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This study investigated an intranasal nose-to-brain delivery strategy to repurpose ondansetron (OND) for anxiety management using PLGA nanoparticles co-loaded with superparamagnetic iron oxide nanoparticles (SPIONs) and incorporated into a Carbopol 940 mucoadhesive gel. Nanoparticles were optimized using an I-optimal experimental design evaluating PLGA concentration and surfactant type. The optimized SPION/OND-PLGA nanoparticles showed a small particle size (141.547 ± 1.31 nm), narrow distribution (PDI = 0.235 ± 0.002), relatively high zeta potential (-34.307 ± 0.53 mV), and satisfactory encapsulation efficiency (42.09 ± 1.34%). The developed nanogel exhibited acceptable organoleptic properties, shear-thinning behavior, sustained drug release, and enhanced ex vivo nasal permeability, with OND permeation values of 996.96 ± 6.53 μg, 621.92 ± 7.54 μg, and 317.87 ± 2.88 μg per cm Show less

Alzheimer's disease (AD) is marked by progressive cognitive decline and memory loss. Emerging evidence underscores the role of long non-coding RNAs (lncRNAs), particularly nuclearenriched abundant transcript 1 (NEAT1), in AD pathogenesis. NEAT1, a pivotal lncRNA that regulates diverse cellular processes, shows dysregulated expression in AD and impairs neuronal survival. This review explores NEAT1's molecular mechanisms, biomarker potential, and therapeutic relevance. NEAT1 contributes to AD pathology by acting as a competitive endogenous RNA (ceRNA) that sequesters protective microRNAs, including miR-124 and miR-107, thereby dysregulating downstream targets. It facilitates PINK1 degradation and potentially drives mitochondrial dysfunction and neuronal injury. Elevated NEAT1 levels are associated with amyloid-beta accumulation, tau hyperphosphorylation, and NF-κB-mediated neuroinflammation. Preclinical studies suggest that modulating NEAT1 expression can alleviate AD‑like pathology, making NEAT1 a promising target for intervention. Increased plasma NEAT1 in patients indicates its value as a non-invasive early diagnostic biomarker. NEAT1 regulates multiple AD-related pathways, including IGF1R, TRAF2, BACE1, CREB/BDNF, and Nrf2/NQO1, and interacts with lncRNAs linked to metabolic and neurodegenerative diseases, such as XIST and KCNQ1OT1. By influencing amyloid processing, synaptic function, mitochondrial health, and inflammatory responses, NEAT1 emerges as a central regulator in AD. Targeting NEAT1 offers dual benefits: advancing precision diagnostics and enabling multi-pathway therapeutic approaches. This review underscores NEAT1's significance as both a biomarker and therapeutic target, providing insights for future strategies to mitigate the burden of AD. Show less

To evaluate the effectiveness of personalized moderate-intensity aerobic brisk walking intervention based on real-time feedback from wrist-worn photoplethysmography (PPG) in improving mild-to-moderate depressive symptoms. Using an N-of-1 randomized crossover trial design, 33 patients with mild-to-moderate depression (PHQ-9 scores 10-19) completed a 6-week trial consisting of three personalized PPG feedback periods (Period A) and three standardized exercise prescription periods (Period B), each lasting 7 days with 2-day washout periods between phases. The personalized group dynamically adjusted exercise intensity based on real-time heart rate variability (HRV) monitoring (40-59% heart rate reserve), while the standardized group adopted fixed intensity parameters (walking speed 5-6 km/h). The primary outcome was change in PHQ-9 depression scale score, with secondary outcomes including heart rate variability, 6-minute walking distance, serum BDNF, and inflammatory cytokine levels. Compared to standardized prescription, personalized intervention additionally reduced PHQ-9 scores by 2.8 points (95% CI: 1.9-3.7, P < 0.001) with an effect size of 0.73; HRV RMSSD increased by 8.7 ms versus 4.3 ms (P < 0.001), and HRV improvement predicted subsequent symptom relief (β = -0.42); exercise adherence rate in the personalized group was 87.3% compared to 82.1% in the standardized group (P = 0.029); BDNF increased by 28.4% versus 18.7% (P = 0.018); participants with baseline HRV < 25 ms derived greater benefit from personalized intervention (additional improvement of 3.8 points versus 2.1 points, P = 0.008). Both intervention conditions produced clinically meaningful within-group PHQ-9 improvements, though the between-group difference of 2.8 points did not reach the minimal clinically important difference (MCID) threshold of 5 points. Both personalized and standardized moderate-intensity walking interventions substantially improved mild-to-moderate depressive symptoms. Personalized exercise intervention based on real-time PPG monitoring provided statistically significant additional benefits over standardized prescriptions, with advantages in physiological adaptation, exercise adherence, and biomarker improvement. The incremental benefit of personalized monitoring was most pronounced among individuals with impaired autonomic function, providing evidence for precision exercise medicine approaches in depression management. Show less

Patients with type 2 diabetes mellitus (T2DM) face a significantly elevated risk of developing cognitive impairment (CI), which has been recognized as an independent risk factor for dementia. Current glucose-lowering medications are limited by poor central nervous system penetration, delayed intervention, and single-target approaches, highlighting an urgent need for safe and effective complementary strategies. Exercise therapy, leveraging its advantage in "metabolic-neural bidirectional regulation," demonstrates considerable potential in ameliorating T2DM-related CI. This article systematically reviews basic and clinical research from the past decade, revealing that: ① Aerobic exercise, Tai Chi, and dual-task training can all significantly improve global cognitive scores (MoCA, MMSE), with effect sizes increasing over longer intervention periods; ② Tai Chi yields the most comprehensive benefits in memory, executive function, and balance-fall prevention, with an adherence rate as high as 79.6%; ③ Exercise exerts its effects through multi-target mechanisms, including upregulation of BDNF/IGF-1, suppression of IL-6/TNF-α, restoration of blood-brain barrier integrity, remodeling of the gut microbiota-butyrate-brain axis, and enhancement of mitophagy. Future research should focus on large-sample, multi-center, long-term follow-up studies to establish personalized exercise prescriptions based on genetic-metabolic-microbiota profiles. Integrating digital health technologies will enable remote monitoring and precise implementation, thereby providing an evidence-based foundation for constructing an integrated "metabolic-cognitive" prevention and treatment model. Show less

Depression is increasingly recognized as a disorder involving immune brain interactions beyond classical monoaminergic dysfunction. Among immune components, T cells have emerged as key regulators linking peripheral immune dysregulation to central neuroinflammation and impaired neuroplasticity. Accumulating clinical and preclinical evidence indicates that alterations in T cell subsets, including regulatory T cells, Th1 cells, and Th17 cells, contribute to depressive pathophysiology through coordinated effects on blood-brain barrier permeability, glial activation, cytokine signaling, and neurotrophic support. This review synthesizes current evidence on the mechanisms by which T cells migrate into the central nervous system and modulate depressive behaviors. Particular emphasis is placed on the T cell regulation of brain derived neurotrophic factor signaling, and a role for T cell derived extracellular vesicles as modulators of immune neural communication and neuroplasticity. Finally, we discuss the therapeutic implications of targeting T cells in depression, including modulation of T cell subset balance, cytokine-based interventions, microbiota immune regulation, and inhibition of pathogenic T cell trafficking into the brain. Together, these findings position T cells as central orchestrators of immune neural crosstalk and promising targets for mechanism informed immunotherapies in depression. Show less

Following their domestication, chickens were translocated around the world to novel environments. Through a combination of natural and artificial selection, chickens adapted to these local conditions, creating significant genetic diversity across populations worldwide. Studying this diversity in the context of local environmental conditions may offer insights into mechanisms of adaptation to environmental stressors. In this study, we analyzed genomic data from the Chicken Genomic Diversity Consortium, applying multiple statistical approaches, including fixation index (F The online version contains supplementary material available at 10.1038/s41598-026-41813-8. Show less

Diabetic neuropathic pain (DNP) is a common and debilitating complication of diabetes that profoundly reduces patient quality of life. Despite extensive research, current treatments remain largely symptomatic, with limited efficacy and significant side effects. Microglia act as pivotal mediators of DNP through RAGE/TLR4/NLRP3-driven IL-1β and BDNF release that amplifies spinal pain signaling. Microglia respond directly to hyperglycemia-induced cues such as advanced glycation end-products, reactive oxygen species, ATP, and pro-inflammatory signals, becoming activated and releasing cytokines, chemokines, and neuromodulators including BDNF that amplify spinal pain signaling. This review synthesizes recent insights into the molecular triggers of microglial activation such as RAGE, TLRs, purinergic receptors, and inflammasomes and the downstream intracellular pathways including NF-κB, MAPK, PI3K/Akt, and BDNF-TrkB that drive neuroinflammation. We further examine neuroimmune crosstalk, including bidirectional microglia-neuron and microglia-astrocyte signaling, which sustains central sensitization. Translational studies linking these pathways to human DNP are evaluated, along with novel technologies that illuminate microglial phenotypes. Emerging therapeutic strategies focus on inhibition of these pathways, including RAGE antagonists and purinergic receptor blockers. However, a critical translational gap persists owing to insufficient human validation of microglial biomarkers and the limited fidelity of current animal models. By integrating basic and clinical findings, we underscore the promise of microglia-focused interventions to complement traditional analgesics and ultimately improve outcomes in DNP patients. Show less

Depressive disorders represent a major contributor to the global burden of disease, with persistently rising prevalence rates posing significant challenges to individual quality of life and public health systems. Existing first-line medications such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) typically require 2-4 weeks to take effect, with complete remission rates below 60%. Approximately one-third of patients discontinue treatment within 90 days due to adverse reactions including gastrointestinal discomfort, weight changes, or sexual dysfunction. Consequently, exploring interventions with faster onset and improved tolerability holds significant clinical importance. A systematic search of seven databases-PubMed, Embase, Web of Science, Cochrane CENTRAL, CNKI, AMED, and Scopus-identified randomised controlled trials (RCTs) and mechanism studies published between 2010 and 2025. A qualitative synthesis method analysed clinical efficacy and adverse reactions, integrating evidence from metabolomics, epigenetics, and network pharmacology. Botanical drug identification was performed in accordance with ConPhYMP guidelines, with all species names validated taxonomically against the Medicinal Plant Names Services (MPNS) and Plants of the World Online (POWO) databases. Twenty-one RCTs (n = 2,766) and three mechanistic studies were included. Findings indicated that Xiaoyao Formula Existing evidence preliminarily supports potential advantages of Xiaoyao Formula in treating depressive disorders, including possibly earlier onset of action, good tolerability, and potential additional benefits in female subgroups. However, given limitations such as small sample sizes, short intervention durations (6-12 weeks), and predominantly combination therapy rather than monotherapy comparisons, these conclusions should be regarded as suggestive or indicative findings rather than definitive efficacy. Long-term efficacy and generalisability across populations require further validation. Future studies should conduct multicentre, large-sample clinical trials with ≥24-week follow-up, incorporating wearable digital phenotyping technologies to confirm its application value in precision psychiatry. Show less

Post-stroke depression (PSD) is a common and clinically significant stroke complication associated with impaired rehabilitation potential and increased mortality risk. The prevalence of PSD varies from 25% to 59% depending on the duration of observation, reaching a peak in the first years after a stroke. The pathogenesis of PSD results from a complex interplay of biological and psychological factors that extends well beyond monoamine deficiency. Damage to monoaminergic pathways, neuroinflammation, hypothalamic-pituitary-adrenal axis dysfunction, decreased neuroplasticity (including BDNF deficiency), and impaired neural network integrity play a key role. The clinical presentation includes a complex of affective (apathy, anhedonia), cognitive (impaired executive functions), and dyssomnia disorders. While selective serotonin reuptake inhibitors remain the first choice for treatment of PSD, the current therapeutic approach requires targeting all pathogenesis links. A promising direction is the use of antidepressants with a complex mechanism of action, such as the original fluvoxamine, which combines serotonergic effects with anti-inflammatory and neuroprotective properties through sigma-1 receptor agonism. Optimizing PSD treatment is possible through a personalized approach that includes thorough screening and comprehensive correction of identified disorders. Show less

Orthodontic tooth movement (OTM) is a biomechanically driven process governed by dynamic cellular and molecular signaling interactions between neural and skeletal systems. This review synthesizes current evidence on neuron-bone cell crosstalk and the coordinated involvement of immune and vascular components in regulating alveolar bone remodeling during OTM. Key neural contributors include sensory neurons (nociceptors), autonomic neurons, central nervous system (CNS) circuits, and Schwann cells, which communicate with osteoblasts, osteoclasts, and periodontal ligament cells to modulate their proliferation, differentiation, and functional activity. These interactions are mediated by defined signaling pathways, including neuropeptide signaling (CGRP-CLR, SP-NK1, NGF-TrkA, BDNF-TrkB), axon guidance signaling (Sema3A-PlexinA/Nrp1), adrenergic signaling (β2-AR-dependent pathways), and intracellular cascades such as Rac1-β-catenin, RhoA/ROCK2, and Notch3. Sensory nerves function as primary initiators by releasing neuropeptides that promote osteoclastogenesis in pressure zones and osteogenesis in tension zones, while simultaneously shaping local immune responses and vascular remodeling. The autonomic nervous system exerts context-dependent regulation, with sympathetic signaling favoring bone resorption and parasympathetic pathways emerging as modulators of osteogenesis and neurovascular homeostasis. CNS circuits integrate sensory and autonomic inputs to coordinate OTM kinetics and pain perception. Together, these neuro-osteogenic signaling networks define mechanistic targets for improving orthodontic outcomes and pain management via neuromodulation. Show less

Electrical stimulation (ES) is emerging as a non-pharmacological neuromodulation strategy, but its direct impact on human dopaminergic neurons and its relationship to rapid-acting antidepressant mechanisms remain unclear. This study aimed to investigate whether brief biphasic low-frequency low-intensity (LF-LI) ES can induce structural and molecular plasticity in human induced pluripotent stem cell (iPSC)-derived mesencephalic dopaminergic neurons, identify the underlying signaling mechanisms, and evaluate its potential to rescue cortisol-induced impairments as in-vitro endocrine model of depression. iPSC-derived dopaminergic neurons were exposed to LF-LI ES using a custom culture-compatible stimulator, and structural plasticity was quantified three days later by computer-assisted morphometry. Pharmacological blockers, quantitative PCR and Western blot analyses were employed to assess calcium influx, brain-derived neurotrophic factor (BDNF)-TrkB-extracellular signal-regulated kinase (ERK)-mTOR signaling, and dopamine D3 auto-receptor roles in mediating LF-LI ES effects. A single 1h LF-LI ES session at 4 mA induced robust increases in maximal dendrite length, primary dendrite number, and soma area, comparable to 1 μM ketamine. LF-LI ES rapidly enhanced ERK and p70-S6K phosphorylation and required L-type voltage-gated calcium channels, TrkB and mTOR, as their inhibition prevented structural remodeling. LF-LI ES increased dopamine D3 auto-receptors mRNA, and its antagonism attenuated LF-LI ES-induced plasticity. In cortisol-treated neurons, LF-LI ES fully reversed dendritic hypotrophy and soma shrinkage. In conclusion, brief LF-LI ES elicits long-lasting, ketamine-like structural and molecular plasticity in human dopaminergic neurons and rescues stress hormone-induced impairments, supporting LF-LI ES-based neuromodulation approaches targeting dopaminergic circuits in major depressive disorder and treatment-resistant depression. Show less

To compare two 16-week high-load, velocity-intentional resistance training programs-elastic bands (HL-VIRT-EB) vs. water-based (HL-VIRT-AQ)-combined with creatine or placebo supplementation on neuroplasticity, oxidative stress, inflammation, strength, physical function, cognition, and quality of life in older adults. In a randomized controlled trial, 103 community-dwelling older adults (57 women, 46 men; 68.2 ± 4.6 y) were assigned to HL-VIRT-EB + Creatine, HL-VIRT-EB + Placebo, HL-VIRT-AQ + Creatine, HL-VIRT-AQ + Placebo, Control+Creatine, or Control+Placebo. Training was performed 3×/week (60 min). Creatine was consumed daily (3 g). Outcomes included brain-derived neurotrophic factor, F2-isoprostanes (F2-iso), glutathione peroxidase (GPx), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), isokinetic strength (knee/elbow, 60°·s Both training modalities produced significant improvements in neurocognitive biomarkers, oxidative/inflammatory profiles, strength, functional performance and quality of life (p < 0.05). HL-VIRT-AQ yielded greater reductions in F2-iso and TNF-α and larger gains in functional tests compared to HL-VIRT-EB (d = 0.12-1.18), which elicited superior upper-limb strength gains. Creatine provided additional benefits, increasing GPx, reducing IL-6/TNF-α and improving strength and function when combined with exercise modalities. Creatine alone reduced F2-iso and TNF-α and improved perceived health versus placebo. High-load, velocity-intentional resistance training-on land or in water-effectively improves neurocognition, oxidative balance, inflammation, strength, function, and quality of life in older adults. Aquatic training is particularly effective for attenuating oxidative stress and inflammation. Creatine supplementation confers complementary, modality-specific benefits and supports their use in combination to high-speed resistance exercise to promote healthy aging. NCT06620666 (ClinicalTrials.gov). Show less

The progressive neurodegenerative disease known as Parkinson's Disease (PD) is represented by deficits in both motor and non-motor functions. Levodopa and dopamine agonists are examples of pharmaceutical treatments that mainly reduce symptoms without having any discernible neuroprotective effects. The potential of exercise-based physical therapy to improve neuroplasticity and slow disease progression has drawn increasing attention. To provide awareness of their complementary roles in enhancing outcomes for people with PD, this narrative review examines the combined neuroprotective effects of pharmaceutical medicines and physical therapy. The aim of the review was to evaluate the effects of both physical and pharmaceutical therapies in the management of Parkinson's disease to enhance motor recovery and retard disease progression. The evidence from previous research is compiled in this review, which focuses on preclinical and clinical trials examining the neuroprotective benefits of medication and exercise-based physical therapy. We searched databases such as PubMed, Scopus, Embase, the Cochrane Library, and Web of Science to identify relevant peer-reviewed articles. The review discusses therapeutic synergies, underlying mechanisms, and how these affect clinical practice. Aerobic, resistance, and balance training are examples of exercise-based physiotherapy that reduce oxidative stress, increase brain-derived neurotrophic factor (BDNF) levels, and promote neuroplasticity. These effects enhance the ability of pharmacological drugs to relieve symptoms. Research indicates that, compared to stand-alone treatments, combined therapies produce superior outcomes in motor function, non-motor symptom management, and overall quality of life. The review also highlights important mechanisms of interaction between various medicines, including neuroprotective signaling pathways and improved dopamine utilization. Combined therapy in Parkinson's disease enhances neuroprotection by boosting BDNF and other neurotrophic factors, reducing oxidative stress and inflammation, and promoting neurogenesis. Exercise and medications work synergistically to improve neuronal survival, cognition, and motor function. However, challenges include poor patient adherence, limited access to structured programs, limited clinical integration, and the need to tailor treatment to disease stage. A possible method for improving neuroprotection in PD is the combination of pharmaceutical therapies and exercise-based physical therapy. Further research is needed to optimize therapy regimens and develop individualized approaches to enhance patient outcomes and slow disease progression. This combined method offers a multifaceted and comprehensive approach to managing Parkinson's disease. Show less

Neurodegenerative and mental disorders impose significant global disease burdens and pose serious social and economic challenges. Physical exercise (PE) exerts beneficial effects on brain health, contributing to a reduction in the risk of Alzheimer's disease (AD), Parkinson's disease (PD), depression, anxiety, and post-traumatic stress disorder (PTSD). To understand these effects of PE, a variety of molecules released from various tissues in response to PE have been discovered, which are collectively called 'exerkines'. In particular, the skeletal muscle acts as an endocrine organ, secreting exerkines and is included in the category of myokines that facilitate direct or indirect crosstalk between the muscle and the brain. Although muscles actively interact with organs such as the liver, pancreas, and adipose tissue, the precise mechanisms of muscle-brain communication have yet to be fully elucidated. In the skeletal muscle, the types of exerkines secreted and their effects vary depending on the PE modality. Furthermore, these exerkines can cross the blood-brain barrier (BBB) to exert direct effects or act indirectly Show less

The increasing prevalence of dementia and age-related decline in cognitive function poses significant public health challenges. Brain Gym exercises and mind-body practices (MBPs), which are nonpharmacological interventions, enhance cognitive reserve and neuroplasticity through integrated breathing, meditative, and physical elements; however, in older adults with cognitive impairment, the evidence remains fragmented. Hence, this scoping review maps the evidence in older adults regarding the effectiveness of Brain Gym and MBPs for improving cognitive function, compares outcomes with conventional or no interventions, assesses feasibility and safety, and identifies research gaps while outlining recommendations. A comprehensive search of PubMed and ScienceDirect (January 2020 to December 2025) identified English-language, full-text original research on MBPs versus comparators in community-dwelling or institutionalized adults. Five reviewers screened records, extracted data on study characteristics, interventions, and findings, and appraised quality using the Mixed Methods Appraisal Tool. A narrative synthesis approach was utilized to present the results. Eleven high-quality studies (n = 19-585; 2020-2025), primarily randomized controlled trials (RCTs) conducted in community settings across Asia, the US, Mexico, and Indonesia, were included. MBPs improved global cognition, memory quotients, executive function, and attention compared with usual care, with mixed superiority over aerobic comparators; Brain Gym enhanced brain-derived neurotrophic factor (BDNF) levels and domain-specific scores. Feasibility was high (81%-100% adherence, 89%-97% retention, no serious adverse events). Neuroimaging revealed gray matter increases in temporal and frontal regions and reduced inflammation. Gaps included short follow-up periods, limited virtual delivery, underrepresentation of frail subgroups, and limited mechanistic depth. Thus, MBPs and Brain Gym demonstrate accessible and promising cognitive benefits via neuroplastic mechanisms, outperforming controls in feasibility and domain-specific gains. Multicenter, long-term studies with diverse, high-risk cohorts and hybrid modalities are essential to refine protocols, address equity, and support integration into geriatric care for dementia prevention. Show less

Neurodegenerative diseases present a significant challenge in modern medicine, largely due to the interplay of oxidative stress, apoptosis, and neuroinflammation. The development of advanced materials capable of simultaneously regulating multiple pathological processes is a critical unmet need. Here, we introduce ionizable pH-responsive lyotropic liquid crystalline nanocarriers as a promising self-assembled materials-based solution for neuroregeneration. We engineered non-lamellar polyunsaturated (DLin-MC3-DMA)-based lipid nanoassemblies with a unique combination of antioxidant, anti-apoptotic, and neurotrophic functionalities. By incorporating a multi-targeted phytochemical blend (quercetin, ginkgolides B and C, and kaempferol), the lipid-based nanomedicines effectively suppress inflammatory mediators (IL-1β, NF-κB, and JNK1/2) and stimulate endogenous antioxidant defenses via NRF2/ARE activation. The mechanistic involvement of the mTOR/AKT/BDNF/GSK3β pathway was examined to assess the in vitro therapeutic potential of the antioxidant‑loaded lipid nanoparticles (LNPs). The designed assemblies activate pro‑survival (p‑AKT/mTOR) and neurotrophic (BDNF) signaling pathways while preserving mitochondrial integrity in a cellular neurodegeneration model. The ionizable nature of DLin‑MC3‑DMA imparts pH‑responsiveness to the LNPs, driving a progressive enrichment of the inverted hexagonal (H Show less

Several lines of evidence suggest that genetic factors underlie variability in response to lithium, although pharmacogenetic studies, particularly in African populations, are limited. This study aimed to examine the genetic factors associated with lithium response among Ethiopian patients diagnosed with bipolar disorder (BD). This study was conducted at Amanuel Mental Specialized Hospital (AMSH) in Addis Ababa, Ethiopia, involving 101 patients diagnosed with BD and on lithium therapy for at least six months. Participants were selected from a larger cohort recruited for the Neuropsychiatric Genetics of African Populations - Psychosis, Ethiopia (NeuroGAP-P-E) project. The study investigated the association between lithium response and genetic polymorphisms of 22 genes with 53 SNPs implicated in lithium's mechanisms of action. Clinical response to lithium was assessed using the Alda scale, where those with total Alda > 7 were categorized as good responders (GR) and those with Alda < 7 as insufficient responders (IR). Genotyping was performed using PCR-free whole-genome sequencing. Among the participants, 32.5% were classified as GR, while 67.5% were IR. Significant associations were identified between lithium's response and specific SNPs. Notably, the BDNF rs6265 variant (Val166Met) showed stronger correlation, with the CC genotype being more frequent (p = 0.0001) in IR, while the rs2030324 A allele and AA genotype were more frequent in GR (p < 0.05). Variants in GSK-3β (rs334558) and dopamine receptor genes, such as DRD1 (rs4532) and DRD2 (rs1800497) also demonstrated significant associations with treatment outcomes (p < 0.05). However, after adjustment for multiple testing using false discovery rate (FDR), only polymorphisms within BDNF and DRD1 remain statistically significant. Multivariable analysis revealed that whilst AKT1_rs10138227 TT (p < 0.05) genotypes were positive predictors, BDNF_rs962339 GG, DRD2_rs1800497 AG/GG and GSK-3β_rs334558 AG were negative predictors of good response. The data collectively show that variants in BDNF, dopamine receptor genes, and the AKT1/GSK3B pathway were linked to lithium's response in BD. AKT1 rs10138227 TT genotypes predicted better response, while BDNF rs962339 GG, DRD2 rs1800497 AG/GG, and GSK-3β rs334558 AG were associated with poor outcomes. These findings highlight the role of genetic variations in predicting lithium's response. 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

This study aims to elucidate the pharmacological basis and antidepressant mechanisms of a combined extract from Eucommia ulmoides Oliv. And Gastrodia elata Bl. (Eucommia-Gastrodia extract), employing an integrated strategy that combines UHPLC-QTOF-MS analysis, network pharmacology, molecular docking, and in vivo validation. This research integrated computational approaches network pharmacology, molecular docking and in vivo experimental investigations. Initially, the active constituents of the EGE were identified through ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS). Potential targets related to depression were predicted using the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) and SwissADME. Protein-protein interaction (PPI) networks were constructed via the STRING database, followed by the development of a comprehensive "drug-active ingredient-target-disease" network. Functional annotation through Gene Ontology (GO) and pathway enrichment analysis based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) were conducted on the intersecting targets using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Molecular docking studies were erformed employing AutoDock software to validate the interactions. Finally, the antidepressant-like behavioral effects were evaluated in treated and non-treated corticosterone-induced mouse models using sucrose preference tests, forced swimming tests, open field tests, and tail suspension tests. The morphological impacts and molecular basis of disease on the hippocampal neurons were assessed using Hematoxylin and Eosin staining (HE) staining, Nissl staining, immunohistochemistry, and Western blot analysis to substantiate the identified through network pharmacology. Network pharmacology analysis revealed a complex interplay between identified active ingredients of Eucommia-Gastrodia extract and depression targets. From an initial pool of 131 active components, 34 identified as interacting with 233 shared depression related molecular targets. These targets were involved in 390 biological processes (BP), 60 cellular compounds (CC), 134 molecular functions (MF), and 148 KEGG-enriched signaling pathways. Molecular docking studies highlighted 20 principal compounds that bind to key targets such as AKT1, SRC, HIF-1, CREB, BDNF, and EPO. The Eucommia-Gastrodia extract alleviated depression like behaviors in a cortisol-induced mouse model, as indicated by increased sucrose preference and mobility time, etc. Additionally, the extract restored the levels of neurotransmitters 5-hydroxytryptamine (5-HT) and dopamine (DA), alleviated hippocampal neuronal damage, and increased the positive expression of EPO and BDNF in the hippocampus. Furthermore, treatment with the extract significantly upregulated the protein expression of HIF-1, EPO, EPOR, CREB, p-CREB, BDNF and p-TrkB, which were otherwise downregulated in cortisol-induced depressive mice. The results indicate that the Eucommia-Gastrodia extract containing bioactive compounds such as oxysophocarpine, aucubin, pinoresinol, leonurine, syringaresinol, formononetin, icaritin, casticin, and 6-gingerol mitigates cortisol-induced neurodegeneration and depressive-like behaviors. This effect is mediated through modulation of the of HIF-1α-EPO/cAMP-CREB-BDNF signaling pathways. Show less

Astroglia, often called as astrocytes, play a crucial role in protecting neurons and preserved the neurophysiological functions. Astrocytes' dysfunction contributes to numerous neurological disorders. Astrocytes are involved in the regulation of oxidative stress and inflammatory process within Central nervous system. Developments in specific transcriptomic and genomics have initiated the discovery of new mechanisms governing astrocyte during oxidative and inflammatory process. Despite the advancements in existing diagnostic and therapeutic methods like targeted ultrasound and NPs mediated administration, these methods still pose risks and have drawbacks. Aptamers, artificial single stranded oligonucleotides have the ability to specific target cells and exhibit strong binding affinity and enhance the administration of therapeutic agents. Research over the last few years has demonstrated that the ability to target specific molecules/intermediates such as reactive oxygen species, interleukins, tumor necrotic factor, vascular endothelial growth factor, brain-derived neurotrophic factor and penetrate the blood brain barrier makes aptamers ideal candidates for addressing the oxidative and inflammatory intermediaries within astrocytes. Present review explores the emerging applications of aptamers in cytoprotection specially focus on their potential to combat oxidative stress and inflammation in astrocytes. We also discuss the capability of aptamers as cell specific molecular probes for advancing tailored diagnostic and therapeutic interventions. Present article also addresses future directions and significant issues. Show less

Post-traumatic stress disorder (PTSD) is a debilitating neuropsychiatric condition triggered by severe trauma, characterised by dysregulated fear circuitry, hippocampal atrophy with impaired neurogenesis, chronic neuroinflammation, neuroendocrine dysregulation, and disrupted prefrontal-limbic connectivity. Existing treatments are largely symptomatic, failing to address underlying neurobiological deficits. Emerging regenerative approaches using human stem cells, particularly induced pluripotent stem cell-derived neural progenitor cells (iPSC-NPCs), human embryonic stem cells (hESCs), mesenchymal stem cells (MSCs), and their extracellular vesicles (EVs), offer mechanistic plausibility for neural repair via direct neuronal replacement, paracrine neurotrophic support (e.g., BDNF, GDNF, VEGF), immunomodulation (e.g., shifting microglia to anti-inflammatory phenotypes), and promotion of synaptic plasticity and epigenetic reprogramming. Preclinical evidence remains limited and largely indirect, with sparse PTSD-specific studies (e.g., one report of iPSC-NPC transplantation reducing fear behaviour and enhancing hippocampal BDNF/neuronal density in a rat model) supplemented by convergent data from adjacent CNS injury paradigms. MSC- and iPSC-derived EVs, enriched with regulatory miRNAs (e.g., miR-124, miR-21, miR-146a), emerge as a safer, cell-free alternative with strong immunomodulatory potential and greater translational feasibility. However, reproducibility is constrained by model variability, lack of independent replication, and absence of PTSD-focused clinical trials. Major challenges include tumorigenicity risks (especially for pluripotent-derived cells), immune rejection, epigenetic/genomic instability, manufacturing scalability, stringent regulatory requirements, and elevated ethical thresholds for invasive therapies in a non-lethal psychiatric disorder. This review examines how stem cell actions align with PTSD brain changes, critically assesses the limited evidence, and suggests a careful translational plan. Show less

Gut microbiota alterations are associated with the onset of depression; however, the underlying mechanisms remain unclear. Activation of hippocampal AMP-activated protein kinase (AMPK) in ulcerative colitis mice with disrupted gut microbiota balance produces antidepressant effects. However, the relationship between hippocampal AMPK and antibiotic treatment (ABX)-induced depression-like behavior remains unclear. Therefore, we aimed to investigate whether 5-aminoimidazole-4-carboxamide 1-β-d-ribofuranoside (AICAR), an AMPK activator, is associated with the prevention of ABX-induced depression-like behaviors. ABX mice exhibited depression-like behaviors, as evidenced by prolonged immobility and reduced sucrose preference. In the hippocampus of the ABX mice, Iba1 and pro-inflammatory microglial markers were upregulated, whereas brain-derived neurotrophic factor (BDNF), CD206, arginase-1, and interleukin-10 were downregulated. Additionally, levels of AMPK phosphorylation, cAMP response element binding protein (CREB), and tropomyosin-related kinase B (TrkB) were decreased. AICAR administration attenuated these behavioral and molecular alterations. Phosphorylated AMPK was colocalized with the neuronal marker-NeuN-and microglial marker-Iba1. AICAR ameliorated the reduction in hippocampal neuron proliferation and survival and reduced microglial activation-associated morphological changes in the hippocampus. These findings suggest that AICAR administration is associated with antidepressant-like effects, potentially involving enhanced neurogenesis and attenuation of neuroinflammation in the hippocampus of ABX mice. Together, this study highlights the significance of hippocampal AMPK phosphorylation in depression associated with gut microbiota alterations, and suggests a potential target for therapeutic interventions. Show less

Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline, synaptic dysfunction, and mitochondrial abnormalities. Mitochondrial dynamics, especially the balance between fusion and fission processes regulated by proteins like mitofusin 2 (Mfn2) and dynamin-related protein 1 (Drp1), play critical roles in neuronal health. However, the relationship between mitochondrial dynamics and synaptic integrity, and cognitive deficits remains incompletely understood. This study aimed to investigate the alterations in Mfn2 and Drp1 expression and their association with synaptic protein levels and also behavioral outcomes in a rat model of AD. Thirty adult male Wistar rats were randomly assigned to control and AD groups. AD was induced through bilateral hippocampal injection of Aβ1-42. Behavioral assessments including the Morris Water Maze, Novel Object Recognition, and Y-maze were conducted to evaluate spatial learning and memory. On day 21 post-induction, gene expression of Drp1, Mfn2, PSD-95, synaptophysin, BDNF, Bax, and Bcl2 in the hippocampus and cortex was measured using real-time PCR. Oxidative stress markers (MDA, SOD, CAT) and inflammatory cytokines (NF-κB, IL-1β) were evaluated in serum using ELISA kits. Results showed significant downregulation of Mfn2 and synaptic proteins, with increased Drp1 and Bax expression in AD rats. These molecular changes were accompanied with increase of oxidative and inflammatory markers and altered cognitive performance. In conclusion, the findings suggest that disrupted mitochondrial dynamics contribute to synaptic loss and cognitive decline in AD. Targeting mitochondrial function and neuroinflammation may represent potential therapeutic targets for AD management. Show less

Anxiety is a common disorder characterized by excessive fear, tension, and physical symptoms, such as sweating and palpitations. There are approximately 16.6 % of patients worldwide affected by anxiety disorders, which have been classified as panic disorder, social anxiety disorder, generalized anxiety disorder, post-traumatic stress disorder, obsessivecompulsive disorder, and phobias. The amygdala plays a central role in regulating fear, anxiety, and aggression, particularly when influenced by trauma or heredity, which can contribute to the development of anxiety disorders. Another contributing factor is oxidative stress, characterized by reduced antioxidant levels and increased cellular damage. Neurotransmitters, such as serotonin, norepinephrine, and Gamma-Aminobutyric Acid, are critical in controlling anxiety. Anxiety also usually involves imbalances, in particular, low levels of serotonin and high norepinephrine. N-Methyl-D-aspartate and Cholecystokinin brain receptors are involved in long-term fear memory encoding, suggesting potential new targets for treating this condition. Although conventional pharmacological treatments such as benzodiazepines and selective serotonin reuptake inhibitors are effective, they are often associated with side effects, dependency, and limited long-term efficacy. In recent years, plant-based bioactive compounds have gained attention as potential alternatives or adjunct therapies for managing anxiety disorders, and they act in Gamma-Aminobutyric Acid modulation and monoamine regulation. Anxiety can be treated through herbal medicine using ethnopharmacology. Show less

Spinal cord injury (SCI) leads to severe sensory, motor, and autonomic dysfunction with limited treatment options. Ginsenosides, the primary bioactive compounds derived from Panax ginseng, have demonstrated neuroprotective potential in SCI. This systematic review aims to evaluate the preclinical evidence regarding the multi-target mechanisms of ginsenosides in SCI Methods: A comprehensive literature search was conducted following PRISMA guidelines across PubMed, Web of Science, and Google Scholar up to January 2025. Of the 385 identified articles, 22 studies met the inclusion criteria, which focused on the pharmacological effects of ginsenosides in SCI using both in vivo and in vitro models. Data on mechanisms, models, and outcomes were systematically synthesized Results: Ginsenosides exerted multi-target neuroprotective effects in SCI models, including antiinflammatory actions via suppression of TLR4/NF-κB and MAPK signaling, leading to reduced TNF-α, IL-1β, and IL-6, antioxidant activity through Nrf2/HO-1 pathway activation, enhancing SOD, CAT, and GSH, anti-apoptotic effects via ASK1/JNK inhibition, lowering caspase-9/3 and Bax while elevating the Bcl-2/Bax ratio, regulation of autophagy by activating PI3K/Akt to prevent excessive self-digestion, promotion of neural repair through upregulation of neurotrophic factors (NGF, bFGF, BDNF, and GDNF) and extracellular matrix components (laminin, fibronectin), inhibition of spinal cord edema via increased AQP4 expression, and facilitation of nerve regeneration by promoting astrocyte-to-neuron conversion and olfactory ensheathing cell migration Discussion: The findings highlight the synergistic mechanisms of ginsenosides in addressing key pathological processes in SCI, including inflammation, oxidative stress, apoptosis, and impaired neural regeneration. While preclinical evidence underscores their therapeutic promise, the translational potential requires validation through rigorous clinical trials to confirm efficacy, safety, and applicability in humans Conclusion: Ginsenosides exhibit multi-target neuroprotective effects in SCI models, positioning them as promising candidates for therapeutic development. Further clinical studies are essential to advance their application in SCI treatment. Show less

Neuropathic pain is a chronic condition initiated by nerve injury and frequently accompanied by affective disturbances, including anxiety and depression. Growing evidence suggests that maladaptive neuroplasticity in the anterior cingulate cortex (ACC) contributes to the persistence and affective dimension of neuropathic pain. To narratively review and critically synthesize current evidence on ACC-related neuroplasticity in neuropathic pain across molecular, circuit, glial, and translational domains. We narratively reviewed experimental and clinical studies addressing ACC-related molecular signaling, synaptic and circuit remodeling, glial and neuroimmune mechanisms, and interventional approaches relevant to neuropathic pain and its affective dimension. At the molecular level, abnormal ACC synaptic plasticity has been associated with long-term potentiation involving N-methyl-D-aspartate (NMDA) receptors-particularly GluN2B-dependent signaling-while the brain-derived neurotrophic factor (BDNF)-TrkB axis may further contribute to dendritic remodeling and maladaptive synaptic strengthening. At the circuit level, the ACC interacts with limbic regions including the insula and amygdala, within distributed networks that appear to contribute to aversive learning and pain-related affect. At the non-neuronal level, alterations in the ACC microenvironment include astrocyte-linked neuroinflammation and microglia-associated synaptic remodeling, which may shift excitation-inhibition balance. Therapeutically, ACC-targeted strategies are evolving from broad pharmacological modulation toward more spatially specific neuromodulation, although major translational challenges remain, including limited target specificity, cross-species differences, and uncertain causal inference in humans. ACC-related neuroplasticity appears to be an important component of neuropathic pain-affect pathophysiology. Future progress will depend on integrating mechanistic insights with network-level interpretation and improving the precision and clinical translatability of ACC-engaging interventions. Show less

Ketamine's ability to lift mood and spur new synapse growth has put glutamate biology at the center of modern neurotherapeutics. Yet the drug's intravenous route, monitoring requirements, and dissociative effects make it a poor candidate for long-term prevention of Alzheimer's disease (AD). This hypothesis article proposes a low-cost oral glutamatergic regimen that targets early synaptic and glutamatergic dysfunction in AD pathogenesis. Here we advance a testable hypothesis: an all-oral "synaptogenic stack" could mimic ketamine's downstream benefits-namely, the rise in brain-derived neurotrophic factor and the activation of mechanistic target of rapamycin (mTOR)-while avoiding its toxicities. The stack combines three inexpensive agents that have decades of human use. First, dextromethorphan, kept in circulation with a small dose of a CYP2D6 inhibitor, provides gentle NMDA antagonism. Second, piracetam acts as a positive modulator of AMPA receptors, boosting fast excitatory transmission. Third, oral L-glutamine replenishes presynaptic glutamate stores and buffers against excitotoxic spill-over. Working in concert, these drugs should reduce extrasynaptic NMDA stress, enhance AMPA throughput, and preserve dendritic spine density in the aging brain. If this mechanism proves sound, the regimen offers a low-cost, scalable way to delay the clinical onset of AD, particularly in people who already show prodromal biomarkers or genetic risk. Prospective trials are needed to evaluate safety, target engagement, and long-term cognitive outcomes. Show less

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive memory impairment and cognitive decline, significantly impacting the quality of life for millions worldwide. Understanding the intricate molecular pathways linking AD pathology to memory dysfunction is crucial for developing effective therapies. This narrative review aims to elucidate the key molecular mechanisms underlying memory impairment in AD. We conducted a comprehensive literature search across major scientific databases (e.g., PubMed, Scopus, Web of Science) focusing on peer-reviewed studies (original research, reviews) exploring the molecular links between AD pathology and memory deficits. The review identifies and details several interconnected molecular pathways driving memory impairment in AD: (1) Synaptic dysfunction and neuronal loss triggered by amyloid-β (Aβ) peptide accumulation and aggregation; (2) Intracellular transport disruption and neurodegeneration caused by tau protein hyperphosphorylation and aggregation; (3) Exacerbation of cognitive deficits by neuroinflammation, mediated through activated microglia and pro-inflammatory cytokines (e.g., IL-1β, TNF-α, IL-6); (4) Impairment of synaptic plasticity and cognitive function due to dysregulation of neurotrophic factors, particularly brain-derived neurotrophic factor; (5) Contributory roles of oxidative stress, mitochondrial dysfunction, disrupted neurotransmission (e.g., acetylcholine, GABA), and apoptotic pathways. This review comprehensively unravels the critical molecular links between AD pathology and memory impairment, emphasizing the interplay of Aβ, tau, neuroinflammation, neurotrophic factor dysregulation, and other mechanisms. Targeting these interconnected pathways represents a promising strategic approach for developing therapies to mitigate cognitive decline and improve outcomes in AD patients. Show less