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Suicide, particularly in treatment-resistant depression (TRD), remains a pressing global health issue, with over 700,000 annual deaths. Existing treatments often have limited efficacy and delayed onset, creating a need for rapid-acting interventions. Ayahuasca, a traditional Amazonian psychedelic, has shown potential for rapidly reducing suicidal ideation. Our systematic review evaluated the clinical evidence regarding ayahuasca's effects on suicidality. From 6,633 initial records, five studies met the inclusion criteria. These studies, despite methodological heterogeneity, consistently demonstrate that ayahuasca administration is associated with rapid and significant reductions in suicidal ideation and depressive symptoms in patients with depressive disorders. The therapeutic effects were attributed to the synergistic action of β-carbolines and DMT present in ayahuasca. Neurobiologically, ayahuasca promotes neuroplasticity, partly through the upregulation of Brain-Derived Neurotrophic Factor, and modulates key brain networks, most notably by decreasing the activity of the Default Mode Network. Psychologically, this neural reconfiguration facilitates profound introspection, emotional processing, and transformative insights, which are central to its therapeutic effects. This review highlights the potential of ayahuasca as a novel therapeutic tool for suicidality but underscores the critical need for large-scale, methodologically rigorous longitudinal studies to establish definitive clinical guidelines for its safe and effective integration into psychiatric practice. Show less

Intracerebral hemorrhage (ICH) has a high rate of death and disability. LncRNA-TUG1 is essential for the pathological changes secondary to ICH. The purpose of this work was to investigate the possible mechanism by which TUG1 inhibits neural repair subsequent to ICH through adjusting miR-381-3p/brain-derived neurotrophic factor (BDNF). After the ICH model was created, miR-381-3p agomir and pcDNA-TUG1 were injected. The neural function of rats was estimated using the modified neurological severity score. To quantify the expression of genes and proteins, western blotting, immunohistochemistry, and qRT-PCR were used. To confirm the interaction between TUG1 and miR-381-3p and between miR-381-3p and BDNF mRNA, a luciferase reporter assay was employed. In rats treated with miR-381-3p agomir, a trend of improvement in neurological dysfunction was observed, while the pcDNA-TUG1-treated ones showed deterioration. Furthermore, miR-381-3p agomir increased, while pcDNA-TUG1 reduced the expression level of BDNF in ICH rats. TUG1 and BDNF mRNA were validated to attach directly to miR-381-3p. Overexpressing TUG1 inhibited the level of BDNF by sponging miR-381-3p and antagonized its protective effect on neural repair in ICH rats. Our study suggests that TUG1 can sponge miR-381-3p to downregulate BDNF expression and inhibit neural repair following ICH, demonstrating a potential signaling pathway that is conducive to a better understanding of the pathological mechanisms of ICH. Show less

We investigated the relationship between cerebrospinal fluid (CSF) and plasma biomarkers of inflammation, neurodegeneration, and neurocognitive performance in people with HIV (PWH), using longitudinal samples from two previously published cohorts: ACTG A5090 (virally suppressed on antiretroviral therapy, ART) and A736 (ART-naïve or failing). We analyzed paired CSF and plasma samples, as well as 7-domain standardized neurocognitive test scores, at baseline and 24 weeks. Biomarkers included markers of inflammation (e.g., TNF-α, IL-6, IP-10) and neurodegeneration (e.g., NFL, p-Tau217, Aβ42), which were quantified via high-sensitivity immunoassays. Associations with cognition were tested using regression, mediation, and interaction models. Cross-sectional analyses revealed nominal associations between inflammatory markers and cognitive performance, with plasma IL-6 and IP-10 at baseline, and CSF TNFα at week 24 showing the strongest correlations (p < 0.05, uncorrected); however, none survived correction for multiple comparisons. Conversely, higher CSF Aβ42 and plasma BDNF were positively associated with memory and executive function. Longitudinally, biomarker changes did not significantly predict change in global cognition (ΔNPZ-8); the strongest trend (p-Tau217, ρ = -0.12, p = 0.38) was not statistically significant, and multivariate models failed to identify robust predictors (R These results suggest a potential role of CSF TNFα in mediating the neurocognitive effects of HIV and highlight compartment-specific inflammatory dynamics. Plasma TNFα, GFAP, and NFL may serve as peripheral indicators of CNS pathology, though with only moderate concordance. Astrocyte-tau interactions require cautious interpretation pending replication in larger cohorts. Show less

Depression is a multifactorial, chronic disorder and represents a leading cause of disability, with women exhibiting nearly twice the lifetime prevalence compared to men. Growing evidence indicates that this disparity cannot be explained by hormonal or psychosocial factors, but rather by dynamic interactions between environmental exposures, neuroendocrine signaling, and epigenetic regulation across development. This mini-narrative review aimed to examine how sex-specific exposome components interact with epigenetic mechanisms and synaptic remodeling processes to influence vulnerability to Major Depressive Disorder in women. The reviewed evidence demonstrates that fluctuations in ovarian hormones modulate HPA axis responsivity, neuroinflammatory signaling, and glutamatergic transmission through epigenetic regulation of stress-responsive genes such as Show less

Luteolin, a flavonoid naturally present in a variety of fruits, vegetables, and medicinal plants, has been recognized as a potentially effective neuroprotective nutraceutical because of its remarkable anti-inflammatory, antioxidant, and neurotrophic properties. Increasing evidence suggests that neuroinflammation and oxidative stress are major contributors to cognitive decline and neuronal degeneration in several prominent neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and multiple sclerosis (MS). Luteolin significantly inhibits microglial activation, reduces pro-inflammatory cytokine production, modulates the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways, and enhances Nrf2-mediated antioxidant mechanisms. Furthermore, it promotes synaptic plasticity through brain-derived neurotrophic factor (BDNF)-associated pathways and mitigates the aggregation of pathological proteins, including Aβ, tau, α-synuclein, and mutant huntingtin. Preclinical studies consistently demonstrate substantial improvements in cognitive function, motor performance, demyelination, and neuronal viability in models of AD, PD, MS, and HD. Preliminary clinical observations also indicate prospective advantages for cognitive function, regulation of inflammatory responses, and alleviation of symptoms, particularly concerning AD and MS. Notwithstanding these encouraging outcomes, obstacles persist due to luteolin's restricted bioavailability, ideal dosing parameters, and the translational discrepancies between experimental models and human pathophysiological conditions. In summary, luteolin emerges as a noteworthy candidate for nutraceutical-oriented approaches designed to alleviate neuroinflammation and cognitive deterioration in the context of neurodegenerative diseases. Show less

To synthesise existing research on the impact of gestational diabetes mellitus (GDM) on fetal neural development and subsequent cognitive function in offspring. A systematic review was conducted following PRISMA guidelines. PubMed, Cochrane Library, and ClinicalTrials.gov were searched from January 1964 to October 2024. Studies comparing offspring of mothers with GDM to those without were included. Quality was assessed using the Newcastle-Ottawa Scale (NOS). Seventeen studies met the inclusion criteria. The findings suggest that GDM is linked to subtle yet significant neurodevelopmental modifications, encompassing delays in communication and language proficiency, behavioural dysregulation, as well as heightened susceptibility to autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). Electrophysiological investigations revealed alterations in cortical activity and extended auditory responses, while neuroimaging studies documented structural variations, including changes in the dimensions of the corpus callosum, ventricular size, and sulcal maturation. Molecular investigations uncovered dysregulated microRNAs that play a role in neurogenesis. Numerous studies emphasised the dose-dependent effects of maternal glucose concentrations and the protective impact of effective glycemic control. Maternal GDM is associated with alterations in fetal brain structure and function, which may predispose offspring to neurodevelopmental risks. While not all deficits persist, these findings highlight the potential value of early glycemic control and postnatal monitoring for at-risk infants. Further longitudinal research is needed to distinguish causal GDM effects from environmental confounders. Show less

Chronic ketamine exposure results in psychotic and cognitive symptoms that resemble those found in patients with schizophrenia. Emerging evidence suggests that patients with schizophrenia exhibit gut microbiota dysbiosis and decreased levels of short-chain fatty acids (SCFAs) and BDNF, which are related to the severity of psychotic and cognitive symptoms. Dietary inulin can regulate gut microbiota, SCFAs, and BDNF. However, the role of gut microbiota, SCFAs, and BDNF in chronic ketamine-induced schizophrenia-like behaviors is unclear. In this study, we found that chronic ketamine exposure for 28 days caused gut microbiota dysregulation, reduced the expression of SCFAs in serum, hippocampus, and feces, elevated gut permeability, downregulated the BDNF-TrkB-ERK1/2-CREB signaling pathway, caused neuronal damage, and decreased the expression of synaptic proteins Syn and PSD-95, which may lead to anxiety-like behaviors, prepulse inhibition (PPI) deficits, and spatial learning and memory deficits. In addition, inulin intervention reversed gut microbiota dysbiosis by decreasing the abundance of Show less

Brain-derived neurotrophic factor (BDNF) is considered to participate in regulating the endometriosis (EM) process. However, other functions and mechanisms of BDNF in EM progression still need to be further studied. Ectopic/normal endometrial stromal cells (ESCs) were isolated from EM tissues/normal control endometrial tissues. BDNF mRNA expression in EM tissues and normal control endometrial tissues was analyzed through quantitative real-time polymerase chain reaction. The protein levels of BDNF and glucose transporter 1 (GLUT1) were detected by Western blot. The function of ESCs was determined through cell counting kit 8 assay, 5-ethynyl-2'-deoxyuridine assay, flow cytometry, Transwell assay, and wound healing assay. The interaction between BDNF and GLUT1 was assessed through a co-immunoprecipitation assay and immunofluorescence staining. BDNF expression was elevated in EM tissues and ectopic ESCs. Functional experiments revealed that BDNF knockdown repressed ectopic ESC proliferation, invasion, migration, and glycolysis and promoted apoptosis. In terms of mechanism, BDNF interacted with GLUT1 to enhance its protein expression. In addition, the repressing effect of BDNF knockdown on ectopic ESCs' growth, invasion, migration, and glycolysis was abolished by GLUT1 overexpression. Our study showed that BDNF could facilitate ectopic ESC function by interacting with GLUT1, thereby providing basic information for finding an effective therapeutic target of EM. Show less

This review aims to elucidate the molecular mechanisms underlying the neuroprotective effects of acupuncture in preclinical models of Parkinson's disease (PD). In PD animal models, acupuncture inhibits oxidative stress by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) while reducing malondialdehyde (MDA) and lipid peroxidation. It regulates autophagy either independently of mammalian target of rapamycin (mTOR) or via mTOR activation, promoting alpha-synuclein (α-synuclein) clearance. Acupuncture also suppresses apoptosis (modulating Bcl-2-associated X protein (Bax)/B-cell lymphoma 2 (Bcl-2)) and pyroptosis (inhibiting NLR family pyrin domain containing 3 (NLRP3) inflammasome and gasdermin D (GSDMD)). It enhances neurogenesis through brain-derived neurotrophic factor (BDNF)/extracellular signal-regulated kinase (ERK)/cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) and glial cell line-derived neurotrophic factor (GDNF) signaling, promoting neural stem cell proliferation and differentiation. Furthermore, acupuncture reduces neuroinflammation by decreasing microglial activation, cyclooxygenase-2 (COX-2), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β). It also modulates gut microbiota composition (e.g., increasing butyrate-producing bacteria like Butyricimonas and reducing pro-inflammatory Erysipelotrichaceae and Bacteroides) and influences lipid metabolism, thereby mitigating dopaminergic neuron loss and motor deficits. Preclinical evidence demonstrates that acupuncture exerts multi-target neuroprotective effects against PD through pathways involving oxidative stress, autophagy, apoptosis/pyroptosis, neurogenesis, neuroinflammation, and gut microbiota-lipid metabolism crosstalk. However, limitations include a focus on preventive rather than reversal effects, lack of long-term efficacy data, and heterogeneity in acupoint selection. Further mechanistic and standardization studies are warranted. Show less

Mitochondrial dysfunction, oxidative stress, and neuroinflammation play a critical role in the occurrence and progression of Alzheimer's disease (AD). MicroRNAs (miRNAs) have been studied recently as potential therapeutic approaches for AD. In this study, we examined the function and underlying mechanism of microRNA-25802 (miR-25802), a newly discovered miRNA in an AD model. In order to evaluate the levels of oxidative stress, mitochondrial damage and neuroinflammation in neuroblastoma cells, four experimental groups were created: control group (neuroblastoma cells, SH-SY5Y), amyloid beta (Aβ)-induced neuroblastoma cells (SY5Y-Aβ), small extracellular vesicles (sEVs)-only group and miR-25802-loaded small extracellular vesicles (sEV-miR25802) administered group. Neuroinflammation, oxidative stress, mitochondrial damage, tau hyperphosphorylation, and Aβ accumulation were evaluated in Aβ-induced neuroblastoma cells. Oxidative stress was analyzed by measuring reactive oxygen species (ROS), malondialdehyde (MDA), lactate dehydrogenase (LDH), superoxide dismutase (SOD), and glutathione peroxidase 1 (GPX1). Inflammatory markers such as tumor necrosis factor-alpha (TNF-α), intercellular adhesion molecule 1 (ICAM1), and brain-derived neurotrophic factor (BDNF) mRNA levels, a neurotrophic factor, were evaluated by RT-qPCR. Neurofilament light chain (NfL), vascular endothelial growth factor-A (VEGF-A), macrophage migration inhibitory factor (MIF), monocyte chemoattractant protein-1 (MCP-1) and cytochrome c (Cyt-c), mitochondrial transcription factor A (TFAM), PTEN-induced kinase 1 (PINK1) and dynamin-1-like protein (DNM1L) protein levels were determined by ELISA. Mechanistically, sEV-miR25802 were shown to provide anti-inflammatory and neuroprotective effects by regulating neuroinflammation, mitochondrial dysfunction, and oxidative stress. These findings reveal the regulatory role of miR-25802 on neuroinflammation, mitochondrial damage, and oxidative stress and suggest that it may be a potential therapeutic target for AD. Show less

Current therapeutic approaches for Alzheimer's disease (AD) demonstrate limited efficacy and fail to address disease progression. In the present study, we present HSN-G1, a novel ginsenoside-enriched pharmaceutical formulation that employs a dual-target mechanism through the modulation of amyloid clearance pathways and cholinergic neurotransmission. HSN-G1 demonstrates a reproducible ginsenoside profile enriched with Re (33.27 mg/g), Rd (25.00 mg/g), and Rg3 stereoisomers (12.18 mg/g), ensuring pharmaceutical-grade reproducibility. HSN-G1 enhanced amyloid-beta (Aβ) clearance in microglial cells, with significantly greater effects observed in SRA-overexpressing cells, suggesting SRA-dependent clearance mechanisms. In APP/PS1 transgenic mice, six-week oral administration of HSN-G1 (100-400 mg/kg) elicited significant dose-dependent improvements in cognitive performance. Male mice exhibited more stable and consistent enhancements in both passive avoidance and spatial memory tests compared to vehicle controls (p < 0.001), while both sexes demonstrated comparable reductions in brain Aβ levels (approximately 45%) and differential increases in acetylcholine (73% in males; 55% in females, p < 0.01). HSN-G1 administration enhanced the expression of neurotrophic factors, with NGF upregulation predominantly observed in males, whereas BDNF, CNTF, and GDNF were consistently elevated across both sexes. These findings establish HSN-G1 as a promising disease-modifying agent with standardized composition and therapeutic efficacy, surpassing the limitations of conventional single-target approaches. The superior efficacy of HSN-G1 compared to existing treatments validates its potential for clinical development, highlighting the significance of sex-specific therapeutic responses in future AD therapeutics. Show less

Despite advances in acute ischemic stroke (AIS) research, identifying reliable biomarkers and regulatory mechanisms remains challenging. We first identified AIS-related genes via extensive literature review, retrieved dataset GSE16561 from the Gene Expression Omnibus (GEO, https://ncbi.nlm.nih.gov/geo/), and performed differential/enrichment analyses. Bioinformatics verified N6-methyladenosine (m Show less

Bodin et al. (2025) provide valuable insights into neurodevelopmental vulnerability by examining radiofrequency electromagnetic fields (RF‑EMF) exposure during early life. Their integrative design, combining whole-body exposure with endpoints such as neonatal brain proteomics, BDNF expression, synaptogenesis, and oxidative stress, offers a comprehensive framework for developmental neurotoxicology. However, interpretation of proteomic clustering relies heavily on principal component analysis (PCA), a linear technique ill-suited for high-dimensional datasets dominated by non-linear dependencies and strong inter-feature correlations. PCA plots (Figure 3) illustrate group separation, yet variance explained (55%) and clustering stability remain underreported, raising concerns about robustness and biological interpretability, particularly given only ten differentially expressed proteins. To enhance inference, future studies should adopt biologically meaningful feature selection and advanced frameworks such as Feature Agglomeration and Highly Variable Feature Selection, alongside non-parametric correlation measures such as Spearman's rho and Kendall's tau. These strategies will improve reproducibility, uncover mechanistic patterns, and strengthen translational relevance for neurodevelopmental research. Show less

Clozapine is the most effective treatment for treatment-resistant schizophrenia but has been linked to cognitive impairment and brain volume reductions. The potential mechanisms underlying these effects remain unclear. Microglial exosomes, which carry microRNAs (miRNAs) and other cargo, act as immune-neuron communication vectors capable of modulating neuronal function and cognition. We compared cognitive performance and inflammatory markers across clozapine-treated individuals, haloperidol-treated individuals, and healthy controls. Human microglial cells were treated with clozapine and assessed for phenotypic changes and exosome production. Exosomes from control and clozapine-treated microglia were applied to neuroblastoma cells and primary murine cortical neurons to assess neurite outgrowth and brain-derived neurotrophic factor (BDNF) expression. C. elegans were exposed to exosomes and evaluated for lifespan, healthspan markers, and cognitive function via olfactory associative learning assays. Exosomal miRNA cargo was characterized by small RNA sequencing. Clozapine-treated individuals exhibited elevated systemic inflammatory markers and lower cognitive performance compared with healthy controls. Clozapine altered microglial morphology, reduced proliferation and migration, and significantly increased exosome production. Small RNA sequencing identified six dysregulated miRNAs in clozapine-induced microglial exosomes, including upregulation of miR-34a-5p. Exposure of neurons to clozapine-induced exosomes reduced neurite length, branch points, and BDNF expression. In C. elegans, clozapine-induced exosomes reduced lifespan and severely impaired learning and short-term memory. These findings identify a neuroimmune exosomal pathway through which clozapine-exposed microglia can impair neuronal structure and cognition, associated with dysregulated miRNA cargo. This work provides a framework linking microglial immune signalling, extracellular vesicle biology, and cognitive vulnerability during clozapine exposure. Show less

Friedreich's Ataxia (FRDA) is an early onset hereditary disorder with a strong neurodegenerative component caused by repeat expansions on the gene encoding for frataxin (FXN) that result in FXN deficiency. This deficit has been linked to a cascade of biochemical alterations, including mitochondrial dysfunction, oxidative stress and neuronal apoptosis, that drives the neurodegenerative process. FRDA is a very incapacitating disease and patients rely on very limited therapeutic alternatives, such as the recently approved drug omaveloxolone, to treat the oxidative stress. Nevertheless, previous studies have suggested the activation of the brain-derived neurotrophic factor (BDNF) may be a promising treatment to regulate FRDA pathophysiology. Herein, we characterize the effects of FXN deficiency in an in vitro model of primary cerebellar granule neurons (CGNs) derived from the FRDA mouse model YG8-800, as well as the therapeutic potential of BDNF partial agonism by the small molecule 7,8-dihydroxyflavone (7,8-DHF). We found evidence of mitochondrial dysfunction concomitant with DNA damage and enhanced cell death due to FXN deficiency in cultured neurons. The treatment with 7,8-DHF was able to reduce the markers of genotoxicity and apoptosis, without restoring the impaired mitochondrial function nor the total cell death, possibly through ferroptosis, revealing a partial neuroprotective effect insufficient to halt the neurodegenerative process in this in vitro model of FRDA. Show less

Sleep and physical activity are modifiable behaviours linked to pain. Sleep disturbance often co-occurs with persistent pain and may contribute to its development. Exercise is a first-line treatment for chronic pain. Previous work showed that sleep disturbance worsens and prolongs postinjury pain behaviours, exercise mitigates these effects, and brain-derived neurotrophic factor may play a mechanistic role. Deeper insight requires a broader assessment of pain behaviours and systemic biomarkers related to inflammation, tissue repair, and neuromodulation. This study addresses these gaps. Twenty-nine adult female Sprague-Dawley rats performed an intensive lever-pulling task for 4 weeks to induce overuse injury and then underwent one of three 4-week interventions: intermittent sleep disturbance, voluntary exercise (via access to a running wheel), or both. Pain-related behaviours and 71 blood analytes were measured immediately preinjury, postinjury, and postintervention. Overuse injury decreased grip strength and increased mechanical sensitivity in the injured forepaws. After cessation of the injury inducing task, these changes persisted with sleep disturbance but recovered to, or exceeded, preinjury levels with exercise, even with concurrent sleep disturbance. Biomarker analyses revealed distinct neuroimmune responses to injury and sleep disturbance, particularly mediators of inflammation and neuroplasticity, that were offset by exercise. Correlations between biomarkers and behavioural outcomes support mechanistic links between injury, sleep, exercise, and recovery. Findings demonstrate that postinjury sleep disturbance induces neuroimmune changes that increase persistent pain vulnerability, whereas aerobic exercise counters these effects. This highlights the interaction between sleep and exercise in recovery and their potential as strategies to prevent and manage chronic pain. Show less

Stress plays a pivotal role in anxiety-like disorders and cognitive decline. The present study investigated the potential effects of prior royal jelly supplementation and environmental enrichment against stress-induced anxiety-like behaviors, serum corticosterone, hippocampal brain-derived neurotrophic factor (BDNF) levels, and cognitive performance deficits in stressed rats. Male Wistar rats were randomly devised into 8 experimental groups. Rats were subjected to royal jelly (200 mg/kg) via oral gavage, standard environmental enrichment, or combination all for 14 days and control rats received saline in the same period of time. Stress induction was done on the 7th day of treatments by exposure to the restrainer under 10°C. Then open field, elevated plus maze, and inhibitory passive avoidance memory tests were used to explore emotional-cognitive behaviour. Also, corticosterone levels, and hippocampal BDNF expression were measured. Stress resulted in an increase in the serum corticosterone levels, anxiety-like behaviors, and decreased hippocampal BDNF expression which reversed by environmental enrichment and royal jelly treatments. Remarkably, the combined treatment exerts a more pronounced effect on the aforementioned outcomes. Our study strongly proposes a novel emerging therapeutic approach through nutritional interventions, emphasizing the potential of these treatments to mitigate stress-induced anxiety and memory impairments prior to stress exposure. Show less

To investigate the protective effects of dexmedetomidine on cerebral ischemia-reperfusion injury through the activation of the brain-derived neurotrophic factor (BDNF)/tyrosine kinase receptor B (TrkB) signaling pathway. This study utilized hippocampal neuronal oxygen-glucose deprivation/reoxygenation (OGD/R) models and rat middle cerebral artery occlusion models, with dexmedetomidine intervention. Compared with the sham-operated group, the model group rats exhibited a significant increase in Zea-Longa scores, a marked prolongation of the escape latency, a notable reduction in the number of platform crossings, a significant increase in the percentage of cerebral infarct size, and a marked decrease in the expression of BDNF, TrkB, and Bcl-2 proteins and mRNA (P < 0.05). The dexmedetomidine group showed significantly better outcomes in all above parameters compared to the model group. Compared with the control group, the OGD/R group exhibited a reduction in hippocampal neuronal cell viability, a significant increase in apoptosis rate, elevated expression of Bax and C-caspase-3 proteins, a marked decrease in Bcl-2 protein levels, and a significant reduction in the expression of BDNF and TrkB proteins and mRNA (P < 0.05). Dexmedetomidine exerts significant neuroprotective effects by activating the BDNF/TrkB signaling pathway, thereby alleviating ischemic brain injury. Show less

Cholinergic dysfunction is a key contributor to cognitive impairment observed in aging and neurodegenerative disorders such as Alzheimer's disease (AD). Although acetylcholinesterase (AChE) inhibitors have been the mainstay of symptomatic treatment for over two decades, their limited efficacy and adverse effects underscore the need for alternative therapeutic approaches. Recent evidence indicates that mechanical stimulation can modulate neuronal and glial signaling through mechanotransduction, suggesting a potential strategy to enhance cognitive function via non-pharmacological means. Here, we developed a head-mounted vibrotactile stimulation system (HVSS) that delivers controlled vibration to the cranium and evaluated its effects in a pharmacological model of acute cholinergic dysfunction induced by scopolamine. To this end, male C57BL/6 mice received scopolamine (1 mg/kg, i.p.; on days 7, 14, and 28) and were exposed to daily vibrotactile stimulation at 20, 40, or 80 Hz for 28 days. Behavioral performance was assessed using passive avoidance and Morris water maze tests, followed by biochemical and histological analyses. HVSS at 40 Hz and 80 Hz significantly improved cognitive performance, enhanced hippocampal cholinergic function, reduced oxidative damage, and upregulated memory-related signaling genes, including BDNF, PI3K, AKt, ERK1/2, CREB, and CAMK4. These findings suggest that high-frequency HVSS improves memory hippocampal cholinergic function via activation of memory-related signaling pathways, highlighting its potential as a safe, non-pharmacological neuromodulatory strategy for cholinergic dysfunction-related cognitive decline. Show less

Since breast milk provides essential nutrients and bioactive compounds, such as adipokines and growth factors, which are indispensable for neonatal growth and metabolic regulation, this review seeks to elucidate the differences in these bioactive components between preterm and term breast milk and to evaluate their potential influence on neonatal development. Adipokines such as leptin, adiponectin, resistin, ghrelin, and visfatin, alongside growth factors including epidermal growth factor, insulin-like growth factor, and brain-derived neurotrophic factor, exhibit variable concentrations in preterm versus term milk. Preterm milk generally contains higher levels, potentially reflecting an adaptive response to support accelerated growth. However, findings are inconsistent across studies, likely due to differences in study design, timing of milk collection, analytical methods, and variability in maternal characteristics. Variations in bioactive component profiles between preterm and term milk suggest compensatory mechanisms in preterm lactation. Further longitudinal studies are warranted to clarify these relationships and to elucidate the long-term effects of breast milk adipokines and growth factors on preterm infant growth and metabolic programming. Show less

Neuropsychiatric dysfunction is increasingly being acknowledged as a disabling complication of non-alcoholic steatohepatitis (NASH), but there are no therapeutic approaches. We investigated in the present study the neuroprotective effectiveness of naringenin, a citrus flavonoid with known anti-inflammatory and neurotrophic effects, in a murine NASH model induced by an 8-week methionine-choline-deficient (MCD) diet. Male C57BL/6 mice (n = 8/group) were treated with naringenin (50 mg/kg/day, i.p.) during the final 4 weeks. In behavioral tests, naringenin counteracted cognitive impairment in novel object recognition, reduced anxiety in both open field and elevated plus maze paradigms, and decreased immobility in the forced swim test, indicating antidepressant-like activity. Mechanistically, naringenin restored hippocampal apoptotic balance, normalizing the MCD diet-induced Show less

Early-life stress is a critical determinant of vulnerability to later-life affective and cognitive dysfunction, yet the mechanisms through which adolescent adversity enhances adult stress susceptibility remain incompletely understood. Here, we employed a two-hit model combining adolescent social isolation stress (SIS) with adult chronic restraint stress (CRS) to examine how developmental stress interacts with adult stress exposure. SIS alone or CRS alone exerted minimal behavioral effects, whereas SIS followed by CRS markedly potentiated depression-like behaviors and impaired spatial and object recognition memory. Two-hit stress produced robust hippocampal neuroinflammatory responses, including increased astrocytic and microglial activation and elevated TNF-α, IL-1β, IL-6, and IL-17A levels. These inflammatory alterations were accompanied by pronounced suppression of the BDNF/TrkB/p-CREB signaling cascade, reduced synaptic protein expression, and diminished dendritic spine density and branching complexity in CA1 pyramidal neurons. Notably, light treatment (LT) administered during CRS exposure significantly reversed two-hit induced behavioral deficits, attenuated glial activation and cytokine upregulation, enhanced BDNF/TrkB and p-CREB signaling, and restored synaptic and structural plasticity. Together, these findings indicate that adolescent SIS primes the hippocampus for exaggerated neuroinflammatory and neuroplastic impairments following adult stress, thereby amplifying stress vulnerability. Furthermore, LT emerges as a safe non-pharmacological intervention capable of mitigating combined stress-induced emotional and cognitive dysfunction by targeting neuroinflammatory and neurotrophic pathways. Show less

Arsenic trioxide (ATO) remains vital in acute promyelocytic leukemia therapy, yet its clinical use is limited by cumulative organ toxicities, particularly neurotoxicity, which compromise tolerability and outcomes. Perindopril and L‑Arginine exert cytoprotective effects through antioxidant and anti‑inflammatory mechanisms. This study evaluated their neuroprotective efficacy against ATO‑induced neurotoxicity, emphasizing mechanistic pathways. Male rats were assigned to five groups: Control, ATO‑only (7.5 mg/kg, intraperitoneally, 14 days), Perindopril (2 mg/kg, orally), L‑Arginine (200 mg/kg, orally), and combined therapy. Interventions commenced seven days prior to the ATO challenge and continued for 21 days. Body weight was documented at baseline and endpoint; survival indices were monitored. Biochemical, histopathological, and molecular evaluations examined oxidative stress, inflammatory mediators, and apoptotic signaling. ATO exposure increased malondialdehyde (MDA) and nitric oxide derivatives (NOx), while reducing glutathione (GSH), superoxide dismutase (SOD), and catalase activities. It elevated tumor necrosis factor‑α (TNF‑α), interleukin‑1β (IL‑1β), and interleukin‑6 (IL‑6), while suppressing brain‑derived neurotrophic factor (BDNF) and nuclear factor erythroid 2‑related factor 2/heme oxygenase‑1 (Nrf2/HO‑1) signaling. Upregulation of Kelch‑like ECH‑associated protein 1/Nuclear factor kappa‑light‑chain‑enhancer of activated B cells (Keap1/NF‑κB), cleaved caspase‑3, and caspase‑3, alongside downregulation of B cell lymphoma‑2 (Bcl‑2), was evident. Histopathological lesions substantiated neurotoxicity. Perindopril and L‑Arginine markedly reversed these perturbations, reinstating molecular and structural homeostasis. Their combination afforded superior neuroprotection compared with monotherapies. Both agents mitigate ATO‑induced neurotoxicity through antioxidant, anti‑inflammatory, and anti‑apoptotic mechanisms, with their co‑administration surpassing individual efficacy. The Keap‑1/Nrf2/HO‑1 axis emerges as a critical therapeutic node, underscoring the translational potential of combined intervention. Show less

Neurodevelopmental disorders have been increasingly associated with maternal immune activation (MIA) during pregnancy, particularly in response to viral infections. However, the impact of human respiratory syncytial virus (hRSV) infection during gestation on offspring neurodevelopment remains poorly understood. This study aimed to characterize hRSV-induced MIA and evaluate its effects on fetal brain development and offspring behavior using a murine model. Pregnant mice were infected with hRSV at gestational day 14, and tissues were analyzed at day 19. Infection induced pulmonary inflammation, evidenced by increased neutrophil infiltration, and viral replication was detected in maternal lungs and placental tissue, but not in fetal organs. Placental infection was associated with increased decidual immune cells and a shift toward a pro-inflammatory cytokine profile, including elevated IL-6, TNF-α, IFN-γ, and IL-1β, along with decreased IL-10 and IFN-λ. Increased levels of IL-6, TNF-α, and IL-4 were also detected in maternal serum and fetal brains, suggesting vertical transfer of cytokines. Additionally, reduced brain-derived neurotrophic factor levels and altered expression of tight junction-related genes were observed in fetal brains. Behavioral analyses revealed that offspring of infected dams exhibited impaired short-term memory and altered anxiety-like and repetitive behaviors, which persisted or intensified with age. These findings demonstrate that maternal hRSV infection induces MIA, disrupts the fetal neuroimmune environment, and leads to long-term behavioral alterations in offspring, highlighting hRSV as a potential risk factor for neurodevelopmental disorders. Show less

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with progressive loss of motor neurons. Insufficiency of neurotrophic factors is suspected to underlie the disease, but direct evidence remains scarce. In this study, we discover that brain-derived neurotrophic factor (BDNF) val/met mutation, which results in a decrease in BDNF secretion, reduces survival time of ALS patients in two separate cohorts. Using a knockin mouse model of the ALS causal gene FUS Show less

This study investigated the therapeutic potential of exercise training and the associated role of Glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1) in an experimental Alzheimer’s disease (AD) model. Using a D-galactose/AlCl [Image: see text] Show less

Impaired nuclear translocation of glucocorticoid receptor (GR) has been implicated in hippocampal vulnerability in Alzheimer's disease (AD), yet the molecular basis of this defect remains poorly understood. This study identified Huntingtin-associated protein 1 (Hap1) as a critical regulator of GR nuclear translocation in the hippocampus. Specifically, Hap1 expression progressively declined in the hippocampus of APP/PS1 mice with advancing age and pathological burden. Hippocampal Hap1 knockdown induced pronounced cognitive deficits and synaptic deterioration, as indicated by reduced dendritic arborization, decreased spine density, impaired long-term potentiation, and exacerbated amyloid-β deposition. Mechanistic analyses showed that Hap1 deficiency increased GR ubiquitination and proteasomal degradation and, more importantly, disrupted ligand-dependent GR translocation to the nucleus, thereby attenuating GR-dependent brain-derived neurotrophic factor transcription. In parallel, Hap1 knockdown elevated corticosterone concentration and induced depression-like behavior, consistent with hypothalamic-pituitary-adrenal axis dysregulation. Collectively, these findings establish defective GR nuclear trafficking driven by loss of Hap1 function as a key pathomechanism linking intracellular transport failure to synaptic dysfunction in AD and highlight Hap1 as a potential therapeutic target. Show less

This study aimed to explore the effect and mechanism of polyphyllin Ⅱ in improving di(2-ethylhexyl)phthalate(DEHP)-induced learning and memory impairment. In the experiment, male C57BL/6 mice were randomly divided into five groups: a control group, a model group(exposed to 5 mg·kg~(-1) DEHP), and polyphyllin Ⅱ groups(5 mg·kg~(-1) DEHP + 0.5 mg·kg~(-1) polyphyllin Ⅱ, DEHP + 1 mg·kg~(-1) polyphyllin Ⅱ, and DEHP + 2 mg·kg~(-1) polyphyllin Ⅱ). The learning and memory function of mice was tested using the Morris water maze. The hippocampal neuron structure was detected by Nissl staining. The expression of casein kinase Ⅱ subunit beta(CK2b), protein kinase B(Akt)-cAMP response element binding protein(CREB) pathway-related proteins, as well as postsynaptic density protein 95(PSD95) and synapsin 1 was determined by immunofluorescence and Western blot. The brain-derived neurotrophic factor(BDNF) expression was measured by enzyme-linked immunosorbent assay(ELISA). The results showed that compared with the control group, DEHP induced learning and memory impairment, as well as hippocampal neuronal apoptosis in mice. Additionally, DEHP downregulated CK2b, inhibited the Akt-CREB pathway, and downregulated the PSD95, synapsin1, and BDNF expression. After polyphyllin Ⅱ administration, DEHP-induced learning and memory impairment was significantly improved, with inhibited hippocampal neuronal apoptosis, restored CK2b expression, reactivated Akt-CREB pathway, as well as restored expression of PSD95, synapsin1, and BDNF. Furthermore, the surface plasmon resonance(SPR) experiment of N2a cells demonstrated that polyphyllin Ⅱ targeted CK2b and stabilized its expression. After using siRNA to inhibit CK2b, the neuroprotective effect of polyphyllin Ⅱ was also significantly inhibited, and neuronal apoptosis was reinduced. In conclusion, polyphyllin Ⅱ can ameliorate DEHP-induced learning and memory impairment, with its potential mechanism involving the Akt-CREB pathway activation via CK2b upregulation, which leads to restored PSD95 and synapsin1 expression, and synaptic plasticity, as well as inhibited neuronal apoptosis, ultimately exerting a neuroprotective effect. This study suggests that polyphyllin Ⅱ possesses a neuroprotective effect and has potential application value in improving cognitive impairment. Show less

Prenatal stress (PS) significantly influences the neurodevelopment of offsprings, potentially resulting in deficits in learning and memory. Mangiferin (MGF) is a naturally occurring flavonoid compound found in many plants, exhibits various pharmacological effects. The study investigates the potential molecular mechanisms of MGF in improving learning and memory deficits in offspring exposed to PS. Animal model of PS offspring and ACR-induced PC12 cell model were used to investigate the effects of MGF. Synaptic plasticity-related proteins and the BDNF signaling pathway were studied, as well as MGF's potential to alleviate endoplasmic reticulum stress (ERS). MGF can mitigate learning and memory impairments and enhance the density of hippocampal neurons, as well as increase the expression of neuronal markers Neurogranin (Ng), DLG4 and activity marker c-fos in the offspring of PS mice. Meanwhile, MGF significantly increased BDNF signaling pathway and synaptic plasticity-related proteins in PS offspring. MGF also efficiently alleviated ERS. Additionally, MGF significantly up-regulated the reduced viability, DLG4 protein expression and synaptic plasticity-related proteins in ACR-induced PC12 cells. MGF can improve endoplasmic reticulum morphology and down regulated the expression of key molecular proteins in the endoplasmic reticulum signaling pathway. MGF could improve the cognitive and memory impairments in the PS offspring mice. The underlying mechanisms involved the alleviation of ERS and improvement of synaptic plasticity-related proteins. The study indicated that MGF holds promise as an effective intervention for ameliorating learning and memory deficits associated with PS, and it offers potential therapeutic effect for neurological disorders linked to ACR dysfunction. Show less