Introduction to evaluate the acute effects of continuous moderate-intensity aerobic exercise and high-intensity interval training (HIIT) on heart rate variability (HRV) and psychoaffective responses in patients with bipolar disorder (BD) and healthy controls.Methods Eight BD patients and eight controls underwent baseline assessments, including anthropometric measurements and a submaximal exercise test to determine VO2Max, followed by two randomized exercise sessions. In one session, participants performed 12 min of continuous exercise at 65%VO2Max, and in the other, during the HIIT protocol, participants engaged in six 45-s bouts at 100%VO2Max, each followed by a 1-min and 15-s recovery period at 40%VO2Max. Pre- and post-exercise measurements included psychoaffective scales (feeling scale - FS, felt arousal scale - FAS, and SUDs anxiety scale) and HRV assessments recorded during a 10-minute rest period under controlled conditions.Results Regarding RMSSD, both participants and sessions demonstrated a significant increase in this indicator (p=0.012). The BD significantly increased VLF and LF values and reduced HF values for both exercise sessions. Meanwhile, the LF/HF ratio showed a significant increase only in the HIIT session. For the control group, only a significant reduction in the HF index in both sessions and an increase in the LF/HF ratio only in the HIIT session. The FAS showed significant increases in bodily activation post-exercise across groups and modalities, while the FS demonstrated significant positive shifts in affective valence, with larger improvements following HIIT. Both exercise protocols produced significant reductions in anxiety levels (p=0.001), with HIIT showing a trend toward superior anxiolytic effects in BD patients.Discussion The improvement in vagal tone and HRV modulates the function of critical brain regions involved in emotional regulation, such as the prefrontal cortex, amygdala, and anterior cingulate cortex. This modulation reduces limbic hyperactivity and impulsivity while influencing monoaminergic pathways, attenuating excessive dopaminergic signaling, thereby contributing to enhanced mood stability and the reduction of affective disturbances in individuals with BD.Conclusion Both continuous moderate-intensity exercise and HIIT elicited favorable acute autonomic and psychoaffective responses in BD patients and healthy controls. Notably, HIIT tended to produce greater affective and anxiolytic benefits in individuals with BD.
Introduction: GABAergic deficits are involved in depressive disorders; the roles of hippocampal GABA(A) receptors in the pathogenesis and pharmacotherapy of depression have not been fully studied. The hippocampal alpha 6 GABA(A) receptors (alpha(6), Gabra6) have a critical role in the pathophysiology of major depressive disorder. The present study determined the roles of alpha(6) subunits in the pathogenesis and antidepressant treatment of depression in a rat model of major depression induced by Chronic Repeated Restraint (CRR). Materials and Methods: Male Sprague-Dawley rats were restrained daily in an air-accessible Plexiglas cylindrical restrainer. The tricyclic antidepressant clomipramine was provided to rats daily by drinking (50 mg/kg) after restraint stress. The novelty suppressed feeding tests, open field tests, and sucrose preference tests were performed to evaluate depressive behaviors in rats. QPCR was performed to measure Gabra6 mRNA levels in rat hippocampus, and immunohistochemistry was performed to detect alpha(6) protein localization in the hippocampus. The patch-clamp technique was used to test the electrophysiological characteristics of evoked inhibitory postsynaptic currents (eIPSCs) and spontaneous inhibitory postsynaptic currents (sIPSCs) in hippocampal CA1 pyramidal neurons. Results: We observed that CRR stress decreased sucrose preference, travel distance, and center time in the open field test, and increased latency to feed in the novelty-suppressed feeding test. alpha(6) subunits were mainly expressed on interneurons in CA1 of the hippocampus. CRR stress down-regulated alpha(6) subunits of the GABA(A) receptor in the hippocampus. Patch-clamp studies revealed that CRR stress decreased the amplitude of eIPSCs while increasing the frequencies and amplitudes of sIPSCs in CA1 pyramidal neurons, indicating that inhibitory synaptic transmission in the hippocampus was altered by CRR stress. Chronic administration of clomipramine ameliorated depressive behaviors, restored the normal expression of hippocampal alpha(6) subunits, and decreased sIPSC frequencies of pyramidal neurons in rats subjected to CRR stress. Discussion: These results suggest that clomipramine-induced upregulation of alpha(6) subunits attenuated abnormal inhibitory synaptic transmission in the hippocampus, which might contribute to its antidepressant actions in relieving depressive behaviors induced by CRR stress. Conclusions: The roles of alpha(6) subunits in the pathogenesis and antidepressant treatment of depression may provide novel therapeutic avenues for the development of antidepressants.
OBJECTIVE:Sleep deprivation poses critical safety risks in high-stakes professions, where traditional stimulants often fail to sustain cognitive performance. Addressing the need for novel cognitive enhancers, this study compared the effects of modafinil and caffeine with novel nicotinic (AVL-3288) and glutamatergic (CX516) positive allosteric modulators on behavior and memory in severely sleep-deprived mice. METHODS:Male C57BL/6 mice underwent 48 hours of paradoxical sleep deprivation before receiving intraperitoneal doses of modafinil (300 mg/kg), caffeine (10 mg/kg), AVL-3288 (1, 2 mg/kg), CX516 (40, 80 mg/kg), or vehicle. A behavioral test series assessed locomotor activity (Open Field), anxiety (Elevated Plus Maze), reward-based working and spatial memory (Eight-Arm Radial Maze), escape-based spatial memory (Barnes Maze), and depressive mood (Tail Suspension). RESULTS:Modafinil markedly increased locomotor activity and suppressed appetite. Caffeine, AVL-3288 (1 mg/kg), and CX516 (40 mg/kg) improved reward-based working memory (Eight- Arm Radial Maze). However, these same agents impaired performance in the escape-based spatial reference memory task (Barnes Maze). No mood-altering effects were observed. The novel modulators displayed complex, non-dose-dependent profiles. DISCUSSION:Under severe sleep deprivation, specific wakefulness-enhancing substances can yield contrasting outcomes, enhancing reward-associated memory while negatively affecting escape-associated memory. These divergent outcomes suggest that neuromodulation during severe sleep deprivation exerts task-dependent behavioral effects, though the precise mechanisms driving the differences between the two maze paradigms remain to be elucidated. CONCLUSION:Pharmacological interventions under severe sleep deprivation can produce complex, bidirectional effects on cognition. This highlights that cognitive enhancement is likely task-dependent rather than global, necessitating a comprehensive assessment of diverse behavioral domains.
BACKGROUND AND OBJECTIVE:An affinity-purified antibody to the calcium-binding protein S100B that has undergone gradual technological processing and was additionally modified with an electromagnetic signal is an active pharmaceutical ingredient of the novel neurotropic drug Prospekta. Earlier studies have shown that the drug possesses a wide range of S100B-mediated pharmacological effects. Here, we investigated Prospekta's impact on baseline brain electrical activity to deepen understanding of its mechanism of action. METHODS:Extradural electrodes were surgically implanted into the skulls of adult male socially submissive mice. Animals were orally administered Prospekta for 5 days starting from the end of the recovery period. Brain baseline activity was recorded for 5 minutes after placing the mice in the arena. EEG band power (1-130 Hz, delta to high-gamma) was then analyzed quantitatively. RESULTS:Prospekta administration reduced theta and alpha band power in the left prefrontal cortex. Additionally, the drug showed a trend toward altering electrical activity coherence between the left prefrontal cortex and the right hippocampus, manifesting as a subtle, visually present phase shift across the examined brain regions. DISCUSSION:In a model recapitulating human cognitive and emotional impairments, Prospektainduced EEG alterations indicate a translational mechanism of neural modulation that may underlie behavioral effects, highlighting the need for future studies connecting these changes with functional outcomes. CONCLUSION:Our findings suggest that Prospekta modulates S100B-dependent processes, as evidenced by altered EEG oscillatory power and coherence. These effects may underlie the drug's influence on cognitive and behavioral regulation.
BACKGROUND:Gliomas are the most frequent Central Nervous System (CNS) tumors in children and adolescents. Angiocentric glioma is a rare subtype of pediatric-type diffuse low-- grade gliomas with a relatively favorable prognosis following gross total resection. More recently, the identification of Anaplastic Lymphoma Kinase (ALK) fusions in glioma has led to the development of targeted therapeutics to improve responses and outcomes. CASE PRESENTATION:Here, we report a 10-year-old boy with pediatric low-grade glioma harboring a KIF5B-ALK fusion. He achieved a durable partial response to the ALK inhibitor brigatinib. The patient presented with nasal congestion, dizziness, and headache. MRI and CT scans revealed multiple masses in the brain, lung, and bone. Pathological review indicated a low-grade glioma, and genetic testing identified a KIF5B-ALK fusion. After surgical resection and molecular diagnosis, the patient was treated with brigatinib. This resulted in rapid tumor reduction and complete remission at 23 months, with no significant adverse effects. CONCLUSION:This case highlights the importance of molecular profiling in guiding targeted therapies for rare pediatric gliomas. Further research is needed to address questions regarding the optimal use of ALK inhibitors and their long-term impact on prognosis and neurocognitive development.
INTRODUCTION:Early neurological deterioration (END) affects approximately 30% of patients with small artery occlusion (SAO) stroke. The combination of tirofiban and nimodipine may simultaneously address microthrombosis and vasospasm, two key mechanisms underlying SAOrelated END. METHODS:In this retrospective cohort study, we analyzed data from consecutive SAO-END patients treated within two hours of END onset between January 2023 and December 2024. The combination group (n=50) received tirofiban plus nimodipine, while the control group (n=53) received tirofiban alone. The primary outcome was early neurological improvement (ENI), defined as a ≥ 2-point reduction in NIHSS score or ≥ 1-point improvement in motor function at 7 days or discharge. Secondary outcomes included a favorable functional outcome (mRS ≤2) at 90 days and safety events. RESULTS:The combination group demonstrated significantly higher rates of ENI (76% vs. 47.2%; adjusted odds ratio [aOR] 3.96, 95% CI 1.32-11.90; p=0.014) and improved 90-day functional outcomes (84% vs. 58.5%; aOR 4.744, 95% CI 1.212-18.567; p=0.025). Higher admission NIHSS scores (aOR 0.759, 95% CI 0.612-0.941; p=0.012) and diabetes (aOR 0.201, 95% CI 0.048-0.840; p=0.028) were inversely associated with ENI. Older age (aOR 0.933, 95% CI 0.876-0.994; p=0.032) and higher admission NIHSS score (aOR 0.592, 95% CI 0.447-0.784; p=0.000) were negatively correlated with 90-day outcomes. Safety profiles were comparable between groups, with no instances of intracranial hemorrhage or hypotension. The addition of nimodipine did not significantly affect blood pressure. DISCUSSION:Combining tirofiban and nimodipine may improve outcomes in SAO-related early neurological deterioration. If validated in future randomized trials, this combination could address a significant unmet need in a common stroke subtype with high risk of deterioration, potentially influencing clinical practice and guiding further research into multimodal neuroprotection strategies for cerebral small vessel disease. CONCLUSION:Tirofiban-nimodipine combination therapy was found to be associated with enhanced early neurological recovery in SAO-END patients, warranting further investigation through larger multicenter randomized controlled trials.
BACKGROUND:Dementia is a prevalent symptom of Alzheimer's Disease (AD), associated with either low levels of acetylcholine or destruction by enzymes. Such enzymes are acetylcholinesterase (AChE) and butyryl-cholinesterase (BuChE). The current research worked on re-purposing of 69 Food and Drug Administration Authority (FDA) approved antiviral agents against targets of AD, including AChE (PDB ID: 4BDT) and BuChE (PDB ID: 5LKT). METHODS:Targets proteins like AChE (PDB ID: 4BDT) and BuChE (PDB ID: 5LKT), and their PDB IDs were retrieved from the Protein Data Bank (PDB), purified through Discovery Studio Visualizer 2016 (DSV-2016), and saved in PDB format. Data of 69 FDA-approved antiviral agents and standard donepezil were obtained from different published literature, and structures were downloaded from the PubChem structure search tool. DSV-2016 was used for the purification of the targets. PyRx was utilized for the docking of 69 test agents and the standard drug donepezil. DSV-2016 was used for post-docking analysis. In addition, Physio-chemical properties, pharmacokinetics, drug-likeness, and medicinal chemistry analysis of three potential compounds (based on binding affinity) and molecular dynamic simulation (MDS) were performed using SWISSADME and AMBER24 software, respectively. RESULTS:Docking revealed the binding affinities of Saquinavir (-9.1 kcal.mol-1 ), paritaprevir (-10.8 kcal.mol-1 ), and simeprevir (-10.1 kcal.mol-1 ) with AChE. The recorded binding affinities against BuChE were Saquinavir (-11.7 kcal.mol-1 ), paritaprevir -11.2 kcal.mol-1 ), and simeprevir (-11.4 kcal.mol-1 ). Saquinavir and paritaprevir constructed one hydrogen bond with Threonine (THR38) and Glycine (GLN291), respectively. Simeprevir with Asparagine (ASN283), Valine (VAL282), and Tyrosine (TYR72), granting three hydrogen bonds. The data on lipophilicity was determined in terms of Log Po/w (ILOGP). Water solubility of Saquinavir, Paritaprevir, and Simeprevir demonstrated that the Log S (ESOL) value is much higher, and hence the mentioned three compounds are water insoluble. Saquinavir, paritaprevir, and simeprevir were subjected to molecular dynamics simulations, which showed good interactions of the test agents with BuChE compared to AChE. DISCUSSION:The study revealed that already approved 69 FDA anti-viral agents showed potential interaction with the selected targets (AChE and BuChE). Three compounds, saquinavir, paritaprevir, and simeprevir, were found with high binding affinities. As they are utilized in human life for various viral infections with known pharmacology and pharmacokinetics data, we can repurpose such a drug to be active against memory loss or cognitive problems. CONCLUSION:Based on the applied computational techniques on 69 FDA-approved agents, including molecular docking, SWISS-ADME, and MDS, we identified saquinavir, simeprevir, and paritaprevir as potential molecules modulating the action of AChE and BuChE to restore memory and cognition. Hence, it is supposed that these agents may serve as anti-Alzheimer agents. Further investigations are needed to find their therapeutic potential in in vitro and in vivo animal models.
INTRODUCTION:Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily characterized by the loss of dopaminergic neurons in the substantia nigra. Sirtuin 3 (SIRT3), a mitochondrial NAD⁺-dependent deacetylase, has emerged as a promising therapeutic target due to its vital role in mitochondrial homeostasis and resistance to oxidative stress. However, existing SIRT3 modulators suffer from poor selectivity, suboptimal CNS penetration, and limited binding affinity. This study aimed to design and evaluate novel oxadiazole-thiazolidin-4-one hybrid compounds as potential SIRT3 modulators with improved neuroprotective profiles. METHODS:A comprehensive computational workflow was carried out using the Schrödinger Suite 2025-1, including ADMET profiling, molecular docking, molecular dynamics (MD) simulations, Thermal MM/GBSA binding free energy estimation, and protein dynamics analyses (DCCM, PCA, FEL). Additionally, Density Functional Theory (DFT) and Fukui function analyses were conducted to elucidate electronic properties and reactive sites relevant to bioactivity. RESULTS:The designed hybrids exhibited higher SIRT3 binding affinities than known modulators, with binding free energies ranging from -8.9 to -4.88 kcal/mol compared to resveratrol (-7.14 kcal/mol). Among them, TZOX04 [3-(5-benzyl-1,3,4-oxadiazol-2-yl)-2-(2,3,4-trihydroxyphenyl)thiazolidin-4- one] demonstrated the strongest binding energy (-8.94 kcal/mol), favorable drug-likeness, and optimal CNS permeability (logBB = 0.42). DISCUSSION:Molecular dynamics confirmed the stability of the SIRT3-TZOX04 complex over 100 ns, while DFT and Fukui analyses identified key electron-rich regions contributing to reactivity and interaction potential. The oxadiazole-thiazolidinone hybridization approach provided a significant improvement in binding and pharmacokinetic behaviour over existing modulators. CONCLUSION:This work represents the first systematic investigation of oxadiazole-thiazolidin-4-one hybrids as SIRT3 modulators. TZOX04 emerged as a promising lead compound with enhanced binding affinity, stability, and pharmacokinetic characteristics for PD therapy. These findings warrant future synthetic and biochemical validation to confirm therapeutic efficacy.
INTRODUCTION:Stroke has found to be the second leading cause of death in China. Research indicates that the immune imbalance of Th17/Treg is an important pathophysiological alteration and the cause of poor prognosis after ischemic stroke, the most common type of stroke. Tetrandrine (Tet), a bisbenzyl isoquinoline alkaloid and potential immunoregulator, has been reported to possess therapeutic effect on ischemic stroke; however, the specific mechanism remains to be clarified. This research aims to explore the molecular mechanisms underlying Tet's effects on cerebral ischemiareperfusion injury (CIRI) through bioinformatics methods and experimental validation. METHODS:Using public databases, we predicted potential therapeutic targets of Tet against CIRI. Common targets were then used to build a protein-protein interaction (PPI) network, from which key gene targets were identified. Functional and pathway enrichment analyses were conducted via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Afterwards, molecular docking and experimental validation were performed to confirm the predictions. The middle cerebral artery occlusion and reperfusion (MCAO/R) mice model was established. Twenty-four hours after Tet injection (intraperitoneally, 25 and 50 mg/kg), behavior index evaluation, cerebral blood flow, and tetrazolium chloride (TTC) staining were performed. Pathological changes on cortex, striatum, and hippocampus were observed using hematoxylin-eosin (HE) staining. Percentages of Th17 cells and Treg cells were determined by flow cytometry analysis. The expressions of mRNAs of Th17/Treg markers were measured by quantitative real-time polymerase chain reaction (qPCR). And the expressions of proteins PI3K/Akt Signaling Pathway were measured by Western blot analysis. RESULTS:Our study identified 52 potential therapeutic targets of Tet for CIRI, with 10 key gene targets selected from PPI network analysis. GO and KEGG enrichment analyses indicated that these targets were primarily associated with the PI3K/Akt signaling pathway and Th17 cell differentiation. Molecular docking suggested potential interactions between Tet and Trp53, Cdk4, and Pik3ca. Experimental validation demonstrated that Tet ameliorated neurological deficits and reduced cerebral ischemic damage. Flow cytometry revealed that, compared to the model group, Tet treatment increased Treg cells while decreasing Th17 cells. Additionally, Tet downregulated RORγt and upregulated FoxP3 at the mRNA level. Western blot analysis further confirmed that Tet reduced the p-Akt/Akt and p-PI3K/PI3K protein expression ratios. DISCUSSION:Our integrated approach demonstrates that tetrandrine alleviates CIRI by restoring Th17/Treg balance via PI3K/Akt signaling - a mechanism previously unreported for this alkaloid. The downregulation of RORγt and upregulation of FOXP3 confirm Tet's immunomodulatory specificity, while reduced p-Akt/Akt ratios mechanistically link its efficacy to PI3K/Akt pathway inhibition. This dual regulation positions Tet as a multi-target therapeutic candidate distinct from single-pathway agents. CONCLUSION:Through the combination of bioinformatics and experimental validation, our study revealed that tetrandrine regulates Th17/ Treg cells balance and mediates PI3K/Akt pathway, presenting a potential therapeutic agent for treating cerebral ischemic injury.
INTRODUCTION:Multiple sclerosis (MS) is a multifactorial autoimmune condition, and existing medications offer limited efficacy, especially regarding the control of disease progression. Our previous research has suggested a significant role for ferroptosis in the mechanism of MS, making it a promising therapeutic target. METHODS:To identify potential treatment targets related to ferroptosis, we conducted Mendelian randomization analysis. We used transcription and proteomic data for 511 ferroptosis-related proteins extracted from 49 tissues in GTEx v8 and deCODE data to derive genetic instruments. We conducted Mendelian randomization based on summary-level data from the International MS Genetics Consortium (47,429 cases and 68,374 controls). Reverse Mendelian randomization, Steiger filtering, Bayesian colocalization, constrained maximum likelihood, and model averaging-based (cML-MA) method, and phenomewide scanning were performed to strengthen findings. Additionally, we explored protein-protein interaction networks to uncover possible links between target proteins and approved MS therapeutics. RESULTS:Under Bonferroni significance (P < 1.52 × 10-4), Mendelian randomization using cisexpression quantitative trait locus instruments revealed nine ferroptosis-related proteins (STAT3, MAPK1, MAPK3, MAP3K11, CISD2, KEAP1, ZEB1, PVT1, PARP1) with significant results in at least one tissue. Bayesian colocalization indicated that four of them (STAT3, PP.H4=0.97; MAPK1, PP.H4=0.95; MAPK3, PP.H4=0.99; ZEB1, PP.H4=0.96) share variation with MS. Under Bonferroni significance (P < 1.11 × 10-3), two proteins also obtained significant proteomic results (STAT3, P = 1.18 × 10-13, MAPK3, P = 3.25 × 10-8). Regional association analysis and phenomewide Scanning suggest a potential involvement of STAT3 in MS. STAT3 and MAPK3 interact with target proteins of current MS drugs, particularly STAT3. DISCUSSION:These findings highlight the causal involvement of ferroptosis pathways in MS pathogenesis, emphasizing STAT3 and MAPK3 as promising therapeutic candidates. This work broadens current understanding of MS biology and suggests new directions for targeted drug development focused on ferroptosis regulation. CONCLUSION:Our analysis indicates that genetically predicted ferroptosis-related protein levels of STAT3, MAPK1, MAPK3, and ZEB1 are associated with MS risk. Among them, STAT3 and MAPK3 emerge as potential therapeutic candidates, with STAT3 warranting particular clinical investigation.
INTRODUCTION/OBJECTIVE:Traumatic Brain Injury (TBI) causes substantial neurological deficits and remains a major therapeutic challenge. This study aimed to evaluate the neuroprotective properties of Vindeburnol (VIND), a semi-synthetic derivative of vincamine, and to identify its potential molecular targets and optimal dosing regimen for post-traumatic treatment. METHODS:Radioligand binding assays were used to determine VIND affinity for 22 CNS receptors, 7 ion channels, and 1 enzyme at a concentration of 10 μM. The in vivo neuroprotective effect was studied in a rat model of TBI induced by controlled cortical impact. VIND was administered intraperitoneally at doses of 10 or 20 mg/kg daily or every other day for 10 days. Neurological recovery was assessed using the beam-walking and limb-placement tests, and brain lesion volume was quantified by MRI on day 14. RESULTS:VIND showed strong inhibition of radioligand binding at α1- and α2-adrenergic receptors (74% and 84.1%, respectively). In vivo, the most pronounced neuroprotective effect was observed at 20 mg/kg every other day, resulting in approximately a twofold reduction in lesion volume (88.7 ± 6.5 mm3 vs 179.4 ± 19.3 mm3 in saline-treated TBI rats, p < 0.001) and a significant improvement in neurological outcomes. The 10 mg/kg dose showed a non-significant trend towards neuroprotection. DISCUSSION:The neuroprotective effect of VIND is likely mediated by the inhibition of excessive adrenergic receptor activation, resulting in improved neuronal survival and functional recovery. These findings highlight adrenergic modulation as a promising therapeutic mechanism for mitigating post-traumatic brain damage. CONCLUSION:Vindeburnol demonstrated significant neuroprotective efficacy in a rat model of TBI and may represent a promising pharmacological candidate for post-traumatic neuroprotection.
INTRODUCTION:Neuroinflammation and microglial dysfunction play central roles in the pathogenesis of Alzheimer's disease (AD). This study investigated whether early intervention with hesperetin, a citrus flavonoid, could attenuate neuroinflammation and modulate microglial polarization in both wild-type (WT) and APPswe/PS1dE9 transgenic (TG) mice. METHODS:Three-month-old male C57BL/6J WT and APPswe/PS1dE9 TG mice were administered hesperetin (10 or 20 mg/kg/day for WT; 20, 40, or 80 mg/kg/day for TG) or vehicle for six months. Neuronal morphology was assessed using thionine staining. Microglial polarization was evaluated via CD11b/iNOS and CD11b/Arginase-1 immunofluorescence. Protein expression of CD11b, iNOS, Arginase-1, and TREM2 was measured by Western blot, and cytokine levels (TNF-α, IL-10) were quantified by ELISA. RESULTS:In WT mice, hesperetin improved neuronal integrity, reduced M1 markers (CD11b⁺/ iNOS⁺ cells, iNOS, TNF-α), and enhanced M2 markers (CD11b⁺/Arginase-1⁺ cells, Arginase-1, TREM2). TG mice exhibited exacerbated neuroinflammation and neuronal loss compared to WT controls, which was significantly mitigated by hesperetin treatment. All hesperetin doses in TG groups reduced pro-inflammatory markers and increased anti-inflammatory and repair-associated factors. DISCUSSION:These results indicate that hesperetin shifts microglial polarization toward the protective M2 phenotype, potentially via TREM2 upregulation, thereby reducing neuroinflammation and neuronal damage. This effect was observed in both age-related and Aβ-driven pathology, suggesting a dual role for hesperetin in immunomodulation and neuroprotection. CONCLUSION:Early hesperetin intervention exerts neuroprotective effects by rebalancing microglial polarization and enhancing TREM2 expression, highlighting its potential as a preventive strategy against AD-related neuroinflammation.
Introduction Dual-task (DT) training may enhance cognitive function in older adults with mild cognitive impairment (MCI). Whether virtual reality (VR)-based DT exercise offers advantages over traditional strength-based DT training remains unclear. This study compared their effects on cognition and dual-task cost (DTC) in Older adults from Montes Claros, Brazil.Methods Twenty independent seniors were randomized to VR-based DT training with Nintendo Wii (n=11) or traditional DT strength exercises (n=9), twice weekly for 26 sessions. Outcomes included global cognition (MoCA), memory (Digit Span), verbal fluency, and DTC (Timed Up and Go + verbal fluency).Results Post-intervention analysis revealed distinct effects between training modalities. Participants in the DT group demonstrated significant improvements in working memory (p=0.02), particularly among individuals without MCI, who improved by an average of 1.66 points on the Digit Span backward test. In contrast, those in the VR group experienced a decrease in working memory performance. However, the VR group showed a significant reduction in DTC, with a 9.92% improvement in task execution time (p=0.01), irrespective of MCI status. Meanwhile, the DT exercise group exhibited a 7.06% increase in DTC, suggesting a potential trade-off between cognitive and functional gains depending on the type of dual-task intervention.Discussion Findings suggest a trade-off: traditional DT training may preferentially benefit a specific cognitive function (working memory), while VR-based DT training may improve task efficiency by lowering DTC.Conclusion Traditional DT exercise appears more effective for working memory, particularly in non-MCI elderly, whereas VR-based DT exercise may better support dual-task performance.
INTRODUCTION:Survivors of global cerebral ischemia (GCI) are at a high risk of developing neurological disorders. Cerebral infarction resulting from GCI may lead to neuronal loss and subsequent brain damage. In the present study, we investigated the effect of one-week 3',4'- Dihydroxyflavonol (DiOHF) supplementation on the oxidant-antioxidant system and neurotransmitter levels in the cerebral cortex of rats subjected to brain ischemia-reperfusion. METHODS:The study was performed on male Wistar albino rats. A total of 28 rats were used in the study, and the groups were formed as follows. Control Group (n=6): No anesthesia or surgical procedure was performed on the animals in this group. Sham Group (n=6): After general anesthesia was induced in the animals in this group, the carotid artery regions were opened and closed. After the application, the vehicle application was performed for 1 week (1 ml DiOHF vehicle). Ischemia- Reperfusion (I/R) Group (n=8): After the carotid arteries were isolated in the rats under general anesthesia, they were ligated for 30 minutes, and ischemia was performed, followed by reperfusion. Following reperfusion, 1 ml of DiOHF vehicle was supplemented for 1 week. Ischemia-Reperfusion Group + DiOHF Supplemented (n=8): After the carotid arteries were isolated in rats under general anesthesia, they were ligated for 30 minutes, followed by ischemia and reperfusion. Subsequently, DiOHF supplementation was performed for 1 week. RESULTS:Experimental cerebral ischemia-reperfusion in rats caused a significant increase in malondialdehyde (MDA) levels, a marker of oxidative stress, in the cerebral cortex, while markedly decreasing antioxidant enzymes such as GPx, SOD, CAT, and Trx2. Additionally, cerebral I/R elevated the levels of neurotransmitters glutamate and GABA. However, one week of DiOHF supplementation following ischemia-reperfusion ameliorated these alterations in the frontal cortex tissue. DISCUSSION:Overall, the findings showed that DiOHF administration for one week after experimental cerebral ischemia-reperfusion in rats exerts beneficial effects on the oxidant/antioxidant system and neurotransmitter levels in frontal cortex tissue. CONCLUSION:This study showed that by lowering oxidative stress and restoring neurotransmitter levels in the frontal cortex, a one-week treatment with 3',4'-Dihydroxyflavonol after cerebral ischemia- reperfusion in rats has protective benefits. Following an ischemic stroke, DiOHF may be a viable treatment for reducing neuronal damage.
INTRODUCTION:Inflammatory and coagulation pathways are crucial in the pathogenesis and clinical progression of ischemic stroke. The objective of this study was to evaluate serum concentrations of interleukin-2 (IL-2) and interleukin-10 (IL-10), as well as the gene expression of tissue factor (TF) in peripheral blood mononuclear cells (PBMCs), and to examine their correlations with stroke severity and clinical outcomes. MATERIALS AND METHODS:We enrolled 148 patients with ischemic stroke and 30 healthy controls matched for age and sex in a cross-sectional design. We used ELISA to measure the levels of IL-2 and IL-10 in serum and real-time PCR to look at TF gene expression in PBMCs. The NIH Stroke Scale (NIHSS) was used to measure the severity of strokes, and the results were compared to clinical variables. RESULTS:Patients with severe stroke showed significantly lower levels of IL-2 and IL-10 (p < 0.001), and TF expression in PBMCs was significantly higher in both mild and severe stroke groups compared to controls (p < 0.001). There was no statistically significant difference between the mild and severe groups (p = 0.213). In severe cases, IL-2 and TF were negatively correlated (p = 0.036). Nonetheless, none of the biomarkers independently forecasted survival outcomes. DISCUSSION:The results show that the immune-coagulation axis is not working properly in severe ischemic stroke. Lower levels of IL-2 and IL-10 may indicate that regulatory T-cells aren't working properly and that anti-inflammatory control isn't working, which can cause monocytes to become active and TF levels to rise. This interaction probably makes thromboinflammatory cascades worse, which leads to more damage to the nervous system. These changes, even though they don't predict survival, give us a better understanding of how strokes work and open up new possibilities for targeted immunomodulatory therapy. CONCLUSION:The changes in IL-2, IL-10, and TF expression indicate a coordinated disruption of immune and thrombotic pathways in individuals with severe ischemic stroke. Although not prognostic of mortality, these biomarkers may indicate disease severity and represent potential targets for future therapeutic interventions. Longitudinal studies are necessary to validate their prognostic significance and investigate their incorporation into clinical decision-making algorithms for stroke.
INTRODUCTION:This study aimed to evaluate the association between magnesium sulfate and mortality in patients with Sepsis-Associated Encephalopathy (SAE), given the lack of established therapies and emerging evidence of magnesium's neuroprotective properties. METHODS:A retrospective cohort study was conducted using data from SAE patients in the MIMICIV database. Patients were stratified into magnesium sulfate-treated and non-treated groups, with 1:1 Propensity Score Matching (PSM) to adjust for baseline imbalances. Outcomes included 28-day all-cause mortality, in-hospital mortality, and Intensive Care Unit (ICU)/hospital Length of Stay (LOS). Cox regression, Kaplan-Meier analysis, and subgroup assessments were performed. RESULTS:A total of 12,296 patients with SAE who met the inclusion and exclusion criteria participated in this study. Before PSM, magnesium sulfate administration correlated with a 36% reduction in 28-day mortality (17.11% vs. 23.77%; Hazard Ratio [HR] 0.64, 95% CI 0.58-0.70) and a 43% decrease in in-hospital mortality (14.32% vs. 18.23%; HR 0.57, 95% CI 0.51-0.63) (both p < 0.001). Post-PSM analysis of 7,236 matched patients confirmed consistent benefits (28-day mortality HR 0.66; in-hospital mortality HR 0.62). However, patients treated with magnesium sulfate had longer median ICU LOS (3.87 vs. 2.64 days; p < 0.001) and hospital LOS (10.12 vs. 8.70 days; p < 0.001). Subgroup analyses demonstrated robustness across demographics and comorbidities. DISCUSSION:The significant association between magnesium sulfate and reduced mortality in SAE patients suggests its potential neuroprotective role, possibly mediated through mechanisms such as blood-brain barrier stabilization, anti-inflammatory effects, and N-methyl-D-aspartate (NMDA) receptor antagonism. The observed prolongation of ICU and hospital stay may reflect survivor bias and the necessary time for neurological recovery in these critically ill patients, rather than a direct adverse effect of the therapy. These findings position magnesium sulfate as a promising adjunctive therapy for SAE, warranting a paradigm shift in its consideration for neuroprotection in sepsis. CONCLUSION:This large-scale retrospective study found that magnesium sulfate administration was associated with reduced 28-day and in-hospital mortality in SAE patients, alongside prolonged length of hospital and ICU stay. These findings highlight magnesium sulfate's potential as an adjunctive SAE therapy, though multicenter randomized trials are warranted to validate this association and optimize dosing protocols.
INTRODUCTION:Glycogen synthase kinase-3 beta (GSK-3β) is a key serine/threonine protein kinase involved in several neural processes. Its overactivity contributes to the pathogenesis of Alzheimer's disease (AD) through tau protein hyperphosphorylation and amyloid-beta (Aβ) accumulation. Thalidomide and lenalidomide, originally developed as anticancer drugs, have shown potential inhibitory effects on GSK-3β in vitro. In this study, we repurposed these compounds to design novel GSK-3β inhibitors for AD therapy using computational methods. MATERIALS AND METHODS:The 3D structure of GSK-3β (PDB ID: 1Q41) was prepared using the Biovia Discovery Studio. A library of 100 ligands (50 each from thalidomide and lenalidomide) was designed using ChemDraw, followed by molecular docking using PyRX. Ligands with better binding affinities than source compounds were further evaluated for pharmacokinetic and ADMET parameters using SwissADME and ProTox II tools. Molecular dynamics (MD) simulations of the best ligand-protein complex were performed using Desmond for 100 ns to analyze the stability of interactions. RESULTS:Seventy-five percent of the designed ligands exhibited stronger binding affinities compared to the source drugs. ADMET analysis identified LS9 as the most promising lead molecule, attributed to its high binding affinity (-11.3 kcal/mol), favorable drug-likeness, and lack of toxicity. Molecular dynamics simulation confirmed the stability of the LS9-GSK-3β complex, with RMSD values ranging from approximately 2.4 to 2.6 Å and consistent protein-ligand interactions. DISCUSSION:This study demonstrates that structure-based ligand modification of repurposed drugs can yield candidates with significantly improved GSK-3β binding and pharmacological profiles. Compared to previous inhibitors, our ligands showed superior docking scores and better drug-likeness. CONCLUSION:LS9 is a promising GSK-3β inhibitor with potential for AD therapy. Its robust binding, safety profile, and MD stability warrant further investigations.
INTRODUCTION:Neuropsychiatric systemic lupus erythematosus (NPSLE) is a severe and complex manifestation of SLE. The pathogenesis of diffuse NPSLE (dNPSLE)-which encompasses cognitive dysfunction, mood disorders, psychosis, and delirium-involves immune-mediated neuronal damage. However, the underlying mechanisms remain incompletely understood, particularly the role of microglial activation. METHODS:We used female MRL/lpr mice as a dNPSLE model, with MRL/mpj mice as controls. Transcriptomic analysis revealed significant upregulation of microglia-related pathways and IL-33 in MRL/lpr mice. IL-33 levels in patient serum and cerebrospinal fluid (CSF) were measured by ELISA. Brain expression of IL-33 in mice was evaluated by qRT-PCR, and its spatial relationship with microglia (IBA1⁺) was visualized via immunofluorescence. Microglial activation and phagocytosis were analyzed by flow cytometry. To inhibit IL-33 in vivo, the decoy receptor soluble ST2 (sST2) was infused intracerebroventricularly into MRL/lpr mice via mini-osmotic pumps. After 4 weeks, anxiety-like behavior and spatial memory were assessed using the open field test and Morris water maze (MWM). In BV2 microglial cells, we measured glycolytic enzyme (LDHA, PKM2, HK2) levels after IL-33 treatment using qRT-PCR and Western blot. Glycolysis was inhibited with 2-deoxy-D-glucose (2-DG), and microglial activation and phagocytosis were evaluated by qRTPCR and flow cytometry. RESULTS:IL-33 levels were elevated in the serum and CSF of dNPSLE patients and in the brains of MRL/lpr mice. Inhibition of IL-33 in vivo improved behavioral performance in the open field and MWM tests and reduced microglial phagocytosis. In vitro, IL-33 promoted anaerobic glycolysis in microglial cells, leading to enhanced activation and phagocytosis through upregulation of the glycolytic enzymes LDHA, PKM2, and HK2. Importantly, the pro-phagocytic and activating effects of IL-33 were abolished by glycolysis inhibition with 2-DG. CONCLUSION:Our findings identify IL-33 as a key contributor to dNPSLE pathogenesis, driving microglial activation and phagocytosis via glycolytic reprogramming. These results highlight IL-33 as a potential therapeutic target for dNPSLE, warranting further investigation into its clinical translation.
INTRODUCTION:Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by Amyloid-β plaques and neurofibrillary tangles. Disrupted circadian rhythms are common in AD and may worsen cognitive decline and psychological symptoms. The link between sleep deprivation and Alzheimer's risk remains unclear. This study aimed to identify potential diagnostic markers for Alzheimer's and sleep deprivation, focusing on the role of immune cell infiltration in disease progression. MATERIALS AND METHODS:We examined AD expression data from the GEO database and sleep deprivation( SD)-related data from GeneCards. Using LIMMA on the GSE15222 dataset, we found 209 DEGs, analyzed them with four machine learning algorithms, and identified four Hub genes. We validated these findings with the GSE33000 dataset. CIBERSORT was employed to analyze 22 immune cell features, and Spearman correlation was used to assess the link between diagnostic markers and immune cells. RESULTS:AD and SD were linked to immune microenvironment changes. Initially, 1568 potential key genes were identified, and Venn analysis revealed 209 overlapping regions. Machine learning validated four key genes, confirming their high predictive accuracy. Significant differences in immune cell expression were found in AD samples, and correlation analysis showed CIT, FASN, ELK1, and GFAP were significantly associated with various immune cells. CONCLUSION:CIT, FASN, ELK1, and GFAP are key genes linked to pathology progression in AD and SD within the immune microenvironment. Identifying molecular subgroups may offer new perspectives for personalized Alzheimer's treatment.
INTRODUCTION:Sodium-glucose transport protein 2 (SGLT-2) inhibition regulates neuronal excitability by shifting glucose metabolism toward ketone utilization and by reducing oxidative stress and inflammation. Based on these mechanisms, this study investigated the anticonvulsant and anti-inflammatory effects of empagliflozin, a SGLT-2 inhibitor with neuroprotective properties, in a penicillin-induced epilepsy model. METHODS:Thirty-five adult male Wistar rats were randomly divided into five groups (n = 7/group): sham, control (penicillin only), empagliflozin (10 mg/kg), diazepam (5 mg/kg), and empagliflozin + diazepam. Penicillin (500 IU) was administered intracortically to induce focal epileptiform activity. Electrocorticography (ECoG) recordings were obtained for 180 minutes to assess seizure latency, spike-wave frequency (SWF), and amplitude. Serum and cortical tissue levels of TNF-α, IL-6, and HMGB-1 were quantified using enzyme-linked immunosorbent assay (ELISA). RESULTS:All treatment groups exhibited a statistically significant increase in latency to the first epileptiform activity compared to the control group. The empagliflozin group showed a marked reduction in SWF between 30 and 180 minutes, particularly during the 121-180-minute period. Tissue TNF-α levels were significantly lower in the empagliflozin + diazepam group compared to the control. Tissue IL-6 levels were lowest in the empagliflozin-only group, whereas serum IL-6 levels were significantly reduced in the combined treatment group. No significant differences in HMGB-1 levels were observed across groups. DISCUSSION:Empagliflozin demonstrated anticonvulsant and anti-inflammatory effects by delaying seizure onset, reducing SWF, and modulating pro-inflammatory cytokine levels. CONCLUSION:Empagliflozin demonstrated anticonvulsant and anti-inflammatory effects by delaying seizure onset, reducing SWF, and modulating pro-inflammatory cytokine levels. These findings suggest that empagliflozin may have therapeutic potential in epilepsy through SGLT-2 inhibition.
