Search Results (149)

SLC26A11, also known as the kidney and brain anion transporter (KBAT), mediates the transport of multiple anionic substrates across the plasma membrane. It is highly enriched in cerebellar Purkinje cells, where loss of KBAT results in hyperpolarized membrane potentials and increased intrinsic firing frequency, correlating with locomotor dysfunction. Despite its physiological significance, the molecular basis of substrate recognition and transport by KBAT remains elusive. Here, we present the structure of full-length human KBAT in an inward-facing conformation with chloride ions (Cl⁻) bound. Sequence analysis of the substrate-binding pockets uncovers the important residue E320 in KBAT. Protonation of E320 abolishes its interaction with S363 and correlates with Cl⁻ binding in the canonical substrate pocket, as substantiated by molecular dynamics (MD) simulations. Quantitative MD contact analysis delineates the rearrangements of residue interactions underlying the alternative access transport, consistent with an elevator-like transport mechanism. The cross-arranged transmembrane helices of the Gate and Core domains require minimal conformational rearrangement to achieve alternating access to the membrane. Collectively, our study provides a critical foundation for comprehensively understanding the recognition and transport mechanisms of human KBAT, with potential implications for developing therapies for neuronal swelling. Full article

Background: Our goal was to evaluate the radiological patterns and clinical outcomes of brain injuries related to trauma, offering insight into the distribution of brain injuries, facial fractures and outcomes across road traffic accidents (RTAs), falls and other causes. Methods: Cerebral CT scans of 536 cases obtained between January 2019 and January 2024 were retrospectively reviewed. The collected data included demographics, etiology, transportation groups (driver, car occupant, pedestrian, motorcyclist, bicyclist), GCS (Glasgow Coma Scale), clinical outcome (ICU (intensive care unit) admission, neurosurgical intervention, mortality) and CT imaging features. Images were analyzed independently by two physicians. The findings reflect a selected population of polytrauma patients who underwent cerebral CT at a single emergency hospital. Results: Brain injury was identified in 39% of all subjects, the most frequent type of lesion being intraparenchymal hematoma (24%), followed by subdural hematoma (23%). Brain injury was numerically more frequent among patients with falls (45%) than among those involved in RTAs (37%), although this difference did not reach statistical significance in either unadjusted or age-, sex-, and mechanism-adjusted analysis (p > 0.05). CT patterns differed across transportation categories, with bicyclists showing associations with intraparenchymal hemorrhage and diffuse brain swelling and pedestrians with intraventricular hemorrhage (p < 0.05). However, given the small bicyclist subgroup (n = 6), these findings should be considered exploratory. Car occupants showed lower unadjusted odds of brain injury compared with drivers (OR: 0.50; 95% CI: 0.30–0.80), but this association was attenuated and no longer statistically significant after adjusting for age and sex (adjusted OR: 0.55; 95% CI: 0.27–1.15; p = 0.112). In multivariable analysis of in-hospital mortality, only age and severe GCS category remained independently associated with death; neither injury mechanism nor transportation category showed an independent association once these factors were accounted for. Conclusions: Brain injury was more frequently observed among patients with falls than among those involved in RTAs. Nevertheless, road traffic accidents accounted for the majority of polytrauma admissions. These findings highlight the importance of both road traffic safety measures and fall-prevention strategies, particularly among older adults. Full article

Gel-based novel drug delivery systems (NDDS) occupy a mechanistically distinct niche among controlled-release platforms because they decouple three design variablesnetwork cross-link density, continuous-phase polarity, and stimulus sensitivitythat in particulate carriers (liposomes, polymeric nanoparticles) are often interdependent. This critical review synthesizes 102 primary and secondary sources published predominantly between 2010 and 2026 to interrogate, rather than merely catalog, how hydrogels, organogels, aerogels, nanogels, in situ gelling systems, and hydrogel-forming microneedles have been engineered for site-specific pharmacotherapy. Beyond a taxonomic overview, the review quantitatively contrasts formulation parameters sol–gel transition temperatures (typically 32–37 °C for poloxamer 407/188 systems), swelling ratios, mesh sizes, and reported drug-release half-lives across oncology, chronic diabetic wound care, ophthalmic and nasal-to-brain delivery, musculoskeletal (intra-articular) therapy, subunit vaccine depots, periodontal pocket therapy, and glucose-responsive insulin delivery. Particular attention is paid to the mechanistic basis of burst release, the porosity–mechanical-integrity trade-off inherent to interconnected hydrogel networks, and the divergence between preclinical rodent efficacy and the comparatively sparse controlled human trial data available for most gel platforms. The review concludes that while stimuli-responsive and 3D/4D-printed gel architectures have matured substantially as engineering constructs, clinical translation remains bottlenecked less by materials science than by inconsistent characterization standards, unresolved terminal-sterilization compatibility, and a paucity of head-to-head comparative trials against existing standard-of-care formulations. Full article

Background/Objectives: Mosquito-borne viruses cause substantial global morbidity and mortality. Mosquito saliva, secreted during biting, facilitates blood feeding and can enhance virus infection. Here, we evaluated whether combining virus-specific antigens with mosquito salivary protein-derived peptides improves protection in Zika virus (ZIKV) and chikungunya virus (CHIKV) mouse models. Methods: Peptides from Aedes and Culex salivary proteins were selected based on conservation, predicted T-cell reactivity, and cellular and humoral immunogenicity in mice. Mice were immunised subcutaneously with a prime and boost two weeks apart using adjuvanted salivary peptides (SAL), commercial ZIKV- or CHIKV-like particles (VLPs), or salivary peptides combined with the relevant VLPs. Vaccine doses contained 0.5 µg VLPs and/or 10 nmol of each salivary peptide, formulated with Montanide ISA-51; when combined, VLPs and SAL were administered on opposite flanks. Two weeks after boosting, mice were challenged with ZIKV or CHIKV plus Aedes aegypti saliva. Challenge teams were blinded to group allocation until data analyses were complete. Results: SAL enhanced the protective effect of VLP vaccination compared with VLPs alone. In the CHIKV model, CHIKV VLP + SAL prevented joint swelling and reduced infectious virus in the inoculated ankle and viral RNA in the contralateral ankle. In the ZIKV model, ZIKV VLP + SAL reduced viral RNA in skin and brain tissue and improved survival. Conclusions: Mosquito salivary peptide antigens improved the protective efficacy of VLP vaccines against ZIKV and CHIKV in mouse models. Salivary antigens may provide a complementary vaccine component for multiple arboviruses transmitted by Aedes and Culex mosquitoes. Full article

Background/Objectives: The aim of this study was to develop and apply a novel integrated approach for predicting local mucosal tolerability of spray-dried chitosan/mannitol microspheres previously developed for nose-to-brain donepezil delivery. Methods: Microspheres were prepared by ultrasonic spray-drying, and process reproducibility was evaluated based on particle size distribution, entrapment efficiency, and process yield across independent batches. A lactose-based formulation served as a comparative control. A novel biomimetic model was developed to investigate water evaporation under simulated nasal conditions, enabling prediction of formulation dehydration and crust-like layer formation on the nasal mucosa during nasal residence time. Donepezil-loaded chitosan microspheres and their physical mixture with mannitol were used as controls. Analyses were complemented by solid-state and rheological characterization to elucidate the effects of formulation composition and processing on the observed behavior. Irritation potential was further assessed using the established slug mucosal irritation (SMI) assay. Results: Reproducible microsphere size distribution (Dv10 11.5 ± 1.1 µm, RSD 9.6%; Dv50 28.4 ± 3.9 µm, RSD 13.7; Dv90 61.3 ± 8.4 µm, RSD 8.4%), entrapment efficiency (99.6 ± 1.8%, RSD 1.8%) and process yield (40.9 ± 5.5%, RSD 13.3%) confirmed the robustness of the ultrasonic spray-drying. Replacing mannitol with lactose failed to achieve the desired particle size distribution, highlighting the key role of mannitol under the investigated processing conditions. The biomimetic model coupled with rheological studies demonstrated that chitosan-based gels formed by microsphere swelling in simulated nasal fluid, maintain viscosity, resist dehydration, and undergo rehydration. Additionally, mannitol enhanced water retention and reduced evaporation without increasing occlusivity or the risk of mucosal dehydration. Furthermore, powders containing mannitol exhibited a lower irritation potential in the SMI assay compared to chitosan microspheres alone. Conclusions: Mannitol is a critical determinant of the performance of donepezil-loaded chitosan-based microspheres, contributing to the desired particle size distribution, process reproducibility, favorable hydration and improved mucosal tolerability, thereby supporting the suitability of this platform for nasal donepezil delivery. Full article

A bioengineered version of recombinant tissue plasminogen activator, i.e., tenecteplase (TNK-tPA), was designed to have a longer half-life, resistance to plasminogen activator inhibitor-1, and fibrin-targeted plasminogen activation. By comparison to tPA, clinical trials suggest that TNK-tPA may be less susceptible to the effects of alpha2-antiplasmin (α2AP), the primary inhibitor of thrombus dissolution. However, preclinical studies are limited, and whether α2AP affects TNK-tPA’s fibrinolytic activity or efficacy in experimental ischemic stroke is unknown. We examined the effects of TNK-tPA and α2AP on the dissolution of human plasma clots (in vitro) and experimental ischemic brain injury from stroke induced by transient middle cerebral artery ischemia. TNK-tPA induced a dose-dependent increase in plasma clot dissolution; inhibition of α2AP with a specific monoclonal antibody caused a synergistic increase in TNK-tPA-mediated clot dissolution. In experimental ischemic stroke with ischemia and reperfusion, TNK-tPA treatment of α2AP^−/− mice significantly reduced ischemic infarct volume, brain swelling, brain hemorrhage, and neurobehavioral disability vs. TNK-tPA-treated α2AP^+/+ (C57BL/6 background) mice with normal α2AP levels (p < 0.05 to p < 0.0001). α2AP impairs the dissolution of human clots in vitro by TNK-tPA and significantly exacerbates ischemic brain injury, swelling, hemorrhage, and neurobehavioral disability after experimental stroke, even with reperfusion. Targeting α2AP may improve the efficacy of TNK-tPA and reduce hemorrhagic complications. Full article

Pathological states associated with metabolic stress, such as traumatic brain injury (TBI), hypoxia, ischemic stroke, and migraine, are considered elevated risk factors for developing Alzheimer’s disease (AD). However, the mechanism underlying the effect of these conditions on the progression of AD remains largely unknown. Here, we determine how metabolic stress associated with spreading depolarization (SD)—a hallmark of stroke, hypoxia, TBI, and migraine—modulates amyloid β (Aβ42) aggregation kinetics through dynamic changes in extracellular space (ECS). To achieve this, we used ThT fluorescence to determine how the formation of different Aβ42 aggregate species depends on Aβ42 concentrations. Based on this input, we build a multiscale computational framework that integrates volume regulation, including its dependence on neuronal ion homeostasis, and Aβ42 aggregation kinetics. Our model predicts that neuronal swelling during SD accelerates aggregation, where the impact of metabolic stress is highly dependent on the timing relative to aggregation progression and the initial monomer concentration. At low monomer concentrations, early SD events promote off-pathway oligomer formation, while at higher concentrations they rapidly drive fibril formation to saturation. In the absence of mature fibrils, recurrent metabolic stress events further amplify oligomer accumulation, whereas pre-existing fibril nuclei suppress oligomer formation at the expense of fibril nucleation and growth. Increasing the intensity of metabolic stress prolongs ECS shrinkage and enhances oligomer formation. These findings reveal a mechanistic link between SD-induced microenvironmental changes and Aβ aggregation dynamics, providing a quantitative framework for understanding how acute brain injury and metabolic stress may contribute to early AD pathogenesis. Full article

Background and Clinical Significance: Kinesio tape (KT) has gained popularity as an adjunctive approach for treating edema during the rehabilitation phase, following traumatic events, as well as for managing edema in breast cancer patients. Its goal is to reduce swelling and improve mobility in the affected extremity; however, its use in critically ill patients remains limited. To our knowledge, this is the first report of its application in this population. Case presentation: This case series involved three patients in the Intensive Care Unit (ICU) who presented with lower extremity edema. One patient developed a cerebrovascular event secondary to moderate traumatic brain injury and two patients experienced sepsis. KT was applied, and extremity circumference, Godet sign, and Stemmer sign were assessed. The bandage was reapplied every 24 h over a 5-day period, with daily evaluations performed by the same nursing staff to ensure measurement consistency. All three patients exhibited a reduction in extremity circumference, along with improvement or resolution of the Godet and Stemmer signs. No adverse effects associated with KT were observed. Conclusions: Our results suggest that KT may be a beneficial adjunctive therapy for edema reduction in ICU patients. Larger-scale studies are needed to confirm its clinical value. Full article

Astrocytes are key regulators of neuronal, metabolic, and vascular homeostasis, yet their morphological diversity and involvement in alcohol-related brain pathology remain incompletely characterized. In this study, we investigated astrocytic morphology in the human striatum of control individuals and subjects with short- and long-term alcohol exposure using immunohistochemistry combined with Sholl-based morphometric analysis, and ultrastructural assessment. GFAP immunohistochemistry was used to identify astrocytes, assess their morphology, and manually quantify GFAP⁺ cells in gray and white matter, followed by Sholl-based morphometric analysis to characterize astrocytic branching architecture and spatial organization. The number of GFAP⁺ astrocytes differed between tissue compartments, with a significant increase in white matter in alcohol-exposed individuals and no detectable change in gray matter. Morphometric analysis revealed pronounced astrocytic heterogeneity across all study groups. Sholl-derived metrics supported the distinction of six recurrent astrocytic morphometric profiles in the human striatum, distinguished by soma size, branching complexity, process length, and cell territory size. These profiles were present across gray and white matter, indicating intrinsic astrocytic structural diversity. Ultrastructural analysis further revealed alcohol-associated alterations at the astrocyte–vascular interface, including swelling of perivascular astrocytic endfeet, accumulation of intermediate filaments, and focal reductions in vascular wall coverage. Together, these findings demonstrate substantial astrocytic structural diversity in the human striatum accompanied by alcohol-related gliovascular remodeling. Full article

Parkinson’s disease (PD) is a common neurodegenerative disorder marked by progressive loss of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of Lewy bodies, intracellular inclusions enriched in α-synuclein. Synphilin-1 interacts with α-synuclein, localizes to Lewy bodies, and has been implicated in inclusion formation and neuroprotection in cellular and animal models; however, its physiological function in vivo remains poorly defined. Here, we generated and characterized a synphilin-1 knockout (Sph-1 KO) mouse by targeted genetic deletion of the Sph-1 locus and performed a comprehensive phenotyping battery including behavioral testing as well as biochemical, histological, structural, and ultrastructural analyses. Sph-1 KO mice survived to nearly two years of age and showed normal body weight, lifespan, motor performance, learning and memory, anxiety-like behavior, attention, and gross brain morphology. Western blot analyses indicated that levels of α-synuclein and synaptic proteins were largely unchanged. While outer mitochondrial membrane proteins were unaffected, the mitochondrial matrix protein HSP60 was reduced, consistent with altered mitochondrial proteostasis in the absence of synphilin-1. Strikingly, histochemical analyses, magnetic resonance imaging, and electron microscopy revealed early-onset hydrocephalus in Sph-1 KO mice associated with severe loss and disorganization of motile ependymal cilia in the ventricular lining, a cell type that normally expresses high levels of synphilin-1. Ultrastructural and immunohistochemical analyses revealed disrupted ependymal architecture, mislocalization of acetylated α-tubulin to the cytoplasm, cellular swelling, and enlarged, aberrant mitochondria, whereas cortical neurons appeared largely structurally unaffected. Together, these findings identify synphilin-1 as a key regulator of microtubule organization and cytoskeletal/organelle homeostasis in ependymal cells, required to maintain motile ciliogenesis, cerebrospinal fluid flow, and ventricular integrity. This unexpected role for synphilin-1 in ciliated brain epithelia, along with a reduction in the critical mitochondrial chaperone HSP60, broadens our understanding of synphilin-1 biology and provides a new framework for its potential relevance to PD-associated pathology. Full article

Background: We evaluated the potential neuroprotective effects of naloxone in moderate traumatic brain injury (TBI), focusing on its ability to alleviate neuroinflammation, reduce cognitive impairment, and to influence Janus tyrosine kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling markers. Methods: Male C57BL/6J mice were used to establish an in vivo model of moderate TBI using a stereotaxic impactor. Immediately post-injury, naloxone was administered intraperitoneally (1 mg/kg/day) for 7 days. A total of 72 mice were divided into four groups: Normal, normal with naloxone, TBI, and TBI with naloxone (18 mice in each group). Immunohistochemical analyses and cognitive functions were evaluated across the groups. Results: TBI mice treated with naloxone exhibited significantly reduced brain swelling and cortical tissue loss compared to untreated mice. Naloxone reduced Transforming growth factor beta 2 (TGF-β2) and increased interleukin 11 (IL-11) expression in the brain. Additionally, levels of JAK2, STAT3, and B-cell lymphoma 2 (Bcl-2) were significantly elevated following treatment, while expressions of Tumor protein p53 (p53), Caspase 3, Microtubule-associated proteins 1A/1B light chain 3B (LC3B), and Sequestosome 1 (p62) were reduced. Fluorescence intensities of ionized calcium binding adaptor molecule (Iba-1) and dichloro-dihydro-fluorescein diacetate (DCFH-DA) were enhanced, indicating decreased microglial activation and reactive oxygen species (ROS) production due to naloxone treatment. Cognitive function tests revealed improved performance in TBI mice treated with naloxone, demonstrated by decreased alteration rates in the Y-maze test and improved preference index scores in the novel object recognition (NOR) test. Conclusions: Naloxone shows potential for neuroprotection and enhanced cognitive performances, which may be associated with modulation of JAK2/STAT3 signaling in a mouse model of moderate TBI. Full article

LRRC8 channels are volume-regulated anion channels (VRACs) activated by cellular swelling, which mediate regulatory volume decrease in many cell types. Recently, it has been shown that these channels contribute to the release of glutamate from astrocytes. Since enhanced extracellular glutamate concentrations produce hyperexcitability, and microdialysis revealed elevated levels of the transmitter in the brains of epileptic patients, we asked whether astroglial glutamate release through LRRC8/VRACs might contribute to the initiation of experimental temporal lobe epilepsy (TLE). Patch clamp, pharmacological, and single-cell transcript analyses were performed in the hippocampus of controls and mice with inducible deletion of LRRC8a in astrocytes. In addition, these mice were exposed to our unilateral intracortical kainate model of TLE. Tonic currents were recorded from CA1 pyramidal neurons as a measure of glutamate release. Our data show that neither expression of LRRC8a nor the amplitude of tonic currents was altered 4 h after status epilepticus-induced TLE. These findings do not suggest that increased astroglial glutamate release through LRRC8 channels contributes to the initiation of experimental TLE. Full article

Background/Objectives: Cerebral angiography is a cornerstone diagnostic and therapeutic procedure for cerebrovascular diseases; however, its potential effects on vascular integrity and cellular homeostasis remain incompletely elucidated. This systematic review aims to comprehensively evaluate endothelial and histopathological alterations induced by cerebral angiographic procedures, with particular emphasis on oxidative stress, inflammation, endothelial dysfunction, and blood–brain barrier disruption. Methods: This systematic review was conducted in accordance with the PRISMA 2020 guidelines. PubMed, Scopus, and Web of Science databases were systematically searched for studies published between 1981 and 2025 using predefined keywords related to cerebral angiography, endothelial injury, oxidative stress, inflammation, and histopathological changes. A total of 1142 records were identified, and 216 duplicates were removed. Following title and abstract screening, 312 full-text articles were assessed for eligibility, of which 112 were excluded due to irrelevance or insufficient endothelial or histopathological data. Ultimately, 200 studies were included in the qualitative synthesis. The literature identification, screening, and selection process are summarized in the manuscript. The review protocol was not prospectively registered. Results: The included studies demonstrated that cerebral angiographic procedures induce endothelial and microvascular alterations through both mechanical and contrast-mediated mechanisms. Iodinated contrast agents were consistently associated with increased reactive oxygen species production, reduced endothelial nitric oxide bioavailability, mitochondrial dysfunction, and activation of pro-inflammatory signaling pathways, including nuclear factor kappa B (NF-κB). Histopathological findings revealed endothelial swelling, vacuolization, apoptosis, microthrombus formation, inflammatory cell infiltration, and disruption of endothelial junctions, leading to increased vascular permeability and blood–brain barrier impairment. Mechanical factors related to catheter manipulation and high-pressure contrast injection further exacerbated endothelial injury by altering shear stress and promoting leukocyte adhesion. The severity of endothelial damage and inflammatory responses was consistently greater in patients with comorbid conditions such as diabetes mellitus, hypertension, and atherosclerotic disease. Conclusions: Cerebral angiography may induce endothelial dysfunction and histopathological vascular injury predominantly through oxidative and inflammatory mechanisms. Optimization of contrast agent selection, refinement of procedural techniques, and implementation of endothelial-protective strategies may mitigate vascular injury and improve procedural safety. Further translational and clinical studies are warranted to identify biomarkers and protective interventions targeting angiography-induced endothelial damage. Full article

Background/Objectives: In recent years, it has been suggested that sedatives may cause brain damage. One possible mechanism is interference with oxidative phosphorylation of brain mitochondria, but much remains unknown. In this study, we focused on dexmedetomidine, midazolam, and propofol, essential sedatives in anesthesia and intensive care, and aimed to understand the effects of these drugs on mouse brain mitochondria. Methods: We measured changes in mitochondrial respiratory capacity and swelling rate upon exposure to these sedatives in a wide concentration range. For the sedative that demonstrated impaired mitochondrial function we explored the possible involvement of mitochondrial permeability transition pore opening using brain mitochondria from cyclophilin D knockout (CypD KO) mice and detected cytochrome c (cyt c) release by Western blot. Results: Of the three sedatives, only high concentrations of propofol exhibited reduced respiratory capacity and mitochondrial swelling, toxicity which was not prevented by CypD KO. Furthermore, propofol did not induce cyt c release. Conclusions: These results suggest that propofol-induced brain mitochondrial dysfunction is a mechanism independent of mPTP opening. Full article

The promise of intracortical neural interfaces—to restore lost sensory and motor function and probe the brain’s activity—has long been constrained by device instability over chronic implantation. Conventional silicon-based probes, composed of heterogeneous materials, often fail due to mechanical mismatch, inflammatory responses, and interface-driven degradation, where stress can induce cracking, swelling, and exposure of cytotoxic elements to neural tissue. Silicon carbide (SiC) offers a compelling solution, combining chemical inertness, structural strength, and biocompatibility in both amorphous and crystalline forms. In this review, we discuss advances in SiC neural interfaces, highlighting contributions from multiple laboratories and emphasizing our own work on monolithic devices, constructed entirely from a single, homogeneous SiC material system. These devices mitigate interface-driven failures and show preliminary indications of magnetic resonance imaging (MRI) compatibility, with minimal image artifacts observed compared to conventional silicon probes, though further in vivo studies are needed to confirm thermal safety at high-field conditions. Collectively, SiC establishes a versatile platform for next-generation, durable neural interfaces capable of reliable, long-term brain interaction for both scientific and clinical applications. Full article