Search Results (1,985)

Background: Mild cognitive impairment (MCI) represents an intermediate state between normal cognitive ageing and dementia. Given the increasing dementia burden in the country, there is a critical need for early detection through the assessment of MCI. However, studies that comprehensively examined the associations between micronutrients, neuronal markers, and cognitive impairment are scarce. Methods: A community-based cross-sectional study was conducted among 184 adults aged 55–85 years in Hyderabad between January 2024 and March 2025. Sociodemographic, anthropometric, biochemical, nutritional, and neuronal biomarkers were estimated. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA) tool. Results: The study reported an MCI prevalence of 36.4% among older adults, significantly associated with higher HbA1c and systolic blood pressure, and elevated neuronal markers such as β-Amyloid, T tau, and Nfl. Vitamin D, B1, B2, B6, and B9 levels were significantly lower in the MCI group, with a higher burden of deficiency. Higher vitamin levels were correlated with better MoCA scores and a lower predicted probability of MCI, especially vitamins D and B6. In particular, B2 and B6 have shown associations with BDNF, tau, and Nfl markers. Conclusions: Lower levels of circulatory vitamins were significantly associated with a higher probability of MCI. Also, neuronal biomarkers were significantly associated with micronutrient deficiencies. These findings suggest that micronutrient deficiencies may be associated with MCI in older adults, highlighting the potential importance of maintaining adequate micronutrient status to support healthy cognitive aging and possibly reduce the risk of dementia. However, given the cross-sectional design of the present study, causal relationships cannot be established. Future longitudinal studies are warranted to validate these associations and further clarify the temporal relationship between micronutrient status and cognitive decline. Full article

Chronic stress is increasingly recognized as a major contributor to Alzheimer’s disease (AD)-related neurodegeneration through mechanisms involving neuroinflammation, oxidative stress, mitochondrial dysfunction, excitotoxicity, and amyloidogenic processing. Here, we investigated the neuroprotective effects of Sesamum indicum whole paste extract (SIPE) using 2D neuron–astrocyte-like cell (ALC) co-cultures and 3D neuron–ALC spheroids exposed to a TNF-α/glutamate/cortisol (TGC) chronic stress paradigm. TGC exposure induced mitochondrial dysfunction, mitochondrial superoxide generation, astrocytic reactivity, NF-κB activation, reduced pro-BDNF expression, intracellular and extracellular Aβ42 accumulation, Tau phosphorylation, and caspase-3 activation, reproducing key hallmarks associated with chronic stress-related neurodegeneration. Among sesame-derived preparations evaluated, SIPE exhibited the strongest neuroprotective effects, preserving mitochondrial membrane potential, reducing oxidative stress, preventing neuronal loss, attenuating gliosis, and suppressing inflammatory, amyloidogenic, and apoptotic signaling. These effects were consistently reproduced in 3D spheroids. Phytochemical analysis revealed that SIPE contained the highest enrichment of sesamin, representing approximately 25% of the detected relative composition. Molecular docking analyses demonstrated favorable sesamin binding affinity toward TNF-α, DJ-1, Aβ42, and caspase-3. Collectively, these findings identify SIPE as a promising multitarget neuroprotective strategy against chronic stress-associated AD-related pathology. Full article

Magnesium is an essential mineral involved in numerous physiological and neurobiological processes. However, the biological effects of distinct Mg forms remain insufficiently characterized. This study compared the systemic and neurobiological effects of a multi-form Mg supplement (Magnesium Breakthrough™, Mg BT™, Reno, NV, USA) with commonly used single-form Mg compounds in a rat model. Sixty-day-old male Wistar rats were assigned to a control group or to groups receiving Mg BT™ or individual Mg compounds (oxide, citrate or glycinate). Treatments were administered by gastric gavage for 30 days at 50 mg/kg/day of elemental Mg. A comprehensive panel of endpoints was evaluated, including Mg distribution in biological fluids and tissues, metabolic markers, glucose tolerance, synaptic protein expression (synaptophysin, PSD95, phospho-PSD95, drebrin), cortical gene expression (NR2B, BDNF), behavioral outcomes, and liver and kidney histology. Magnesium from the multi-form supplement increased serum Mg without affecting glucose homeostasis and modulated proteins involved in synaptic plasticity, accompanied by mild anxiolytic-like effects without changes in locomotion. No adverse histological alterations were observed, while preserved renal CLDN-19 expression indicated maintained tubular integrity. These findings suggest that supplementation with the multi-form Mg BT™ supplement influences multiple evaluated biological domains, including systemic, behavioral and molecular parameters, with effects comparable to those observed with individual magnesium compounds under the experimental conditions applied. Full article

Ziziphi Spinosae Semen (ZSS) is a traditional East Asian sedative–hypnotic herb with over 2000 years of clinical application. Spinosin (SPI), a characteristic flavone-C-glycoside, is the official quality marker and principal bioactive constituent of ZSS. Despite extensive research on SPI in recent years, a timely, comprehensive review integrating its pharmacological mechanisms, pharmacokinetic barriers, and translational strategies remains absent. Herein, a systematic literature search was conducted up to 31 May 2026, and we synthesize all available evidence on SPI’s chemical properties, natural sources, pharmacology, pharmacokinetics, toxicology, structural derivatives, and advanced drug delivery systems. Our analysis reveals that SPI exerts broad-spectrum pharmacological activities via multi-target modulation of serotonergic/GABAergic neurotransmission, the ERK/CREB/BDNF axis, and the Nrf2/HO-1 pathway. However, its clinical translation is severely hindered by extremely low oral bioavailability (<1%) and limited blood–brain barrier penetration due to poor aqueous solubility and P-glycoprotein-mediated efflux. Novel formulations have achieved up to 5-fold enhancement in oral bioavailability in preclinical models. While toxicological studies support a favorable safety profile, long-term toxicity and human pharmacokinetic data are lacking. This review critically discusses key translational bottlenecks and proposes evidence-based future directions to advance SPI as a natural neurotherapeutic agent. Full article

Residential greenness has been consistently associated with multiple health benefits; however, the underlying molecular mechanisms remain insufficiently understood. DNA methylation-based epigenetic clocks have emerged as robust biomarkers of biological aging and provide a valuable framework for investigating environmental influences on aging processes. This systematic review synthesizes current human evidence linking greenspace exposure to epigenetic age acceleration and DNA methylation changes. Following PRISMA 2020 guidelines, we searched Scopus and Web of Science databases (inception to May 2026). Studies were eligible if they assessed quantitative indicators of greenspace exposure and DNA methylation-based aging biomarkers in human populations. Out of 97 identified records, 14 studies met the inclusion criteria. Higher levels of greenspace exposure were consistently associated with a deceleration of GrimAge acceleration, with effect sizes ranging from 1.0 to 1.6 years per interquartile range increase in greenness. At the molecular level, greenspace-associated differentially methylated regions (DMRs) were consistently enriched in genes involved in neurodevelopment (HTR2A, BDNF, SLC6A3, SDK1), immune regulation (HLA-DRB5, IL6), stress response (NR3C1), and extracellular matrix remodeling (ADAMTS2). Overall, greenspace exposure is associated with slower epigenetic aging and differential DNA methylation across key biological pathways. These findings support the concept of greenspace as an epigenomic resilience factor and highlight its potential role in modulating molecular mechanisms of aging. Full article

Brain-derived neurotrophic factor (BDNF) is a key mediator of central sensitization and chronic pain through activation of TrkB receptors. Although the Pannexin 1 (Panx1) channel has been implicated in chronic pain, its involvement in BDNF-TrkB signaling remains unclear. Here, we investigated the functional relationship between TrkB activation and Panx1 using a BDNF-induced pain model in rats. Animals received a single intrathecal administration of BDNF, and mechanical nociception was assessed using the Randall–Selitto test. Behavioral analyses were combined with pharmacological interventions, Western blotting, confocal microscopy, YOPRO-1 uptake assays, and ATP quantification in spinal cord tissue. Intrathecal BDNF induced a robust mechanical hyperalgesia that persisted for up to 10 days. Blockade of Panx1 with 10Panx significantly attenuated BDNF-induced hyperalgesia. BDNF increased Src416 phosphorylation, Panx1 phosphorylation, and YOPRO-1 uptake in dorsal horn neurons, indicating enhanced channel activation. These effects were prevented by the TrkB antagonist ANA12, demonstrating that Panx1 acts downstream of BDNF-TrkB signaling. Inhibition of Src-family kinases with PP2 reduced both hyperalgesia and Panx1 activation, supporting a TrkB-Src-Panx1 signaling cascade. Furthermore, BDNF enhanced ATP release from spinal cord slices, an effect abolished by ANA12, PP2, and 10Panx. Together, these findings identify Panx1 as a downstream effector engaged by BDNF-TrkB signaling during the onset of mechanical hyperalgesia. While persistent TrkB activation appears to be required for the prolonged nociceptive state, the Src family kinase-Panx1 pathway contributes primarily to the early phase of BDNF-induced sensitization. Full article

Major depressive disorder (MDD) has been linked to oxidative stress, mitochondrial dysfunction, and impaired neuronal plasticity, but the reproducibility of related transcriptomic alterations across postmortem brain cohorts remains uncertain. We performed a targeted cross-platform analysis of a prespecified 14-gene panel spanning antioxidant defense, mitochondrial-redox regulation, cellular stress responses, neurotrophic signaling, synaptic plasticity, and polyamine metabolism across seven postmortem dorsolateral prefrontal cortex cohorts comprising 146 MDD cases and 179 controls. Primary support required Fisher-combined evidence, Benjamini–Hochberg correction across the panel, and concordant MDD-minus-control direction across all available cohorts. NPTX2, EGR1, VGF, BDNF, and SAT1 met these criteria, with lower expression in MDD. The same five-gene pattern was supported by weighted signed Stouffer analysis, one-stage generalized least-squares models, random-effects meta-analysis, and 200,000 disease-label permutations; none produced at least five genes meeting the complete primary-support criterion (empirical p = 5.0 × 10⁻⁶). The most robust cross-cohort finding was a convergent lower-expression pattern across genes supporting redox-linked stress adaptation, polyamine homeostasis, neurotrophic signaling, activity-dependent transcription, and synaptic plasticity. This pattern suggests impaired molecular capacity for neuronal stress resilience and adaptive plasticity in MDD. Full article

Encapsulation of resveratrol (RVT), a natural polyphenol, in mixed Pluronic F127/P123 micelles (mRVT) has enhanced its pharmacological efficacy in experimental dementia models. The aim of this study was to evaluate neurochemical and behavioral parameters of mRVT treatment in healthy subjects. For this purpose, pure RVT and mRVT (both at 10 mg/kg i.p.) were applied for 9 consecutive days in healthy male Wistar rats. Memory performance was assessed using the novel object recognition and passive avoidance tests. Neurotransmitter levels, neurotrophic and transcription factors, and oxidative stress markers were quantified in the cortex and hippocampus using enzyme-linked immunosorbent assay kits. Our results showed that neither treatment altered locomotor activity or short-term memory performance. Both RVT and mRVT treatments reduced hippocampal acetylcholinesterase activity to a similar extent and elevated acetylcholine levels in the cortex and hippocampus, with mRVT producing significantly more pronounced effect in the hippocampus. Compared to pure RVT, mRVT elicited a greater increase in noradrenaline and serotonin levels in both brain regions and comparably upregulated BDNF and pCREB protein levels in the cortex. Furthermore, mRVT uniquely reduced cortical lipid peroxidation—an effect absent with pure RVT treatment. These findings demonstrate that micellar encapsulation substantially amplifies the neurochemical efficacy of resveratrol under physiological conditions without adverse behavioral effects. Full article

Background/Objectives: Stroke remains a leading global cause of death and disability, resulting from acute focal injury to the central nervous system. The brain-derived neurotrophic factor (BDNF) gene has been extensively investigated for its involvement in post-stroke neuroplasticity and recovery. This systematic review examines the influence of the BDNF Val66Met (rs6265) variant on functional recovery during the acute and early subacute phases of primary stroke. Methods: The review followed PRISMA guidelines and was registered in PROSPERO (CRD42024549967). Comprehensive literature searches were performed in PubMed, Web of Science, and the Virtual Health Library in December 2024 to identify observational and interventional studies involving adults with acute or subacute primary stroke that evaluated this polymorphism. Results: Of 475 records identified, 11 studies met the inclusion criteria. Sample sizes ranged from 14 to 829 participants, with follow-up intervals ranging from 2 days to 3 months post-stroke. All studies included ischemic stroke, and seven also included hemorrhagic stroke cases. Outcomes assessed were motor recovery, cortical excitability, swallowing, and language function. Overall, most studies reported poorer recovery among Met allele carriers (Val/Met or Met/Met), particularly in motor outcomes. Evidence for cortical excitability and swallowing also suggested unfavorable effects, while language outcomes were inconclusive. Methodological heterogeneity contributed to inconsistent findings. Conclusions: The Met carriers were the most prevalent and frequently associated with poorer post-stroke outcomes, though results varied. These findings underscore the complex interplay between genetics and post-stroke recovery and indicate the need for more robust, standardized research across diverse populations. Full article

Distinguishing seizures from other causes of transient loss of consciousness in the emergency department (ED) is challenging. This PRISMA-guided systematic review evaluated serum brain injury biomarkers for the acute diagnosis of seizures in adults. We searched PubMed and Web of Science for studies published between 2015 and 2025 and included 14 studies in which blood sampling occurred shortly after the event, reflecting the ED diagnostic window. Given the heterogeneity across studies, the overall certainty of the evidence was low. Neuron-specific enolase (NSE) and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) were consistently elevated after epileptic seizures compared to healthy controls. NSE effectively differentiated seizures from syncope, while UCH-L1 and glial fibrillary acidic protein (GFAP) distinguished epileptic from psychogenic non-epileptic seizures (PNESs). Neurofilament light chain (NfL) remained stable after a single seizure but increased markedly in status epilepticus (SE). S100B and BDNF results were inconsistent. Although no single biomarker serves as a standalone test, NSE and UCH-L1 are promising complementary diagnostic tools for identifying epileptic seizures in adults. Furthermore, NfL is a strong candidate marker for SE, reflecting neuroaxonal injury. Larger prospective, standardized studies are needed before routine ED implementation. Full article

Background/Objectives: This exploratory comparative cross-sectional observational study investigated brain fog symptoms, cognitive function, sleep quality, quality of life, and selected serum biomarkers related to inflammation and neurocognitive function in newly diagnosed patients with celiac disease (ND-CeD), patients with CeD on a gluten-free diet (GFD-CeD), and controls. Methods: A total of 62 participants were included: ND-CeD patients (n = 18), GFD-CeD patients (n = 17), and healthy controls (n = 27) with no statistically significant differences in age or sex distribution across groups. Brain fog symptoms and severity, cognitive function, sleep quality, and quality of life were assessed using the Brain Fog Scale (BFS), Brain Fog Severity Score (BFSS), Montreal Cognitive Assessment (MoCA), Single-Item Sleep Quality Scale (SQS), and World Health Organization Quality of Life Questionnaire-Brief Form-TR (WHOQOL-BREF-TR), respectively. Serum BDNF, S100B, TLR4, IL-6, and nitric oxide (NO) levels were measured by ELISA. Results: ND-CeD patients had higher BFSs and BFSSs and lower MoCA, SQS, and WHOQOL-BREF-TR scores than healthy controls (p < 0.05). GFD-CeD patients showed numerically intermediate or more favorable scores than ND-CeD patients in several outcomes; however, most differences from controls were not statistically significant. Compared with ND-CeD patients, GFD-CeD patients had higher WHOQOL-BREF-TR General Health, Psychological Health, and Social Relationships scores (p < 0.05). In exploratory within-group analyses, after correction for multiple comparisons, higher BFS scores were associated with poorer psychological health and lower MoCA scores, and higher MoCA scores were associated with better psychological and physical health domains, particularly in the ND-CeD group. In the adjusted regression model, older age, income status, and newly diagnosed disease status were independently associated with MoCA scores. No statistically detectable between-group differences were observed in serum IL-6, NO, BDNF, S100B, or TLR4 levels. Conclusions: These preliminary findings suggest that brain fog symptoms, cognitive performance, sleep quality, and quality of life may deserve greater attention at diagnosis and during follow-up in celiac disease. Although GFD-CeD patients showed more favorable scores in some outcomes, these cross-sectional differences should not be interpreted as treatment-related improvement. Larger longitudinal studies with objective assessment of gluten-free diet adherence, disease activity, micronutrient status, sleep quality, and gut–brain axis-related biomarkers are needed to confirm these findings. Full article

Background and Objectives: Cornerstone therapies for metastatic prostate cancer include androgen deprivation and androgen receptor pathway inhibition, but cognitive impairment is a recognized, life-altering potential adverse effect of this treatment. Abiraterone acetate (AA), an androgen receptor pathway and CYP17A1 inhibitor, suppresses androgen synthesis and may contribute to cognitive changes. This cell culture-based study uses the BE(2)M17 human male neuroblastoma model to investigate AA-induced alterations in gene and protein expression that may underlie cognitive decline, laying the foundation for a mechanistic investigation aimed at identifying molecular targets to mitigate cognitive impairment in men with prostate cancer receiving androgen-directed therapies. Materials and Methods: BE(2)M17 cells were pretreated for 12 h with dihydrotestosterone (DHT; 5 nM) or vehicle control, then exposed to AA (0, 5, 10 µM, 24 h). RNA and protein were analyzed by qRT-PCR and Western blot for markers of amyloid processing, neuronal health, and mitochondrial function. Results: AA significantly altered multiple neurobiological markers. BACE1 mRNA increased in DHT + 10 µM AA compared to control and DHT alone (p = 0.0416 and p = 0.0118). However, BACE1 protein decreased in 10 µM AA + DHT versus DHT alone (p = 0.0132). Immunoblot revealed reduced amyloid precursor protein (APP) in 10 µM AA versus control (p = 0.0057) and 10 µM versus 5 µM (p = 0.0263). APP was reduced in 10 µM AA + DHT versus control (p = 0.0015) and versus DHT alone (p = 0.0467). LRP1 and BDNF were significantly reduced with 10 µM AA versus 5 µM AA (p = 0.0092 and p = 0.0081), while synaptophysin decreased in 10 µM AA + DHT versus DHT alone (p = 0.0049). BDNF also declined in 10 µM AA + DHT compared to 5 µM AA + DHT (p = 0.0301). PGC1α mRNA increased in AA + DHT versus DHT alone (p = 0.0332). MitoTracker analysis showed reduced fluorescence with 5 µM AA alone but increased fluorescence with 5 µM AA + DHT relative to control and DHT (p = 0.0019; p < 0.0001), while 10 µM AA + DHT reduced fluorescence compared to 5 µM AA + DHT (p = 0.0003). Conclusions: AA, alone or combined with DHT, disrupts key pathways involved in neuronal health, amyloid processing, and mitochondrial function. These findings suggest a potential mechanistic link between AA treatment and cognitive impairment. Full article

Background/Objectives: Serum brain-derived neurotrophic factor (BDNF) is linked to post-stroke neuroplasticity, but its temporal dynamics and clinical relevance during early rehabilitation remain unclear. We investigated changes in serum mature BDNF, proBDNF, and matrix metalloproteinase-9 (MMP-9) during the early subacute phase of stroke and their associations with functional improvement under standardized inpatient rehabilitation. Methods: In this prospective observational study at a tertiary inpatient rehabilitation unit, 100 stroke patients were enrolled and 84 were analyzed. Serum biomarkers and clinical assessments—including the National Institutes of Health Stroke Scale (NIHSS), Korean Mini-Mental State Examination, Fugl-Meyer Assessment, and Berg Balance Scale—were obtained at baseline (T0) and after two weeks of rehabilitation (T1). Correlation and multivariable regression analyses examined relationships between biomarker changes and functional outcomes, adjusting for age, sex, time from onset, and BDNF genotype. Results: An increase in serum mature BDNF from T0 to T1 was significantly associated with NIHSS improvement (r = −0.273, p = 0.014), which persisted after multivariable adjustment (β = −0.737, p = 0.009). Changes in proBDNF and MMP-9 showed no significant associations. Conclusions: Greater individual increases in serum mature BDNF during early subacute rehabilitation were independently associated with greater reductions in stroke severity, whereas the group-level mean did not increase over time. Serum mature BDNF may serve as a time-sensitive, objective biomarker of neurobiological recovery, potentially supporting individualized rehabilitation strategies. Full article

Major depressive disorder (MDD) involves dysregulation of the hypothalamic–pituitary–adrenal axis, neuroinflammation, serotonergic dysfunction, and impaired neurotrophic signaling. Whether combining corticosterone (CORT) with chronic restraint stress (CRS) produces a more comprehensive depression-like phenotype than either model alone remains unexplored. Male C57BL/6N mice were assigned to four groups—Sham (n = 7), CORT (20 mg/kg s.c.; n = 7), CRS (3 h/day; n = 7), and CORT + CRS (C+C; n = 8)—and evaluated by behavioral tests, hippocampal qRT-PCR, Western blot, LC-MS/MS metabolomics, and immunohistochemistry. All experimental groups showed elevated immobility in tail suspension and forced swim tests without inter-group differences. Two-way ANOVA revealed a behavioral–molecular dissociation: FST immobility showed CORT and CRS main effects without a significant interaction, whereas hippocampal LC-MS/MS analytes exhibited strong CORT × CRS interactions. The C+C group showed the strongest 5-HT1A receptor (HTR1A) upregulation, the greatest reductions in Trk-b and DCX, and unique decreases in serum dopamine, glutamine, and adenosine. Representative Western blot densitometry indicated the largest p-ERK/ERK reduction in C+C (54%), while p-CREB/CREB was most suppressed in CRS (52%). BDNF and NeuN proteins were lowest in C+C (68% and 61% reductions). Combined CORT + CRS produces the most comprehensive depression-related molecular profile, integrating multiple pathological domains. Full article

Background: Depression-associated memory impairment is a clinically significant comorbidity that responds poorly to conventional antidepressants. Dihydromyricetin (DHM), a natural dihydroflavonoid, exhibits neuroprotective and antidepressant-like effects, but its impact on stress-induced memory deficits and the underlying mechanisms remain unclear. Methods: A chronic restraint stress (CRS) mouse model was employed. DHM was intraperitoneally administered daily (20 mg/kg bodyweight) for 8 consecutive days. Depression-like behavior and memory functions were assessed with the tail suspension test, the object recognition memory (ORM) task, and the Y-maze test. Network pharmacology, molecular docking, and molecular dynamics (MD) simulations were integrated to predict potential targets and associated signal pathways. Expression of hippocampal PKA, p-CREB, CREB, and BDNF was measured through Western blotting. Results: CRS significantly increased immobility time in the tail suspension test and impaired both recognition memory (ORM) and spatial working memory (Y-maze), without affecting locomotor activity. DHM treatment effectively reversed behavioral despair and memory deficits. Network pharmacology identified 47 intersecting targets between DHM and depression-related memory impairment, with CREB1, ESR1 and NOS1 as core hub nodes. KEGG enrichment particularly implicated the involvement of the cAMP signaling pathway and other signaling pathways, which are associated with depression and/or memory impairment. Molecular docking predicted strong binding affinities of DHM to CREB1 (−9.225 kcal/mol), NOS1 (−9.113 kcal/mol) and ESR1 (−7.903 kcal/mol). MD simulations confirmed the thermodynamic stability of DHM-ESR1 and DHM-NOS1 complexes. Western blot analysis demonstrated that DHM treatment significantly increased the levels of hippocampal PKA, p-CREB and BDNF, without altering total CREB expression in CRS mice. Conclusions: DHM alleviated CRS-induced depression-like behaviors and memory deficits, possibly through regulation of multiple signaling pathways, including the hippocampal PKA-CREB-BDNF signaling pathway. These findings highlight DHM as a promising natural therapeutic candidate for depression-associated cognitive impairment. Full article