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Brain-derived neurotrophic factor (BDNF) is a growth factor that has a central role in sustaining brain function. Besides the brain, BDNF is also expressed in immune cells. In preclinical models, anthocyanins (AC) consumption has been associated with benefits in BDNF homeostasis. This study investigated in healthy adults if the simultaneous consumption of a high-fat meal (HFM) with a cyanidin/delphinidin-rich extract (CDRE) could affect circulating BDNF, and Show less

Intrinsic Capacity (IC) is defined as the composite of physical and mental abilities an individual possesses, encompassing five domains: cognition, psychological health, sensory function, vitality, and locomotion. This construct is central to the World Health Organization's framework for assessing functional ability in older adults. Growing evidence highlights the critical role of the musculoskeletal system in maintaining these domains, while conditions such as sarcopenia, osteoporosis, and their coexistence as osteosarcopenia (OS) are increasingly associated with IC decline. This narrative review compiles current evidence on the modulatory role of muscles and bones in IC and the impacts of sarcopenia, osteoporosis, and OS. Most findings suggest that musculoskeletal tissues influence IC not only through biomechanical functions but also as secretory organs, releasing myokines and osteokines with endocrine, paracrine, and autocrine effects. Among the most studied are brain-derived neurotrophic factor, irisin, osteocalcin, and interleukin-6. Dysregulation of these pathways, along with biomechanical dysfunction and systemic inflammation, links sarcopenia, osteoporosis, and OS to IC impairment. Further research is needed to clarify the specific mechanisms involved, particularly in the sensory and vitality domains, to inform targeted interventions that promote healthy aging. Show less

Perioperative neurocognitive disorders (PND), primarily including postoperative delirium (POD) and postoperative cognitive dysfunction (POCD), are common and serious complications in elderly surgical patients. However, the exact mechanisms underlying PND are not fully understood. The lung-brain axis has recently been recognized as an important pathway in neurodegenerative diseases such as Alzheimer's disease (AD). Given that PND shares pathological features with AD, such as amyloid-β (Aβ) accumulation, the lung-brain axis may also represent a plausible mechanistic contributor to PND. Furthermore, elderly surgical patients often receive inhalation anesthetics and undergo mechanical ventilation during general anesthesia, which directly affect the lungs and may alter the pulmonary microenvironment. Therefore, we hypothesize that the lung-brain axis plays a role in the development of PND. In this article, we discuss potential mechanisms by which surgery and anesthesia-especially inhalation anesthetics and mechanical ventilation-may influence cognitive function via the lung-brain axis. Potential mechanisms include changes in the pulmonary microbiota, secretion of brain-derived neurotrophic factor, and lung-derived inflammatory responses. These pathways may disrupt the blood-brain barrier, promote neuroinflammation, and exacerbate Aβ deposition, ultimately leading to cognitive impairment. Exploring the role of the lung-brain axis could provide new insights into PND pathophysiology and reveal potential targets for prevention and treatment of PND by targeting pulmonary-mediated cascades. Show less

The olfactory mucosa has emerged as a promising source of mesenchymal stem cells with neurogenic potential. These cells exhibit neural, glial, and mesenchymal properties, making them attractive candidates for regenerative medicine, particularly in treating neurodegenerative and immunemediated disorders. This systematic review analyzed existing literature on the isolation, characterization, and therapeutic applications of olfactory mucosa mesenchymal stem cells. The review assessed variations in isolation techniques, culture conditions, and differentiation potential, as well as preclinical and clinical applications. Olfactory mucosa mesenchymal stem cells express key neural and mesenchymal markers, including Nestin, SRY-box 2, Olfactory mucosa mesenchymal stem cells represent a promising avenue for neurological and regenerative therapies. Despite their potential, further research is needed to optimize isolation techniques, enhance reproducibility, and navigate regulatory hurdles. Collaborative efforts between researchers, clinicians, and regulatory bodies will be essential to translating OM-MSC research into viable clinical applications. Show less

Brain-derived neurotrophic factor (BDNF) is a protein crucial to the survival, growth, and differentiation of neurons in the brain and spinal cord. BDNF is monitored across many populations as an indicator of one's cardiometabolic disease (CMD) and mental health (MH) risk. Adults living with a traumatic spinal cord injury (tSCI) are at a higher risk of developing CMD and MH issues, with symptoms often going unrecognized. Establishing serum BDNF as a screening tool within the tSCI population has the potential to improve CMD and MH symptom recognition. This systematic review aims to: (1) explore the tSCI literature to determine whether an association exists between serum BDNF, MH, and CMD risk(s); and; (2) identify best-practice BDNF sampling techniques within the tSCI population. A comprehensive search strategy was developed in collaboration with a University Health Network Librarian. Six databases (MEDLINE, Embase, CENTRAL, APA PsycInfo, CINAHL Ultimate, and Web of Science Core Collection) were searched to identify English-language studies published from inception to July 2025. Studies which reported serum BDNF in the tSCI population in addition to either MH or CMD and have three or more human participants with acute or chronic tSCI were included. Duplicate abstracts were removed and the remaining titles and abstracts reviewed and selected for full-text screening. Study quality was assessed for potential risk of bias using Downs and Black Checklist (Clinical Trials), Newcastle-Ottawa Score (Case-Control Study), or Joanna Briggs Institute Checklist (Cross-sectional Study), prior to data extraction. The serum BDNF analytic methods were reviewed in detail. A total of 2,148 potential studies were identified via the searches, of which 631 duplicates were removed, 1,488 abstracts were excluded for inappropriate population, outcome measure, or study design, and 29 articles were selected for full-text screening, with four studies included in the final review. All studies sampled and analyzed serum BDNF. A total of 271 participants (AIS: A-D, NLI: C1-L5), predominantly male (n = 224), with acute (n = 165) and chronic (n = 51) injuries aged 14-75 as well as healthy controls (n = 55) were included. One study investigated the influence of an intervention and three studies were cross-sectional. No identified study included a description or indication of the prevalence for MH conditions or CMD risk factors. Based on the reviewed literature, links between serum BDNF and MH disorders or CMD risk have not yet been established for individuals with acute or chronic tSCI. The selected studies demonstrated no consistent sampling or analysis methods, with limited adherence to prior established standards in the general population, bringing into question the reliability, validity, and quality of the available outcome data. Show less

The obesity pandemic continues to increase in prevalence in children and adolescents, with its increase outpacing the rate of adult obesity; the human developmental index, body mass index, and family income all display associations to childhood obesity. There are numerous adverse complications of childhood obesity, including cardiovascular, endocrine, and gastrointestinal manifestations. Obesity is thought to be an interaction of several different factors, such as leptin, proopiomelanocortin, glucose uptake in adipocytes, melanocortin receptor 4, protein convertase 1/3, brain-derived neurotrophic factor, fat-mass and obesity-associated gene, melanocortin receptor 4, tumor necrosis factor, interleukin-6, and long noncoding RNA. Epigenetic regulation, the unique gut microbiome role in contributing to obesity, environmental factors, and the social context of a child can precipitation of childhood obesity. In this review, we hope to explore the different medications for obesity, orlistat, glucagon-like peptide-1 agonists, liraglutide, semaglutide, exenatide, setmelanotide, metreleptin, naltrexone, lorcaserin, phentermine, metformin, fluoxetine, lisdexamfetamine, and zonisamide, while also reviewing surgeries such as the Roux-en-Y gastric bypass, laparoscopic or vertical sleeve gastrectomy, and adjustable gastric banding. Show less

Yueju pill (YJ), a classical Traditional Chinese Medicine formula for "six stagnations", has long been used for mood disorders. We have previously demonstrated that YJ exerts rapid-onset antidepressant effects. However, the long-lasting antidepressant effects and its underlying neurobiological mechanisms remain elusive. To evaluate the sustained antidepressant efficacy of YJ in a chronic restraint stress model and elucidate its underlying molecular mechanisms through the integration of transcriptomic, pharmacological, and molecular biological analyses. We first assessed quality consistency of YJ via HPLC quantification. YJ's long-lasting antidepressant actions were conducted using behavioral paradigms (NSF, TST, FST, SPT, OFT) from 30 min 5 day in normal or chronic restraint stress model (CRS) mice after acute administration. Hippocampal key targets in mice affecting the therapeutic onset and long-lasting antidepressant efficacy of YJ were anchored through RNA-sequencing. The expression alterations of these identified targets in mouse hippocampus following YJ treatment were further confirmed by Western blot and PCR. Bidirectional causal validation was achieved by region-specific pharmacological antagonism (PACAP6-38) and RNA interference (AAV-PACAP-shRNA) in the dentate gyrus (DG), elucidating the necessity of this pathway for enduring antidepressant responses to YJ. Elisa was utilized to quantify hippocampal synaptic protein expressions in response to YJ and to assess its association with PACAP. Multi-component analysis via simultaneous identification and quantification of four marker constituents established the inter-batch homogeneity of YJ, with determined mean levels of shanzhiside methylester (0.2594 mg/kg), geniposide (44.2805 mg/kg), ferulic acid (0.1031 mg/kg), and gentiobioside (0.6720 mg/kg). In dose-response testing (1.0-2.5 g/kg), YJ at 1.0 g/kg exhibited the optimal antidepressant-like profile, characterized by rapid onset (reduced feeding latency in NSF at 30 min), short-term efficacy (decreased TST immobility at 3 h), and prolonged therapeutic effects (reduced immobility persisting up to 5 days). In the CRS model, acute YJ administration rapidly and robustly reversed stress-induced behavioral deficits, as evidenced by improved performance in NSF at 30 min, TST at 2 h, and SPT at day 1, with sustained antidepressant-like effects observed in FST at day 3. Notably, these behavioral changes occurred without alterations in locomotor activity or center time in OFT. Hippocampal transcriptomic analysis revealed distinct time-dependent molecular signatures following YJ administration. At 30 min, YJ induced a unique transcriptional shift characterized by qPCR-confirmed upregulation of ADCYAP1 (encoding PACAP). Conversely, at 3 days, a separate signature emerged with CSPG4 (NG2) identified and validated as upregulated. Furthermore, YJ treatment increased hippocampal PACAP levels at 30 min and NG2 expression at 3 days in CRS-exposed mice. Intra-dentate gyrus infusion of PACAP6-38 eliminated YJ's rapid antidepressant-like effects (NSF at 30 min; TST at Day 1) but left Day 3 FST efficacy and NG2 upregulation partially intact. However, AAV-shRNA-mediated PACAP knockdown in the dentate gyrus completely blocked both rapid and sustained behavioral benefits and abolished NG2 induction at 3 days and also blocked the acute YJ-induced enhancement of hippocampal synaptic proteins (synapsin 1 and PSD95) and BDNF expression at both 30 min and 3 days post-administration. Our study demonstrates that YJ achieves sustained antidepressant effects through a time-dependent hippocampal mechanism involving sequential PACAP and NG2 activation, ultimately converging on synaptic protein enhancement and BDNF signaling. This multi-component, multi-target, and multi-temporal mode of action embodies the holistic essence of TCM and offers a compelling alternative to current monoamine-based therapies with limited efficacy and delayed onset. Show less

Obesity and excessive weight gain have emerged as significant global health concerns in recent years and are often comorbid with numerous contemporary diseases, including cardiovascular disorders, diabetes, and cognitive impairments. L-carnitine, a vital cofactor in mitochondrial energy metabolism, possesses potent antioxidant and anti-inflammatory properties that merit investigation for mitigating obesity-associated neuronal damage. Consequently, this study investigated the potential neuroprotective effects of L-carnitine on anxiety- and depression-like behaviors in adolescent rats subjected to neonatal monosodium glutamate (MSG) exposure, a model known to induce obesity and associated neurobehavioral alterations. Neonatal rats received MSG (4 g/kg, s.c.) on alternate postnatal days (PND) 2-10. Subsequently, L-carnitine (200 mg/kg) was administered via oral gavage daily from PND 60 to 81 (subchronic treatment). Anxiety- and depression-like behaviors were assessed using the Forced Swim Test (FST), Elevated Plus Maze (EPM), and Open Field Test (OFT). All molecular and histological analyses were conducted in the prefrontal cortex (PFC), a region selected for its susceptibility to excitotoxicity and critical role in emotional regulation. Oxidative stress was evaluated through measurements of total oxidant and antioxidant levels. To elucidate the underlying molecular mechanisms, gene expression analyses focused on neuronal survival and apoptosis (BDNF, Bax, Bcl-2), while immunohistochemical evaluations targeted neuroinflammation and cell death pathways (TNF-α, Caspase-3, IL-1β, and Bcl-2). The findings reveal that neonatal MSG exposure leads to pronounced anxiety- and depression-like behaviors, accompanied by metabolic dysregulation, oxidative stress, neuroinflammation, and apoptosis. Although L-carnitine treatment did not reverse obesity-related metabolic alterations, it exhibited notable sustained anxiolytic effects. The neuroprotective potential of L-carnitine was further supported by its ability to reduce cortical neuroinflammation and neurodegerenative damage through suppression of proinflammatory cytokines and restoration of antioxidant balance. Overall, this study offers valuable insights into the cognitive, genetic, and histological outcomes associated with obesity-related mood disturbances and contributes to understanding the complex biological mechanisms underlying these conditions. Show less

As a complex physiological and psychological phenomenon, pain has a wide impact on the quality of life of patients. Chronic pain represents one of the most challenging public health issues, and ensuring effective pain management is not only a fundamental right of individuals but also a sacred duty of healthcare providers. This review focuses on recent advancements (within the past five years) in understanding how electroacupuncture (EA) alleviates pain-related affective disorders, such as anxiety and depression. By integrating findings from clinical trials and mechanistic studies, we highlight three key mechanisms: (1)Brain functional regulation: EA modulates brain regions (e.g., prefrontal cortex, insula, thalamus) and networks (default mode network, salience network) via functional magnetic resonance imaging (fMRI)-observed functional connectivity changes. (2)Neurotransmitter and receptor modulation: EA regulates pain and emotions by altering BDNF, β-endorphin, TRPV1, NMDARs, and P2Y12 receptor signaling, supported by studies on chronic pain and depression models. (3)Immune factor adjustment: EA reduces neuroinflammation by targeting TLR4/NF-κB pathways and pro-inflammatory cytokines (IL-1β, TNF-α), improving pain-related affective disorders. Clinical and preclinical evidence demonstrates EA's safety, efficacy, and multi-target effects, however, optimal treatment parameters and individualized strategies require further investigation. Future research should combine multi-omics, large-scale multi-center clinical studies , and precision medicine approaches to deepen understanding of EA's mechanisms and clinical applications. Show less

Neuroblastoma (NB) represents a paradigmatic developmental malignancy in which lineage specification, oncogenic signalling, and epigenetic regulation converge to define tumour behaviour. Among the molecular axes shaping NB heterogeneity, neurotrophin receptors of the tropomyosin receptor kinase (Trk) family (TrkA, TrkB, and TrkC) and the p75NTR occupy a central position at the intersection between neuronal differentiation programs and malignant plasticity. While high TrkA and TrkC expression is associated with adrenergic identity, differentiation competence, and favourable clinical outcome, TrkB, frequently sustained by BDNF-driven autocrine loops, characterises mesenchymal-like, therapy-resistant states enriched in metabolic and inflammatory adaptations. Importantly, in NB, the dysregulation of neurotrophin signalling rarely arises from recurrent genetic alterations of neurotrophic tyrosine receptor kinase ( Show less

Adult neurogenesis, the generation of new neurons in the adult brain, acts as a fundamental driver of neural plasticity within specialized microenvironments. The integrity of the hippocampal subgranular zone, essential for pattern separation and mood regulation, relies on a functional syncytium formed by the vasculature, glial cells, and neural stem cells (NSCs). This review delineates the architecture of this system, detailing how the vascular pillar provides angiocrine support via vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF), while the glial pillar-comprising astrocytes and microglia-orchestrates metabolic homeostasis and immune surveillance. The dynamic regulation of this local ecosystem by systemic factors, including physical exercise and the gut-brain axis, is also explored. Furthermore, the breakdown of this alliance is examined as a pathological hub in aging, Alzheimer's disease (AD), and chronic stress. Crucially, the text addresses the significant translational gap between rodent models and human physiology. The ongoing controversy regarding the persistence of adult human neurogenesis is critically evaluated, attributing conflicting data to methodological variables such as postmortem interval (PMI) and fixation kinetics. Additionally, the risks of maladaptive plasticity, where aberrant neurogenesis contributes to conditions like epilepsy, are discussed. Finally, future directions involving high-resolution omics and imaging are highlighted, emphasizing that therapeutic strategies must navigate the complex biological risks of neural repair. 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

Age-related cognitive decline is a growing public health concern, yet early molecular indicators remain poorly defined. Since brain changes often precede behavioral symptoms, identifying early markers of vulnerability is critical. Here, we investigated whether dopamine regulation and synaptic or inflammatory signaling might provide early indicators of cognitive decline, prior to behavioral impairment. Method and Finding: Female hooded-Lister rats at 6 (young) and 12 (age-unimpaired) months of age were tested using the novel object recognition (NOR) task, with no observable cognitive deficits found in either group. Biochemical analyses revealed marked molecular differences in the prefrontal cortex (PFC) of aged-unimpaired rats. Synaptic proteins BDNF, PSD-95, and synaptophysin were significantly reduced, indicating synaptic destabilization. Concurrently, expression of COMT and NET, key regulators of dopamine catabolism and reuptake, was increased, suggesting reduced dopaminergic tone. Inflammatory signaling also shifted: Nfkb and Socs3 were increased at the transcriptional level in the PFC, while Il-6 and Cox2 remained stable. In contrast, the hippocampus showed relative resistance to these changes, with no significant alterations in most markers, although NF-κB activation was detected at the mRNA level, indicating posttranscriptional regulation. Our findings suggest that the PFC undergoes a latent vulnerability phase during midlife, marked by synaptic and dopaminergic dysregulation alongside low-grade inflammation, despite preserved cognitive performance. The hippocampus appears more resilient at this stage. Together, these early molecular changes may indicate later cognitive decline and offer a critical window for preventive intervention. Targeting these early shifts in the aging brain could hold transformative potential for delaying cognitive impairment. Show less

Housing conditions, particularly environmental enrichment (EE), can influence experimental outcomes and welfare. While EE is generally regarded as beneficial, a male bias exists in research supporting this. This study investigated whether sex differences exist in levels of BDNF in the brain and peripheral tissues in environmentally enriched mice. Expression of the catecholamine biosynthetic enzymes of the adrenal glands, key to the sympathoadrenal medullary system and stress response, was also investigated. We showed that female mice exposed to EE exhibited increased anxiety-like behaviors. EE in male mice did not induce anxiety-like behavior, and it was associated with increased hippocampal and pituitary BDNF expression, suggestive of enhanced neurotrophic support. In the adrenal gland, the levels of adrenal catecholamine biosynthetic enzymes, specifically total tyrosine hydroxylase and PNMT levels, were increased in females, but not in males. In conclusion, EE may serve as a mild stressor in female mice. In male mice, EE may have induced neurotrophic support of the hippocampus since hippocampal BDNF levels were increased with minimal changes to adrenal catecholamine synthetic enzymes. This study highlights the importance of considering sex as a biological variable in translational neuroscientific research. Show less

With population aging, the incidence of osteoporosis continuously elevates worldwide, resulting in increased fracture risks and clinical demand for orthopedic fixation. However, under osteoporotic conditions, the stability and longevity of implants are severely compromised by the pathological microenvironment, thus developing effective therapeutic interventions to achieve successful osteoporotic osseointegration remains a critical challenge in the regenerative medicine field. Herein, the parathyroid hormone (PTH) is encapsulated in Sr Show less

Alzheimer's disease (AD) involves progressive neurodegeneration, with abnormal receptor signaling and disrupted cell-cycle activity leading to neuronal loss. Here, we identify a previously unknown mechanism linking β-amyloid (Aβ) exposure to the nuclear translocation of the Insulin-like Growth Factor 1 Receptor (IGF1R) in differentiated SH-SY5Y neuronal cells. The differentiated cholinergic model induced by retinoic acid and BDNF expresses acetylcholinesterase (AChE) and indicates that under amyloidogenic stress, IGF1R may transition from homeostatic membrane and vesicular signaling to a nuclear-centric function. We show that prolonged Aβ treatment causes phosphorylation-dependent nuclear import of IGF1R, confirmed by confocal imaging and biochemical fractionation. IGF1R is conventionally located in the membrane and vesicular membranes; however, under amyloidogenic stress, we show here that it is imported to the nucleus and exerts transcriptional control. The buildup of nuclear IGF1R coincided with increased Cyclin D1 levels and redistribution of neurons into S and G₂ phases, indicating abnormal cell-cycle re-entry. Chromatin immunoprecipitation demonstrated increased IGF1R binding at the CCND1 and JUN promoters after Aβ exposure, suggesting a direct role in gene transcription. Pharmacological blockade of IGF1R phosphorylation by PPP or SUMOylation by Ginkgolic acid significantly reduced Cyclin D1 elevation, implying that both post-translational modifications are involved in receptor nuclear trafficking. Co-immunoprecipitation and confocal imaging identified Nucleophosmin (NPM1) as a putative IGF1R interacting partner, potentially contributing to its nuclear transport and stabilizing receptor-chromatin complexes. These results establish IGF1R as a signaling-transcription connector linking extracellular amyloid stress to nuclear gene regulation, providing a mechanistic explanation for faulty neuronal cell-cycle re-entry in AD. We suggest that abnormal IGF1R-NPM1 interactions contribute to receptor mislocalization and cell-cycle failure, highlighting new targets for therapeutic intervention aimed at receptor trafficking and neuroprotection in Alzheimer's disease. Show less

A vital question in neuroscience is whether and how efficiently cellular models may be differentiated into functional neuronal cells in culture. Despite the frequent use of the human neuroblastoma cell line SH-SY5Y, differentiation protocols vary extensively, with the most common being differentiation via the addition of retinoic acid and brain-derived neurotrophic factor. However, due to the lack of a reliable evaluation method, their adequacy as synaptic models remains unclear. Here, we investigate whether SH-SY5Y cells constitute a functional model for synaptic studies by phenotypically and ultrastructurally analyzing synaptogenesis in SH-SY5Y cells subjected to different differentiation protocols. Electron microscopy (EM) techniques, including conventional EM, cryo-EM, and cryo-electron tomography, were systematically applied to characterize synaptogenesis in SH-SY5Y cells. Further characterization was performed using immunostaining and functional assays, such as live exocytosis assays and whole-cell patch-clamp electrophysiology. Despite exhibiting some presynaptic-like features, differentiated SH-SY5Y cells do not form morphologically or functionally complete synapses under the conditions tested. Immunostaining results were consistent with previous findings, showing synaptic markers. However, functional investigations did not detect synaptic activity. High-throughput EM analyses revealed an absence of synaptic structures in these cells. Additionally, an alternative differentiation approach incorporating additional neurotrophic factors promoted the formation of presynaptic-like compartments containing synaptic vesicle-like vesicles (SVLVs). In contrast to typical synaptic vesicles, these SVLVs exhibited a pleomorphic size distribution and lacked connectors. These findings underscore the need for cautious interpretation of results derived from SH-SY5Y cells when investigating molecular synaptic architecture or function, as well as neurodegenerative diseases. Show less

Inflammation has emerged as a prominent feature of bipolar disorder (BD) pathophysiology, drawing attention to brain barriers known to regulate immune-brain interactions. While perturbation of the blood-brain barrier has been reported in BD, the blood-cerebrospinal fluid (CSF) barrier formed largely by the choroid plexus (ChP) remains underexamined. To address this gap in knowledge, we used a multiplex array to measure cytokine protein abundance in postmortem ChP tissue from individuals with BD and unaffected controls, revealing elevated levels of CCL2 and SPP1, factors associated with monocyte and macrophage recruitment and activation. In contrast, expression of cytokines involved in tissue homeostasis, trophic support, and immune signaling, including OSM, IGF-1, CX3CL1, TGFB3, GDNF, LIF, BDNF, SCF, and FGFs, was reduced. Several cytokines, including CCL2 and PLGF, exhibited condition-specific divergent age trajectories. Bulk RNA sequencing of the same cohort revealed a modest set of differentially expressed genes, including transcripts associated with oxidative stress, mitochondrial function, and immune regulation that were upregulated in BD. Notably, the BD CSF biomarker NELL2 was downregulated in the ChP. Gene set enrichment analysis highlighted activation of inflammatory and cellular stress pathways, as well as reduced expression of junction-related gene programs. These findings suggest a shift in ChP function in BD characterized by increased pro-inflammatory signaling and reduced trophic and barrier-supportive activity. Together, these data identify the ChP as an active site of immune dysregulation in BD and support the broader notion of brain barrier dysfunction in mood disorder pathology. Show less

Nerve Guidance Conduits (NGCs) are crucial for reducing trauma during nerve repair, directing axonal growth, and preventing scar tissue formation. In this study, tubular functional NGCs were developed based on vertically aligned electrospun poly(lactic-co-glycolic acid) (PLGA) nanofibers (vNGC). They were functionalized by conjugating them with bioactive mimetic peptides: a laminin-derived peptide (LD-BP) to promote vascularization, and nerve growth factor (NGF-BP) and brain-derived neurotrophic factor (BDNF-BP) mimetic peptides to support neural differentiation. The vascular differentiation of HUVECs in response to LD-BP, and the neuronal differentiation of PC12 cells in response to NGF-BP and BDNF-BP, were assessed. The results demonstrated that this approach enabled the fabrication of tubular vNGCs with various diameters, and that vertically aligned PLGA nanofibers significantly improved their structural integrity. Furthermore, BP-conjugated vNGCs outperformed non-conjugated control groups in promoting both vascular and neural differentiation. Importantly, peptide conjugation did not induce cytotoxicity or significantly alter the biodegradability of the vNGCs, supporting their suitability for biomedical applications. Finally, bifunctional vNGCs (BiF-vNGCs), conjugated with LD-BP, NGF-BP, and BDNF-BP, were tested in a rat model of sciatic nerve injury. The BiF-vNGCs showed superior performance compared to unmodified vNGC, Control and s-Control groups, effectively promoting vascularization and neural regeneration in vivo, offering a viable alternative to conventional nerve regeneration methods. Show less

Naringenin (NGN), a flavonoid widely utilized in agricultural and pharmaceutical applications, has increasingly become a source of environmental concern. This study systematically evaluated the developmental toxicity of NGN in zebrafish embryos. Our results showed that NGN exposure caused dose-dependent increases in embryonic mortality and induced a range of developmental malformations, including reduced body length, impaired eye and ear development, and cardiac dysfunction. Behavioral analyses revealed significant deficits in locomotor activity and sensory responses at concentrations of 5 and 10 mg/L. Molecular assessments via RT-qPCR demonstrated that NGN disrupted the expression of multiple genes critical for cardiac (kcnh2a, kcnh2b, hand2, has2, myh7, tnnt2a), otic (col2a1a, sox9a, sox9b), liver (hhex, leg1.1), visual (gnat1, gnat2), apoptotic (bax, casp9, casp3), and neurodevelopmental (pomca, bdnf, gfap, mbpa, s100b) pathways. Notably, NGN at 10 mg/L inhibited apoptosis and altered liver function, whereas a concentration of 15 mg/L promoted apoptosis, and these results suggest that NGN may interfere with the developmental processes of zebrafish embryos through different mechanisms at low and high concentrations, exhibiting a non-monotonic dose-response relationship. These findings highlight the potential ecological hazards of NGN contamination in aquatic environments, emphasizing the need for stricter management and further research into its long-term and combined effects with other pollutants. Our research offers new perspectives into the molecular and phenotypic mechanisms of NGN toxicity and underscores the importance of comprehensive risk assessment for emerging environmental contaminants. Show less

Physical exercise and nutritional strategies have become powerful tools for improving brain health, boosting cognitive performance, slowing cognitive decline, and reducing the risk of neurodegenerative diseases, primarily by influencing neurotrophic factors such as brain-derived neurotrophic factor (BDNF). This review examines the impact of various exercise types (endurance, high-intensity interval training, and resistance) along with dietary approaches (ketogenic diet and intermittent fasting) on BDNF, with a focus on their potential to promote cognition and neuroprotective benefits, particularly in the middle-aged and older population. Several molecular and physiological pathways may be involved, including activation of the PGC-1α-FNDC5-BDNF pathway, lactate signaling, increased blood flow to the brain and body, splenic platelet release, and stimulation of TrkB, IGF-1, irisin, and cathepsin B. Nutritional interventions may also boost BDNF through mechanisms involving β-HB and Notch 1 signaling. Research from both animal and human studies highlights the potential benefits of exercise and dietary modifications in supporting brain health and cognitive function. However, differences in study design and methodological limitations make it difficult to draw firm conclusions. These effects appear to be influenced by factors such as exercise characteristics (intensity, modality, and duration), the timing of blood collection, and the type of cognitive assessments. Future studies should focus on identifying the most effective intervention protocols and mechanisms, as well as understanding the individual factors that influence responsiveness to neurotrophic changes. Overall, targeted exercise and dietary strategies offer a promising approach to maintain brain health and reduce cognitive decline associated with aging and disease. Show less

The cell-intrinsic capacity of neurons to regenerate axons requires widespread coordination of the transcriptome, activation of multiple kinases, and reorganization of the cytoskeleton. Axonal repair is also influenced by extrinsic activating factors, such as neurotrophins. Here, we found that the neurotrophin BDNF amplifies multiple neuron-intrinsic programs to foster axonal regeneration in human iPSC-derived lower motor neurons (i Show less

P2X receptors, a family of ATP-gated ion channels, are increasingly recognized as key contributors to the pathophysiology of major depressive disorder. Among them, P2X7 plays a central role in stress-induced neuroinflammation by driving microglial activation, inflammasome signaling, and downstream reductions in BDNF and neuroplasticity. Additional P2X subtypes, including P2X4, further modulate neuronal and glial communication relevant to mood regulation. Evidence from animal models, human genetic studies, and early therapeutic trials supports the involvement of P2X signaling in depressive phenotypes and highlights P2X7 antagonists as promising candidates for novel antidepressant strategies. Overall, targeting P2X receptors offers a mechanistically distinct approach to understanding and treating depression. Show less

Irritable bowel syndrome (IBS) associated with early-life stress (ELS) commonly manifests as anxiety and visceral hypersensitivity. However, the pathogenic mechanisms underlying these effects are not fully understood. This study aims to investigate the role of brain-derived neurotrophic factor (BDNF) as a key mediator of ELS-induced changes through the brain-gut axis. A Sprague-Dawley male maternal separation (MS) rat model was used to induce anxiety and visceral hypersensitivity associated with ELS. BDNF levels were measured in the limbic system (cingulate gyrus, amygdala, and hippocampus) and serum. The correlation between BDNF levels, anxiety, and visceral hypersensitivity was analyzed. Corticotropin-releasing factor (CRF) expression in the hippocampus and the extent of visceral hyper-sensitivity were assessed in control, MS, and MS+K252a (a BDNF receptor antagonist) groups. MS rats exhibited higher levels of anxiety and visceral hypersensitivity compared to controls. BDNF production in the hippocampus was elevated in MS rats and positively correlated with anxiety (r = -0.78, p < 0.05) and visceral hypersensitivity (r = 0.93, p < 0.01). CRF expression, a key mediator of stress and visceral hypersensitivity, was also increased in the hippocampus of MS rats. Inhibition of BDNF signaling using K252a reduced CRF expression and alleviated visceral hypersensitivity. This study demonstrates that BDNF may mediate ELS-induced anxiety and visceral hypersensitivity through hippocampal TrkB-CRF signaling, providing a mechanistic basis for targeting BDNF in stress-related IBS. Show less

Inflammatory bowel disease (IBD) is a chronic gastrointestinal disorder with a high incidence of anxiety and depression. However, the underlying mechanisms of these symptoms remain to be fully elucidated. This study investigated the effects and mechanisms of a 20% ethanolic extract of Show less

Thyroid hormones (THs) and estrogen (E2) play essential roles in neuronal differentiation and plasticity during brain development. S-equol, a plant-derived isoflavone metabolite, is a selective E2 receptor (ER) ligand that exhibits neurotrophic effects; however, its interaction with TH receptor (TR) signaling remains unclear. In this study, we investigated the effects of S-equol on TR Show less