Search Results (109)

Macrophages are among the earliest responders to tissue injury and remain associated with the wound throughout the healing process. Calcium (Ca²⁺) signaling regulates many immune cell behaviors, yet its role in macrophage responses to injury in vivo remains poorly defined. Here, we used transgenic zebrafish (Danio rerio) and Danionella cerebrum lines that specifically express the genetically encoded Ca²⁺ indicator, GCaMP, in macrophages. Live confocal imaging was used to monitor macrophage Ca²⁺ dynamics during the early wound response. We found that injury triggers macrophage recruitment to the wound site, where cells exhibit robust and repetitive intracellular Ca²⁺ transients that persist for several hours. Pharmacological perturbation revealed that endoplasmic reticulum Ca²⁺ stores contribute to sustaining these transients, while additional Ca²⁺ sources likely participate in macrophage Ca²⁺ signaling in vivo. Functionally, these Ca²⁺ transients do not appear to be required for chemotaxis, phagocytosis, or TNFα activation during the early stages of wound healing. Together, these findings uncover a previously uncharacterized macrophage Ca²⁺ signaling behavior and highlight the complexity of Ca²⁺ regulation during tissue injury responses in vivo. Full article

Multiple sclerosis is a chronic immune-mediated central nervous system disorder marked by neuroinflammation, demyelination, and neurodegeneration, and effectively modeled by experimental autoimmune encephalomyelitis. The objective of this study was to elucidate the roles of T follicular helper and T follicular regulatory cells in the progression of experimental autoimmune encephalomyelitis and to assess their association with IL-21 expression and central nervous system tissue pathology. In this study, experimental autoimmune encephalomyelitis was induced in 25 adult female C57BL/6 mice. Fluorescent double immunostaining for CXCR5 in combination with PD-1, ICOS, CD4, and FOXP3 was performed, along with the analysis of IL-21 mRNA expression. Histopathological assessment was conducted on the cerebrum, cerebellum, and medulla spinalis to evaluate neuroinflammation and myelin loss. A significant increase in CXCR5⁺PD-1⁺ and CXCR5⁺ICOS⁺ T follicular helper-like cells was observed in brain tissue, indicating immune activation and T follicular helper cell involvement. Simultaneously, a marked decrease in FOXP3⁺ T follicular regulatory-like cells suggested impaired immune tolerance and enhanced autoimmune activity. The infiltration of T follicular helper-like cells was identified as a key driver of inflammation and demyelination in the central nervous system. Additionally, the elevated IL-21 mRNA expression highlighted B cell activation and the initiation of antibody-mediated responses. These findings suggest that dysregulation of the T follicular helper/T follicular regulatory axis and elevated IL-21 expression contribute to the immunopathogenesis of experimental autoimmune encephalomyelitis, providing further insight into the mechanisms underlying multiple sclerosis development. Full article

Background/Objectives: Eye infection with herpes simplex virus type 1 (HSV-1) can result in keratitis, a leading cause of corneal blindness. We evaluated whether an experimental vaccine containing HSV-2 immunogens to prevent genital herpes also protects against HSV-1 eye infection and neuroinvasion. Methods: Mice were immunized twice, one month apart, with PBS or a nucleoside-modified lipid nanoparticle vaccine containing mRNA encoding for gC2, gD2, and gE2. One month later, 10⁶ plaque forming units (PFU) (10 lethal dose 50, LD₅₀) of the HSV-1 McKrae strain were added to the intact cornea of each eye. Results: The vaccine prevented death and markedly reduced eyelid and attached conjunctival inflammation (blepharoconjunctivitis) and weight loss compared with the PBS group. Tissues from the ocular conjunctiva and eye bulb, olfactory bulb/peduncle, trigeminal ganglia, and brain (brainstem, cerebrum, and cerebellum) were harvested 5 days post-infection from 5 mice each in the PBS and vaccine groups, and from another 10 mice in the vaccine group 7 weeks post-infection. At 5 days, HSV-1 was not detected in any tissue in the vaccine group, while viral titers were positive in 16 of 25 (64%), and HSV-1 DNA was detected in 22 of 25 (88%) individual tissues in the PBS group. Histopathological and immunohistochemical analysis at 5 days post-infection confirmed that the vaccine protected against inflammation; however, some animals experienced breakthrough blepharoconjunctivitis. At 7 weeks, 3 of 10 (30%) mice in the vaccine group had HSV-1 DNA detected in the eyes or trigeminal ganglia tissues, but no animal had HSV-1 DNA detected in brain tissues. The vaccine produced cross-reactive HSV-1 neutralizing antibodies and gD1 IgG binding antibodies, but low or undetectable cross-reactive binding antibodies to gC1 and gE1. Conclusions: Despite occasional mild, localized breakthrough infections, the vaccine provided disease-modifying immunity and was neuroprotective. The results suggest that a single herpes vaccine effective against genital HSV-2 may be neuroprotective against HSV-1 following eye infection. Full article

The poor clinical outcomes of pediatric high-grade glioma (pHGG) highlight the urgent need for new therapies. Oligodendrocyte lineage transcription factor 2 (OLIG2) is a pro-mitotic transcription factor highly expressed in glioma stem cells and may represent a novel therapeutic target. To evaluate the therapeutic efficacy of an OLIG2 inhibitor CT-179 in pHGG, we determined the OLIG2 mRNA expression in 10 patient-derived orthotopic xenograft (PDOX) models. In vitro activities of CT-179 were analyzed in monolayer and neurosphere cells (0–10 µM) with and without radiation (XRT) (0–8 Gy), brain penetration was evaluated in tumor-bearing PDOX mice, and in vivo efficacy was determined at 15–240 mg/kg (oral) alone or combined with XRT (2 Gy/day × 5 days). Changes in animal survival times were analyzed using the Kaplan–Meier method, followed by pair-wise comparisons. Increased OLIG2 mRNA expression was detected in seven out of ten PDOX models. CT-179 inhibited cell viability in a time- and dose-dependent manner in all eight pGBM xenograft tumors (IC₅₀ 0.03–10 µM) and was potentiated by XRT (0.03–1 µM). Oral gavage (24 mg/kg) of CT-179 for 5 days led to effective penetration in mouse cerebrum (3232.7 ± 569.2 ng/g), cerebellum (1563.3 ± 269.6 ng/g), brain stem (1685.3 ± 309 ng/g), and PDOX tumors (1814 ± 110.3 ng/g) vs. 361.3 ± 1.5 ng/mL in serum. CT-179 alone was not active at 200 mg/kg in four models, although it was moderately effective at 240 mg/kg in one model. When combined with XRT, a significant extension of animal survival times was observed in two out of four models. Doses needed to eliminate OLIG2 expression in vitro varied from 0.3 to >1 µM in pGBM cells. In summary, our data showed that orally administered CT-179 penetrated the blood–brain barrier (BBB) and exhibited potential for inhibiting pGBM growth when combined with XRT. Full article

Background/Objectives: SLC13A5 encodes a sodium–citrate cotransporter implicated in early-onset epileptic encephalopathy and metabolic brain dysfunction, yet its developmental regulation and molecular context in the human brain remain incompletely defined. Methods: Leveraging human developmental transcriptomes from the Evo-Devo resource, we delineated tissue trajectories and network context for SLC13A5 across the fetal–postnatal life. Results: In the cerebrum, SLC13A5 expression rises from late fetal stages to peak in the first postnatal year and then declines into adulthood, while cerebellar levels increase across the lifespan; liver shows a fetal decrease followed by sustained postnatal upregulation. A transcriptome-wide scan identified extensive positive and negative associations with SLC13A5, and a signed weighted gene co-expression network analysis (WGCNA) built on biweight midcorrelation placed SLC13A5 in a large module. The module eigengene tracked brain maturation (Spearman rho = 0.802, p = 8.62 × 10⁻⁶) and closely matched SLC13A5 abundance (rho = 0.884, p = 2.73 × 10⁻⁶), with a significant partial association after adjusting for developmental rank (rho = 0.672, p = 6.17 × 10⁻⁴). Functional enrichment converged on oxidative phosphorylation and mitochondria. A force-directed subnetwork of the top intramodular members (|bicor| > 0.6) positioned SLC13A5 adjacent to a densely connected nucleus including CYP46A1, ITM2B, NRGN, GABRD, FBXO2, CHCHD10, CYSTM1, and MFSD4A. Conclusions: Together, these results define a developmentally tuned, mitochondria-centered program that co-varies with SLC13A5 in the human brain across the lifespan. It may provide insights to interrogate age-dependent phenotypes and therapeutic avenues for disorders involving citrate metabolism. Full article

Background: Common variable immunodeficiency is a heterogeneous disorder characterized by defects in antibody production and immune dysregulation, associated with infections and autoimmunity. Although structural and cognitive effects of CVID on the central nervous system have attracted attention in recent years, studies jointly addressing volumetric brain imaging and neurocognitive evaluation remain limited. Materials and Methods: In this retrospective cross-sectional study, 35 patients with common variable immunodeficiency and 40 age- and sex-matched healthy controls were evaluated. Cognitive performance was assessed in all participants using the Montreal Cognitive Assessment. High-resolution T1-weighted brain magnetic resonance imaging scans underwent automated segmentation using the volBrain platform, yielding quantitative volumetric measurements of cortical, subcortical, and cerebellar structures, as well as ventricles and cerebrospinal fluid. Intergroup comparisons were performed using independent t-tests and analysis of variance. Results: MoCA scores were significantly lower in patients with CVID. Volumetric analysis revealed prominent reductions in the volumes of total brain tissue, gray matter, cerebrum, cerebellum, limbic system, thalamus, and basal ganglia. Paralleling these findings, cerebrospinal fluid and lateral ventricle volumes were increased. Additional volume losses were detected in CVID patients with low MoCA scores. In CVID patients with autoimmunity, volume loss affected broader areas. Conclusions: CVID appears to be associated with structural brain changes and cognitive impairments. Chronic inflammation and immune dysregulation may contribute to these neurodegenerative processes. Regular neurocognitive monitoring and further prospective studies are warranted in patients with CVID. Full article

Reactive oxygen species (ROS), inevitable by-products of aerobic metabolism, act both as regulators of signaling pathways and as mediators of oxidative stress and aging-related damage. Protein oxidative post-translational modifications (Ox-PTMs) are recognized hallmarks of aging and metabolic decline, yet the persistence of protein oxidation under different physiological conditions, such as age and diet, remains unclear. Here, we applied proteomics to mitochondrial and membrane-enriched fractions of male Fischer 344 rat cerebrum and heart, comparing Ox-PTMs across young and aged animals subjected to ad libitum nutrition (AL) or calorie restriction (CR). We identified 139 mitochondrial and membrane-associated proteins consistently exhibiting high levels of oxidation, including tricarboxylic acid (TCA) cycle enzymes, respiratory chain subunits, ATP synthase components, cytoskeletal proteins, and synaptic vesicle regulators. Functional enrichment and network analyses revealed that oxidized proteins clustered in modules related to mitochondrial energy metabolism, membrane transport, and excitation–contraction coupling. Notably, many proteins remained persistently oxidized, predominantly as mono-oxidation, without significant changes during aging or CR. Moreover, the enzymatic activity of mitochondrial complexes was not only preserved but significantly enhanced in specific contexts, and the structural integrity of the respiratory chain was maintained. These findings indicate a dual strategy for coping with oxidative stress: CR reduces ROS production to limit oxidative burden, while protein and network robustness enable functional adaptation to persistent oxidation, collectively shaping mitochondrial function and cellular homeostasis under differing physiological conditions. Full article

Background/Objectives: The guinea pig is a unique experimental model because of the evolutionary loss of the GULO gene, which encodes an enzyme involved in vitamin C synthesis. Since vitamin C plays an essential role in collagen biochemistry, numerous studies have investigated the effects of pre- and postnatal vitamin C deficiency. However, only a few studies, including ours, have indicated a possible link between vitamin C deprivation and potential weakening of the basement membrane, which may lead to significant alterations in brain structure. Methods: The experiment included guinea pig foetuses completely deprived from the 10th (E2 group) and the 20th (E1 group) to the 50th day of intrauterine life. Tissue samples from the cerebrum and cerebellum were taken for biochemical, molecular, and immunohistochemical analyses. Results: In the E2 group alone, we found marked gross changes: cerebral bleeding, porencephaly, and a lissencephalic cerebellar surface. Microscopic examination revealed diffuse bleeding in the cerebrum along with a loss of neurons in the area of the defect, specifically in the E2 group. The complete maturation of ectopic neurons characterised dysplastic changes in the cerebellum. Hydroxyproline analysis of both the cerebrum and cerebellum showed no significant differences among the E1, E2, and control groups. However, decreased expression of COL1, COL4A1, and SLC23A1 was observed solely in the cerebellar tissue of the E1 group. Conclusions: The morphological, biochemical, and molecular results represent preliminary associations with vitamin C deficiency, but require further validation. Full article

Pituitary abscess syndrome (PAS) is a rare neurological disorder, typically associated with progressive dysfunction of the cerebrum and brainstem. Reporting PAS in ruminants is essential to broaden the global veterinary understanding of this condition. The present study describes the epidemiological, clinical, laboratory, microbiological, and pathological findings of nine ruminant cases diagnosed with PAS. Neurological signs were the most prominent clinical manifestations and included altered mentation, tongue hypotonia, nystagmus, blindness, ear ptosis, circling, facial hypoalgesia, head pressing, and proprioceptive deficits. Hematological alterations in some animals comprised leukocytosis by neutrophilia, a degenerative left shift, and hyperfibrinogenemia. Serum biochemical abnormalities were inconsistent and varied among cases. Cerebrospinal fluid (CSF) analysis revealed marked variability, ranging from normal parameters to mild or marked pleocytosis, often accompanied by hyperproteinorrachia. Microbiological cultures from CSF samples or abscess material yielded Trueperella pyogenes, Streptococcus spp., and Corynebacterium spp. Gross pathological findings primarily included pituitary hyperemia, abscess formation, or diffuse suppurative inflammation characterized by a creamy yellow to greenish exudate. Histopathological examination revealed severe multifocal suppurative inflammation composed predominantly of neutrophils, occasional histiocytes, abundant bacteria, areas of necrosis, and encapsulated abscesses. This retrospective study provides novel insights into the clinical, laboratory, and pathological characteristics of PAS in ruminants under field conditions, thereby contributing to improved recognition and diagnostic understanding of this uncommon disease. Full article

Alzheimer’s disease (AD) is considered to be one of the most common types of dementia, threatening the health of elderly individuals. Enhancing the brain’s cholinergic activity is currently the primary therapeutic strategy for treating AD patients. Acetylcholine and butyrylcholine are key targets in this approach, as they function as neuromodulators within the cerebrum—particularly in its various cholinergic regions responsible for essential functions like memory, thought, inspiration, and excitement. Oxidative stress and free radicals are considered to play a crucial role in the pathogenesis of AD and may be key factors in its etiology. Additionally, oxidants and oxidative stress-induced products can upregulate amyloid precursor protein (APP) expression, promoting Aβ aggregation. Another major factor in the pathogenesis of AD is the imbalance of metal homeostasis in the brain. Notably, the mammalian brain contains significantly higher concentrations of Cu, Zn, and Fe ions compared to other tissues. The present review focuses on novel bifunctional metal chelators with potential antioxidant activity for the treatment of AD. Full article

Background and Objectives: The objective of this research is to make a comparative evaluation of the correlation between the volumetric examination of subcortical cerebral regions and white matter hyperintensities classified according to the Fazekas scoring system. Materials and Methods: A total of 236 cases with cranial MRI studies were retrospectively analyzed. This study included patients aged over 45 years who had white matter hyperintensities and who did not have a prior stroke diagnosis. White matter hyperintensities were evaluated in axial FLAIR images according to Fazekas’s grading scale. Patients with Fazekas 0 and 1 were grouped in group 1 and the patients with Fazekas 2 and 3 were grouped in group 2. MRI data processing and subcortical volumetric analyses were performed using the volBrain MRI brain volumetry system. Results: There were statistically significant differences between groups 1 and 2 in terms of cerebrospinal fluid total brain white and gray matter (p < 0.001), total brain white and gray matter (p = 0.009), total cerebrum (p < 0.001), accumbens (p < 0.001), thalamus (p < 0.001), frontal lobe (p < 0.001), parietal lobe (p < 0.001), and lateral ventricle (p < 0.001) volumes. Conclusions: Our study finds a strong link between white matter hyperintensity burden and brain atrophy. This includes volume reductions in total brain white and gray matter, frontal and parietal lobe atrophy, increased cerebrospinal fluid (CSF), and atrophy in specific brain regions such as the accumbens and thalamus. Full article

Dysregulated inflammatory processes contribute to depression, and gene–environment interactions may influence an individual’s risk and resilience. Reduced brain-derived neurotrophic factor (BDNF) expression increases susceptibility for developing depressive symptoms, and the Val66Met (rs6265) single-nucleotide polymorphism (SNP) on the BDNF gene is linked to mood disorders. However, whether Val66Met confers increased vulnerability to inflammation-induced depressive tendencies is unknown. Here, we tested the hypothesis that the Val66Met SNP increases vulnerability to inflammation-induced depressive symptoms in a mouse model of lipopolysaccharide (LPS)-induced depression-like behavior. Behavior and neuroinflammation, following a 24 h LPS challenge, were measured in mice expressing the human BDNF Val66Met gene variant or Val66Val littermates (control). The Val66Met genotype did not affect the peripheral inflammatory response, acute neuroinflammation, or the acute sickness behavior response. Val66Met mice exhibited anhedonia-like behavioral responses following LPS challenge, and we found increased mRNA expression of IL-1β and TNFα in the cerebrum compared to controls. The mRNA expression of IL-1β and TNFα in the hippocampus and the nucleus accumbens of Val66Met mice was increased following LPS, and a significant genotype × LPS interaction was detected for CD68 expression in the nucleus accumbens. In summary, these data suggest that immune activation in Val66Met mice increased susceptibility to anhedonic behavior and dysregulated negative regulation of inflammation. Full article

Background: Cerebral amyloid angiopathy (CAA) represents a progressive cerebrovascular disorder, characterized by aberrant accumulation of beta-amyloid isoforms in cortical and leptomeningeal vessel walls of cerebrum and cerebellum. Methods: We sought to investigate the clinical manifestations, current different diagnostic tools, various therapeutic strategies and most uncommon subtypes of the disease. Results: The vast majority of CAA remains sporadic, with increasing prevalence with age and very frequent coexistence with Alzheimer’s disease. Clinically, CAA can present with spontaneous lobar intracerebral hemorrhage, transient focal neurologic episodes attributed to convexity subarachnoid hemorrhage or cortical superficial siderosis, and progressive cognitive decline leading to dementia. Inflammatory CAA subtype should be recognized early and treated promptly so that better functional outcomes may be achieved. Moreover, genetic and iatrogenic CAA forms are rare, yet increasingly recognized during the last years. Therapeutic management remains challenging for clinicians, especially when markers indicative of higher bleeding risk are present. A targeted therapy does not currently exist. However, various clinical trials are in progress, focusing on offering new promising insights into the disease treatment. Conclusions: This review aims to deepen our understanding of CAA diagnosis and therapeutic approach but also summarizes current evidence on the most uncommon subtypes of this cerebral small-vessel disease. Full article

Introduction: Achieving long-term impacts from cognitive remediation (CR) interventions is a key goal in rehabilitative care. Integrating virtual reality (VR) with psychoeducational approaches within CR programs has shown promise in enhancing user engagement and addressing the complex needs of individuals with bipolar disorder (BD). A previous randomized controlled crossover feasibility trial demonstrated the viability of a fully immersive VR-CR intervention for BD, reporting low dropout rates, high acceptability, and significant cognitive improvements. This secondary analysis aimed to evaluate the stability of these outcomes over time. Methods: This paper presents a 6- to 12-month follow-up of the initial trial. Secondary cognitive outcomes were assessed, including visuospatial abilities, memory, attention, verbal fluency, and executive function, using validated assessment tools. Statistical analyses were conducted using Friedman’s test. Results: A total of 36 participants completed the 6- to 12-month follow-up. Overall, cognitive functions showed a trend toward stability or improvement over time, except for visuospatial and executive functions, which demonstrated inconsistent trajectories. Significant improvements were observed in language (p = 0.02). Conclusion: This study highlights the overall stability of cognitive functions 12 months after a fully immersive VR-CR program for individuals with BD. To sustain long-term clinical benefits, an integrated approach, such as incorporating psychoeducational strategies within cognitive remediation interventions, may be essential. Further follow-up studies with control groups and larger sample sizes are needed to validate these findings. Full article

Background/Objectives: Cerebral Palsy (CP) is a non-progressive clinical condition characterized by secondary issues, including speech impairments. Our study aims to evaluate the volumes of brain areas related to speech in patients diagnosed with CP between the ages of 0–17. Methods: this study includes the images of 84 children: 42 in the control group who applied to the hospital between the specified dates and were reported as healthy by MRI from the patient records, and 42 patients with CP. Results: in the CP group, white and gray matter, cerebrum, cerebellum, thalamus, lobus frontalis, lobus temporalis, lobus parietalis, lobus insularis, gyrus cinguli, and nuclei basales volumes were observed to decrease statistically significantly compared to the control group (p ˂ 0.001). Conclusions: we found a significant decrease in the volumes of speech-related brain areas in CP patients, indicating that CP can significantly impact the brain’s speech-related regions. Full article