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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

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

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

Lycopene shows potential against aging-related cognitive decline but suffers from poor stability, low blood-brain barrier penetration, and inefficient delivery. Native rHuHF is biocompatible yet achieves only ∼6% lycopene encapsulation due to its hydrophilic cavity. Here, a recombinant mutant human heavy-chain ferritin (rXHF) with a hydrophobic interior was engineered by replacing four polar residues with tryptophan. rXHF maintains the 24-mer nanocage structure and exhibits enhanced hydrophobicity. It achieves 74.9 ± 2.5% encapsulation efficiency and 17.8 ± 0.6% loading efficiency (2.9-fold that of rHuHF). At a molar ratio of 1:200, the DPPH scavenging rate reached 30.06 ± 9.2%. In D-galactose-induced aging mice, rXHF-LYC dose-dependently improved spatial learning/memory, reduced hippocampal senescence, and modulated oxidative stress, neuroinflammation, and synaptic plasticity via BDNF/TrkB. PC12 assays confirmed endocytic uptake, ROS scavenging, apoptosis inhibition, and preserved acetylcholine synthesis. Thus, hydrophobic ferritin modification enables brain-targeted lycopene delivery, offering a novel strategy for age-related neurodegenerative diseases. Show less

Fentanyl is a potent, fast-acting synthetic opioid that has played a major role in the opioid overdose crisis in the United States for over five decades, with opioid-related deaths increasing sharply in recent years. This study investigates the behavioral, histological, and molecular changes in the hippocampus of rats subjected to sub-acute fentanyl exposure. Two groups of rats were studied: one group received multiple fentanyl injections over approximately one week, while the control group received no fentanyl. A battery of behavioral tests related to memory and depression-including the Y-maze, shuttle box, tail suspension test, elevated plus maze, Barnes maze, Morris water maze, and forced swimming test-was administered. Electrophysiological assessments, including field potential recording and electromyography (EMG), were conducted to evaluate neural activity. Western blot analysis was performed to quantify the expression of brain-derived neurotrophic factor (BDNF) and RE1-silencing transcription factor (REST), while immunohistochemical analyses assessed hippocampal cellular alterations. Results showed that sub-acute fentanyl administration impaired behavioral performance in memory assessment tests (Y maze ( Show less

Chemotherapy-related cognitive impairment (CRCI) is a prevalent and distressing issue among older adults with cancer, affecting quality of life and treatment adherence. While its mechanisms remain unclear, biomarkers have emerged as promising tools for understanding CRCI. This systematic review aimed to explore the relationships between cognitive impairment following chemotherapy and biomarkers in older patients with cancer. A comprehensive search was conducted through December 2024 across PubMed, CINAHL, Embase, PsycINFO, and the Cochrane Library. An additional hand search was performed through July 2025. The focus was on patients over 60 years old with chemotherapy-related cognitive impairment and associated biomarkers. The review adhered to PRISMA 2020 guidelines, and the methodological quality of included studies was assessed using the Joanna Briggs Institute checklist to ensure rigor and reliability. Six of the initial 6,324 articles met the inclusion criteria, and seven additional studies were identified through manual searching. In total, 13 studies identified several biomarkers associated with CRCI in older patients with cancer. These included serum hemoglobin, brain-derived neurotrophic factor, percent cerebral oxyhemoglobin, functional network connectivity, and individual alpha peak frequency. This review highlights several biomarkers potentially associated with CRCI in older patients with cancer, though consistent and definitive biomarkers remain elusive. Further research is needed to clarify the biological mechanisms underlying CRCI and inform the development of interventions aimed at preventing cognitive decline in this vulnerable population. The identification of validated biomarkers will be critical for advancing personalized nursing and improving clinical outcomes in older adults with cancer. Show less

Gestational intermittent hypoxia (GIH), which serves as a model for obstructive sleep apnea (OSA), is associated with adverse maternal and neonatal outcomes, especially cognitive impairments in offspring. Growing evidence supports that the anti-inflammatory actions of melatonin significantly influence the peripartum environment and contribute to the mitigation of neurodegeneration. However, the full impact of GIH on offspring cognition and the molecular mechanisms by which melatonin modulates these effects remain uncertain. Thus, in this study, we explored the neurobiological changes in GIH-exposed offspring and the mechanism underlying maternal melatonin supplementation in preventing these alterations using a murine model. C57BL/6J mice were exposed to GIH between gestational Days 15 and 21. Concurrently, dams received either vehicle or melatonin. The Morris water maze test was employed to evaluate offspring cognitive function, after which the offspring were euthanized at 2 months of age. The hippocampal levels of glial markers (ionized calcium-binding adapter molecule 1 [Iba-1], glial fibrillary acidic protein [GFAP]), NOD-like receptor thermal protein domain-associated protein 3 [NLRP3], nuclear factor-kappa B [NF-κB], tight-junction proteins (zonula occludens-1 [ZO-1], occludin), and synaptic plasticity-related proteins (brain-derived neurotrophic factor [BDNF], tropomyosin receptor kinase B [TrkB], postsynaptic density protein 95 [PSD-95], synaptophysin [SYN]) were quantified by enzyme-linked immunosorbent assay and western blot. Maternal melatonin supplementation significantly attenuated learning and memory impairments, reduced the protein levels of Iba-1 and GFAP by suppressing NLRP3/NF-κB signaling, and elevated those of ZO-1, occludin, BDNF, TrkB, PSD-95, and SYN. Additionally, melatonin mitigated inflammatory responses, glial cell activation, blood-brain barrier (BBB) leakage, and synaptic dysfunction induced by GIH in mice. Our results demonstrated that GIH-exposed mice exhibit cognitive deficits, alongside neuroinflammatory responses, leading to inflammasome activation, glial reactivity, BBB breakdown, and synaptic deficits. However, melatonin exerted significant protective effects against these deleterious effects. Show less

Myokines and cytokines are signaling proteins released by skeletal muscle cells during exercise that act as messengers, influencing the function of various organs, including the brain. We examined whether a single bout of walking exercise induces distinct changes in plasma myokine and cytokine concentrations in older adults with and without mild cognitive impairment (MCI). In 146 older adults characterized based on the Montreal Cognitive Assessment (MoCA) scores in non-MCI (MoCA score ≥26, n = 55) vs MCI (MoCA score <26, n = 91), we measured cognitive performance by battery, body composition by DXA, and functional performance by 6 min walk test (6MWT) distance. In addition, plasma myokine and cytokine concentrations were assessed before and immediately after 6MWT by MILLIPLEX® Human Myokine Magnetic Bead Panel (HMYOMAG-56K) and Immunology Multiplex Assay (HCYTA-60K-PXBK38) using Luminex® 200™ and MagPix system. Analysis was performed by GLMM to test the effects of group (Non-MCI vs MCI) and walking exercise. The MCI group had worse cognitive performance on trail-making test, stroop color word test (SCWT), phonemic and semantic fluency test, digit span backward, and the Rey auditory verbal learning test (AVLT) delayed memory (all P < 0.02). Body weight, BMI, lean mass, and (visceral) fat mass were comparable between non-MCI and MCI groups. There was a trend toward significantly lower 6MWT distance in the MCI (P = 0.067). We found lower baseline GM-csF concentration (P = 0.006) and a smaller increase in BDNF, FABP-3, and Osteocrin concentration in response to 6MWT in the MCI, even after adjustment for age and 6MWT distance (P < 0.003). Lower BDNF response to exercise was further associated with advancing age and worse cognitive function (MoCA, SCWT) (P < 0.04), but not with changes in lifestyle (habitual physical activity or dietary intake). We observed 6MWT-induced increases for the other myokines (apelin, BDNF, EPO, osteonectin, IL-15, myostatin, FABP-3, FSTL-1, IL-6, FGF-21, and osteocrin), and nearly all cytokines were independent of the group studied (all P < 0.02). A single bout of 6-minute walking exercise elicits a suppressed increase in BDNF, FABP-3, and Osteocrin in individuals with MCI, with a particularly blunted BDNF response in those who are older and more cognitively impaired. Whether disturbances in muscle-brain crosstalk, mediated by suppressed exercise induced BDNF response, contribute to cognitive decline in older adults warrants further investigation. Show less

To evaluate the preventive effect of dipeptidyl peptidase-4 inhibitors (DPP-4i) on post-stroke cognitive impairment (PSCI) in patients with type 2 diabetes mellitus (T2DM) and concurrent acute ischemic stroke (AIS). A retrospective cohort study was conducted on 236 patients with T2DM+AIS recruited from April 2021 to October 2024. Patients were grouped based on DPP-4i use: an observation group (107 cases) with DPP-4i therapy and a control group (129 cases) without. Patients' baseline demographics, clinical features, laboratory indices, and follow-up data were extracted from the electronic medical record system. The primary outcome measure was the incidence of PSCI, defined as a Montreal Cognitive Assessment Scale (MoCA) score <26 at six months after AIS. Secondary outcomes included inflammatory cytokines, oxidative stress markers, neuroprotective factors (BDNF), glycemic metabolism indicators, and life quality [Barthel Index (BI), Functional Independence Measure (FIM), and Instrumental Activities of Daily Living (IADL)]. At 6 months after AIS, the incidence of PSCI was significantly lower in the observation group than in the control group (P<0.05). Furthermore, inflammatory and oxidative stress marker levels were decreased whereas BDNF level was significantly elevated in the observation group compared to the control group (all P<0.05). According to the quality-of-life assessment, patients receiving DPP-4i had higher BI, FIM, and IADL scores (P<0.05), along with a lower all-cause readmission rate (P<0.05). Subgroup analysis indicated that different DPP-4i types (e.g., sitagliptin, saxagliptin) had consistent cognitive protective effects (P>0.05). DPP-4i can lower PSCI risk in T2DM+AIS patients. Its mechanism involves multi-dimensional effects like anti-inflammation, anti-oxidation, insulin sensitivity enhancement, and neuroprotection. Show less

This study examines neuroanatomical and molecular changes that may be responsible for cognitive impairment in the BTBR mouse model of autism. Compared to control C57Bl/6 mice, BTBR mice exhibited cognitive inflexibility, impaired in an operant learning task. MRI revealed significant brain abnormalities, including reduced cortical volume, smaller ventricles, and asymmetry in the dorsal hippocampus, accompanied by neuronal loss. BTBR mice also showed impaired cerebrospinal fluid dynamics, with reduced production and outflow. Molecular analysis revealed brain region-specific reduction in the expression of Bdnf exons 1, 2, 3, and 4 in untrained BTBR mice. Furthermore, learning induced changes in transcription of Bdnf exons exclusively in BTBR. Elevated proBDNF levels and an increased proBDNF/mature BDNF ratio in the frontal cortex and striatum indicated aberrant BDNF processing. These findings suggest that ASD-related cognitive impairments are linked to a complex of neurodevelopmental abnormalities, potentially connected to disrupted transcription, processing, and signaling of BDNF. Show less

Retigabine (RTG) shows notable neuroprotective efficacy in multiple brain injury models; however, its interplay with endoplasmic reticulum stress (ERS) is poorly understood. This study was designed to explore the therapeutic potential of RTG against CRS-induced depression-like behaviors and cognitive deficits in mice and to uncover the associated molecular mechanisms. A depression-like and cognitive impairment model was established in C57BL/6 male mice using chronic restraint stress (CRS). Six-week-old C57BL/6 male mice were randomly assigned to the following groups: control (Con), model (CRS), RTG (10 mg/kg), XE-991 (2 mg/kg) or tunicamycin (Tm, 2 mg/kg). Behavioral tests were conducted to assess depression-like behaviors and cognitive function. Hippocampal neuronal morphology was examined by H&E and immunofluorescence staining, while changes in endoplasmic reticulum stress (ERS)-related signaling pathways were analyzed by Western blot. Retigabine treatment reduced hippocampal neuronal damage and the expression of ERS-related factors (GRP78, CHOP) and the pro-apoptotic factor BAX in CRS-induced mice, while it increased the levels of BDNF. These effects were antagonized by XE-991 and the ERS agonist tunicamycin (Tm). Retigabine may alleviate CRS-induced depressive-like behaviors and cognitive impairment by inhibiting ERS-mediated apoptosis, suggesting its potential as a novel therapeutic strategy for depression. Show less

Mental illness conditions and neurodegenerative diseases are an emerging worldwide burden, with depression affecting over 300 million people and dementia cases projected to triple by 2050. Oxidative stress and inflammation are central mechanisms for neuronal injury and cognitive impairment. This review discusses the neurotherapeutic promise of egg-derived antioxidants. Importantly, yolk in polypeptide complex (isolated from egg yolk with immunoglobulin Y) enhances cognitive function by upregulating brain-derived neurotrophic factor via cAMP/PKA and PI3K/Akt signaling. We discuss their molecular modes of action such as reactive oxygen species scavenging, regulation of inflammatory cytokines, maintenance of mitochondrial function, and promotion of neurogenesis and synaptic plasticity. Further, bioavailability, allergenicity, and targeted delivery issues across the blood-brain barrier are addressed in light of progress in nanocarrier systems and encapsulation methods. Comparative observations with other diet-based antioxidants like curcumin, polyphenols, and omega-3 fatty acids are presented to put egg-derived compounds into perspective within the overall nutraceutical regime. Lastly, future directions highlight the importance of targeted clinical trials, regulatory factors, and inclusion in public health initiatives designed to prevent cognitive degeneration and mental illness through accessible nutritional interventions. This review highlights the promising potential of antioxidants derived from eggs as adjunctive neuroprotective therapy and indicates the need for interdisciplinary investigations to extend these findings into the clinic. © 2026 Society of Chemical Industry. Show less

Cognitive impairment in schizophrenia (SCZ) is associated with neuroinflammation and neurotrophic dysregulation. The role of pro-inflammatory interleukins and brain-derived neurotrophic factor (BDNF) in cognitive deficits remains unclear. We aimed to examine the associations between IL-1β, IL-2, IL-6, BDNF, and cognitive function in patients with SCZ with typical or atypical antipsychotics. Participants included 162 healthy controls (mean age = 33.6 ± 2.0 years), 88 patients with SCZ receiving typical antipsychotics (36.4 ± 6.4 years), and 62 receiving atypical antipsychotics (34.0 ± 4.0 years). Cognitive performance was evaluated using a battery of attentional, executive, and visuospatial working memory tasks. Data were analyzed using machine-learning approaches, multivariate statistics, and structural equation modeling. SCZ Patients exhibited marked cognitive impairments alongside lower BDNF concentrations and elevated interleukin levels, with the greatest deviations observed among those receiving typical antipsychotic treatment. Higher medication dosages and longer illness duration were associated with greater cognitive decline and stronger neuroimmune dysregulation. The findings indicate that elevated cytokines and reduced neurotrophic support may contribute to cognitive impairment, whereas persistent cognitive dysfunction can further amplify inflammatory activity. This complexity suggests the need to broaden current assessment approaches and systematically examine biomarkers together with clinical features. Show less

Interleukin 1 receptor-associated kinase 1, 4 (IRAK 1/4) inhibitor exerts anti-inflammatory and immuno-modulatory effects; however, its role in high-fat diet-induced vascular dysfunction and cognitive impairment is not known, and therefore investigated in the present study. Animals were fed either a high-fat diet (60% Kcal fat) or a chow diet (10% Kcal fat) for 12 weeks to induce hyperlipidemia and weight gain. High-fat diet-fed animals were then treated with vehicle, IRAK1/4 inhibitor (2.2 mg/kg, i.p.) and a reference drug, Orlistat (20 mg/kg, oral gavage), for 4 additional weeks. Protein levels were assessed by ELISA or Western blotting, and mRNA by RT-PCR. IRAK1/4 inhibitor and reference drug, Orlistat treatment, prevented HFD-induced increase in body weight gain, fasting blood glucose and plasma lipids, improved discrimination between the familiar and the novel arm in the Y-Maze test, alleviated percent avoidance in two-way active avoidance, and freezing percent in contextual fear conditioning test. The treatments attenuated the levels of systemic inflammatory cytokines IL-1β, CRP, as well as TNF-α, IL-6 and protein expression of Iba-1, GFAP, HIF-1α, and restored the BDNF levels in the pre-frontal cortex of HFD-fed treated mice. IRAK 1/4 inhibitor exerted these effects by blocking proteasomal degradation of IκB-α protein in the pre-frontal cortex of HFD-treated mice. In addition, the treatments prevented HFD-induced increase in vascular ICAM-1, VCAM-1, MCP-1, COX-1 and COX-2 mRNA expression, and restored vascular eNOS mRNA levels as well as the Acetylcholine (300 ρM-300 μM) induced relaxations of PE (1 µM) pre-contracted aortic rings. IRAK1/4 inhibitor attenuates HFD-induced inflammation, vascular dysfunction and cognitive impairment in obese mice. Show less

Recent evidence has shown that bone marrow mesenchymal stem cells (BMSCs) have multiple biological applications and play an important role in improving cognitive dysfunction. However, it is still unclear whether BMSCs play a role in cognitive impairment induced by chronic pain. This study aimed to evaluate the therapeutic effect of BMSCs on neuropathic pain-induced cognitive dysfunction and explore its potential mechanisms. A mouse chronic constriction injury (CCI) model was established, and the new object recognition task and fear conditioning were used to detect cognitive function; the expression of CXCL12/CXCR4 in blood and hippocampus was detected. After intravenous injection of BMSCs, changes in cognitive function and expression of the CXCL12/CXCR4 pathway, dentate gyrus neurogenesis, and excitability of hippocampal neurons were detected. In addition, induction of cognitive impairment in normal mice by CXCL12 recombinant protein was used to clarify whether the CXCL12/CXCR4 pathway mediates the cognitive function improvement effect of BMSCs. Our results found CCI mice showed significant cognitive impairment 21 days after surgery, with significantly increased expression of CXCL12/CXCR4 in blood and hippocampus. Intravenous injection of BMSCs significantly improved cognitive function, inhibited expression of CXCL12/CXCR4 in blood and hippocampus, promoted neurogenesis in dentate gyrus of CCI mice, and increased expression of BDNF and c-Fos in the hippocampus. In addition, BMSCs alleviate cognitive impairment induced by intravenous injection of CXCL12 recombinant protein in mice. In summary, BMSCs improve chronic neuropathic pain-induced cognitive dysfunction through peripheral blood CXCL12/CXCR4, and BMSCs may develop into therapeutic targets for chronic pain induced cognitive impairment. Show less

N-Acetylcysteine (NAC), a thiol-containing antioxidant, has demonstrated neuroprotective potential in various neurological disorders. Recently, cold atmospheric plasma (CAP) technology has emerged as a promising approach for modifying the physicochemical properties of biomolecules. This study investigated the neuroprotective effects of plasma-activated N-acetylcysteine (PAN) in a rat model of intracerebroventricular streptozotocin (icv-STZ)-induced cognitive impairment, with particular emphasis on redox homeostasis and cholinergic function. The physicochemical properties of PAN were characterized using FTIR, LC-MS/MS, and DPPH assay. Male rats received a single icv-STZ injection (3 mg/kg) on day 0, followed by oral administration of NAC or PAN (50 mg/kg) every other day for three weeks. Cognitive performance and anxiety-like behaviors were assessed using the shuttle box, novel object recognition, and elevated plus maze tests. Subsequently, oxidative stress indices (TAC, GSH, SOD, CAT, MDA, NO), cholinergic markers (AChE activity, ACh levels), and the expression of AChE, α7 nAChR, Nrf2, Keap1 and BDNF genes were quantified in the hippocampus and cerebral cortex. FTIR and LC-MS/MS analyses revealed plasma-induced chemical modifications in NAC, resulting in the generation of novel compounds. The DPPH assay further demonstrated superior radical scavenging activity of PAN compared with NAC. Behaviorally, PAN administration significantly alleviated STZ-induced cognitive deficits and anxiety-like behaviors. Biochemically, PAN normalized TAC, GSH, MDA, NO, and ACh levels, increased CAT and SOD activities, and reduced AChE activity. At the transcriptional level, PAN upregulated α7 nAChR, Nrf2 and BDNF expression while downregulating AChE and Keap1. Collectively, these findings suggest that PAN mitigates behavioral impairments in the icv-STZ rat model of Alzheimer's disease, potentially through attenuation of oxidative stress and restoration of cholinergic neurotransmission. Show less

Growing evidence highlights that long-term orbital flight may lead to structural changes in brains and cognitive impairments in astronauts. However, effective strategies to counteract these effects remain limited. Compound Gastrodia elata Formula (CGEF), composed of Gastrodia elata Bl., Polygonatum sibirium Red., and Poria cocos (Schw.) Wolf has been shown to improve learning and memory. The present study aimed to evaluate the effects and underlying mechanisms of CGEF in attenuating cognitive deficiency induced by simulated weightlessness in mice. A cognitive impairment model was induced in mice using Hindlimb unloading (HU) method. Cognitive function was assessed through Object recognition test (ORT), the Morris water maze (MWM), and the Step-down Test (SDT). Serum and hippocampus levels of inflammatory markers, including Interleukin-1 beta (IL-1β), Tumor Necrosis Factor alpha (TNF-α), and Interleukin-6 (IL-6) were evaluated using ELISA. Neurotransmitter concentrations in the hippocampus and cortex were measured using LC-MS/MS. While Brain-derived neurotrophic factor (BDNF) / Tropomyosin receptor kinase B (TrkB) protein expression signaling pathway in hippocampus was evaluated by western blot. Results showed that CGEF treatment significantly reversed the memory deficits induced by four weeks of HU exposure. Furthermore, CGEF treatment markedly suppressed the production of inflammatory factors. It also assisted in the recovery of neurotransmitter balance and regulated tryptophan metabolism to improve cognitive disorder. Western blotting analysis revealed that CGEF treatment upregulated the expression of Synaptophysin, Postsynaptic density 95 proteins, while also activating the brain-derived neurotrophic factor-Tropomyosin receptor kinase B pathway. These findings suggest that CGEF has substantial potential for development as an aerospace health product to improve memory decline associated with spaceflight. Show less

This study investigated the neuroprotective effects and mechanisms of cycloastragenol (CAG) on oxidative stress and neurological function in cerebral ischemia-reperfusion injury (CIRI) and oxygen-glucose deprivation/reoxygenation (OGD/R) models. In vivo, rats were given oral CAG daily for 28 days before CIRI induction. Cerebral infarction and hippocampal injury were assessed using TTC, Nissl, and HE staining. Neurological scores, morris water maze, grip strength tests, and brain water content were used to evaluate functional outcomes. Oxidative stress was determined by biochemical assays, DHE staining, and transmission electron microscopy, while Western blotting was performed to measure neuroprotective proteins. In vitro, primary neurons were treated with CAG and subjected to OGD/R. Cell viability was tested by CCK-8 assay, apoptosis and mitochondrial membrane potential were analyzed by flow cytometry, ROS levels were quantified, and MDA, SOD, and GSH were measured biochemically. Western blot further evaluated BDNF and NeuN expression to confirm in vivo findings. In vivo, CAG reduced infarct volume and edema, improved neurological deficits, preserved the structural integrity of neurons in the hippocampal CA1 region. CAG also promoted motor function recovery, markedly reduced MDA levels, increased SOD and GSH activity, and upregulated BDNF and NeuN expression. In vitro, CAG enhanced cell viability in the OGD/R model, reduced apoptosis, restored mitochondrial membrane potential, and significantly suppressed oxidative stress induced by ischemia-reperfusion. CAG effectively alleviated injury caused by cerebral and cellular ischemia-reperfusion by maintaining redox homeostasis, inhibiting oxidative stress, and promoting the expression of neuroprotective proteins, demonstrating promising neuroprotective potential. Show less

Obesity is closely associated with cognitive dysfunction, and markedly increases the risk of developing neurodegenerative diseases. Currently, obesity-related cognitive impairment lacks effective therapeutic interventions. Shenling Baizhu Powder (SLBZ) is a classical formula used to strengthen the spleen and promote the ascent of clear qi in traditional Chinese medicine (TCM). According to the TCM, this formula has great potential for the treatment of obesity-related cognitive impairment. However, research on SLBZ has focused primarily on its gastrointestinal effects, leaving its neurocognitive mechanisms largely unexplored. This study aimed to elucidate the therapeutic mechanisms of SLBZ in obesity-related cognitive impairment. Obese mice were obtained by subjecting male mice to a 16-week high-fat diet (HFD, 60 kcal % fat). During the final four weeks of the study, a SLBZ decoction (10 and 20 g/kg/day) was administered orally. The mice were then subjected to two behavioral tests and a glucose tolerance test. To evaluate the therapeutic effects of HFD on metabolic dysregulation, neuroinflammation, and intestinal barrier impairment, a range of analytical techniques, including biochemical analysis, immunofluorescence, RT-qPCR, and Western blotting, were used. Subsequently, 16S rRNA gene sequencing and metabolomic profiling were used to detect changes in the gut microbes and metabolite levels. Finally, fecal microbiota transplantation was performed to assess the functional link between SLBZ remodeling of the gut microbiota, metabolic alterations, and hippocampal cognitive function. Our study demonstrated that HFD-fed mice developed significant cognitive impairment, supporting the notion that obesity adversely affects cognitive function. In the Morris water maze and open-field tests, SLBZ administration effectively ameliorated HFD-induced cognitive dysfunction. This improvement was accompanied by the restoration of the hippocampal synaptic ultrastructure and the recovery of the key synaptic proteins BDNF and PSD95. In agreement with this, SLBZ suppressed microglial activation and associated neuroinflammatory responses in HFD-fed mice. In the colon, SLBZ administration markedly alleviated HFD-induced gut barrier impairment, as evidenced by increased colonic mucus thickness and elevated expression of tight junction proteins, ZO-1, Occludin, and Claudin-1. Furthermore, SLBZ reduced endotoxin translocation and downregulated the expression of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6. Notably, HFD-induced gut microbiota dysbiosis was remodeled by the SLBZ treatment, which was characterized by an increased capacity for microbial vitamin B6 synthesis. SLBZ increased the serum levels of vitamin B6 in HFD-fed mice. Intriguingly, fecal microbiota transplantation from SLBZ-treated HFD-fed mice facilitated the amelioration of cognitive deficits, including superior performance in behavioral tests and synaptic repair in the hippocampus compared to recipients of HFD-microbiota. Our findings highlight that SLBZ is a promising therapeutic agent mitigating obesity-related cognitive impairment via the "gut microbiota-vitamin B6-neuroprotection" axis. Show less

With the rapid progression of global population aging, the incidence of cognitive dysfunction-related disorders is steadily increasing. In recent years, growing attention has been directed toward the interaction between the gut microbiota and the central nervous system (CNS). The gut-brain axis (GBA), as a bidirectional communication pathway, plays an increasingly recognized role in regulating cognitive functions. Ganoderma lucidum polysaccharides (GLP), a traditional medicinal and edible substance, can regulate gut microbiota homeostasis and short-chain fatty acid (SCFAs) levels through the GBA. GLP reduces the Firmicutes/Bacteroidetes ratio, significantly increases the abundance of Lactobacillus, and further suppresses oxidative stress and inflammatory responses by controlling microglial overactivation and neuroinflammation, thereby enhancing the expression of synapse-associated proteins and brain-derived neurotrophic factor (BDNF). Consequently, GLP shows potential for improving cognitive dysfunction. This review systematically summarizes the bioactivities of GLP, explores the neurodegenerative mechanisms of aging, and proposes the possibility that GLP mitigates aging-induced inflammation and improves cognitive function via modulation of the gut microbiota. Show less