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The brain-derived neurotrophic factor (BDNF) is a potent neuroprotective factor; however, its large molecular size limits its ability to cross structural barriers such as the blood-spinal cord barrier. This study explores the therapeutic potential of exosome-mediated delivery of engineered circular BDNF (circBDNF) to promote spinal cord injury (SCI) repair through activation of the PI3K/AKT/mTOR signaling pathway. A synthetic circBDNF sequence encoding BDNF was used to construct a circBDNF overexpression plasmid, which was transfected into HEK293T cells to generate circBDNF-loaded exosomes (circBDNF-EXO). These exosomes were characterized via transmission electron microscopy, nanoparticle tracking analysis, and Western blotting. In vitro, the protective effects of circBDNF-EXO were evaluated in an oxygen-glucose deprivation/reperfusion (OGD) injury model in HT22 cells, focusing on cell viability, reactive oxygen species (ROS) levels, apoptosis, inflammation, and signaling pathways. In vivo, a T10 SCI mouse model was employed to assess therapeutic efficacy, using behavioral, electrophysiological, histological, and molecular analyses. In vitro, circBDNF-EXO treatment significantly increased BDNF expression, enhanced cell viability, reduced ROS levels, mitigated inflammation, and inhibited apoptosis in HT22 cells following OGD injury. In vivo, administration of circBDNF-EXO resulted in improved motor function recovery, evidenced by increased Basso Mouse Scale scores, enhanced gait coordination, and better motor-evoked potentials. Histological analyses demonstrated elevated BDNF expression, decreased apoptosis, reduced oxidative stress, and enhanced axonal regeneration in the injured spinal cord. Mechanistically, circBDNF-EXO activated TrkB receptors and upregulated the PI3K/AKT/mTOR signaling pathway, as confirmed by Western blot analysis. Exosome-mediated delivery of circBDNF promotes SCI repair by activating the PI3K/AKT/mTOR pathway, suppressing apoptosis, oxidative stress, and inflammation, and enhancing axonal regeneration. This innovative approach holds substantial promise for SCI treatment and deserves further exploration in preclinical and clinical studies. Show less

Scientific scepticism, as an epistemic orientation, remains under-researched. This study investigated the interplay between belief in science, supernatural credence, and cognitive processing styles in a sample of 300 participants ( Show less

This study aimed to investigate the current status of career calling among novice nurses, to identify potential subtypes and their population characteristics, and to further explore the factors associated with the different subtypes. A cross-sectional descriptive study was used. From January to February 2024, 845 novice nurses from 11 hospitals in Shanxi Province were selected for an online questionnaire survey using convenience sampling. The demographic questionnaire, transition shock of newly graduated nurses scale, medical staff resilience scale, and career calling scale were used as study instruments. Latent profile analysis (LPA) was used to explore the subtypes of novice nurses' career calling, and multifactorial logistic regression was used to analyze the related factors of novice nurses' career calling. Three subtypes of career calling of novice nurses in this study were identified, namely, lacking-calling group (10.3%), stable-calling group (50.0%), and sufficient-calling group (39.7%). Education, weekly working hours, weekly frequency of night shifts, reasons for choosing nursing, level of transition shock, and level of resilience were significantly associated with the three latent profiles of career calling of novice nurses in this study. Novice nurses' career calling presents 3 latent profiles and is heterogeneous in this study. Nursing administrators could pay attention to the differences in the level of career calling of novice nurses and adopt targeted management strategies based on the type of characteristics of the population in order to improve the level of career calling of novice nurses, help them develop their careers, and stabilize the nursing workforce. Show less

Elevated lipoprotein(a) [Lp(a)] levels have been strongly related to cardiovascular (CV) risk. However, its association with Hypertension Mediated Organ Damage (HMOD) and CV events in the primary prevention setting remains unclear. To evaluate in these patients, the correlation between Lp(a) levels and: (i) heart, vessels and kidney HMOD and; (ii) CV events and all-cause mortality in a primary prevention setting. 747 low CV risk subjects were recruited between 2009 and 2014. HMOD was assessed through Pulse Wave Velocity, carotid Intima-Media Thickness (IMT), presence of carotid plaques, Left Ventricular Hypertrophy (LVH) and Ejection Fraction and glomerular filtration rate. All-cause mortality and CV events up to 2021 were retrieved by electronic health records, for a median follow-up time of 10 years (I-III quartiles 9.6-11.1). Mean age was 50.8 ± 13.0 years and 63.5% of the subjects were men. The prevalence of hypertension was 37.9%, dyslipidemia 67.2%, smoking 17.8%, and diabetes mellitus 8.7%. Median Lp(a) value was 17 mg/dL (5.9-56.0), and 26.5% of patients had values above 50 mg/dL. Regarding HMOD, 10.3% subjects had arterial stiffness, 7.2% increased IMT, 19.8% carotid plaques while only 0.7% had LVH. No significant correlation was found between Lp(a) levels and indices of subclinical HMOD. Furthermore, no relationship was found between CV events and all-cause mortality and Lp(a) levels. In this primary prevention cohort, elevated Lp(a) levels were not associated with significant structural damage to the heart, carotid arteries, or increased aortic stiffness and were not associated with CV events and all-cause mortality. Show less

Many factors, such as lifestyle, medication, and environmental exposures, are reported to cause thyroid hormone system disruption (THSD) in humans, however studies linking THSD to health effects are sparse. Adverse Outcome Pathways (AOPs) provide mechanistic links from molecular events to adverse outcomes, with effect biomarkers serving as a tool to empirically anchor key events and health effects and to assess biological relevance. This review aims to identify and evaluate effect biomarkers for thyroid hormone system-related AOPs for further validation in experimental and epidemiological studies. Using AOP-wiki, we extracted and analysed thyroid-related AOPs, focusing on the eleven AOPs with mammalian evidence. We did systematic literature search to identify potential effect biomarkers for future epidemiological studies. In an AOP network analysis of the eleven thyroid-related AOPs, we identified four AOP clusters, including hippocampal alterations, impaired learning and memory, thyroid follicular cell adenomas/carcinomas, and kidney toxicity. For the clusters on hippocampal alterations and impaired learning and memory, brain-derived neurotrophic factor emerged as a promising effect biomarker. For the cluster on thyroid follicular cell adenomas/carcinomas, no promising effect biomarkers with high specificity were identified, but interleukin-34, oxidative stress, and expression of several genes were found to be related to the adverse outcome. For kidney toxicity, a panel of effect biomarkers were identified, such as clusterin, cystatin-C, kidney injury molecule-1, N-acetyl-beta-d-glucosaminidase, neutrophil gelatinase-associated lipocalin, and osteopontin. This review operationalizes the AOP framework to support the use of mechanistically anchored effect biomarkers in human studies on THSD. By aligning key biological events with measurable endpoints, human matrices, and feasibility considerations, it provides a scientifically grounded path from mechanistic understanding to population research application. This enables more targeted biomonitoring, strengthens interpretation of epidemiological findings, and informs research and regulatory priorities for future validation efforts. Show less

Serum extracellular vesicle (EV) microRNAs (miRNAs) are promising biomarkers for ischemic stroke (IS), but their role in transient ischemic attack (TIA) remains unclear. This study aimed to evaluate EV miRNAs as non-invasive diagnostic tools for IS and TIA. Using single-molecule sequencing, miRNAs were profiled in pooled sera from 50 IS patients and 50 controls. Altered miRNAs were validated via individual qRT‑PCR in the same cohort and tested in expanded internal (100 IS, 40 TIA, 100 controls) and external validation cohorts (32 IS, 8 TIA, 32 controls). Diagnostic performance was assessed via ROC and logistic regression analyses. Bioinformatics and in vitro oxygen-glucose deprivation/reperfusion (OGD/R) models were employed to explore mechanisms. Initial screening identified 134 differentially expressed EV miRNAs (36 upregulated, 98 downregulated) in IS. Validation confirmed significantly decreased let-7f-5p in IS and TIA, and elevated miR-486-5p and let-7b-5p in IS, with let-7b-5p higher in IS than TIA. A combined EV miRNA panel may effectively distinguish IS and TIA from controls, and stratify IS severity and TIA subsequent stroke risk. Multivariable logistic regression showed increased EV let-7b-5p independently associated with IS, and reduced let-7f-5p with IS/TIA. Bioinformatic analysis predicted FOXO1 and BDNF as key targets; decreased FOXO1 and increased BDNF were observed in IS serum and serum EVs, and FOXO1 downregulation was replicated in an OGD/R cellular model. A serum EV miRNA signature (downregulated let-7f-5p, upregulated miR-486-5p and let-7b-5p) may serve as a non-invasive biomarker panel for assessing IS severity and TIA stroke risk. Dysregulation of these miRNAs and their targets may contribute to ischemic injury pathology. Show less

This study aimed to identify different symptom profiles of complicated grief/bereavement-related posttraumatic stress disorder (PTSD) and examine the associations with social life factors, posttraumatic growth, and quality of life in a sample of parents whose children died in Sewol ferry accident. A total of 272 bereaved parents affected by the Sewol ferry accident participated and completed self-report scales about traumatic loss-related symptoms. The latent profile analysis (LPA) of complicated grief and posttraumatic symptoms was classified. To examine the predictors (interpersonal stress/familial conflict/social support) and outcomes (posttraumatic growth/quality of life) of the traumatic loss symptom profiles, an automatic three-step approach was chosen. The LPA identified three symptom profiles of complicated grief and posttraumatic stress: low symptomatology group (30.4%), moderate symptomatology group (49.6%), and high symptomatology group (20.0%). Higher perceived interpersonal stress significantly increased the odds of moderate and high symptomatology, while higher family stress was a significant predictor for high symptomatology compared to both low and moderate symptomatology groups. In addition, higher perceived social support significantly decreased the odds of being in both moderate and high symptomatology groups compared to the low group. The low symptomatology group showed the highest quality of life, followed by the moderate and high groups. Posttraumatic growth was also significantly different between the classes, with the moderate symptomatology group reporting higher growth than the low symptomatology group. Our findings suggest that managing the mental health of people who have experienced a traumatic loss will be a critical component of their quality of life in the future. In addition, interventions to help reduce family conflict and interpersonal stress may be necessary to reduce difficulties associated with psychopathology. Show less

Lipoprotein(a) (Lp(a)) is increasingly recognised as an independent and causal risk factor for atherosclerotic cardiovascular disease. Although the underlying mechanisms remain incompletely defined, evidence supports a multifactorial role for Lp(a) in atherogenesis. Lp(a) contributes to endothelial dysfunction, promotes vascular inflammation and enhances lipid retention and oxidation within the arterial wall. These changes drive foam cell formation and smooth muscle cell activation, hallmarks of early plaque development. In addition, Lp(a) exerts prothrombotic effects through structural homology with plasminogen, interfering with fibrinolysis and promoting thrombosis, which may increase the risk of plaque rupture and acute events. Collectively, these overlapping mechanisms underscore the unique contribution of Lp(a) to both the development and progression of atherosclerosis. As novel targeting therapies emerge, a deeper understanding of Lp(a) biology will be essential for translating these insights into clinical benefit. Show less

Nurses' voice behavior is critical for patient safety and organizational improvement. However, its manifestation is not uniform among nurses. This study aimed to identify latent profiles of nurses' voice behavior using Latent Profile Analysis (LPA) to understand this heterogeneity and explore its influencing factors, with a specific focus on differences across work motivation dimensions (rooted in Self-Determination Theory, SDT). A multicenter cross-sectional design was adopted. Data from 701 clinical nurses across six hospitals in Guangxi Province were analyzed: LPA identified four distinct profiles, and Multinomial Logistic Regression was used to examine predictors. Work motivation was measured by the Multidimensional Work Motivation Scale (MWMS), and voice behavior by the Voice Behavior Scale (VBS). LPA identified four distinct profiles (Conservative, 5.42%; Balanced Risk-Taker, 26.39%; Transitional, 34.38%; Challenging, 33.8%), and Multinomial Logistic Regression was used to examine predictors. Work motivation was measured by the Multidimensional Work Motivation Scale (MWMS), and voice behavior by the Voice Behavior Scale (VBS). Results showed autonomous motivation (e.g., intrinsic drive) strongly predicted active voice behavior, while amotivation predicted conservative profiles. Nurses exhibited high work motivation (MWMS: 93.02 ± 21.09) and moderately high voice behavior (VBS: 39.27 ± 8.736). The research found that nurses exhibited high work motivation and moderately high voice behavior, with autonomous motivation being a pivotal predictor. Differentiated strategies targeting intrinsic motivation enhancement are critical for fostering nursing innovation and improving care quality. 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

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

Acute respiratory distress syndrome (ARDS) is a severe clinical syndrome driven by inflammation, oxidative stress, and pulmonary tissue injury, for which effective therapy drugs remain lacking. In this study, the therapeutic potential and underlying mechanisms of dipotassium glycyrrhizinate (DG) in ARDS were systematically evaluated through both In an A549 cell model, DG exhibited no cytotoxicity within the tested concentration range and significantly suppressed LPS-induced excessive reactive oxygen species (ROS) generation and pro-inflammatory cytokine expression, including Tumor necrosis factor (TNF)- In conclusion, DG alleviates ARDS-associated inflammation and oxidative stress through coordinated modulation of multiple signaling pathways, providing a theoretical and experimental foundation for its potential development as a natural therapeutic agent against ARDS. Show less

Fear of progression (FoP) is a prevalent psychological issue among stroke patients. Previous studies failing to distinguish characteristics of patient groups with varying FoP levels. Latent profile analysis (LPA) classifies individuals into distinct subgroups via continuous FoP indicators, boosting classification accuracy by accounting for variable uncertainty. Given FoP's heterogeneity, investigating FoP profiles and their influencing factors in stroke patients is clinically significant for personalized psychological care and improved patient quality of life. A total of 366 stroke patients were selected as study subjects through convenience sampling, and a cross-sectional survey was conducted. FoP was assessed using the Fear of Progression Questionnaire-Short Form (FoP-Q-SF, 2 dimensions, 12 items). Independent variables included demographic characteristics, clinical indicators, the Recurrence Risk Perception Scale for Stroke patients (RRPSS), and the Medical Coping Modes Questionnaire (MCMQ). LPA was performed on the FoP-Q-SF items to identify subgroups. The R3STEP method was used to analyze influencing factors of subgroup membership, and the BCH method was applied to compare differences in distal outcomes across subgroups. Statistical significance was set at The study sample had a mean age of 63.93 ± 10.58 years, with 70.5% males and 65.0% first-ever stroke patients. Two latent profiles were identified: Low-FoP Adaptive Type (C1, 48.6%) and High-FoP Sustained Type (C2, 51.4%). The R3STEP showed that age 18-59 years (OR = 0.476, 95%CI = 0.245-0.924, This study revealed significant heterogeneity in FoP among stroke patients. Age, hypertension comorbidity, excessive recurrence risk perception, MCMQ-confrontation, and MCMQ-avoidance were associated with high FoP. Healthcare providers should prioritize identifying high-risk individuals and develop tailored interventions to reduce FoP and improve rehabilitation outcomes. Show less

Early vascular regeneration is important for the speedy recovery of neurological function following ischemic stroke. M2-like microglia polarization decreases and vascular regeneration weakens with aging. The function of mitochondrial respiratory chain is dependent on M2-like polarization in microglia. A murine model of middle cerebral artery occlusion (MCAO) was used to perform animal behavioral assessments, immunoblotting, tube formation and chick embryo chorioallantoic membrane assays. A D-galactose-induced cellular senescence model was established in BV2 cells. Aging significantly exacerbates acute brain injury 24 hours post-cerebral ischemia-reperfusion, with increased expression of M1-like microglial markers and a concomitant decrease in M2-like microglial markers. Additionally, aging can inhibit DARS2 protein expression, adversely affect angiogenesis and reduce brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor A (VEGFA) expression. In vitro, oxygen-glucose deprivation/reoxygenation and re-glucose (OGD/R) demonstrated that This study suggests that aging impedes M2-like microglial polarization by downregulating DARS2 expression in microglia, thereby impairing emergency angiogenesis during acute ischemic stroke and exacerbating neuronal damage. 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

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

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

To characterize the clinical, radiological, and molecular characteristics of CNS tumors associated with Noonan syndrome (NS) and other non-Neurofibromatosis type 1 RASopathies. Twenty-four patients with concern for NS underwent clinical and central radiological review in this multi-institutional study. Whole-exome sequencing, RNA sequencing, and methylation analyses of peripheral blood and/or tumor specimens were performed. Nineteen (79%) of 24 participants had NS, 17/19 (89%) of which had a germline 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

The global obesity crisis and the limited success of current treatments underscore the need to identify novel regulatory pathways. While central administration of α-Klotho exerts anti-obesity effects in rodents through AgRP neurons, the intracellular signaling mechanisms that mediate this process remain undefined. To define the role of FGFR1 within the α-Klotho signaling pathway in AgRP neurons, we performed a targeted deletion of the receptor in adult mice using an AAV-mediated CRISPR/Cas9 system alongside transgenic models. Deletion of FGFR1 in AgRP neurons disrupted energy homeostasis, promoting weight gain induced by a high-fat diet. Electrophysiological recordings revealed that FGFR1 loss increased the intrinsic firing rate of AgRP neurons and abolished the suppressive effect of α-Klotho on their activity. At the molecular level, FGFR1 knockdown decreased phosphorylation of the transcription factor FOXO1 and elevated AgRP mRNA expression. Our results define a crucial FGFR1 signaling axis in AgRP neurons that coordinately regulates their electrical activity and peptide expression, thereby establishing FGFR1 as an essential regulator of energy homeostasis. Show less

Hepatitis B virus (HBV) infection can cause liver damage through oxidative stress (OS) and immune-inflammatory responses. This study aims to explore the clinical significance of fibroblast growth factor 21 (FGF21) in the development and progression of chronic hepatitis B (CHB). A total of 336 participants were recruited, including 320 CHB patients and 16 healthy controls. The expression of FGF21, immune cytokines, and OS-related molecules in peripheral blood mononuclear cells (PBMCs) was detected using real-time quantitative polymerase chain reaction. The methylation level of the FGF21 gene promoter in PBMCs was detected using TaqMan probe-based quantitative methylation-specific PCR. The expression level of FGF21 in the peripheral blood of CHB patients was higher than that of HC, but the methylation level of the FGF21 promoter was lower than that of HC, especially in patients during the immune activation phase. The mRNA expression levels of CXCR3 and CCL5 in PBMCs of CHB patients during the immune activation and reactivation phases were higher than those in other clinical stages. Single-cell analysis revealed that CXCR3 and CCL5 expression in the immune tolerance and immune activation phases with high HBsAg expression was closely related to T lymphocytes (T cells) and natural killer cells (NK cells) and was highly expressed in CD4 and CD8 T cells and NK cells. In addition, the mRNA expression levels of Nrf2 and GPX4 in the reactivation phase were higher than those in other clinical stages. The mRNA expression level and methylation level of FGF21 in PBMCs of CHB patients were correlated with the viral load, immune inflammation, and OS levels during the antiviral treatment course of CHB. The methylation level of the FGF21 promoter has the potential to become a non-invasive biomarker for monitoring the progress of antiviral treatment in CHB.IMPORTANCEThis study conducted an in-depth exploration of the application of methylation detection technology, analyzing its value and driving mechanism in the oxidative stress and immune-inflammatory balance during the course of chronic hepatitis B. The study analyzed the methylation patterns of the FGF21 promoter and the expression levels of its receptor FGFR1, as well as the expression levels of chemokines CXCR3, CCL5, and oxidative stress factors GPX4 and Nrf2 in the immune tolerance period, immune clearance period, immune control period, and reactivation period of chronic hepatitis B. It clarified the association between these molecules and the FGF21/FGFR1 axis and revealed the synergistic or antagonistic mechanisms of these molecules in the oxidative stress and inflammatory vicious cycle. At the same time, this study also explored the value of FGF21 promoter methylation in disease diagnosis and prognosis, providing a theoretical basis for evaluating the antiviral treatment effect and disease progression of chronic hepatitis B. Show less

Orofacial clefts (OFCs) are one of the most prevalent congenital abnormalities that affect the lip and/or palate and can cause significant growth retardation in newborns. Several studies have revealed that children with congenital defects or genetic syndromes have their own growth pattern, which may differ from that of normal children. However, during infancy and until around age two, these babies usually show a period of catch-up growth in length, weight, and head circumference for both boys and girls. It was noted out that both genders had smaller physical dimensions than normal children. In order to partially elucidate the biological mechanism affecting children with non-syndromic OFCs, this systematic review aims to assess the relative expression and localization of growth factors and their receptors in craniofacial tissues. A comprehensive literature search was carried out on May 1, 2025, using three important databases: Web of Science Core collection, PubMed, and Scopus. The search was limited to only English-language studies involving human subjects, but it was not limited by publication date. To find potentially relevant publications, specific keywords and database-specific search techniques were used. Based on predefined inclusion criteria, 20 studies were selected from a total of 191 articles following a thorough screening process. Growth factors and susceptibility to OFCs were found to be significantly correlated in the analysis of the reports of the chosen studies. Particularly, OFCs and their risk were consistently associated with fibroblast growth factor receptor ( The reviewed studies indicate a role of growth-related proteins in the pathophysiology of non-syndromic OFCs. This is demonstrated by the fact that The online version contains supplementary material available at 10.1186/s12903-026-07715-x. 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

Alzheimer's disease (AD) is characterized by progressive synaptic failure, neuroinflammation, amyloid and tau pathology, yet effective disease-modifying therapies remain limited. Cannabidiol (CBD) has shown neuroprotective potential in AD, but its direct molecular targets and signaling mechanisms remain unclear. Here, we demonstrate that CBD ameliorates cognitive and emotional deficits in 3×Tg-AD mice by restoring synaptic integrity and plasticity. At the mechanistic level, CBD activated TrkB signaling independently of BDNF, leading to suppression of tau hyperphosphorylation via the PI3K/AKT/GSK3β pathway and attenuation of neuroinflammation and amyloid pathology through inhibition of the JAK2/STAT3/SOCS1 axis. Using isothermal shift assays combined with biophysical binding analyses, we identified FRS2, a core adaptor protein of TrkB, as a direct molecular target of CBD. Molecular dynamics simulations further revealed that CBD stabilizes the FRS2-TrkB interface, thereby facilitating TrkB activation. Importantly, genetic knockdown of FRS2 abolished CBD-induced TrkB signaling and its downstream neuroprotective effects in both cellular and in vivo AD models. Together, these findings identify FRS2 as a critical signaling node mediating BDNF-independent TrkB activation by CBD and establish a mechanistic framework linking CBD to disease-modifying pathways in AD. Show less

The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor with an essential role in appetite suppression and energy homeostasis. Genetic mutations in the receptor and components of its signalling pathway that cause obesity in humans, dogs and rodent models have revealed important insights into how the receptor signals and what regulates its cell surface expression. Structural studies have identified calcium as a critical cofactor for agonist binding and receptor function, while several transmembrane proteins have been shown to modulate MC4R activity. Here, we describe recent developments in our understanding of how accessory proteins and cofactors, identified using genomic approaches and screens for protein interaction, modify MC4R trafficking and signalling. We discuss how signalling by G 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

Atherosclerosis (AS), a chronic inflammatory disorder initiated by vascular endothelial dysfunction (ED), is prominently triggered by hemodynamic low-shear stress (LSS). Interferon regulatory factor 6 (IRF6) is a transcription factor that regulates the inflammatory response following injury. In this work, the LSS-induced AS model was induced by the partial ligation of the left carotid artery in high-fat diet-fed ApoE Show less

Rhubarb, traditionally used in China for neurological disorders, has recently attracted considerable scientific attention for its neuroprotective and cerebrovascular benefits. The main therapeutic components of rhubarb are anthraquinones, including emodin, aloe-emodin, chrysophanol, rhein, and physcion. Accumulating experimental evidence indicates that anthraquinones are of importance in neurodegenerative diseases (NDDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. However, as a promising candidate for drug development, the mechanisms by which anthraquinones treat NDDs have not been systematically reviewed. Therefore, this article outlines the anti-neurodegenerative effects of anthraquinones, focusing on their molecular mechanisms. This article reviews recent research progress of anthraquinones in NDDs, focusing on their potential targets and pathways to provide new ideas for the intervention and treatment of NDDs. A comprehensive search of PubMed, Web of Science, and Google Scholar was conducted for articles on the intervention of anthraquinones in NDDs in the past 20 years. The collected information was then summarized and analyzed. Anthraquinones ameliorate NDDs through multiple mechanisms. They exhibit antioxidant and anti-inflammatory effects, protect mitochondria, and regulate microglial polarization. Furthermore, anthraquinones inhibit pyroptosis, apoptosis, tau phosphorylation, Aβ/α-synuclein aggregation, and acetylcholinesterase activity, while restoring metal homeostasis, activating estrogen receptors, modulating gut microbiota, increasing BDNF levels, and preserving blood-brain barrier permeability. More notably, these compounds play a neuroprotective role by mediating multiple signaling pathways and targets, including Nrf2, ERK1/2, PI3K/mTOR, ROS/TXNIP, SIRT1/PCG-1α, NLRP3, PI3K/Akt, MAPK, TLR4-NFκB, CaM/CaMKIV, and Ca The pleiotropic actions of anthraquinones highlight their potential as therapeutic candidates for NDDs, yet clinical validation remains essential. Future studies should emphasize rigorously designed clinical trials and optimized brain-targeted delivery platforms. This review consolidates current evidence to support their translational development. Show less