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Although traditional rehabilitation training can partially improve motor function in patients with post-stroke motor disorders, its impact on neural plasticity remains limited. Transcutaneous auricular vagus nerve stimulation (taVNS), a non-invasive method targeting the auricular branch of the vagus nerve, represents a promising neuromodulatory approach. This prospective study aimed to assess the therapeutic effects of taVNS on functional recovery in this population. A total of 147 patients with post-stroke motor disorders were consecutively enrolled between February 2023 and November 2024. After excluding 8 dropouts, 139 patients were randomly assigned via a random number table to either an electrical stimulation group (taVNS group) or a rehabilitation group (conventional training). The taVNS group initially included 73 patients, with 3 dropouts yielding a final sample of 70. The rehabilitation group initially included 74 patients, with 5 dropouts resulting in 69 participants. All participants underwent comprehensive assessments at baseline and following a 4-week intervention period. Outcome measures encompassed neuroelectrophysiological parameters (motor evoked potential latency and amplitude), clinical functional evaluations (Action Research Arm Test, Fugl-Meyer Assessment for Upper Extremity, Modified Barthel Index), serum biomarker levels (brain-derived neurotrophic factor, S100 calcium-binding protein β), and systematic documentation of adverse events. Based on post-treatment Fugl-Meyer Assessment-Upper Extremity (FMA-UE) scores, patients were further categorized into improvement and non-improvement subgroups for additional comparative analysis. Pearson correlation analysis was utilized to examine potential relationships between functional scores, neurophysiological data, and biomarker concentrations. Baseline characteristics were comparable between groups ( taVNS is an effective and safe adjunctive therapy for post-stroke motor recovery. It enhances neuroelectrophysiological function, improves motor and daily living abilities, and favorably modulates biomarkers of neural injury and repair. The consistent correlations among functional, neurophysiological, and biochemical outcomes highlight an integrated recovery pathway, supporting the integration of taVNS into standard neurorehabilitation protocols. Show less

Perineural invasion (PNI) represents a uniquely distinctive pathway for tumor metastasis, but its underlying molecular mechanisms and therapy remain unclear. Bioinformatics analysis and transcriptomic sequencing were first employed to investigate the involvement of the BDNF/TrkB axis in the ESCC PNI, which was validated with ESCC cells co-cultured with a dorsal root ganglia system (ESCC/DRG model), a mouse PNI model, and ESCC tissues, mainly using microscopic imaging, IVIS Spectrum The BDNF/TrkB axis is closely associated with the PNI in ESCC. This pathway plays a pivotal role in driving PNI progression via Akt signaling. Deguelin was identified as an effective inhibitor of PNI in ESCC. Mechanistically, BDNF was revealed to be a key binding target of Deguelin, which disrupts PNI development by modulating the BDNF/TrkB/Akt axis. Notably, overexpression of BDNF can counteract Deguelin's inhibitory effects on ESCC growth and PNI progression. The BDNF/TrkB axis promotes the progression of ESCC PNI, and Deguelin inhibits ESCC PNI by targeting this axis, enhancing the understanding of PNI's molecular mechanisms and offering new therapeutic options. Show less

Spinal cord injury (SCI) represents significant central nervous system trauma and has consistently been a focal point of research in the domain of neural regeneration and repair. Currently, there is no effective treatment available. Various modalities of magnetic stimulation have emerged for recovery from spinal cord injuries; however, the underlying mechanisms remain unclear, significantly hindering the application of magnetic stimulation technologies in treating such injuries. This study aims to elucidate these relevant mechanisms by establishing a simulated closed-loop magnetic stimulation system. In this study, we established a right hemisection model at T8 in mice and administered continuous simulated closed-loop magnetic stimulation targeting the left motor cortex and right L5 nerve root over six weeks. We subsequently utilized a spinal cord dorsal hemisection model to examine regeneration of the corticospinal tract (CST). Motor-evoked potential assessments and calcium imaging techniques were employed to explore neural circuit repair. Additionally, we integrated transcriptomics, proteomics, and metabolomics approaches to investigate related mechanisms. The findings indicate that simulated closed-loop magnetic stimulation effectively restores motor function in the hind limbs, promotes the regeneration of corticospinal tracts in mice with spinal cord injuries, and facilitates the reconstruction of sensorimotor circuits and functions within the spinal cord. Simulated closed-loop magnetic stimulation significantly enhances axonal regeneration of the CST following SCI. This effect may be mediated through the activation of the AMPK-CREB-BDNF signaling pathway, which promotes neurotrophic factor secretion and subsequently induces nerve axon regeneration. This study suggests that simulated closed-loop magnetic stimulation represents a promising therapeutic approach for the treatment for impaired gait following SCI. Show less

(ACR)-induced neurotoxicity, focusing on oxidative stress, endoplasmic reticulum (ER) stress, neuroinflammation, and apoptosis mechanisms. Fifty male Sprague-Dawley rats were divided into five groups: Control, ACR, GA50 +ACR, GA100 +ACR, and GA100. GA (50 and µmg/kg) and ACR (50 mg/kg) were administered intraperitoneally for 14 days. ACR exposure significantly decreased antioxidant enzyme activities (SOD, GSH, GPx, CAT) and increased malondialdehyde (MDA) levels, pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), neuronal nitric oxide synthase (nNOS), and apoptosis-related gene expression (Bax and caspase-3). Histopathological analysis revealed neuronal degeneration and vascular hyperemia, while BDNF, Nrf2, and HO-1 immunoreactivity decreased in the ACR group. GA treatment, particularly at 100 mg/kg, markedly ameliorated these biochemical, molecular, and histopathological alterations. These findings indicate that GA exerts significant neuroprotective effects against ACR-induced brain injury by modulating oxidative stress, ER stress, inflammatory, and apoptotic pathways. Show less

This study aimed to investigate the effect of different preferences of food-derived odors (common food flavors/spices) on the appetite, immune system, and CNS of mice through 15 days of olfactory exposure. According to the ranking of sniffing duration, beef essence was chosen as a pleasant odor, while garlic essence was chosen as an unpleasant odor. Results showed that food intake and body weight gradually increased in all groups, with the lowest values observed in the garlic odor group. Unpleasant garlic odor suppressed the mRNA transcription levels of agouti-related protein (AgRP) and neuropeptide Y (NPY) in the hypothalamic arcuate nucleus, along with elevated leptin levels, thereby inhibiting food intake and causing body weight loss. In addition, the serum TNF-α, IL-2, and IL-6 levels in the garlic odor group were significantly higher than those in the beef and control groups, which indicated that the immune system may be impaired by the exposure to unpleasant garlic odor. Furthermore, pleasant beef odors could promote the differentiation of hippocampal neurons and the levels of brain-derived neurotrophic factors and glial cell line-derived neurotrophic factor, which may have great potential in improving neurological disorders. Conclusively, unpleasant odors may suppress immune function or modulate the CNS by establishing an odor-CNS-immune pathway, while pleasant food odors affect only the CNS. The present study preliminarily provides novel insights that different preferences for food odors could affect the body weight, immune system, and CNS. It may serve as a reference for further research and development of aromatherapy as an adjuvant medicine and therapeutic method. Show less

Given the limitations of current treatments for Alzheimer's disease (AD), this study aims to comprehensively evaluate the therapeutic efficacy of human umbilical cord mesenchymal stem cells (hUCMSCs) in AD mouse models through a systematic review and meta-analysis. Additionally, we explore the impact of transplantation dose and route on treatment outcomes to identify the optimal window for clinical application. In accordance with the PRISMA guidelines, we systematically searched four major databases to identify randomized controlled trials involving hUCMSCs in AD mouse models. We used the standardized mean difference (SMD) to synthesize effect sizes and performed subgroup analyses based on pre-defined transplantation routes and doses. A total of 13 studies were included in the analysis. The meta-analysis revealed that hUCMSCs transplantation significantly improved spatial learning and memory in AD model mice, with a marked reduction in escape latency (SMD = -2.55; 95% CI: -3.34 to -1.75; Human umbilical cord mesenchymal stem cells can improve behavioral and pathological outcomes in AD mouse models via multiple mechanisms of action. The intravenous route using medium to high doses emerges as a critical factor for achieving optimal effects, providing important evidence and informing future experimental design and clinical translational research. Show less

Aging in dogs is a multifactorial process involving behavioral, cognitive, immunological, and microbiota-related changes, yet distinguishing healthy from pathological aging remains challenging. This exploratory study aimed to evaluate physiological indicators of health by integrating pain evaluation and cognitive testing in senior companion dogs. Eighteen companion dogs aged ≥8 years underwent standardized behavioral and cognitive evaluations (Mini C-BARQ, DISHAA, object choice test), chronic pain assessment (Helsinki Chronic Pain Index), and quality-of-life (QoL) scoring. Hematological parameters, serum brain-derived neurotrophic factor (BDNF), and Th1/Th2 ratios were measured as physiological indicators, while fecal samples were analyzed via 16S rRNA sequencing for microbiota profiling. All dogs scored above the chronic pain threshold (mean HCPI: 28.72), although caregiver-reported QoL ratings suggested good overall wellbeing. Cognitive testing yielded low average scores on the DISHAA (mean: 9.05), with only one dog showing mild cognitive decline; however, mean performance on the object choice test was low (1.94/5). Mean serum BDNF concentration was 0.154 ng/dL (SD: 0.082) and correlated positively with red blood cell (RBC) count and negatively with MCV, MCH, and MCHC ( These preliminary findings highlight potential interactions between pain, microbiota composition, and immune dysregulation, suggesting their possible utility as candidate indicators for differentiating healthy from pathological aging in dogs. Show less

Integration of the hepatitis B virus (HBV) genome into the host chromosome of infected patients poses a threat to those with HBV-associated hepatocellular carcinoma (HBV-HCC) due to challenges in early diagnosis and poor prognosis. CircRNAs are known for their oncogenic and biomarker potential in various cancers, including HBV-HCC, by sequestering tumor suppressive miRNAs, which, when free, can silence the expression of oncogenic mRNAs. Therefore, we aimed to develop a bioinformatic model to identify the circRNA-miRNA-mRNA axis in HBV-integrated HCC cell lines and to identify prognostic biomarkers specific to HBV-HCC patients. We identified dysregulated host circRNAs and mRNAs in HBV-negative and HBV-integrated cells using RNA-seq, followed by differential gene expression analysis with DESeq, and performed pathway analysis using Gene Set Enrichment Analysis (GSEA). Junctional sequences of the circRNAs were validated by Sanger sequencing of the amplified products. RT-qPCR further confirmed the dysregulation of 9 randomly selected circRNAs chosen from those with the highest fold-change and adjusted p-values. The miRNA partners for each circRNA were identified using mirDB. miRNA expression validation was performed using the publicly available Gene Expression Omnibus (GEO) database of the same cells, and Empirical Cumulative Distribution Function (ECDF) plots were generated to assess the fold change of mRNAs in potential binding miRNA partners. The mRNA targets for 10 miRNA ECDF plots were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and hub genes were identified using Search Tool for the Retrieval of Interacting Genes (STRING) Cytohubba protein-protein interaction (PPI) analysis. Survival analysis of hub genes was plotted, and a competitive endogenous RNA (ceRNA) network was constructed using Cytoscape. We identified 494 dysregulated circRNAs, 346 dysregulated miRNAs, and 10,419 dysregulated mRNA in HBV-integrated cells through a comprehensive bioinformatic model. circADGRL2 (~ 25-fold) showed the highest upregulation and miR-361-5p acted as a central node of multiple circRNAs: circADGRL2, circPROX1 and circPALS2. BDNF, a target mRNA of miR-361-5p, was identified as the highest risk ratio in HBV-HCC patients, suggesting a possible circADGRL2-miR-361-5p-BDNF axis involved in HBV-HCC. The target mRNAs of miRNAs were predicted to be associated with several cancer pathways, such as MAPK and RAS. Our data suggest a potential dysregulated circRNA-miRNA-mRNA axis in HBV-integrated hepatocytes, which may indicate a poor prognosis for HBV-HCC patients. Show less

Juvenile idiopathic arthritis (JIA) is the most common childhood chronic arthritis, and pain may persist despite controlled inflammation, potentially due to central sensitization. This study aimed to evaluate the effects of very early-onset arthritis on pain, behavior, and cognition using a collagen-induced arthritis model in juvenile rats. Thirty-six three-week-old male Wistar rats were divided into control, sham (saline), and arthritis (type II collagen with incomplete Freund's adjuvant) groups. Disease severity was monitored via joint thickness and VAS. Pain (hot plate, Randall-Selitto), behaviors (EPM, MFST), and cognition (PAT) were assessed. Locomotor activity was assessed. Joints were analyzed histologically (H&E); hippocampal BDNF and TNF-α were examined immunohistochemically. Arthritis severity progressed over six weeks, with increased joint thickness and VAS scores in the arthritis group (p < 0.05). Mechanical hyperalgesia showed a paw- and time-dependent pattern, with earlier changes in some paws and more consistent reductions during the late phase (weeks 4-6). Locomotor activity did not differ among groups, indicating no motor deficits. The arthritis group exhibited greater anxiety (EPM, p = 0.001) and depression-like behavior (FST, p = 0.004), while cognition (PAT) remained unaffected. Hippocampal TNF-α increased, whereas BDNF was unchanged. Very early-onset arthritis is associated with mechanical hyperalgesia and emotional disturbances, accompanied by hippocampal TNF-α alterations, and exhibits features consistent with central sensitization, without significant effects on cognition or hippocampal BDNF expression. Early juvenile arthritis showed mild severity with delayed mechanical hyperalgesia. Thermal hyperalgesia and locomotor deficits were not observed in arthritic rats. Hippocampal TNF-α increase was linked to anxiety and depression-like behaviors. Hippocampal BDNF levels remained stable, suggesting intact learning processes. Show less

Schizophrenia is a severe mental disorder whose molecular mechanisms remain poorly understood. Investigating brain-derived neurotrophic factor (BDNF)-dependent signaling pathways and their contribution to schizophrenia pathogenesis is a promising research direction in schizophrenia research. BDNF activates multiple intracellular cascades, among which the MAPK/ERK pathway plays a central role. In this study, expression levels of key regulatory proteins of the MAPK/ERK signaling pathway (ERK1/2, STAT3, STAT5, NF-κB, IGF1R, IRS1, IR, TSC2, and CREB1) were examined in lysates of peripheral blood mononuclear cells (PBMCs) from schizophrenia patients using multiplex analysis. The study group included 58 patients diagnosed with schizophrenia (F20); the control group included 60 healthy individuals. The results revealed significantly increased expression of ERK1/2 and STAT3, along with decreased NF-κB levels, in PBMCs from schizophrenia patients compared to controls. Moreover, patients with leading positive symptoms exhibited elevated expression of CREB1 and ERK1/2. These findings suggest that dysregulation of the MAPK/ERK signaling may play a significant role in the pathogenesis schizophrenia. BDNF-dependent signaling pathways may therefore represent promising targets for diagnostics and therapy of this disorder. Show less

Overactive bladder (OAB) syndrome, characterised by urinary urgency, frequency, and nocturia can significantly impacts patients' quality of life. Current diagnosis is clinical, but complex cases often require invasive urodynamic studies (UDS), which are costly, subjective, and carry risks like discomfort and infection. Therefore, we hypothesise that urinary biomarkers could serve as noninvasive diagnostic tools for OAB. Establishing a reliable biomarker profile could ultimately lessen the reliance on invasive US, provided clinical validity is confirmed. Following PRISMA guidelines and registered under PROSPERO (ID: CRD420251026279), a comprehensive search across six major databases was conducted from their inception until September 2025, yielding 39 studies for qualitative analysis. This qualitative review identified several promising biomarkers for OAB diagnosis. Notably, NGF and BDNF consistently emerged as elevated in OAB patients and were responsive to treatment. Additionally, TNF-α, MIP-1β, Tie2, and CCL2 showed diagnostic potential, with TNF-α and MIP-1β particularly useful for differentiating OAB from interstitial cystitis/bladder pain syndrome (IC/BPS) and urinary tract infections (UTIs). However, limitations such as variability in measurement protocols and a lack of specificity for certain biomarkers (e.g. MMP-1, 8-OHdG) were noted. Urinary biomarkers offer a promising noninvasive approach to diagnosing OAB. Further validation of promising markers, particularly NGF, BDNF, TNF-α, MIP-1β, and CCL2, could lead to individualised therapies. While promising, the routine replacement of UDS remains an aspirational goal dependent on future large-scale validation. Show less

Annotation of regulatory elements is essential for understanding mechanisms underlying gene regulation, particularly tissue-specific regulation in human and animals. Here, we characterize 274,682 enhancers and 25,975 promoters across 24 tissues from an adult female sheep using ChIP-seq, ATAC-seq, CAGE-seq, RRBS, WGBS, and RNA-seq. We identify seven neural development-related genes with over 10 enhancers in brain tissues, highlighting the role of tissue-specific regulation. Cis-regulatory enhancer-promoter combinations provide insights into tissue-specific enhancers, such as the cerebellum-specific enhancer (chr15: 57390520-57390685) regulating BDNF, which is expressed in both the cerebellum and cerebral cortex. Comparative analysis of enhancer-promoter combinations in human, mouse, pig, cattle, and sheep reveals ruminant-specific pathways, including pentose catabolism and long-chain fatty acid import regulation. A milk fat yield quantitative trait locus (QTL) identified within an enhancer interacts with the fat metabolism-related gene COMMD1, and a birth weight-associated QTL detected within a cerebellum-specific enhancer regulates XKR4. This study provides a robust framework for exploring cis-regulatory mechanisms and tissue-specific regulation, advancing the functional annotation of the sheep reference genome. Show less

Resveratrol (RSV), a dietary polyphenol widely present in traditional medicinal plants and foods, exhibits antioxidant and anti-inflammatory properties that are relevant to ethnopharmacological strategies for protecting against environmental neurotoxicants. Given increasing real-world co-exposure to lead (Pb) and cadmium (Cd), elucidating RSV's capacity to preserve gut-brain axis (GBA) homeostasis has direct translational relevance for populations relying on phytochemical interventions. Sprague-Dawley rats were randomized into control, Pb-Cd model, and RSV treatment groups (10, 20, or 40 mg/kg). For 4 weeks, rats received Pb (300 mg/L) and Cd (50 mg/L) in drinking water with daily RSV. Cognitive function was assessed by Morris water maze; barrier integrity by Evans blue assay, histology, and Western blot for ZO-1/Occludin; synaptic ultrastructure by TEM; microbiota composition by 16S rRNA sequencing; and short-chain fatty acids (SCFAs) by GC-MS. Neurotransmitters (5-HT, GABA, SP, VIP) and cytokines (IL-6, IL-1β, TNF-α) were measured by ELISA. RSV improved spatial learning, reduced EB extravasation, preserved synaptic ultrastructure and proteins (BDNF, SYN, PSD-95), and restored intestinal architecture with increased ZO-1/Occludin. RSV attenuated cytokine release, normalized goblet cells, reversed dysbiosis by restoring Lactobacillaceae/Prevotellaceae, and increased acetate, propionate, and butyrate. It reinstated 5-HT and GABA while reducing SP and restoring VIP across serum, colon, and hippocampus. RSV attenuated Pb-Cd-associated neurotoxicity and was accompanied by improved intestinal and BBB-related readouts, partial normalization of gut microbiota features and SCFA levels, and preservation of synaptic and neurotransmitter-related markers, consistent with a link to gut-brain axis function. This study is among the first to test RSV in a Pb-Cd co-exposure model using a multi-dose regimen with integrated behavioral, barrier, microbial, and neurochemical endpoints. Show less

Pacific salmon (Oncorhynchus spp.) rely on olfactory information learned in their natal rivers to guide their homing migration. Although molecules associated with synaptic plasticity show marked changes in the olfactory system during periods linked to imprinting, the contribution of brain-derived neurotrophic factor (BDNF/Bdnf), a key regulator of neural development and plasticity, has not been fully examined in salmonids. In this study, we isolated the complete coding sequence of masu salmon (O. masou) pro-bdnf and analyzed its expression profile across the olfactory system using wild individuals at multiple developmental stages. The deduced amino acid sequence of masu salmon pro-Bdnf was highly conserved among vertebrates. Pro-bdnf mRNA was strongly expressed in under-yearling parr prior to smoltification, particularly in the olfactory rosette and olfactory bulb at the sensitive period for imprinting. In the telencephalon, a higher olfactory center homologous to the mammalian cerebrum, pro-bdnf expression remained stable across stages, consistent with ongoing neurogenesis in this region. These results provide molecular evidence that pro-bdnf expression mirrors developmental changes in the olfactory system and support the idea that Bdnf contributes to the formation and refinement of olfactory circuits essential for imprinting and homing in Pacific salmon. Show less

Recent evidence suggests that reduced peripheral levels of brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of bipolar disorder (BD), although its relevance in young populations remains uncertain. This systematic review synthesized studies that evaluated serum BDNF levels in children and adolescents with BD, examining its potential as a risk marker. Following PRISMA 2020 guidelines and a protocol registered in PROSPERO, searches were conducted in the Cochrane, MEDLINE, SciELO, and Scopus databases. Studies including participants aged 0-19 years diagnosed with BD according to DSM criteria were included. Studies with mixed samples (adults, children and adolescents) without separate age-group analyses were excluded. After screening and eligibility assessment, seven studies were included. Five of them included a control group, from which a meta-analysis was performed. Moderate methodological heterogeneity was observed and corrected after sensitivity analysis, reinforcing the robustness of the findings, although no statistically significant difference in serum BDNF levels was found between patients with bipolar disorder and controls. Current evidence does not support BDNF as a diagnostic biomarker for pediatric BD. Future studies with greater sample power and methodological standardization are needed to clarify its role in the risk and course of early-onset bipolar disorder. Show less

Cognitive decline during aging may be influenced by peripheral factors, including neuroproteins and pro-inflammatory cytokine levels, body composition, and physical fitness. However, the specific associations between these factors and cognitive performance remain underexplored. A comprehensive assessment, including peripheral cytokine and neuroprotein levels, body composition, physical performance (aerobic fitness and muscle strength), and cognitive function was performed in a cohort of 87 older adults (mean age: 69.3 ± 3.4 years; 66 females, 21 males) with a range of Body Mass Index (BMI): 19.7 - 41.9. Elevated blood levels of N-lactoyl-phenylalanine (Lac-Phe) were associated with better psychomotor speed (r = -0.223, p = 0.034) as measured by the Trial Making Test-A (TMT-A). Elevated pro-inflammatory cytokines (IL-6, IL-8, IL-12) and peripheral clusterin concentrations were also associated with poorer cognitive performance. No significant associations were found between cortisol, brain-derived neurotrophic factor and cognitive function. BMI and fat mass (kg) were positively associated with performance on the Stroop Test, suggesting a negative effect of increased adipose tissue on inhibitory control. In contrast, greater skeletal muscle mass was positively associated with better memory. Physical fitness parameters, including VO Show less

Mutations in INTS11, the catalytic subunit of the Integrator complex essential for RNA processing and transcriptional termination, have been linked to neurodevelopmental disorders (NDDs), yet the underlying mechanisms remain poorly understood. To address this gap, we developed and characterized a novel ints11 loss-of-function zebrafish model using CRISPR/Cas9 and morpholino-based approaches, which recapitulates key phenotypic traits observed in human patients, including motor and behavioral deficits. ints11 deficiency led to marked impairments in locomotor activity and visual motor response, consistent with the neurological manifestations reported in INTS11-mutated patients. These behavioral abnormalities were paralleled by significant dysregulation of neurodevelopmental gene expression, including decreased expression of islet1, map2, gfap, and mag, and upregulation of the progenitor marker nestin, indicating defective neuronal differentiation and glial maturation. Interestingly, the observed phenotypes are rescued not only by mRNA-mediated re-expression of ints11, but also through pharmacological administration with brain-derived neurotrophic factor (BDNF) and the GM1 ganglioside-derived oligosaccharide (OligoGM1). These findings highlight neurotrophic signaling as a potential compensatory axis counteracting RNA-processing defects. In conclusion, our work establishes the first in vivo zebrafish model of INTS11-associated neurodevelopmental dysfunction, uncovering conserved molecular mechanisms that link Integrator complex activity, neurotrophic support, and neuronal maturation and providing a valuable platform for dissecting disease mechanisms and evaluating therapeutic strategies targeting RNA processing pathways and neurotrophic support in NDDs. Show less

Neurotrophins are a class of proteins that maintain the health and phenotype of neuronal cells under normal physiological conditions. Nerve growth factor was the first neurotrophin to be discovered, supporting the survival and cholinergic phenotype of basal forebrain cholinergic neurons, which are crucial in maintaining cognitive function in healthy individuals. Nerve growth factor metabolism is altered in Alzheimer's disease and, along with the degeneration of basal forebrain cholinergic neurons and loss of cholinergic pathways in the affected brain, contributes to cognitive problems. These findings initiated the application of nerve growth factor supplementation as a regenerative strategy against Alzheimer's disease in the late 20 th century. Later decades witnessed the development of drugs that support cholinergic activity, namely, cholinesterase inhibitors offering small but persisting cognitive benefits in Alzheimer's disease patients. Further developments in the Alzheimer's disease field have witnessed the rise of anti-amyloid immunotherapies that target the amyloid plaques in Alzheimer's disease brains in an attempt to reduce disease pathology. Over the years, several reports have appeared in support of or undermining the therapeutic claims of each strategy, while many other therapeutic approaches are being presently tested. In this narrative review, we present broader perspectives regarding cholinergic therapeutic strategies against Alzheimer's disease, highlighting aspects in the Alzheimer's disease field that need to be addressed, and propose future perspectives. We provide a special focus on neurotrophic molecules, especially on nerve growth factor, due to its close association with cognitive pathways and its relationship with cholinergic pathways, since cholinesterase inhibitors remain a widely used medication for Alzheimer's disease patients even after 30 years of research. Show less

Peripheral nerve injuries often lead to painful neuroma formation and chronic neuropathic pain, and the optimal surgical strategy for prevention remains debated. Targeted muscle reinnervation (TMR), regenerative peripheral nerve interfaces (RPNI), and nerve-in-muscle implantation (NIM) are surgical techniques developed to mitigate neuroma-related pain, but their relative efficacy has not been compared systematically. This preclinical study compared TMR, NIM, and two RPNI variants in a rat tibial nerve transection model to identify which approach best reduces neuroma formation and pain. Sprague-Dawley rats underwent right tibial nerve transection and were randomized into five groups: control (no repair), NIM, W-RPNI (wrapped RPNI), E-RPNI (embedded RPNI), or TMR. Behavioral outcomes including gait analysis (CatWalk), mechanical hypersensitivity (von Frey test), thermal hyperalgesia (Hargreaves test), and neuroma tenderness were assessed over 12 weeks. At week 12, distal nerve stumps and L4-L5 dorsal root ganglia (DRG) were harvested for histological evaluation, immunohistochemistry/immunofluorescence, and molecular analyses (qRT-PCR and Western blot) targeting pain- and inflammation-related biomarkers. By 12 weeks, TMR-treated rats showed the most robust improvements, including significantly longer stance duration, larger paw contact area, near-baseline withdrawal thresholds, and minimal neuroma tenderness, whereas untreated controls developed gross neuromas and persistent hypersensitivity. TMR also preserved organized nerve architecture with orderly axonal regeneration and minimal collagen I/III fibrosis at the stump. Molecular assays confirmed that TMR markedly attenuated nociceptive and inflammatory signaling, with TMR rats exhibiting the lowest expression of pain-related mediators (c-Fos, TRPA1, TRPV1, CGRP, NPY, BDNF) and pro-inflammatory/fibrotic markers (galectin, α-SMA, IL-1β, TNF-α, TGF-β) in nerve and DRG tissues. Conversely, the anti-inflammatory cytokine IL-10 and axonal ion pump subunits ATP1A2/ATP2B1 were significantly upregulated with TMR. Outcomes for the two RPNI groups were similar to each other and generally intermediate between TMR and control. TMR was superior to RPNI variants and NIM in preventing neuroma formation and alleviating neuropathic pain in this animal model. These findings support TMR as a promising surgical strategy to mitigate post-amputation neuroma pain. Show less

Substance use disorder (SUD) is a complex neurobiological disorder characterized by the consolidation of maladaptive neuroplasticity affecting dopaminergic, glutamatergic, and neurotrophic systems, as well as cortical and subcortical networks critical for executive control, emotional regulation, and associative learning. This systematic review was conducted in accordance with PRISMA 2020 guidelines and integrated 57 studies published between 2020 and 2025 to analyze neuroplastic mechanisms involved in vulnerability to substance use disorder and brain recovery following chronic substance exposure. The findings revealed consistent alterations in synaptic density, BDNF/TrkB signaling, glutamatergic homeostasis, and epigenetic regulation, along with structural and functional neuroimaging changes in regions such as the prefrontal cortex (PFC), nucleus accumbens (NAc), and amygdala. Four core therapeutic domains for neuroplastic restoration were identified: neuromodulation approaches (including repetitive transcranial magnetic stimulation, transcranial direct current stimulation, and deep brain stimulation), compounds that promote neuroplasticity via neurotrophic signaling, epigenetic and anti-inflammatory interventions, and psychological therapies based on memory reconsolidation processes. These strategies demonstrated the capacity to normalize prefrontal activity, modulate reward networks, strengthen emotional regulation, and reduce craving. Despite significant advances, important gaps remain, including methodological heterogeneity, scarcity of longitudinal studies, and limited clinical generalizability. Overall, the evidence suggests that recovery from substance use disorder requires multimodal interventions simultaneously targeting molecular, synaptic, and circuit-level plasticity, with growing emphasis on personalized approaches guided by neurobiological biomarkers. 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

This narrative review systematically synthesizes recent clinical and pre-clinical evidence to elucidate the latest neurobiological mechanisms underlying acupuncture for post-stroke insomnia combined with cognitive impairment (PS-ICI). PS-ICI is characterized pathologically by a hippocampal-prefrontal circuitry-mediate "sleep-cognition vicious cycle" and clinically by concurrent cognitive decline and sleep-architecture disruption, both of which markedly impede post-stroke neurological recovery. Grounded in the Traditional Chinese Medicine (TCM) principle of "regulating Shen and re-animating the brain, "acupuncture exerts bidirectional modulation on cognition and sleep, significantly improving core functional outcomes and activities of daily living. Up-to-date studies confirm that synergistic, multi-dimensional effects are achieved through regulation of the BDNF-TrkB-PI3K/Akt signaling axis, preservation of neurovascular unit integrity, restoration of gut-brain axis homeostasis, normalization of circadian immune rhythms, and reshaping of default-mode network (DMN) plasticity. Given the high heterogeneity of included studies, a qualitative integrative approach was employed. Current evidence is nevertheless limited by small sample sizes, short follow-up durations, and substantial heterogeneity in acupuncture parameters (frequency and point selection); future work must therefore focus on dissecting inter-pathway interactions, standardizing therapeutic protocols, and integrating multi-omic technologies to propel acupuncture toward precision, evidence-based management of PS-ICI. Show less

Indigenous chickens in tropical regions routinely survive high environmental temperatures (40-45 °C) that cause significant mortality and production loss in commercial breeds, yet the genetic mechanisms of thermotolerance remain poorly understood. This study integrated genome-wide selective scans across 14 geographically and climatically diverse chicken breeds with multi-tissue expression data, gene expression quantitative trait locus (eQTL) analysis, transcriptome-wide association study (TWAS), and cross-species phenome-wide association study (PheWAS) to validate candidate genes. We identified 25 high-confidence genes under selection, with ATP1A1, PLCB4, RYR2 and AKT3 forming a regulatory hub coordinating cardiovascular, calcium and survival signaling. These genes converge on interconnected adrenergic, calcium, and GnRH signaling pathways, with coordinated expression across heart, hypothalamus, and liver forming an integrated thermoregulatory axis. The eQTL integration analysis using ChickenGTEx data identified 359 tissue-specific cis-eQTLs in selected regions. Additionally, TWAS analysis linked ATP1A1 to 145 gene-trait associations across 13 tissues and 14 trait categories (hepatic regulation, β = -2.13, p = 4.21 × 10⁻¹²), and cross-species PheWAS validated conserved roles in cardiovascular function (RYR2, resting heart rate p = 4.9 × 10⁻¹²), and ionic homeostasis (ATP1A1, chloride p = 1.18 × 10⁻³). In parallel, we also identified robust genomic signatures of domestication in classic candidate genes (TSHR, TBC1D1, BDNF), highlighting how initial separation from Red Jungle Fowl and subsequent adaptation to diverse climates have shaped the genetic and physiological diversity of the domesticated chicken. Collectively, our results reveal an integrated cardio-neuroendocrine calcium network driving heat adaptation, providing potential targets for breeding heat-tolerant chickens. Show less

Psychedelic compounds such as psilocybin, Lysergic Acid Diethylamide (LSD), N,Ndimethyltryptamine (DMT), and 3,4-methylenedioxymethamphetamine (MDMA) are emerging as novel therapeutics for neuropsychiatric disorders, including depression, Post-Traumatic Stress Disorder (PTSD), and addiction. Acting primarily through serotonin 5-HT2A receptor agonism, they activate intracellular cascades involving Brain-Derived Neurotrophic Factor (BDNF), Tropomyosin receptor kinase B (TrkB), and the mammalian target of rapamycin (mTOR) pathway, leading to enhanced neuroplasticity and synaptogenesis. Recent evidence demonstrates direct TrkB binding and sustained cortical remodeling, underlying their rapid and durable antidepressant effects. Advanced Drug Delivery Systems (DDS)-including liposomes, Solid Lipid Nanoparticles (SLNs), and Poly(lactic-co-glycolic acid) (PLGA) carriers-are being engineered to achieve controlled, braintargeted, and stimuli-responsive release while minimizing systemic toxicity. Integration with microfluidic fabrication, Artificial Intelligence (AI)-based dosing, and non-invasive routes such as intranasal and transdermal delivery improves precision and patient adherence. By merging neuropharmacology with materials science, these innovations are redefining psychedelic-assisted therapy through enhanced safety, personalized dosing, and translational potential for central nervous system disorders. Show less

Huntington's disease (HD) is a progressive neurodegenerative disorder marked by motor, cognitive, and psychiatric impairments, with depression as a major comorbidity. Existing treatments for Huntington-related depression are inadequate, highlighting the need for strategies that target molecular mechanisms underlying mood dysregulation. This review examines the mechanistic interplay between environmental enrichment (EE), a paradigm enhancing sensory, cognitive, and social stimulation and Neuropeptide S (NPS), a neuropeptide involved in stress modulation and emotional regulation. It focuses on their potential synergistic effects in modulating depression-associated molecular pathways in HD. EE activates signalling cascades that promote synaptic plasticity and neurogenesis, including the upregulation of brain-derived neurotrophic factor (BDNF), enhanced activation of cAMP response element-binding protein (CREB), and remodelling of glutamatergic and GABAergic transmission. NPS exerts antidepressant-like effects by attenuating hyperactivity of the hypothalamicpituitary- adrenal (HPA) axis, modulating corticotropin-releasing factor (CRF) signalling, and influencing monoaminergic systems. Evidence indicates that EE may enhance NPS receptor (NPSR1) expression and downstream intracellular calcium signalling, reinforcing adaptive plasticity in the striatum and prefrontal cortex regions vulnerable in HD. Integrating EE with NPS-targeted therapy could provide a multimodal approach to restore molecular homeostasis and alleviate depressive phenotypes in HD. Further research should elucidate optimal intervention timing, dose-response relationships, and potential cross-talk between EE-induced BDNF pathways and NPS-mediated stress resilience for translational application in neurodegenerative depression. Show less

Major Depressive Disorder (MDD) is a multifactorial psychiatric disease influenced by a combination of genetic and environmental factors. Among the genes linked to MDD, the Melanocortin 1 Receptor (MC1R), Catechol-O-Methyltransferase (COMT), Brain-Derived Neurotrophic Factor (BDNF), and the serotonin transporter (5-HTT) are of particular interest due to their critical roles in stress regulation and neural function. Despite their biological significance, the contribution of specific polymorphisms within these genes to MDD risk remains understudied. This retrospective observational case-control study included 87 Colombian patients diagnosed with MDD according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). The control group comprised Latino/admixed individuals without, sourced from the gnomAD v2.1.1 database. The complete coding region of the MC1R gene and three polymorphisms: 5-HTTLPR Insertion/Deletion 44 bp, BDNF-c.196G>A, and COMT-c.472G>A were genotyped using PCR and Sanger sequencing. The polymorphisms rs885479 and rs4680 were identified as protective factors against MDD, while the polymorphisms rs796296176, rs779504604, rs1805005 were associated with an increased risk of developing MDD (OR:22.87, OR:51.26, OR: 1.97, respectively). Several of the analyzed polymorphisms (rs796296176, rs779504604, rs1805005) increase the risk for MDD. Notably, we provide novel evidence of these polymorphisms in MC1R as a risk to MDD. Show less

This study aimed to investigate whether aerobic exercise (AE) and AE combined with whole-body vibration (AE+WBV) exert distinct effects on neurocognitive outcomes and circulating myokines, and to further explore the potential molecular mechanisms underlying exercise-induced neurocognitive changes. A total of 72 postmenopausal women were randomly assigned to an AE, AE+WBV, or control group. At baseline and after the 16-week intervention or control period, both behavioral and event-related potential (ERP) indices were assessed during a visuospatial working memory (WM) task, and serum myokine concentrations of brain-derived neurotrophic factor (BDNF), irisin, insulin-like growth factor-1 (IGF-1), osteocalcin (OC), interleukin-6 (IL-6), and IL-15 were measured. Reaction times, ERP P2 amplitudes, and P2 and P3 latencies remained unchanged postintervention. However, AE significantly improved accuracy rates (ARs) under the two-item WM condition and increased P3 amplitudes under both the two- and four-item conditions. AE+WBV produced broader improvements in both ARs and P3 amplitudes under the two- and four-item conditions. Regarding molecular outcomes, neither intervention affected IL-6 concentrations. In the AE group, BDNF and irisin levels increased significantly postintervention, whereas IL-15 levels decreased. In the AE+WBV group, IGF-1, irisin, and OC levels increased postintervention and IL-15 levels decreased. Changes in neurocognitive performance were significantly associated with BDNF and OC in the AE group, and changes in neurophysiological performance were significantly associated with IGF-1 and irisin in the AE+WBV group. Collectively, these findings suggest that AE and AE+WBV promote distinct myokine profiles and partially improve neurocognitive performance in postmenopausal women, with AE+WBV demonstrating stronger effects, likely mediated by different molecular pathways. Show less