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Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a rare lung malignancy characterized by an aggressive clinical course and an unfavorable prognosis. Next-generation sequencing (NGS) has revealed that LCNECs exhibit molecular features resembling either small-cell lung carcinoma (SCLC-like LCNEC) or non-small cell lung carcinoma (NSCLC-like LCNEC). This study aimed to characterize the incidence of actionable gene variants in a retrospective cohort of LCNEC patients using a targeted NGS approach. Microscopic diagnosis was established according to the 2021 World Health Organization (WHO) classification using a standard immunohistochemical (IHC) panel. In total, 216 LCNEC tumor samples were analyzed for molecular variants in 17 genes using the RNA-based Archer FusionPlex Lung NGS assay (Integrated DNA Technologies, USA) and the MiSeq platform (Illumina, USA)-an algorithm utilized for routine NSCLC diagnosis. Overall, 46 variants were identified in 46/216 (21.3%) tumor samples, with 28/216 (13%) LCNECs harboring at least one actionable molecular variant potentially targetable by registered or investigational agents. 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

Ischemic stroke is a leading cause of death and disability among youth, with sex-specific differences in risk and outcomes, including post-stroke cognitive impairment. However, the neurodevelopmental factors underlying these pathological states are unclear. This study examined hypoxia-inducible factor-1 alpha (HIF-1α) and brain-derived neurotrophic factor (BDNF) levels in bilateral common carotid artery occlusion/reperfusion (BCCAO/R)-induced ischemic stroke in rats. It focused on post-stroke cognitive decline in male and female adult offspring following BCCAO/R-induced ischemic stroke, after prenatal immune activation (PIA) and late-trimester intermittent maternal hypoxic stress (IMHS). PIA was induced by lipopolysaccharide (0.1 mg/kg, i.p.) injection at gestational day (GD) 15, followed by IMHS exposure from GDs 17 until delivery. Thereafter, offspring (n = 10, male and females) from sham control, LPS-exposed, hypoxia-exposed, and combined LPS + hypoxia group were exposed to BCCAO/R-induced ischemic stroke at postnatal day 90. Neurological deficits and post-stroke cognitive function were assessed using Y-maze and novel-object recognition tests at 1-day and 5-days post-surgery. The prefrontal cortex and striatum, where structural and functional alterations have primarily been described in stroke patients, were isolated for BDNF and HIF-1α ELISA quantification. In female rats, non-spatial working memory was acutely reduced after BCCAO/R-induced stroke following PIA-IMHS exposures, but males were unaffected. Rats co-exposed to LPS + hypoxia show decreased HIF-1α in the male striatum compared to sham or LPS/hypoxia groups. The two-hit factor increased striatal BDNF levels compared with LPS alone. In females' prefrontal cortex, LPS + hypoxia versus controls, but LPS + hypoxia reduces BDNF more than LPS alone, indicating a synergistic and sex-dependent role of PIA and IMHS in stroke vulnerability at adulthood. Show less

Chronic stress is a risk factor for the development of anxiety, depression, and comorbid systemic conditions. Ayahuasca (AYA) has been used for hundreds of years and it elicits antidepressant and anxiolytic effects. However, it remains unknown whether AYA elicits a behavioral and biochemical protective effect in chronic stress. Therefore, we evaluated the therapeutic potential of AYA in reversing or attenuating the behavioral and biochemical alterations induced by an unpredictable chronic stress (UCS) paradigm in adult zebrafish. Zebrafish underwent an unpredictable chronic stress (UCS) protocol for 14 days or were left undisturbed in their tanks. On the 15th day, AYA was added to the tank at a dose of 0.5 or 1 mL/L for one hour. On day 16, fish underwent the sociability test and the novel tank test. The levels of whole-body cortisol and brain-derived neurotrophic factor (BDNF) were measured via ELISA. AYA restored stress-induced sociability impairments, anxiety-like behavior, and stress-induced hyperlocomotion and increased moving velocity in the novel tank test. Additionally, AYA reversed the stress-induced increase in whole-body cortisol and the stress-induced decrease in whole-brain BDNF. A single exposure of zebrafish to AYA restored the chronic stress-induced impairments in sociability, stress-induced anxiety-like behavior, and biochemical markers of stress and impaired neuroplasticity. These findings support the potential of AYA to reverse stress-induced behavioral and neuroendocrine alterations. Clinical studies are warranted to evaluate the translational relevance of these effects in individuals exposed to chronic stress. 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

TF (transcription factor) Prdm16 (positive regulatory domain-containing protein 16) regulates hematopoietic and neuronal stem cell homeostasis, adipose differentiation, and cardiac development. Its role in the circulatory system extends beyond the heart, as Prdm16 loss in arterial endothelial cells (ECs) impairs arterial reperfusion of ischemic mouse limbs due to endothelial dysfunction, and Zebrafish were used to analyze vascular development, arteriovenous endothelial specification, and the emergence of arteriovenous malformations in the absence or presence of Prdm16 or Notch signaling. Lentiviral-mediated Prdm16 overexpression in human endothelial (progenitor) cells was coupled to qRT-PCR (real-time quantitative polymerase chain reaction), Western blot, and transcriptional profiling to document Prdm16's importance for arterial lineage specification. Coimmunoprecipitation in HEK293 (human embryonic kidney 293) cells was performed to assess physical interaction between Prdm16 and the Notch pathway. Existing mouse and human data sets were reanalyzed to evaluate Prdm16 expression in mammalian arteriovenous malformations. Prdm16 actively promotes arterial EC identity while suppressing venous fate. Like in mice, Prdm16 is expressed by arterial ECs early during vascular development in zebrafish, where it synergistically coordinates arterial development together with canonical notch signaling, as their combined loss in zebrafish leads to arteriovenous malformations. PRDM16's arterializing effect on human ECs is dependent on canonical Notch activity, as it is blunted in the presence of canonical Notch inhibitors and potentiated in the presence of delta-like ligand 4. Mechanistically, Prdm16 does not increase the protein levels of the cleaved intracellular domain of Notch receptors (notch intracellular domain) but rather potentiates the effect of the latter via physical and functional interaction. Prdm16 further finetunes Notch signaling and arterial development by complexing with Hey2 (Hes-related family bHLH TF with YRPW motif 2), the basic helix-loop-helix TF acting downstream of canonical Notch during arterial lineage specification and development. Together, our data demonstrate an intricate interplay between Prdm16 and Notch in ECs and indicate that Prdm16 signaling may constitute a novel therapeutic target for arteriovenous malformations. 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

Depression is a prevalent mental disorder that profoundly affects patients' quality of life and work efficiency. The exploration of effective and safe treatment options remains a research focus for alleviating depression. This study aimed to assess the potential of We initially investigated the effects of GM12 on corticosterone (CORT)-induced injury in PC12 cells. Subsequently, the male Sprague-Dawley rats ( GM12 improved the viability of PC12 cells, reduced LDH release and apoptosis, thereby exerting protective effects against CORT-induced cell damage. GM12 administration significantly ameliorated depressive-like behaviors, restored 5-HT levels, normalized HPA axis hormone imbalances, reduced inflammatory response and upregulated of BDNF level and the BDNF/CREB protein expression in rats. The beneficial effects of GM12 may be mediated via multiple mechanisms, including regulation of gut microbiota composition and homeostasis, inhibition of inflammation and the modulation of the microbiota-gut-brain axis. This study can provide early evidence for the research of in-depth mechanism and development of this strain. Overall, GM12 shows promise as a potential treatment strategy or dietary supplement for depression, with significant potential for future application. Show less

Frailty is associated with increased risks of falls, disability, hospitalization, and mortality. The 24-h movement behaviors (24HMB) framework conceptualizes sleep, sedentary behavior (SB), light-intensity physical activity (LPA), and moderate-to-vigorous physical activity (MVPA) as mutually constrained components of daily time use and may inform frailty prevention and management. This scoping review maps evidence on associations between 24HMB and frailty and identifies methodological gaps to inform future research and nursing practice. This review adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) and follows Joanna Briggs Institute (JBI) guidance. We searched PubMed, Embase, CINAHL, and Web of Science. We included observational studies of adults aged ≥18 years. Exposures were objectively measured or validated self-reported sleep, SB, LPA, and MVPA, including step counts, breaks in SB, isotemporal substitution models (ISM), and compositional data analysis (CoDA). Outcomes were frailty or prefrailty assessed using validated instruments. Quality was appraised with JBI tools. Thirty-three studies showed good methodological quality. Longer SB, particularly prolonged, uninterrupted bouts, was associated with higher frailty. Greater MVPA was consistently associated with lower frailty. Light-intensity physical activity was generally beneficial but often attenuated when MVPA or total activity volume was modeled. Sleep fragmentation and poor sleep quality were associated with frailty. Isotemporal substitution models and compositional data analysis indicated that reallocating sedentary time to MVPA would yield the largest theoretical benefit, followed by reallocating to LPA. Higher daily step counts and more frequent or higher-intensity breaks in SB were associated with lower frailty. Evidence supports a 24-h integrated movement-behavior approach centered on MVPA, combined with reducing prolonged SB and improving sleep quality, for the prevention and nursing management of frailty. The study design and analytical protocol were prospectively registered on the Open Science Framework (OSF). The unique identifier is S39Y4, and the publicly accessible URL is https://doi.org/10.17605/OSF.IO/S39Y4. Show less

Obesity and Alzheimer’s disease (AD) are epidemiologically associated. The locus coeruleus (LC)—the brain’s primary and most significant source of norepinephrine—is one of the earliest sites of neurodegeneration in AD. The LC participates in feeding behavior through connections with the hypothalamus. The cellular composition of the LC has been characterized at single-cell resolution. However, the constituent cellular signatures of genes related to energy homeostasis—such as the melanocortin pathway genes—in the LC are unclear. We performed single-nucleus RNA sequencing and spatial transcriptomics (Visium) in the human LC, and HiPlex RNAscope in the LC of mice. The melanocortin pathway gene The online version contains supplementary material available at 10.1186/s40478-026-02287-x. Show less

High mobility group AT-hook 1 (HMGA1) is a chromatin regulator overexpressed in various cancers, often predicting poor outcomes. However, its role in head and neck squamous cell carcinoma (HNSCC) remains unclear. A hallmark of HNSCC is the rapid growth of its vasculature. Here, we identify an epigenetic mechanism whereby HMGA1 promotes tumor progression and angiogenesis via upregulation of fibroblast growth factor-binding protein 1 (FGFBP1). 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

Aging is associated with disturbances in brain energy metabolism, mitochondrial dysfunction, and increased oxidative stress, all of which increase neuronal vulnerability and contribute to the development of neurodegenerative disorders. Growing evidence indicates that physical exercise exerts neuroprotective effects through the release of exerkines-exercise-induced signaling molecules that mediate communication between peripheral tissues and the brain. Among them, irisin, a proteolytic cleavage product of the membrane protein FNDC5, has emerged as an important mediator of the muscle-brain axis. This review summarizes current knowledge on the molecular mechanisms underlying irisin activity in the central nervous system, with particular emphasis on the AMPK-PGC-1α-FNDC5/BDNF signaling axis, rapid receptor-mediated pathways involving the cAMP/PKA/CREB and ERK/CREB cascades, and the regulation of mitochondrial homeostasis, including biogenesis, dynamics, autophagy, and mitophagy. Experimental studies suggest that irisin may improve neuroplasticity, neuronal survival, mitochondrial function, and reduce oxidative stress, thereby alleviating cognitive deficits in models of aging and neurodegeneration. Although the precise receptor mechanisms and intracellular signaling events remain incompletely understood, accumulating evidence identifies irisin as a promising therapeutic target linking metabolic adaptation with neuroprotection. Further investigation of irisin-dependent pathways may facilitate the development of novel strategies aimed at preserving brain function and delaying the progression of age-related neurodegenerative diseases. Show less

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare inherited white matter disorder. Initially, a "classic" phenotype has been characterized, presenting early-onset macrocephaly, cerebellar ataxia, mild spasticity, and a distinctive neuroimaging pattern of diffuse white matter abnormalities with subcortical cysts. An "improving" phenotype has also been described, featuring milder or absent neurological signs and a remitting pattern on neuroimaging. Mutations in four genes, MLC1, HEPACAM, GPRC5B and AQP4 have been associated with MLC. We describe clinical and genetic features of a cohort of genetically confirmed Italian MLC patients, representing the largest Italian cohort reported to date. We conducted a retrospective, multicenter, observational study. Patients were included based on clinical and neuroimaging features consistent with MLC, along with a confirmed genetic diagnosis. Data were collected using a standardized database and included demographic, clinical, neuroimaging, neurophysiological, and genetic information. Thirty-three patients from eight Italian centers were enrolled. Twenty-seven harbored biallelic MLC1 variants (23 distinct mutations, including three novel variants), while six had three distinct heterozygous HEPACAM variants. All MLC1-mutated patients exhibited the "classic" phenotype, frequently accompanied by orthopedic, gastrointestinal, and respiratory comorbidities. HEPACAM-mutated patients were consistent with the "improving" phenotype. No patients harbored mutations in GPRC5B or AQP4. Our findings expand the mutational spectrum of MLC1, further characterize the disease phenotype, and provide valuable insights into its presence in Italy. They also underscore management needs of individuals with MLC, highlighting the importance of multidisciplinary care. 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

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

This study employs latent profile analysis (LPA) to identify potential categories of nurse burnout and to analyze differences in characteristics and influencing factors across burnout categories. From June to August 2025, a mixed sampling approach combining convenience and snowball sampling was used to recruit nurses from hospitals of varying levels in Southwest China. Three tools were used for data collection: A self-designed routine information questionnaire, Maslach Burnout Inventory-General Survey (MBI-GS) and Practice Environment Scale of the Nursing Work Index (PES-NWI), LPA identifies potential categories of nurses' professional burnout and uses multivariate logistic regression analysis to explore the factors associated with these categories. This study comprised a total of 809 participants. LPA identified four distinct latent classes of nursing burnout: Class 1, low-burnout-high-efficacy (11.5%); Class 2, mild-burnout-unfulfilled (33.9%); Class 3, moderate-burnout-exhausted (44.6%); and Class 4, severe-burnout-dysfunctional (10.0%). Multivariate logistic regression analysis showed that age, years of work experience, hospital level, nurses' participation in hospital management, nursing quality standards, staffing and resource adequacy, and medical care cooperation are significant predictors of burnout among nurses ( Nurse burnout in southwest China is mainly moderate to severe and exhibits distinctive characteristics. It is recommended to implement personalized interventions tailored to the specific characteristics of nurses' professional burnout to alleviate the situation. Particular attention should be given to nurses with fewer than five years of experience by providing enhanced job support and psychological assistance to help them navigate critical periods of professional burnout. These measures aim to safeguard nurses' physical and mental health, improving the overall quality of nursing, and promoting the healthy development of global medical care. 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

Hypertension-linked renal fibrosis leads to the gradual loss of renal function and eventually progresses to end-stage renal failure, which exhibits poor clinical efficacy and is difficult to reverse. Therefore, clarifying the development mechanism of hypertension-linked renal fibrosis is crucial for its prevention and treatment. In this review, we conducted an in-depth exploration of the pivotal elements, along with their detailed mechanistic linkages in the pathogenesis of hypertension-linked renal fibrosis. It was found that the renin-angiotensin-aldosterone system (RAAS) is overactivated in hypertension. Angiotensin II (Ang II) and aldosterone (Aldo) jointly cause the abnormal accumulation of reactive oxygen species (ROS) by increasing the activity and expression of Nox2 and Nox4, inducing the inhibition and uncoupling of endothelial nitric oxide synthase (eNOS), enhancing expression of selected microRNAs (miRNAs), and reducing glucose-6-phosphate dehydrogenase (G6PD) expression. In turn, elevated ROS trigger renal inflammation by activating the mitogen-activated protein kinase (MAPK)-nuclear factor-kappa B (NF-κB) pathways as well as ferroptosis. Thereafter, renal inflammation can promote the process of renal fibrosis by activating the transforming growth factor β (TGF-β), platelet-derived growth factor (PDGF), and lysophosphatidic acid (LPA). This review not only emphasizes the core role of the mechanistic axis that plays a crucial role in the development of hypertension-driven renal fibrosis-the "RAAS-ROS-inflammation-fibrosis" axis-but also proposes promising therapeutic strategies targeting this axis, including modulating RAAS activity, controlling the increase in ROS, inhibiting inflammation, and blocking fibrotic progression. It aims to provide novel insights and potential therapeutic directions for hypertension-related renal fibrosis in the future. Show less

To synthesize clinical, cognitive, safety, and mechanistic evidence on supervised high-intensity interval training (HIIT) after stroke and translate key findings into practice. We conducted a narrative review of supervised HIIT interventions in adults after stroke. Electronic searches of PubMed and Web of Science identified studies published between January 1, 2014, and September 30, 2025. Eligibility criteria emphasized feasibility, safety, and neurofunctional outcomes (six-min walk distance, gait speed, peak aerobic capacity, activities/participation, and cognition). Quantitative pooling was not performed, and the findings were qualitatively synthesized. To explain biological plausibility, mechanistic and translational sources were reviewed irrespective of the year and summarized separately. HIIT was feasible under guideline-concordant screening and monitoring, with no serious adverse events. Consistent gains were observed in aerobic capacity, walking endurance, and usual gait speed, whereas activity/participation effects were mixed. Cognitive benefits were domain-specific and the clearest for executive functions. Mechanistic signals (e.g., brain-derived neurotrophic factor (BDNF), frontal oxygenation, and endothelial function) support biological plausibility. Supervised HIIT appears safe and clinically useful for augmenting locomotor and aerobic outcomes after stroke and may preferentially enhance executive cognition. Implementation should complement task-specific therapy and follow standard screening and monitoring procedures. Future work should refine dose- and phase-specific protocols to maximize application to daily function. Show less

This study investigates the independent and interactive effects of apolipoprotein E (APOE) genotypes and white matter hyperintensities (WMH) on distinct neuropsychiatric symptom (NPS) phenotypes in patients with Alzheimer's disease (AD). We enrolled 325 AD patients consecutively diagnosed at a specialized memory clinic between May 2024 and May 2025. All participants underwent comprehensive clinical assessments-including the Chinese Mini-Mental State Examination (CMMSE), Activities of Daily Living (ADL) scale, and the Neuropsychiatric Inventory (NPI)-as well as 3T brain MRI for WMH quantification and APOE genotyping. First, we compared NPS profiles and cognitive/functional scores across APOE genotype groups (ϵ2/ϵ2-ϵ2/ϵ3, ϵ3/ϵ3, ϵ3/ϵ4, ϵ4/ϵ4) using analysis of variance (ANOVA) or Kruskal-Wallis tests, as appropriate. Second, we applied mediation analysis (PROCESS macro Model 4, 5,000 bootstrap samples) to examine whether WMH burden mediates the association between APOE genotype (X) and outcomes including CMMSE total score and domain-specific NPS subscores (delusions, agitation, irritability, euphoria). Significant differences emerged across APOE genotypes in both cognition (CMMSE, p < 0.05) and functional status (ADL, p < 0.05). At the symptom level, carriers of at least one ϵ4 allele exhibited higher agitation scores than non-carriers (p < 0.05); notably, the ϵ4/ϵ4 homozygotes showed significantly greater severity in delusions, agitation, irritability, and euphoria compared with all other genotype groups (all p < 0.05). Mediation analyses revealed no statistically significant indirect effect of APOE genotype on any outcome via WMH, indicating that WMH does not mediate these associations. Instead, APOE genotype exerted robust direct effects on both cognitive performance and specific NPS domains. APOE genotype-particularly the ϵ4/ϵ4 homozygous status-is associated with more pronounced cognitive decline and a distinct, severe NPS profile in AD, especially involving delusions, agitation, Euphoria, and irritability. These associations are independent of WMH burden, suggesting that APOE exerts direct neurobiological effects on neuropsychiatric manifestations. Thus, APOE genotyping holds dual clinical value: not only as a well-established biomarker for AD risk and diagnosis but also as a potential prognostic indicator for behavioral and psychological symptoms-offering actionable insights beyond conventional neuroimaging markers. Show less

Neuropathic pain (NP) frequently co-occurs with depression (DP), exhibiting complex pathogenesis and limited clinical treatment options. This study aims to investigate the efficacy of Eupalinolide B (EB) in alleviating NP co-occurring with DP and its potential molecular mechanisms. Combining network pharmacology, molecular docking, and molecular dynamics simulations to screen potential targets for EB, validated through transcriptomic data. Using a sciatic nerve branch-preserving injury (SNI) mouse model, we assessed pain and depression-like behaviors through von Frey testing, hot plate testing, tail suspension testing, forced swimming testing, and open field testing. Concurrently, Western blotting, immunofluorescence, and Nissl staining were employed to analyze relevant molecules and neuropathological alterations. Network pharmacology and bioinformatics analysis identified EGFR, PTGS2, and JUN as the key targets for EB in treating NP combined with DP. Behavioral studies showed that 20 mg/kg of EB significantly alleviated pain in SNI mice and improved depressive-like behaviors. Mechanism research indicated that EB downregulated the expression of EGFR and PTGS2, inhibited the activation of microglia and astrocytes, and reduced neuronal damage. Additionally, EB could upregulate the expression of synaptic proteins (PSD95, SYN1, and BDNF) in the hippocampus. EB alleviates neuroinflammation by reducing EGFR and PTGS2 protein expression, modulates synaptic plasticity, and improves pain-depression comorbidity. EB may represent a promising therapeutic approach for pain-related depression. Show less

Chronic Unpredictable Mild Stress (CUMS) is a well-established model for inducing behavioral, cognitive, neurochemical, and metabolic impairments associated with neurobehavioral alterations. This study assessed the neuroprotective, antidepressant, and metabolic regulatory effects of Lonafarnib, a selective farnesyltransferase inhibitor, in mice subjected to chronic unpredictable mild stress (CUMS) for 28 days. The in silico docking analysis revealed encouraging binding energies of Lonafarnib with AChE (- 11.58 kcal/mol), CRF1 (- 10.94 kcal/mol), BDNF (- 5.99 kcal/mol), 5HT1A (- 10.48 kcal/mol), and 5HT2A (- 10.77 kcal/mol). This suggests a potential structural compatibility with cholinergic, serotonergic, neurotrophic, and stress-related proteins as preliminary results which requires experimental validation. The in -vivo study of Lonafarnib (20 or 40 mg/kg, i.p.) were effective in preventing the neurobehavioral alterations in CUMS mice. As, the behavioral evaluations demonstrated that CUMS resulted in anxiety-like behaviors, depressive-like behaviors, and cognitive impairments (p < 0.0001), all of which were significantly alleviated by Lonafarnib, particularly at a dosage of 40 mg/kg. The administration of Lonafarnib resulted in significant improvements in behavioral performance, a reduction in oxidative and inflammatory markers (IL-6, TNF-α), stabilization of HPA-axis related parameters, normalization of corticosterone, glucose, and lipid profiles, along with an increase in BDNF levels. Histological findings also indicated the preservation of neuronal structure within the hippocampus. In conclusion, these findings suggest that Lonafarnib may offer protective advantages against neurobehavioral and metabolic dysfunction caused by CUMS. However, a comprehensive mechanistic validation of prenylation-dependent signaling pathways is essential for further investigation. Show less

Individuals with cancer often experience disrupted sleep, sedentary behavior, and reduced physical activity. This exploratory analysis examined the feasibility of continuous 24-h monitoring using wrist-worn accelerometers and characterized movement behaviors during a 12-week supervised resistance training program in individuals with cancer. We additionally aimed to evaluate whether daily movement behaviors (moderate-to-vigorous physical activity (MVPA), light physical activity (LPA), sedentary time, and sleep) differed between exercise and non-exercise days. Thirty individuals with cancer wore Axivity accelerometers continuously while participating in supervised resistance training (2-3 sessions/week). Feasibility was assessed via wear-time compliance. Movement behaviors were analyzed descriptively across exercise and non-exercise days throughout the intervention. Participants demonstrated high adherence to continuous monitoring, with valid wear data on 70% of all days of the intervention. Within-person comparisons revealed significantly higher MVPA (+3.3 min) and LPA (+10.9 min) on exercise days. No significant changes were observed in sleep duration or sedentary time across the intervention or between exercise and non-exercise days. Continuous wrist-worn accelerometry is a feasible method for long-term behavioral monitoring in individuals with cancer. Supervised resistance training produced modest acute increases in physical activity but did not impact sleep or sedentary time. Show less

Neuroinflammation, driven by β-amyloid peptide accumulation, plays a critical role in the pathogenesis of Alzheimer’s disease, resulting in neurodegeneration and cognitive decline. Inflammatory cytokines, particularly tumor necrosis factor (TNF), adversely affect neuronal function and survival by counteracting the neuroprotective effects of neurotrophins. Importantly, brain-derived neurotrophic factor (BDNF) has been shown to alleviate the neurotoxic effects of pro-inflammatory cytokines. While the mechanisms through which pro-inflammatory cytokines disrupt BDNF/TrkB signaling are well understood, the specific ways in which BDNF protects neurons from inflammatory damage remain unclear. We present evidence that BDNF reduces cytotoxicity and neuritic damage in cholinergic neurons (SN56) induced by TNF and β-amyloid peptide, through the downregulation of c-Jun N-terminal kinase (JNK) activation. BDNF inhibits TNF-induced JNK activation by stimulating p38 mitogen-activated protein kinase. These findings indicate that BDNF restores neuronal functionality by modulating the signaling pathways of inflammatory cytokines, such as TNF, and highlight potential therapeutic strategies to mitigate neuroinflammation-associated neurodegeneration in Alzheimer’s disease. The online version contains supplementary material available at 10.1007/s11064-026-04740-8. Show less

Chronic stress induces detrimental effects on cognition, behavior, and hippocampal integrity. An enriched environment (EE) has been shown to enhance learning and memory; however, its role against chronic immobilization stress (CIS)-induced alterations and the underlying mechanisms remain insufficiently explored. This study aimed to investigate the protective effects of EE on CIS-induced behavioral, molecular, and structural changes in the hippocampus of adult male rats. Thirty-two adult male Wistar albino rats were assigned to four groups: control, control + EE, CIS, and CIS + EE. Rats were subjected to CIS (4 h/day) followed by EE exposure (2 h/day) for 28 days. Behavioral assessments were conducted. Serum corticosterone levels, hippocampal brain-derived neurotrophic factor (BDNF), and mRNA expression of aquaporin-4 (AQP4) and glutamate receptors (GluA1 and GluA2) were evaluated. Histopathological, ultrastructural, and immunohistochemical (LC3) examinations were performed. EE significantly ameliorated CIS-induced cognitive and behavioral impairments and restored hippocampal histological and ultrastructural integrity. These effects were associated with reduced serum corticosterone levels, increased hippocampal BDNF levels, and upregulated expression of AQP4, GluA1, and GluA2 mRNA. These findings suggest that EE is a promising non-pharmacological strategy for mitigating stress-induced hippocampal dysfunction and cognitive decline. Show less

Neuritin 1 (NRN1) has emerged as a multifaceted regulator of synaptic plasticity, neuronal excitability and structural remodelling. This review synthesises knowledge of NRN1 function across the central and peripheral nervous systems, with a focus on its roles in sensory neurones and neuronal repair following injury. We discuss evidence that NRN1 interacts with classical neurotrophic pathways, including brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), while engaging distinct cellular mechanisms that span activity-dependent trafficking, modulation of calcium and potassium channel function and regulated local axonal mRNA translation. Accumulating data indicate that NRN1 contributes to injury-induced plasticity and functional recovery through both cell-autonomous neuronal mechanisms and non-cell-autonomous signalling involving glial and stromal cells. In long-projecting sensory axons, regulated transport and local translation of Nrn1 mRNA position NRN1 as a spatially restricted effector of axonal growth, excitability and regeneration. Dysregulation of NRN1 expression and signalling has been implicated in pathological contexts including neurodegeneration, diabetic peripheral neuropathy and inflammatory pain, where restoration of NRN1 activity promotes axonal integrity, Schwann cell survival and neurotrophic support. Beyond neurons, NRN1 also modulates inflammatory and angiogenic pathways, including VEGF and CXCR4 signalling, linking neuronal plasticity to broader tissue and immune responses. Together, these findings support a model in which NRN1 acts as a molecular integrator of neurotrophic, metabolic and injury-associated signals, coordinating plasticity while also presenting potential routes to maladaptive sensitisation. We highlight key mechanistic and translational challenges that must be addressed to harness NRN1 biology therapeutically aimed at enhancing neuronal repair while limiting persistent sensory dysfunction. Show less

The utility of emerging lipid markers-apolipoprotein B (apoB) and lipoprotein(a) (Lp[a])-for improving atherosclerotic cardiovascular disease (ASCVD) risk assessment beyond traditional lipid measures remains uncertain, particularly in young adults. To evaluate associations of traditional and emerging lipid markers with ASCVD and assess the incremental value of emerging markers beyond established risk models. This prospective cohort study included adults aged 18 years or older without cardiovascular disease from 3 US cohort studies (Coronary Artery Risk Development in Young Adults, the Framingham Heart Study Offspring, and the Multi-Ethnic Study of Atherosclerosis [MESA]). Data were analyzed from April to June 2025. Lipid markers, including low-density lipoprotein (LDL) cholesterol, non-high-density lipoprotein (HDL) cholesterol, remnant cholesterol, total-to-HDL cholesterol ratio, apoB, and Lp(a). Hazard ratios (HRs) for incident ASCVD per-SD increase in lipid marker levels, estimated using Cox proportional hazards regression models adjusted for demographic and clinical factors, and model performance metrics (Harrell concordance index [C-index], net reclassification improvement [NRI], and mean calibration) comparing models including the risk estimated by the Predicting Risk of Cardiovascular Disease Events (PREVENT) base equations against models that additionally included each lipid marker. Among 10 519 participants (mean [SD] age, 48.3 [15.7] years; 53.0% female), 1103 ASCVD events occurred during a median follow-up of 21.3 (IQR, 16.5-26.0) years. ApoB was positively associated with ASCVD events, especially in younger adults aged 18 to 39 years (adjusted HR [AHR] per-SD increase, 1.53; 95% CI, 1.30-1.79) vs those aged 40 years or older (AHR, 1.13; 95% CI, 1.06-1.20) (P < .001 for interaction). Lp(a) as a continuous variable was associated with a marginal increase in ASCVD in adults aged 40 years or older (AHR, 1.07; 95% CI, 1.00-1.16) but not in younger adults (AHR, 1.02; 95% CI, 0.87-1.19) (P = .61 for interaction). When dichotomized (>50 vs ≤50 mg/dL), Lp(a) was associated with ASCVD in adults aged 40 years or older (AHR range, 1.36; 95% CI, 1.13-1.64) but not in younger adults (AHR, 0.98; 95% CI, 0.66-1.45) (P = .42 for interaction). Adding apoB to 10-year ASCVD risk estimated by the PREVENT base equations was associated with improved risk reclassification in younger adults (continuous NRI, 0.67; 95% CI, 0.23-1.09) but not in those aged 40 years or older (continuous NRI, 0.16; 95% CI, -0.05 to 0.27). ApoB was also associated with improved 30-year risk reclassification in younger adults (continuous NRI, 0.47; 95% CI, 0.02-0.84). Dichotomized Lp(a), but not continuous Lp(a), was associated with improved 10-year NRI only in MESA (0.13; 95% CI, 0.03-0.24). In this cohort study of 10 519 adults, adding apoB to PREVENT-estimated ASCVD risks was associated with improved risk reclassification, particularly in younger adults. However, the clinical importance of these modest improvements remains uncertain. 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