Search Results (385)

Background: Dystonia is a severe neurological disorder with enigmatic pathogenesis. Current treatment options are limited in preventing the disease progression, underscoring the urgent need for new targeted therapeutic agents to develop more effective therapies. Methods: We performed a proteome-wide Mendelian randomization (MR) study and sensitivity analyses to evaluate the causal relationships between dystonia and proteins. GO and KEGG enrichment analysis of dystonia-associated proteins was conducted. Then, we built PPI network and identified the expression of hub-genes in specific brain neurons in single-cell sequencing data. Additionally, we performed drug enrichment analysis of hub-genes, and employed network pharmacology and molecular docking methods to identify potential drugs for dystonia. Results: Our study identified genetically predicted associations consistent with a potential causal effect between 51 proteins and risk of dystonia. GO and KEGG enrichment analyses revealed that these proteins are involved cellular response to transforming growth factor-β stimulation and cytokine-cytokine receptor interaction. Notably, the PPI network exhibited 21 community relationships within the regulatory network among the 51 dystonia-associated proteins identified. The single-cell RNA annotations for brain cluster specificity revealed Tumor necrosis factor (TNF) was highly expressed in microglia cells. Drug enrichment analysis identified five traditional Chinese medicine monomers (paeoniflorin, artesunate, ginsenoside Rh1, psoralen, and quercetin dihydrate) as candidates for molecular docking analysis. Among these, paeoniflorin-TNF, quercetin dihydrate-TNF, and artesunate-TNF exhibited the highest binding energy (−9.1 kcal/mol). Conclusions: Our molecular-docking analysis suggested that traditional Chinese medicine monomers including paeoniflorin, quercetin dihydrate, and artesunate may serve as promising candidates for future drug development. Full article

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by rapid motoneuron degeneration. Hydrogen sulfide (H₂S), a signaling molecule that regulates post-translational modification, has recently been implicated in the pathophysiology of ALS. Our study aimed to design, synthesize, and investigate the potential effects of (2S)-2-aminopentanethioic S-acid (POM16), an isomer of the slow-releasing H₂S donor thiovaline, in a genetic ALS model. FUS [1-359]-tg mice, which recapitulate ALS syndrome, and their wild-type (WT) littermates received POM16 (at a dose of 50/mg/kg) or standard ALS therapy riluzole (at a dose of 8 mg/kg/day) dissolved in drinking water, or vehicle, for six weeks starting at nine weeks of age. The onset of paralysis, physiological and motor functions, muscle atrophy, density of spinal cord motoneurons, gene expression of proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor (TNF), and concentration of oxidative stress marker malondialdehyde (MDA) in the spinal cord were studied. POM16-treated mutants displayed significant improvements in body weight, water and diet intake, as well as behavior in the rotarod, wire, and pole tests. The percentage of mice with paralysis on the 6th week of dosing was reduced from 48% in vehicle-treated mutants to 16% in POM16-treated FUS [1-359]-tg mice, while in the riluzole-treated group, it was 38%, not reaching significance. Notably, muscle weight was not significantly improved by the latter treatment, unlike the dosing with POM16. In comparison with vehicle-treated FUS [1-359]-tg mice, POM16-treated mutants had significantly higher motor neuron density in the spinal cord, lower MDA levels, and reduced muscle atrophy ranking. Thus, new compound POM16 has a therapeutic potential to counteract ALS pathology that is likely mediated via anti-oxidative stress mechanisms. Given that any effective treatment of this devastating disease is currently lacking, it is hoped that POM16 can be a promising therapy for ALS. Full article

A pro-inflammatory state, characterized by elevated levels of pro-inflammatory cytokines, is frequently reported among individuals presenting with primary first-episode psychosis (FEP), particularly those with environmental risk factors such as maternal infections and early childhood traumatic experiences. These findings suggest that immune system disturbances may play a crucial role in the onset of psychotic disorders. Building on this, cytokines may contribute to the risk of FEP from the stage of neurodevelopment, where they can induce aberrant changes in neuronal growth. During early childhood, these cytokine-mediated processes may disrupt normal neuronal maturation and lead to brain alterations that increase vulnerability to primary psychotic disorders. Furthermore, pro-inflammatory cytokines exhibit strong bidirectional modulatory interactions with dopamine, a key neurotransmitter implicated in the pathogenesis and persistence of psychosis. Notably, these cytokines may also influence the clinical presentation and severity of psychosis. In addition, antipsychotic medications can partially modulate cytokine levels, and this modulation has been correlated with the efficacy of antipsychotics in treating various psychotic symptoms. Frequently reported cytokines in this context include interleukins (IL-1β, IL-2, IL-4, IL-6, IL-8, and IL-10), tumour necrosis factor-α (TNF-α), and interferon-gamma (IFN-γ). We conducted a non-systematized literature search on Google Scholar and PubMed for studies looking at cytokines in primary psychotic disorders during FEP. In this narrative review, we provide an overview of the literature on immune dysregulation in FEP, with a particular emphasis on cytokines. Full article

Excessive dietary dextrose intake and its misuse in sports raise significant concerns about health outcomes across life stages. To investigate how biological maturity influences small intestinal responsiveness to dextrose overexposure, we subjected 1-month-old (young maturing) and 14-month-old (middle-aged) male Wistar rats to a 20% or 60% dextrose drinking regimen for 8 weeks. The middle-aged rats receiving the 60% dextrose solution exhibited the most pronounced alterations, including compromised barrier integrity, reduced crypt proliferation, and accelerated enterocyte apoptosis and necrosis. These structural changes coincided with weakened antioxidant defences, tissue iron accumulation, and elevated lipid peroxidation. Altered neuroendocrine and purinergic pathways, marked by increased serotonin, neuron-specific enolase (NSE), cytosolic high mobility group box 1 (HMGB1), and ATP synthase, alongside downregulated P2X7 receptor expression and a reduced nuclear factor kappa B p65/nuclear factor erythroid 2-related factor 2 (NF-κB p65/Nrf2) ratio, indicate potential observational associations with metabolic exhaustion and impaired inflammatory responsiveness under a chronic high-dextrose regimen. In conclusion, while fasting homeostatic model assessment of insulin resistance (HOMA-IR) values remained stable, a high-dextrose drinking regimen promotes maturity-dependent small intestinal changes and molecular signalling weakness, providing a preliminary pathophysiological framework for understanding potential health outcomes of dextrose overexposure across different life stages. Full article

Neuroprotection in childhood developmental and epileptic encephalopathies may require approaches, distinct from adult brain injury models of neuroprotection, with a primary focus on preservation of synaptic density rather than prevention of cellular necrosis. There is growing evidence to indicate early-life seizures activate complement cascade proteins C1q and C3. Subsequently, localized microglia may excessively phagocytose structurally intact synaptic neurons disrupting normal brain maturation. This review incorporates kinetic models of neuro-immune interactions based on human histopathology from epileptogenic tissues and quantitative neuro-immune biomarkers to provide suggestions that complement-mediated synaptic pruning may contribute to structural network disruption and cognitive decline in pediatric epilepsy. While standard anti-seizure medications effectively stabilize electrical activity, they do not mitigate underlying neuro-inflammatory responses. Consequently, targeted pharmacological inhibition of the complement microglia axis may provide a potential disease modifying strategy to protect developing neural circuits. The translational feasibility of using targeted complement inhibitors should be evaluated addressing critical challenges such as central nervous system drug delivery across the blood–brain barrier, immunosuppression management and the application of non-invasive biomarkers to define the precise therapeutic window for intervention. Full article

Background and Objectives: Synthetic cannabinoids (SCs) are new psychoactive substances associated with acute intoxications. Experimental data obtained under controlled and comparable conditions remain limited for this category of compounds. This descriptive, hypothesis-generating screening study aimed to characterize the acute toxicity profile of three SCs, JWH-007, AM-694, and MAB-CHMINACA. Materials and Methods: Acute toxicity was evaluated in female Swiss Albino mice, in accordance with the OECD 423 guideline, following oral and intraperitoneal administration. Animals were monitored for 14 days for behavioral and clinical signs of toxicity. At the end, histopathological examination was performed to describe organ-level changes. Serum concentrations of the tested compounds were quantified by LC-ESI-MS/MS 24 h after intraperitoneal administration. Results: The three compounds were associated with distinct behavioral, clinical, and histopathological observations. JWH-007 was associated with transient behavioral depression and histopathological changes in peripheral organs. AM-694 was associated with histopathological changes in systemic organs and limited behavioral manifestations. MAB-CHMINACA was associated with acute behavioral toxicity and central nervous system lesions, including neuronal vacuolization, necrosis, oedema, and inflammatory changes. Conclusions: These preliminary findings describe compound-specific in vivo toxicity patterns and may inform the design of future confirmatory studies on SCs’ toxicity. The observed behavioral and histopathological changes should be interpreted as hypothesis-generating and require statistical validation before conclusions can be drawn regarding comparative toxicity, structural class effects, or predictive value for risk stratification. Full article

Blood-based biomarkers offer a promising “biochemical imaging” approach for acute ischemic stroke (AIS) management, providing objective and accessible tools to complement conventional neuroimaging. This narrative review synthesizes recent advances in biomarkers derived from multiple neurovascular unit (NVU) compartments, including glial fibrillary acidic protein (GFAP), S100 calcium-binding protein B (S100B), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), neuron-specific enolase (NSE), neurofilament light chain (NfL), matrix metalloproteinase-9 (MMP-9), Claudin-5, Occludin, brain-derived neurotrophic factor (BDNF), interleukin-33 (IL-33), tumor necrosis factor-alpha (TNF-alpha), PARK7/DJ-1, glycogen phosphorylase BB (GP-BB), and circulating microRNAs. We focus on their stage-specific clinical utility across three scenarios: (1) ultra-early differentiation between ischemic stroke and intracerebral hemorrhage in prehospital and emergency settings; (2) dynamic prediction and monitoring of hemorrhagic transformation after reperfusion therapies; and (3) assessment of infarct burden, neurorepair potential, and long-term functional outcomes. Despite their promise, clinical translation remains hindered by assay platform heterogeneity, lack of standardized cut-off values, limited cost-effectiveness data, and insufficient prospective validation adjusted for key covariates such as age and renal function. We further discuss multi-marker panel construction, including strategies to address biomarker collinearity and overfitting. Future directions emphasize stage-specific panels, point-of-care testing devices, and artificial intelligence algorithms to advance precision medicine in stroke care. Full article

Insulin (Ins) regulates multiple intracellular signalling pathways involved in cell survival, oxidative stress responses, and tau phosphorylation. Dysregulation of these pathways has been implicated in neurodegenerative disorders, including Alzheimer’s disease (AD). The present study evaluated the effects of insulin on protein kinase B/glycogen synthase kinase-3 beta (AKT/GSK-3β) signalling, tau phosphorylation, and oxidative stress-related markers in SH-SY5Y neuroblastoma cells. Cell metabolic activity was assessed using the (diphenyltetrazolium bromide) MTT assay, while cell number and viability were evaluated by Trypan Blue exclusion, necrosis by lactate dehydrogenase (LDH) release, and apoptosis by Caspase-3 activity. Western blot analysis was performed to evaluate the expression of phosphorylated AKT (p-AKT), phosphorylated GSK-3β (p-GSK-3β Ser9), phosphorylated TAU (pTAU), nuclear factor erythroid 2-related factor 2 (NRF2), manganese superoxide dismutase (Mn-SOD), and copper/zinc superoxide dismutase (Cu/Zn-SOD). Lipid peroxidation was determined by measuring malondialdehyde (MDA) levels using a colorimetric/fluorometric assay. Insulin treatment increased MTT reduction (31.25%) and cell metabolic activity (119.15%) while reducing LDH release (19.2%) and Caspase-3 activity (31.26%). In addition, insulin significantly increased p-AKT (34.2%) and p-GSK-3β (Ser9) (19.9%) levels. A reduction in pTAU levels (53.39%) was also observed following insulin treatment. Furthermore, insulin increased NRF2 expression (18.77%), Cu/Zn-SOD (37.29%), and Mn-SOD (50.16%) and reduced MDA levels (13.95%). These findings indicate that insulin modulates signalling pathways associated with tau phosphorylation and cellular redox regulation in SH-SY5Y cells. Insulin treatment was associated with increased AKT and GSK-3β phosphorylation, reduced tau phosphorylation, and changes in oxidative stress-related markers in SH-SY5Y neuroblastoma cells. These findings support a role for insulin in the modulation of molecular pathways implicated in cellular stress responses and tau regulation. Further studies using differentiated neuronal models and disease-relevant conditions are required to determine the relevance of these observations to neurodegenerative disorders. Full article

Major depressive disorder (MDD) is a complex and heterogeneous psychiatric disorder with a high prevalence. Neuroinflammation may define biologically distinct patient subgroups with different mechanisms, clinical phenotypes, and treatment responses. This narrative review integrates current evidence around three linked questions: how neuroinflammatory processes contribute to depression, how biomarkers can identify clinically relevant inflammatory phenotypes, and how these findings can inform anti-inflammatory treatment strategies. The major mechanisms discussed include microglial activation and neuroimmune signaling, hypothalamic–pituitary–adrenal axis dysregulation and glucocorticoid receptor resistance, kynurenine pathway alterations, and cytokine-driven impairment of neurogenesis and synaptic plasticity. These pathways interact with stress responses, neurotransmitter systems, and neuronal function, while their expression may vary according to sex, age, hormonal status, disease stage, and treatment exposure. These interconnected pathways may contribute to depressive symptoms by disrupting neurotransmitter systems and impairing neural plasticity. In addition, this review discusses several candidate biomarkers, including C-reactive protein (CRP), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), brain-derived neurotrophic factor (BDNF) and transforming growth factor-β1 (TGF-β), which may support patient stratification, treatment prediction, and assessment of target engagement. Clinical trials of anti-inflammatory agents have shown inconsistent and generally modest effects in unselected MDD populations. By integrating mechanistic evidence with biomarker-guided therapeutic implications, this review aims to clarify how neuroinflammatory research may inform more precise and individualized treatment strategies for depression. Full article

This study investigates the nuclear distribution of phosphorylated tau (AT100) in the frontal cortex and cerebellum of 12 cetaceans stranded along the Galician coast (NW Spain). Using Bayesian beta regression, we identified a suggestive positive trend between aging and tau phosphorylation, with posterior probabilities of 85.7% in the cortex and 89.7% in the cerebellum. Although the 95% credible intervals include zero in both models, reflecting the limited sample size, the direction and magnitude of the age effect were stable across multiple prior specifications and outlier-exclusion sensitivity analyses, suggesting a consistent age-related pattern rather than a data artefact. We hypothesize that the translocation of tau to the nucleus may act as a “nuclear shield” against cumulative oxidative stress, a process potentially intensified by the intermittent hypoxia characteristic of diving in these mammals; this hypothesis awaits direct empirical validation. A strong inter-regional correlation ($r=0.932$; Spearman $\rho =0.923$) points to a potentially coordinated regulation of tau phosphorylation across brain regions. Furthermore, markedly elevated AT100 levels in a subadult with cerebral necrosis suggest its potential as a marker of acute neuronal distress. These findings provide a preliminary baseline for understanding neuroprotection in cetaceans, with tau phosphorylation as a candidate mechanism for preserving neuronal genomic integrity under extreme physiological conditions. 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

Bergamot essential oil (BEO) has demonstrated antidepressant potential, but its oral application is limited by poor water solubility and undesirable organoleptic properties. In this study, a BEO-loaded beverage was developed based on a whey protein-stabilized oil-in-water emulsion system. The optimal formulation, determined via single-factor experiments combined with orthogonal optimization, consisted of inulin (0.5 g/50 g), milk powder (2.0 g/50 g), sucralose (0.008 g/50 g), and sodium carboxymethyl cellulose (0.04 g/50 g). The resulting beverage remained stable without visible phase separation during 4 months of storage at 4 °C. In a chronic corticosterone treatment (CCT)-induced mouse model of depression, oral administration of the BEO beverage increased activity in the central area of the open field test and exploratory behavior in the elevated plus maze, while reducing repetitive stereotyped behaviors in the marble burying test. At the molecular level, the BEO beverage was associated with reduced levels of interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and corticosteroid (CORT), and increased levels of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), serotonin (5-HT), dopamine (DA), and norepinephrine (NE). Additionally, the BEO beverage was associated with observed alleviation of neuronal damage in the hippocampal CA3 region, upregulation of brain-derived neurotrophic factor (BDNF), improved gut microbial diversity, and altered host metabolic profiles. Collectively, these findings suggest that the BEO emulsion beverage is a feasible intervention for alleviating depression-like behaviors in the mouse model, and provide initial associative evidence supporting its potential as a functional food for mood management. Full article

Background and Objectives: The pathogenesis of liver steatosis is associated with obesity and systemic inflammation, particularly in subjects with body mass index (BMI) above 40 kg/m² and altered serum levels of tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10). Recent evidence suggests that disruption of the blood–brain barrier (BBB) may be associated with the development of steatosis, although limited data are available in humans. Thus, we assessed serum levels of neuron-specific enolase (NSE), transglutaminase 2 (TGM2), and glial fibrillary acidic protein (GFAP) as indirect markers of BBB dysfunction and examined their associations with steatosis severity, TNF-α and IL-10 in patients with morbid obesity. Materials and Methods: We biopsied the liver during bariatric surgery to assess steatosis by histology and serum markers by ELISA. Results: Most study subjects were women aged 38.7 ± 9.9 years with an average BMI of 42.3 ± 7.9 kg/m² and a steatosis prevalence of 78.9%. After grading steatosis as none (n = 8), mild (n = 17), moderate (n = 8), or severe (n = 5), we found no differences in sex, age, BMI, comorbidities, or laboratory variables, including liver enzymes. One-way ANOVA showed that serum IL-10 was 4-fold less in severe steatosis than in mild steatosis (p = 0.038), whereas TNF-α levels increased twice in severe steatosis compared to no steatosis (p = 0.029). NSE and GFAP serum levels, but not TGM2, increased proportionally to steatosis stage, showing differences between severe steatosis and no steatosis (p = 0.012 and p = 0.0002, respectively). Pearson correlation coefficients showed that NSE and GFAP were significantly associated with TNF-α (r = 0.600 and r = 0.402, respectively), but not with IL-10. Conclusions: Steatosis severity is significantly associated with markers of BBB disruption and systemic inflammation in patients with morbid obesity, suggesting a link between the BBB and liver steatosis. Full article

Background: Intracerebral hemorrhage (ICH) is a devastating subtype of stroke, in which neuroinflammation and blood–brain barrier (BBB) disruption are secondary pathophysiological events that drive progressive brain injury. Histone lysine demethylase JMJD3 (Jumonji C domain-containing protein 3) is a master epigenetic switch governing inflammatory signaling; however, its participation in ICH-induced vascular disruption and its possible mechanism remain elusive. Objective: To examine the expression patterns of JMJD3 in the context of ICH and to evaluate the therapeutic potential of its specific inhibitor, GSK-J4, in attenuating neuroinflammation and BBB disruption in a murine ICH model. Methods: Hemin treatment of a mouse C8-D1A astrocytic cell line was used to develop an in vitro ICH model. The transcript level of the Jmjd3 gene and its correlation with pro-inflammatory signaling were analyzed with or without GSK-J4 pretreatment. ICH in vivo was created experimentally in adult male C57BL/6 mice through stereotactic striatal injection of collagenase IV, and the mice were randomly assigned to sham, ICH + vehicle, and ICH + GSK-J4 (30 mg/kg intraperitoneally (i.p.), every other day starting three days before ICH) groups. At three days post-ICH, ipsilateral brain tissues were collected to detect JMJD3 cellular localization, pro-inflammatory mediator levels, tight junction protein expression, BBB ultrastructure, and hematoma volume. White matter integrity and neuronal recovery were assessed on day 7, and sensorimotor function was assessed longitudinally on days 1, 3, 5, 7, and 14. Results: Jmjd3 gene transcription was upregulated in hemin-treated astrocytes and correlated positively with IL-6 pro-inflammatory signaling activation. In vivo, the co-localization of JMJD3 with the astrocytic identifier glial fibrillary acidic protein (GFAP) was markedly increased in the area adjacent to the hematoma at three days post-ICH. GSK-J4 administration significantly suppressed the pro-inflammatory signaling cascade by decreasing the levels of inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), and matrix metalloproteinase-9 (MMP-9), enhanced brain vascular structural and functional integrity by upregulating tight junction proteins zonula occludens protein-1 (ZO-1) and claudin-5, improved BBB ultrastructural integrity, and decreased hematoma volume at three days post-ICH. Furthermore, GSK-J4 administration promoted white matter integrity (increased myelin basic protein [MBP] expression) and neuronal recovery (increased neuron-specific nuclear protein [NeuN] expression) at seven days post-ICH and significantly improved the performance of ICH mice in sensorimotor behavioral tests. Conclusions: Astrocytic JMJD3 is upregulated following ICH and promotes neuroinflammation, which in turn mediates BBB disruption. Pharmacological inhibition of JMJD3 by GSK-J4 attenuates neuroinflammation and subsequent BBB damage, accelerates hematoma resolution, and promotes histological and functional recovery after ICH, likely by downregulating MMP-9 expression. These findings identify astrocytic JMJD3 as a novel epigenetic therapeutic target for acute ICH. Full article

Titanium dioxide nanoparticles (TiO₂ NPs), widely used as food additives, frequently coexist with high-fat diets (HD) in modern dietary patterns, yet their combined in vivo toxicity remains poorly understood. This study investigated the multi-organ effects of co-exposure to TiO₂ NPs or food-grade E171 and HD in male C57BL/6J mice. Mice were randomly assigned to six groups and fed regular or high-fat diets containing 1 wt% TiO₂ NPs or E171 for 13 weeks. Histopathology, serum biochemistry, organ coefficients, and open-field behavioral tests were used to assess tissue injury and functional alterations. Co-exposure to TiO₂ NPs and HD markedly exacerbated tissue damage across multiple organs. In the liver, more severe ballooning degeneration, necrosis, and inflammatory infiltration were observed, accompanied by altered liver enzymes and reduced organ coefficients. Intestinal injury was characterized by crypt distortion and increased inflammation, particularly in the HD + TiO₂ group. Testicular tissues showed disorganized seminiferous tubules, loss of spermatogenic cells, and interstitial hyperplasia. In the brain, hippocampal neurons exhibited pyknosis and disarray, with decreased brain coefficients and impaired exploratory behavior. E171 induced similar but milder effects. These findings indicate that HD enhances TiO₂ NPs induced multi-organ toxicity, highlighting the health risks of realistic co-exposure to dietary nanoparticles and high-fat foods. Full article