homeostasis, governing the integrity of the blood–brain barrier (BBB), supporting synaptic plasticity via Perineuronal Nets (PNNs), and facilitating the glymphatic clearance of metabolic waste. This review and perspective examines the pivotal role of the ECM within the “tripartite” NVU, the interface connecting vascular cells, CNS glia, and perivascular nerves. We discuss how the dysregulated activity of matrix metalloproteinases (MMPs) and the alteration of basement membrane components compromise the architectural defenses of the NVU. We describe how these structural failures can transform vascular insults into progressive neurodegenerative decline by unmasking inflammatory binding sites and disrupting cell–matrix signaling. Specifically, we highlight (1) the physiological architecture of the NVU and its dependence on specific collagen organization, (2) the mechanistic pathways of ECM disruption in VaD pathogenesis, including the feedback loop between ischemia and proteolysis, (3) the emerging therapeutic potential of targeting matrix components to restore neurovascular stability, and (4) a novel mechanochemical hypothesis framing pathological collagen functionalization as an epidemiological bimodal switch. Uncovering the interplay between structural remodeling and vascular function offers novel targets to halt the progression of dementia. Full article

We recently identified the U1 small nuclear ribonucleoprotein (U1-snRNP) antibodies in patients with Guillain–Barré syndrome (GBS), which is associated with the breakdown of the blood–nerve barrier (BNB). The objective of this study was to clarify the clinical significance of U1-snRNP antibodies in patients with GBS and its variants. We measured U1-snRNP antibodies using an enzyme-linked immunosorbent assay from the serum samples of patients with GBS (n = 106), Miller Fisher syndrome (MFS) (n = 24), and MFS/GBS overlap syndrome (MFS/GBS, n = 8). We compared the clinical characteristics of U1-snRNP positive and U1-snRNP negative GBS patients (n = 106). The cerebrospinal fluid (CSF)/serum albumin quotient (QALB)/QALBLIM [calculated as(age/15) + 4)] was calculated. The prevalence of U1-snRNP antibody positivity was 39% (41/106) in GBS, 0% (0/24) in MFS, and 50% (4/8) in MFS/GBS. The rate of U1-snRNP antibody positivity in the GBS and MFS/GBS groups was significantly higher than that in the MFS group. Levels of CSF proteins and QALB/QALBLIM were higher in U1-snRNP antibody-positive GBS than in U1-snRNP antibody-negative GBS among all GBS patients, as well as GBS patients with a preceding Campylobacter jejuni infection or AIDP. In conclusion, the U1-snRNP antibody-positive GBS group had a more severe breakdown of the BNB in U1-snRNP antibody-positive GBS patients than in U1-snRNP-negative GBS patients. The presence of U1-snRNP antibodies may be a clinical biomarker for predicting the progression of MFS to MFS/GBS. Full article

Background and Purpose: Contrast-enhanced MRI findings of leptomeningeal enhancement (LME) indicate dysfunction of the blood–brain barrier and can be seen in various neoplastic, infectious, and inflammatory conditions. To the best of our knowledge, systematic evaluation of different patterns of LME remains limited. This case series aims to describe and compare MRI patterns of leptomeningeal enhancement across diverse etiologies. Materials and Methods: We retrospectively evaluated six patients with known or suspected leptomeningeal disease on contrast-enhanced MRI studies of the brain and/or spine with regard to pattern, distribution, localization, and thickness of LME. Results: The patterns of neoplastic causes (glioblastoma, lymphoma, and adenocarcinoma) were characterized by diffuse, thick, and nodular LME, as well as frequently affected cranial nerve and nerve-root involvement. The infections caused various patterns: in cases of tuberculous meningitis, LME was focal and basal in nature, accompanied by parenchymal lesions; whereas in cases of HIV-related meningitis, LME was diffuse and exhibited a pseudocisternogram pattern. The inflammation (suspected neurosarcoidosis) revealed smooth-to-nodular LME with spinal and suprasellar involvement. Conclusions: Although LME patterns are not specific, systematic evaluation of enhancement characteristics may provide useful diagnostic clues and assist in narrowing the differential diagnosis. Full article

Non-invasive drug delivery for ocular diseases remains a significant challenge in ophthalmology, as conventional eye drops offer less than 5% bioavailability due to pre-corneal barriers and the corneal epithelium. This review explores the intranasal (IN) route as a promising strategy for targeting both the anterior and posterior segments of the eye. The IN route leverages several distinct pathways: the nasolacrimal reflex for remote physiological stimulation; the “neural bridge” through the cribriform plate, allowing direct perineural and vascular transport via the olfactory and trigeminal nerves to bypass the blood–retinal barrier; and systemic absorption that avoids hepatic first-pass metabolism. Pre-clinical evidence indicates that IN administration of agents such as erythropoietin, nerve growth factor, and insulin achieves superior retinal concentrations compared to topical or systemic dosing, offering neuroprotection in models of retinal degeneration and glaucoma. Clinically, varenicline nasal spray is already FDA-approved for dry eye disease, while intranasal steroids demonstrate a favorable ocular safety profile without significantly increasing intraocular pressure. Although limited by mucociliary clearance and small delivery volumes, the IN route offers a painless, non-invasive alternative to intraocular injections, potentially enhancing patient compliance. Future advancements in mucoadhesive nanocarriers are essential to optimize drug residence time and realize the full potential of nose-to-eye delivery in chronic ophthalmic care. Full article

Diabetic peripheral neuropathy (DPN) remains a leading cause of disability in diabetes, yet current care is largely symptomatic and does not directly address early neurovascular-immune pathology. This narrative review synthesizes clinical, redox, vascular, and immunological evidence into a peripheral nerve neurovascular unit (PNVU)/blood–nerve barrier (BNB)-centered framework for DPN. First, the review outlines the diagnostic and translational endpoint landscape of DPN, emphasizing that commonly used clinical, neurophysiological, small-fiber, and imaging-based tools capture important disease domains but do not directly assess early BNB dysfunction. It then reviews the anatomical and functional basis of the PNVU and BNB, including endoneurial microvascular endothelial cells, pericytes, basement membrane components, immune cells, and tight-junction proteins. Next, it discusses how chronic hyperglycemia and dyslipidemia drive metabolic-to-vascular coupling, redox imbalance, antioxidant defense failure, advanced glycation end products (AGEs), receptor for AGEs (RAGE), and nuclear factor-κB (NF-κB) signaling, endothelial activation, leukocyte recruitment, macrophage polarization, and junctional disassembly, culminating in increased BNB permeability and exposure of peripheral nerves to pro-inflammatory and neurotoxic mediators. Finally, it evaluates incretin-based therapies—including glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors, DPP-4is), and emerging multi-agonists—as potential modulators of oxidative and inflammatory stress within this framework. Although semaglutide and related agents show mechanistic plausibility and preclinical promise, direct evidence for incretin-mediated BNB stabilization in human DPN remains limited. By reframing DPN as a redox-driven neurovascular-immune disorder, this review highlights barrier-focused biomarkers, translational endpoints, and hypothesis-generating therapeutic opportunities that require clinical validation. Full article

Major depressive disorder (MDD) is a mental illness with high mortality, suicide, and relapse rates that could become the leading cause of health problems worldwide by 2030. The microbiota–gut–brain axis involves bidirectional communication between the human gut microbiota and the central nervous system (CNS). The gut microbiome is a complex ecosystem of approximately 100 trillion microorganisms, including viruses, bacteria, and fungi. The gut microbiota has recently been recognized for its impact on various diseases and health concerns. Several factors influence the composition and structure of gut microbes, ultimately affecting human physiology, with the nervous system being particularly vulnerable. The gut–brain–microbiota axis influences several important brain functions through numerous pathways, including vagus nerve signaling, gut microbial synthesis of metabolites, and immune-related chemicals. These factors can influence neurotransmitter activity, neuroinflammation, behavior, and mental health. Despite increased interest, the possibility of modifying the gut microbiota as a therapeutic approach remains unclear. Although numerous studies suggest that microbiota play an important role in many illnesses, the precise mechanisms are yet to be elucidated, and there are currently no evidence-based, microbiota-focused treatments for these illnesses. Recent research indicates that gut dysbiosis (GD) causes increased intestinal permeability (leaky gut), initiates systemic inflammation, and contaminates the blood. Opportunistic microbial metabolites cross the blood–brain barrier, triggering a neuroinflammatory cascade and apoptotic pathways while affecting neurogenesis and neurotransmitters, ultimately resulting in the development of MDD and anxiety. This review examined the factors influencing normal gut microbiota and GD-mediated MDD, as well as possible therapeutic options. The study outlines its objectives and methodological approaches, including the screening and filtering of research on GD-induced depression. Furthermore, it explored the daily use of dietary supplements, revealing new paths for clinical and preclinical research. Full article

Impairment in blood supply to the brain deprives its cells of the much-needed nutrients and molecules such as oxygen and glucose necessary for its development, growth and survival. This will set up a host of pathological processes such as impaired homeostasis, energy failure, excitotoxicity, oxidative stress, impaired protein synthesis, inflammation, cytokine-mediated toxicity and impairment of blood–brain barrier. These pathological processes will result in the damage or death of the cells depending on the extent of the deprivation. Similarly, they will impair synthesis of acetylcholine (Ach) and norepinephrine (NE), which are important neurotransmitters in the cholinergic and adrenergic systems responsible for cellular communication and functions. Thus, interventions to help arrest and/or modulate the initial and subsequent pathological states and help recover the functions of the brain are needed. One of such interventions is vagus nerve stimulation, which helps activate the cholinergic and the adrenergic systems via projections of the afferent fibers of the vagus nerve to the nucleus of the solitary tract (NTS). Activation of the cholinergic and the adrenergic systems results in reduction in pro-inflammatory factors such as tumor necrosis α, increase in pro-angiogenic factors and increase in firing of adrenergic neurons in the central nervous system (CNS). Full article

Trauma-induced heterotopic ossification (tHO) is characterized by aberrant ectopic bone formation in soft tissue following high-energy trauma, affecting >60% of combat-related amputees and >50% of major burn patients. Current prophylactic strategies (including NSAIDs, bisphosphonates, and low-dose radiation) lack mechanistic specificity, carry significant side effects, and surgical excision carries a 27% recurrence rate. This review reframes tHO pathogenesis through the neural–immune axis, arguing that ectopic bone formation is a downstream consequence of dysregulated neuroimmune signaling rather than a primary osteogenic event. Following trauma, nociceptor activation drives nociception-induced neural inflammation (NINI), releasing substance P (SP) and calcitonin gene-related peptide (CGRP), which disrupts the blood–nerve barrier, mobilizes neural crest-derived progenitor cells, and, alongside BMP-2/SMAD1/5/8 signaling and M1-polarized macrophage activation, establishes a permissive osteogenic microenvironment. A BMP-2/CGRP positive feedback loop sustains aberrant osteogenesis, converging on osteogenic transcription factors Runx2, SOX5/6/9, and Osterix. Dysregulated noncoding RNAs represent promising pre-radiographic biomarkers. This neural–immune framework motivates mechanism-based therapeutic strategies targeting CGRP (fremanezumab, erenumab), SP/NK1 signaling (aprepitant), and macrophage polarization (metformin, palovarotene, rapamycin), with multi-node combination approaches tailored to the temporal stages of tHO offering the most promise for precision prophylaxis. Full article

Cerebral venous thrombosis (CVT) is a rare but potentially life-threatening subtype of stroke, characterized by thrombus formation within the dural venous sinuses and cerebral veins. Recent advances have deepened our understanding of CVT pathophysiology, highlighting a multifactorial process that encompasses thrombus initiation, subsequent thrombus propagation, venous hypertension with blood–brain barrier disruption, and secondary parenchymal brain injury. Comprehensive clinical assessment, including diagnosis and differential diagnosis, disease severity scores, imaging-based metrics, and prognostic scoring systems, enables accurate evaluation and risk stratification. Emerging therapeutic strategies, including direct oral anticoagulants, corticosteroids for selected patients, natural-origin agents, immunomodulatory therapy, endovascular treatment, optic nerve sheath fenestration, and neuromodulation, provide novel and alternative options for the management of CVT. This review provides a comprehensive overview of CVT pathophysiology, clinical assessment tools, and novel therapeutic strategies to guide clinical decision-making and inform future research. Full article

Background: Connexins (Cx) are a family of transmembrane proteins that form gap junctions and connexin hemichannels (HCs), enabling direct intercellular communication within the nervous system. Connexin 43 (Cx43), the principal astrocytic connexin, exhibits a context-dependent dual role: under physiological conditions it maintains tissue homeostasis and metabolic support, whereas under pathological conditions excessive activation of Cx43 hemichannels promotes neuroinflammation, excitotoxicity, blood–brain barrier disruption, and secondary neural tissue damage. Other connexin isoforms also contribute to the pathogenesis of neurological and psychiatric disorders through alterations in neuronal synchronization, glial signaling, and myelin integrity. Objective: To systematize current evidence on the role of key connexin isoforms in acute nervous system injuries—including stroke, traumatic brain injury, spinal cord injury, and peripheral nerve injury—as well as chronic disorders such as neurodegenerative diseases, epilepsy, and psychiatric disorders, with particular emphasis on the functional duality of connexin channels and the therapeutic potential of their selective modulation. Methods: A systematic literature search was conducted in the PubMed, Scopus, and Web of Science databases in accordance with the PRISMA framework and the PRISMA Extension for Scoping Reviews guidelines. The review included data from experimental models, postmortem brain studies, genetic association analyses, and pharmacological intervention studies. The retrieved studies were screened, assessed for eligibility, and integrated using a qualitative narrative synthesis approach. Results: In acute neural injuries, hyperactivation of Cx43 hemichannels amplifies inflammatory signaling, edema formation, and neuronal death, whereas selective HCs inhibitors reduce lesion volume and improve functional outcomes in experimental models. Connexin 36 (Cx36) contributes to cortical spreading depolarization and seizure propagation, while Connexin 32 (Cx32) and Connexin 47 (Cx47) are critically involved in oligodendrocyte function and white-matter demyelination. In PNI, Cx43 upregulation contributes to neuropathic pain, whereas mutations in Cx32 cause hereditary demyelinating neuropathies. In neurodegenerative diseases—including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis—Cx43 hemichannel activity promotes neuroinflammation and pathological protein accumulation, while reduced Cx32/Cx47 expression disrupts metabolic support of axons. In psychiatric disorders such as major depressive disorder, bipolar disorder, and schizophrenia, decreased astrocytic connexin expression (Cx43 and Cx30) has been associated with impaired glial–neuronal communication and cognitive–emotional dysfunction. In epilepsy, increased Cx43/Cx30 expression contributes to neuronal hypersynchronization and blood–brain barrier dysfunction, whereas selective hemichannel blockade suppresses seizure activity. Conclusions: Cx—particularly Cx43—occupies a central position in the molecular mechanisms of secondary neural injury and network dysfunction. The dual functional properties of gap junctions and hemichannels determine their context-dependent effects across neurological and psychiatric diseases. Selective inhibition of pathological HCs activity shows significant neuroprotective and anticonvulsant potential and represents a promising direction for the development of targeted therapeutic strategies. Further studies are required to determine optimal therapeutic time windows, tissue-specific effects, and the long-term safety of Cx modulation. Full article

Central nervous system (CNS) disorders represent a growing healthcare burden, and various drugs are developed for their treatment. However, the blood–brain barrier (BBB) prevents over 98% of therapeutics from reaching brain tissue. Intranasal delivery provides a promising alternative by exploiting olfactory and trigeminal nerve pathways to circumvent the BBB. This review surveys recent advances in nose-to-brain delivery technologies, from carrier design to evaluation methods. Polymeric and lipid-based nanocarriers show enhanced mucosal penetration and prolonged residence time, and microneedle platforms further enable controlled drug release with minimal discomfort. To evaluate these delivery strategies, sensor-integrated organ-on-chip models provide more physiologically relevant testing than static cultures. Although persistent challenges such as rapid mucociliary clearance and formulation stability remain, combining nanotechnology with microfluidic devices and computational modeling shows potential for developing patient-specific therapeutics. Full article

Background/Objectives: Platelet-rich plasma (PRP) is an autologous blood-derived biologic enriched in platelets and bioactive mediators. In urology and sexual medicine, PRP has been promoted for erectile dysfunction (ED) and a growing range of urogenital disorders on the premise that it may support angiogenesis, neuroregeneration, immune modulation, and tissue remodeling. However, clinical uptake has outpaced high-quality evidence, while heterogeneity in PRP preparation, characterization, and delivery limits interpretability and reproducibility. This structured narrative review aims to critically integrate mechanistic, preclinical, and clinical evidence regarding PRP use in ED, Peyronie’s disease (PD), stress urinary incontinence (SUI), interstitial cystitis/bladder pain syndrome (IC/BPS), and selected emerging indications. We further aim to identify sources of heterogeneity and propose an actionable minimum reporting framework (PRP-Uro Checklist) to guide future research. Methods: A structured search of PubMed/MEDLINE was conducted for studies published between 2021 and 2025. The relevant literature on PRP use in ED, PD, SUI, IC/BPS, and related indications was included for critical narrative synthesis. Emphasis was placed on PRP classification and preparation variables, outcome measure validity, and sources of heterogeneity across studies. Results: Mechanistic and preclinical evidence supports PRP’s potential to modulate nerve repair, angiogenesis, extracellular matrix remodeling, and immune polarization through a complex secretome of growth factors, cytokines, and extracellular vesicles (EVs). Clinical evidence suggests that intracavernosal PRP may improve erectile function in selected populations, but effect size, durability, and superiority over placebo remain uncertain due to small trials, substantial placebo effects, short follow-up, and incomplete biologic characterization. Evidence for PRP in PD, SUI, and IC/BPS remains preliminary and is derived largely from small cohorts, proof-of-concept studies, or uncontrolled designs, although early findings suggest potential symptom benefit and acceptable short-term tolerability. Across indications, inconsistent PRP reporting, particularly the absence of absolute platelet dose, leukocyte quantification, activation method, and standardized treatment protocols, represents a major barrier to reproducibility and evidence synthesis. Conclusions: PRP is biologically plausible and appears broadly safe, but its role in urology and sexual medicine remains investigational and is not yet supported by guideline-level evidence. To enhance reproducibility and interpretation, we propose a Minimum PRP Reporting Checklist for Urology and Sexual Medicine Trials (PRP-Uro Checklist). Future progress requires rigorous standardized reporting, indication-specific biologic characterization, rigorously designed sham-controlled trials, clinically meaningful endpoints, and longer-term follow-up. Full article