👤 Yong Cui

Hypothalamic melanocortin 4 receptors (MC4Rs) play a central role in regulating food intake and energy homeostasis. In fact, inactivating mutations in the MC4R gene are the most common form of monogenic obesity. Agonist activation of MC4Rs reduces food intake by modulating hypothalamic signaling circuits. Thus, a detailed understanding of the signaling pathways that regulate MC4R activity is of considerable translational relevance. Ligand-activated MC4Rs interact not only with heterotrimeric G proteins but can also recruit beta-arrestin-2 (barr2) to the receptor. The potential functional role of barr2 in regulating the anorectic effects of MC4R signaling remains unexplored. In the present study, we used mutant mouse models to demonstrate that MC4R-mediated activation of barr2/ERK signaling in MC4R neurons of the paraventricular nucleus leads to reduced food intake. We also found that the appetite-suppressing effect of setmelanotide, an MC4R agonist approved by the FDA for the treatment of certain types of obesity, requires the presence of barr2 in MC4R-containing neurons. These data suggest that MC4R agonists able to promote MC4R/barr2 interactions with high efficacy may become useful as appetite-suppressing drugs. Show less

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

Acute hepatitis is a major pathological process underlying acute liver injury (ALI) and acute liver failure (ALF), both of which are associated with high mortality. Yet, no effective treatment is currently available, underscoring the pressing need for novel therapeutic targets. By integrating multiple transcriptomic datasets, this study finds that the expression of brain-derived neurotrophic factor (BDNF) is consistently downregulated in hepatocytes across various ALI/ALF models. Mechanistically, this downregulation is attributed to transcriptional repression of BDNF by RE1-silencing transcription factor. Restoration of endogenous BDNF or exogenous administration of recombinant BDNF significantly alleviates LPS/DGal-induced ALI/ALF. Correlation analysis and proteomic profiling reveal that BDNF exerts potent anti-inflammatory effects by directly binding to and antagonizing Toll-like receptor 4 (TLR4) on macrophages. Structural analysis identifies amino acids 233-244 of BDNF as the key functional domain responsible for this effect. A synthetic 12-mer peptide derived from this region, termed BDP12, retains TLR4-antagonizing ability, demonstrating strong anti-inflammatory efficacy and a favorable safety profile in cultured macrophages and mouse ALI/ALF models. In conclusion, this study identifies hepatocyte-derived BDNF as an endogenous antagonist of TLR4 and a critical immune checkpoint in acute hepatitis. BDNF and its mimetic peptide BDP12 represent promising therapeutic candidates for treating acute hepatitis-mediated ALI/ALF. Show less

Cellular and synaptic plasticity in ventral tegmental area (VTA) play a key role in alcohol use disorder (AUD). Here, we first delineated the in vivo dynamics of dopamine (DA) neuron activity in VTA during chronic intermittent ethanol exposure: initial sensitization was followed by a phase of attenuated and dysregulated response upon the first high-concentration exposure, culminating in stable hyper-responsiveness. Chronic ethanol exposure impaired long-term potentiation of GABAergic synapses (LTP Show less

The objective of our investigation was to explore the features of gut microbiota dysbiosis and the concentrations of gut metabolites in relation to white matter injury (WMI). Furthermore, we sought to evaluate the influence of gut dysbiosis on neuroinflammation in WMI via intestinal metabolites, and its contribution to pathogenesis. A cerebral hypoxia-ischemia-induced WMI model was established in 3-day-old Sprague-Dawley rats. Liquid chromatography-mass spectrometry/gas chromatography-mass spectrometry analyses and 16S rRNA gene sequencing were undertaken to ascertain WMI biomarkers. Mechanistic experiments were used to analyse activation of the H3K9ac/BDNF/TrkB pathway and neuroinflammation. The analysis of 16S rRNA sequencing disclosed gut microbiota dysbiosis in WMI rats, quantified using linear discriminant analysis effect size. Overall, 341 differentially expressed metabolic markers between the WMI and Sham groups were discovered. The Kyoto Encyclopedia of Genes and Genomes network enhancement evaluation revealed significant downregulation of 20 metabolic processes in the WMI group, which is strongly related to changes in fecal microbial metabolites, and the synthesis process of unsaturated fatty acids was the most significant. Gut microbiota dysbiosis may influence WMI by downregulating metabolites such as eicosapentaenoic acid (EPA). Fecal microbiota transplantation increased EPA concentration in the brain tissue of WMI rats. Gut microbiota-derived EPA promoted H3K9ac and BDNF/TrkB expression and inhibited the transcription of pro-inflammatory TNF- WMI induces gut dysbiosis involving down-regulation of unsaturated fatty acid synthesis. Fecal microbiota transplantation leads to increased levels of EPA. Gut microbiota-derived EPA increases levels of acetylated histone H3K9ac, causes activation of the BDNF/TrkB pathway, reduces neuroinflammation, and improves WMI-associated myelination disorders. It provides a basis for targeted treatment of white matter injury in the future. Show less

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

The brain-derived neurotrophic factor ( A total of 43 first-episode mania patients (FEM), 110 multiple-episode mania patients (MEM) and 80 healthy controls were enrolled in our study. We investigated the impact of We found a significant interaction between This is the first study to demonstrate that The online version contains supplementary material available at 10.1186/s12888-026-07949-7. Show less

This study investigated the expression of brain-derived neurotrophic factor (BDNF) signaling components (BDNF-TrkB-AKT1) and apoptosis-related factors (Bcl-2 and Bax) in yak brain regions at different altitudes. The cerebral cortex, cerebellum, hippocampus, thalamus, and medulla oblongata were collected from 3-year-old yaks living at low and high altitudes. The relative mRNA expression of BDNF, TrkB, AKT1, Bcl-2, and Bax was assessed by qRT-PCR. Protein abundance and cellular localization of BDNF, TrkB, AKT1, Bcl-2, and Bax were evaluated by Western blotting and immunohistochemistry, with immunoreactivity quantified by optical density analysis. Within each altitude group, BDNF, TrkB, AKT1, and Bcl-2 mRNA expression and the corresponding protein levels (BDNF, TrkB, AKT1, and Bcl-2) were significantly higher in the cerebral cortex and hippocampus than in the cerebellum, thalamus, and medulla oblongata (P < 0.05). In contrast, Bax mRNA and Bax protein levels did not differ significantly among the five regions. Compared with low-altitude yaks, high-altitude yaks showed significantly higher BDNF, TrkB, AKT1, and Bcl-2 mRNA expression and higher BDNF, TrkB, AKT1, and Bcl-2 protein levels in brain tissues (P < 0.05), whereas Bax protein expression did not differ between altitude groups. Immunohistochemistry revealed immunoreactivity for BDNF, TrkB, AKT1, Bcl-2, and Bax in both altitude groups, with prominent labeling in cortical pyramidal neurons and across the pyramidal cell layer in the hippocampal CA region. Immunoreactivity was also detected in large neurons of the thalamus and medulla oblongata. In the cerebellum, labeling was strongest in Purkinje cells, with weaker signals in the granule cell layer and molecular layer. BDNF-TrkB-AKT1 pathway components and Bcl-2 showed relatively higher expression in the cerebral cortex and hippocampus within each altitude group, whereas Bax expression did not vary across regions. These patterns are consistent with an association between BDNF-TrkB-AKT1 signaling and increased Bcl-2 expression without a corresponding increase in Bax, which may support neuronal adaptation in the cerebral cortex and hippocampus. Elevated expression of BDNF, TrkB, AKT1, and Bcl-2 at high altitude suggests enhanced adaptation to hypoxia in high-altitude yaks; the underlying mechanisms require further investigation. Show less

Substance use disorders (SUDs) present a global health challenge with high relapse rates. Emerging evidence implicates gut microbiota dysbiosis in SUD pathophysiology via the gut-brain axis. This 24-week randomized controlled trial investigated whether precision exercise interventions could modulate the gut microbiota-emotion axis to improve psychological outcomes in individuals undergoing compulsory drug rehabilitation. Thirty male participants were randomized to a precision exercise group (n = 15; individualized aerobic + resistance training, 4-5 sessions/week) or control group (n = 15; standard rehabilitation activities). Multi-dimensional assessments included weekly fecal (16S rRNA sequencing), urine (SCFAs via GC-MS), and saliva samples (cortisol, serotonin, BDNF via ELISA), alongside psychological evaluations (SCL-90-R, POMS) and physiological measures. The exercise group exhibited significant increases in gut microbial diversity (Shannon index: +18.2%, p < 0.001; Cohen's d = 2.14) and enrichment of beneficial taxa (e.g., Faecalibacterium, Bifidobacterium; LDA >3.5). Urinary SCFAs increased markedly (butyrate: 3.12-fold, p < 0.001), correlating with elevated salivary BDNF (+82%, p < 0.001) and reduced cortisol (-41.1%, p < 0.001). Psychological outcomes improved substantially: SCL-90-R Global Severity Index decreased by 43.3% (p < 0.001), and 78.6% of exercise participants achieved clinically meaningful improvement. Machine learning models predicted treatment response (AUC = 0.91) using baseline microbiome features. Precision exercise restores gut microbiota homeostasis, enhances neuroactive metabolite production, and improves emotional regulation in SUD recovery. The gut microbiota-emotion axis represents a viable target for non-pharmacological interventions, with microbiome profiles enabling personalized treatment strategies. Show less

The neurotrophic factor (NTF) family has recently expanded its role beyond neurological conditions, but its involvement in acute inflammatory lung diseases remains largely unclear. Using well-established acute lung injury (ALI) and sepsis models, we demonstrate that brain-derived neurotrophic factor (BDNF), a key NTF, is impaired in pulmonary epithelial cells and negatively correlates with the inflammatory response. Raising the BDNF level alleviates inflammatory lung injury, but these effects are absent in macrophage-deleted mice. Both in vivo and in vitro results show BDNF inhibits macrophage inflammation, and further proteomics analysis identifies macrophage TLR4 as a receptor that BDNF antagonizes via direct binding. The BDNF fragment (aa 104-115) is critical for BDNF-TLR4 interaction, and the corresponding synthetic BDNF-derived dodecapeptide (BDP-12) retains TLR4-antagonistic and anti-inflammatory effects both in vitro and in vivo, without pro-proliferative side effects. In conclusion, our findings reveal that epithelial-derived BDNF prevents macrophage inflammation by directly targeting TLR4 and highlights BDP-12 as a potential therapeutic agent for acute inflammatory diseases. Show less

Alzheimer's disease is a common neurodegenerative disease characterized by progressive memory loss, cognitive decline, and behavioral changes. Blood-based biomarkers have recently gained significant attention due to their accessibility and cost-effectiveness. This review highlights the latest progress in multiple key areas of bloodbased biomarkers for Alzheimer's disease. For early diagnosis, blood-based biomarkers such as amyloid-β and phosphorylated tau can identify Alzheimer's disease even before clinical symptoms emerge. Dynamic changes in blood-based biomarkers, including p-tau217 and neurofilament light chain, reflect disease progression and correlate with cognitive decline, enabling continuous monitoring of Alzheimer's disease progression. Additionally, bloodbased biomarkers such as p-tau181 and glial fibrillary acidic protein aid in differential diagnosis by distinguishing Alzheimer's disease from other dementias such as frontotemporal dementia. Blood-based biomarkers related to nerve repair have opened up new avenues for tracking nerve regeneration and therapeutic response, especially brain-derived neurotrophic factor. Furthermore, advanced detection technologies such as single-molecule array and immunoprecipitation-mass spectrometry have significantly improved the sensitivity and specificity of bloodbased biomarkers, facilitating their clinical translation. In summary, blood-based biomarkers hold strong potential to improve early diagnosis, monitor progression, differential diagnosis, and evaluate therapies in Alzheimer's disease. This review provides a comprehensive and updated evaluation of the translational potential of bloodbased biomarkers, emphasizing their practical utility in clinical settings and offering insights into future directions for large-scale application. This review emphasizes the need to prioritize the allocation of scientific resources, expedite the transition of blood-based biomarkers to clinical implementation, and ultimately achieve precise treatment of Alzheimer's disease using these biomarkers. Show less

Ginsenoside Rd, a protopanaxadiol abundant in Panax ginseng and Panax notoginseng, possesses well-documented neuroprotective properties but suffers from low bioavailability. Here, we engineered nanoparticles from zein, chitosan-α-lipoic acid copolymer, and sodium alginate for the delivery of ginsenoside Rd (Rd) and evaluated their efficacy in alleviating scopolamine-induced memory impairment in a mouse model. The results demonstrated that the nanoparticles successfully encapsulated Rd, with an encapsulation efficiency of approximately 73.23 %, and exhibited a hollow spherical morphology. Additionally, the carrier exhibited exceptional stability under varying temperature and salt ion conditions, along with the ability to be readily redispersed. The incorporation of Rd into nanoparticles significantly improved its antioxidant efficacy, as well as its stability and sustained release profile in the gastrointestinal environment. In vivo experiments demonstrated that Rd-loaded nanoparticles significantly improved scopolamine-induced memory deficits, oxidative stress, cholinergic system dysfunction, and neuronal damage in the hippocampal region of mice, outperforming the effects of ginsenoside Rd alone. Western blot results indicated that Rd-loaded nanoparticles improved memory-impaired mice by upregulating p-CaMKII, p-CREB, and BDNF protein expression through modulating the long-term potentiation pathway. We further found that Rd-loaded nanoparticles treatment increased the richness and diversity of gut microbiota. This study provides a promising strategy for the effective treatment of improving learning memory. Show less

This study aims to elucidate the role of Enterococcusin the progression from inflammatory bowel disease to colorectal cancer (CRC), with a focus on identifying key metabolites and host genes regulated by Enterococcusand their influence on CRC development. Using the database gutMGene, gutMDisorder and MACdb, we mined the key metabolites and human genes. We acquired the activated genes (panel 1) and inhibited genes (panel 2), and metabolite associated genes (MAGs, panel 3). Subsequent analyses included protein-protein interaction (PPI) network construction, functional enrichment, differential expression and survival analysis in CRC, and immune infiltration assessment. We screened 12 activated genes (Panel1: Show less

In order to address the challenge of early detection of ascending aortic dilation (AAD) in patients with bicuspid aortic valve (BAV), a machine learning prediction model integrating ultrasound hemodynamics and serum markers was developed to break through the limitations of traditional anatomical indicators. A total of 51 patients with BAV were prospectively enrolled and divided into ascending aortic dilation group (BAV-D, AAoV, AAoMPG and HDL-C in the BAV-D group were significantly higher than those in the BAV-ND group (all The machine learning model constructed by integrating hemodynamics (AAoV) and metabolic markers (HDL-C and ApoB) for the first time can accurately quantify the risk of AAD in BAV patients, and its performance is significantly better than that of a single anatomical parameter, providing a visual decision-making tool for early intervention. Show less

Lanthanum (La), the second most produced rare earth element, is detected in various environmental and human samples. Epidemiological studies have reported a strong association between La exposure and liver injury. However, the effects of early La exposure on liver development and underlying mechanisms remain limited. Here, we evaluate the hepatotoxicity of LaCl Show less

Dietary intake is a primary route of exposure to polychlorinated biphenyls (PCBs). The absorption and adverse effects of pollutants are markedly influenced by sex. However, insights into sex-specific differences in PCB oral bioavailability remain limited. In this study, PCB oral bioavailability was assessed in adult female and male Balb/c mice. At different exposure doses, the oral bioavailability of PCBs in female mice (14.2-22.8%) was significantly higher than that in male mice (12.3-18.8%). Correspondingly, males excreted a greater proportion of PCBs via feces, with fecal excretion percentages of 9.50-10.4% in males compared to 6.98-8.13% in females. Mechanistic analyses revealed that the higher PCB oral bioavailability in females was associated with greater dietary lipid assimilation efficiency and elevated postprandial serum apoB-48 levels, which are key indicators of chylomicron-mediated transport of lipophilic pollutants. Gut microbiota analysis revealed a more pronounced increase in Show less

Vascular smooth muscle cell (VSMC) phenotype switching plays a significant role in the pathogenesis of atherosclerosis (AS). However, the subtypes of VSMC transdifferentiation and their impact on AS progression and atherosclerotic plaque instability remains unclear. We reanalysed scRNA-seq datasets of GSE155513 and GSE253903 and performed single-sample gene set enrichment analysis (ssGSEA) in three transcriptome datasets from unstable plaques to determine the major subtypes contributing the most to plaque instability. Using high-dimensional weighted gene co-expression network analysis (hdWGCNA), we identified hub genes in macrophage (MP)-like smooth muscle cells (SMCs) of unstable plaques. We conducted cell communication analysis according to tensin1 (TNS1) gene levels in VSMCs. TNS1 expression was analysed in human AS plaques. Finally, an AS model was established in VSMC-specific Tns1 knockout ApoE MP-like SMC was identified as the key subtype for plaque instability. hdWGCNA analysis for MP-like SMC identified blue module as the key gene module involved in unstable plaques. Decreased TNS1 expression in VSMCs was positively correlated with the down-regulation of contractile VSMC marker genes, SRF and MYCOD genes, negatively correlated with the up-regulation of CD68 and KLF4 genes, and activated VCAM, PDGF, THBS and CXCL signalling pathways. TNS1 mRNA expression levels were lower in human atherosclerotic arteries than in healthy arteries, and even lower in unstable plaques than in early and stable plaques. TNS1 protein levels in VSMCs were lower in human atherosclerotic plaques than in healthy arteries, and even lower in advanced plaques than in early plaques. VSMC-specific Tns1 gene deficiency aggravated AS progression and enhanced plaque instability with increased MP-like SMC transdifferentiation. The reduction of TNS1 gene in VSMCs might drive contractile VSMC transdifferentiation into MP-like SMC, the major subtype contributing to plaque instability. In vivo experimental results confirmed the role of Tns1 gene in contractile VSMC transdifferentiation into MP-like SMC and plaque instability. Show less

Alzheimer's disease (AD) is one of the most pressing public health challenges in an aging world. However, effective therapeutic strategies are still lacking. Imbalance in lipid homeostasis is a key driver of AD. Given the established link between dysregulated lipid metabolism and amyloid-beta (Aβ) aggregation, we investigated whether chicoric acid (CA), a dietary polyphenol with reported lipid-modulating properties, could mitigate Aβ pathology by modulating lipid metabolism in 5xFAD transgenic mice. In the brain, we found that CA upregulated the expression of liver X receptor Beta (LXR-β) and ATP-binding cassette transporter A1 (ABCA1) in 5xFAD mice. Through this pathway, it promoted apolipoprotein E (ApoE) lipidation and enhanced the expression of Aβ-clearance proteins (IDE and LRP1). Notably, in the periphery, CA reshaped the gut microbiota in 5xFAD mice, which reduced serum neurotoxic bile acid levels and preserved the integrity of the peripheral Aβ clearance system. Together, our study first demonstrated that CA globally regulated lipid homeostasis to alleviate Aβ pathology by coordinating cerebral cholesterol efflux with peripheral bile acid metabolism. The findings facilitated exploring active compounds from traditional Chinese medicine that may reduce Aβ deposition by targeting lipid metabolism pathways. Show less

N6-methyladenosine (m6A) RNA modification can govern cell fate by co- or post-transcriptionally regulating gene expression. VSMCs can undergo phenotypic switching, contributing to other cells within atherosclerotic plaques, including foam cell- and macrophage-like cells. However, the role of VSMC m6A in atherosclerosis development remains unclear. While PPAR-α and PPAR-γ have been extensively studied in macrophages for their roles in atherosclerosis, the epigenetic regulation of these nuclear receptors under high cholesterol conditions remains poorly understood. We utilized murine and human atherosclerotic aortas, along with VSMC-specific Mettl3 and Mettl14 knockout mice, to evaluate the role of VSMC m6A in atherosclerosis. Lineage tracing was used to assess macrophage-like VSMCs. The epigenetic regulation of Ppara and Pparg transcription by Methyltransferase-like 14 (METTL14) was investigated through a variety of methods, including histological, cellular, genomic, transcriptomic, metabolomic, lipidomic, computational, and pharmacological approaches. The therapeutic potential of VSMC Mettl14 in atherosclerosis was analyzed using adeno-associated virus-mediated expression in ApoE-/- mice.We showed that the METTL3/METTL14 methyltransferase complex was reduced in both murine and human atherosclerotic VSMCs. The levels of METTL3, and consequently m6A, were regulated by METTL14, which was in turn influenced by ox-LDL. Notably, while VSMC METTL3 or m6A did not contribute to atherosclerosis, VSMC-specific Mettl14 knockout mice exhibited accelerated foam cell formation, enhanced vascular inflammation, and exacerbated atherosclerosis. These effects were driven by impaired beta-oxidation and reduced mitochondrial oxidative phosphorylation (OXPHOS). Replenishment of Mettl14 significantly attenuated these adverse effects. Specifically, METTL14 regulated phenotypic switching of VSMCs and modulated the number of VSMC-derived macrophage-like cells, rather than infiltrating macrophages, within atherosclerotic plaques. Furthermore, we demonstrated that METTL14 regulates the transcription of Ppara and Pparg, master regulators of lipid metabolism that promote cholesterol efflux, by enhancing SETD1A-mediated H3K4 trimethylation in an m6A-independent manner. Activation of PPAR-γ with rosiglitazone restored impaired mitochondrial OXPHOS in Mettl14-deficient VSMCs, leading to reduced lipid accumulation. Lastly, recapitulating Mettl14 expression in atherosclerotic vessels through AAV gene therapy effectively inhibited atherosclerosis progression without compromising liver function. We have unveiled that METTL14 promotes lipid metabolism and inhibits atherogenesis through activating PPAR-α/γ expression. These experiments highlight the therapeutic potential of the endogenous METTL14/PPAR-α/γ axis for treating atherosclerotic and metabolic diseases. Show less

Accurate prediction of progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) is critical for early intervention. Many existing models lack the ability to capture the nonlinear nature of cognitive decline and individual heterogeneity. This study employed a semi‑parametric joint model to analyze longitudinal cognitive trajectories and identify robust predictors of conversion. Data from 596 participants (184 AD converters, 412 stable MCI) were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Longitudinal assessments included ADAS‑Cog13, ADAS‑Cog11, CDR‑SB, FAQ, RAVLT‑IR, RAVLT‑L, and MMSE. A semi‑parametric joint model combining B‑splines for the longitudinal process with a Cox survival submodel was fitted for each cognitive measure. Model performance was evaluated using AIC, BIC, intraclass correlation coefficient (ICC), time‑dependent C‑index, dynamic AUC, and calibration curves. Subgroup analyses were conducted by APOE‑ε4 carrier status. In multivariable joint models, APOE‑ε4 carriage was a consistent risk factor (HR range: 1.38-1.77). Higher scores on ADAS‑Cog13 (HR = 3.71 per SD), ADAS‑Cog11 (HR = 2.71), CDR‑SB (HR = 3.79), and FAQ (HR = 2.85) increased the hazard of conversion, whereas higher scores on RAVLT‑IR (HR = 0.23), RAVLT‑L (HR = 0.14), and MMSE (HR = 0.53) were protective. All models showed high ICCs (0.94-0.98) and moderate‑to‑good predictive accuracy over 2, 5, and 8 year horizons (C‑index: 0.585-0.668). CDR‑SB and FAQ exhibited the strongest effect sizes and clearest dose‑dependent trajectories across APOE‑ε4 subgroups. Calibration curves demonstrated good agreement between predicted and observed survival. The semi‑parametric joint model effectively captures nonlinear cognitive‑functional decline and provides validated predictions of AD risk. APOE‑ε4 genotype combined with longitudinal monitoring of CDR‑SB and FAQ offers a robust framework for stratifying progression risk in clinical MCI management. Show less

G9A, a histone methyltransferase that facilitates H3K9 dimethylation, has been implicated in the epigenetic regulation of vascular processes. This study encapsulates its involvement in the calcification and stability of atherosclerotic plaques, further investigating its interaction with bone morphogenetic protein 2 (BMP2), a pivotal factor in vascular calcification, unveiling that G9A fosters plaque calcification and instability via the BMP2 signaling pathway. The progression of unstable plaques, histone methylation status, and vascular calcification incidence were monitored in the carotid plaques of ApoE In ApoE Our findings indicate that G9A amplifies vascular calcification through the activation of Bmp2 signaling, a fundamental mediator of vascular calcification. The relationship between vascular calcification and the emergence of unstable plaques may be intricately associated with histone methylation. Show less

Atherosclerotic plaque destabilization during acute infections such as pneumonia represents a critical clinical challenge, yet the underlying molecular dynamics remain poorly characterized. This study introduces a furin-responsive photoacoustic/fluorescence dual-modal probe (FRP) to investigate intraplaque furin activity in ApoE Show less

Atherosclerosis currently lacks effective therapeutic strategies specifically targeting and inhibiting foam cell formation. In this study, we engineered a macrophage nanoparticle composite drug delivery system that utilizes macrophages for competitive lipid uptake, coupled with ROS-responsive statin nanoparticles aimed at inhibiting cholesterol synthesis. This integrated system embodies a "smart immunomodulatory" approach, leveraging the inherent activity and targeted capabilities of immune cells. Experimental results demonstrated that this system significantly reduced lipid accumulation within foam cells by inhibiting cholesterol uptake, promoting cholesterol efflux and inhibition of apoptosis. These effects were mediated through microenvironmental optimization and upregulation of ABCA-1 and SR-BI expression. In an APOE knockout mouse model of atherosclerosis, the system effectively lowered lipid levels, modulated inflammatory responses, and significantly reduced foam cell formation and atherosclerotic plaque development. The system enhanced Treg cell proliferation and TGF-β secretion. Moreover, the system demonstrated high biocompatibility and therapeutic efficacy, training macrophages to revert to a low-lipid and M2 phenotype. This targeted drug delivery system integrates multiple therapeutic mechanisms, including inhibition of cholesterol uptake, enhancement of cholesterol efflux, and immunomodulation, providing a promising new strategy for the treatment of atherosclerosis. Show less

Sex differences in the association between vascular factors and cognitive outcomes remain unclear. We aimed to investigate the associations of blood pressure metrics (hypertension, systolic blood pressure [SBP), pulse pressure, ankle and brachial pressures, and ankle to brachial pressure index [ABI]) with the risk of cognitive decline and dementia. We conducted a population-based longitudinal analysis using data from the Atherosclerosis Risk in Communities (ARIC) study (begun in 1987-1989) in the United States. We analyzed a total of 12,268 participants aged 45-64 years who had validated exposure measurements, cognitive function tests (first administrated 1990-1992), and followed up for incidence of dementia through December 2019. Cognitive function was assessed using the Digit Symbol Substitution Test, the Delayed Word Recall Test, and the Word Fluency Test. Dementia cases were identified through a standardized clinical evaluation process, mostly adjudicated by expert reviewers. We performed sex-stratified analyses to examine the associations of blood pressure metrics and APOE ε4 allele with the risk of cognitive decline and dementia. Over a median follow-up of 26.4 years, 2698 participants developed dementia. Women aged 55-64 had a significantly higher incidence of dementia than men aged 55-64 (14.8 vs. 11.8 per 1000 person-years; p < These findings highlight notable sex differences in the association between vascular factors and cognitive decline and dementia risk. Women appear more vulnerable to both genetic and vascular risk factors, emphasizing the need for sex-specific approaches in research, prevention, and intervention strategies for cognitive impairment. NIH. Show less

Bovine tuberculosis (bTB) is a chronic infectious disease caused by the Mycobacterium bovis (M. bovis). Rapid, cost-effective, and accurate diagnosis of bTB remains a significant clinical challenge globally. In this study, we performed a comprehensive proteomic analysis to evaluate the discriminatory power of plasma and plasma exosomes for bTB diagnosis. We compared protein expression profiles across three groups: M. bovis-negative controls (bTB_N, n = 10), M. bovis-positive cases (bTB_P, n = 10), and co-infected animals (Other_P, n = 10) with Brucella, infectious bovine rhinotracheitis virus (IBRV), and bovine viral diarrhea-mucosal disease virus (BVDV). Quantitative analysis identified 3820 exosomal proteins-2.27-fold more than the 1686 plasma proteins detected. Exosomal proteins exhibited superior sample clustering and discriminative capacity for infected groups. Notably, 227 plasma and 861 exosome-derived proteins were uniquely differentially expressed in bTB (bTB-specific DEPs). Pathway enrichment analysis revealed that exosome-specific DEPs were significantly enriched in TB-related pathways, including neutrophil extracellular trap (NET) formation, endocytosis, and tuberculosis, exhibiting greater biological relevance compared to plasma-specific DEPs. Furthermore, eight candidate proteins (APOE, FBLN5, VDAC1, ABCE1, LMAN1, PLG, SPP1, and SRP9) demonstrated high specificity for bTB discrimination, with two (FBLN5 and SPP1) displaying stage-specific expression patterns during M. bovis infection. This study underscore plasma exosome as a highly promising source of biomarkers for bTB diagnosis, offering enhanced sensitivity and deeper mechanistic insights over conventional plasma proteome. Show less

Endometrial carcinoma (EC) is a common malignancy of the female reproductive system. Rab35 is widely recognized as an oncogenic driver and has been implicated in the progression of various malignant tumors. However, its regulatory mechanism and pathobiological roles in EC remain unclear. Rab35 expression in EC was systematically profiled via integrative analysis of clinical endometrial specimens and multi-omics databases (CPTAC and GEO). The association between clinical prognosis and Rab35 expression was examined using Kaplan-Meier analysis. Mechanistic investigations included transwell assays, western blotting, and immunofluorescence in Rab35-overexpressing and CRISPR/Cas9-mediated Rab35-knockout EC cells. A mouse xenograft tumor model was established to confirm the effects of Rab35 in vivo. The Rab35 content increased gradually from normal endometrium to atypical hyperplastic endometrium to EC. Moreover, the findings indicated that elevated Rab35 expression was significantly associated with advanced disease characteristics and poor overall survival in patients with EC. In addition, Rab35 enhanced the migratory and invasive nature of EC cells. The expression of Rab35 was inversely linked to that of the β-catenin destruction complex-related proteins Axin-1 and GSK3β, leading to the increased nuclear translocation of β-catenin in EC cells. Animal experiments further verified that Rab35 augmented EC progression by regulating the nuclear translocation of β-catenin. The study revealed that high expression of Rab35 was strongly correlated with EC progression and a poor clinical outcome. Furthermore, Rab35 promoted EC cell metastasis by accelerating the nuclear translocation of β-catenin. These findings suggest that Rab35 serves as a valuable biomarker and therapeutic target for EC. Show less

Synaptic vesicle glycoprotein 2A (SV2A), a transmembrane protein widely localized to synaptic vesicles, serves as a key indicator of synaptic loss in Alzheimer's disease (AD). In this study, adeno-associated virus (AAV) was injected by brain stereotactic injection technique to construct SV2A-overexpressing APP/PS1 mice, then the effects of SV2A on amyloid precursor protein (APP) degradation and its molecular mechanism were further explored in vivo or in vitro. Our results demonstrated that SV2A overexpression significantly reduced Aβ plaque deposition in brain tissue of APP/PS1 mice. Mechanistically, SV2A was identified as a novel APP-binding protein that attenuated the amyloidogenic processing of APP by inhibiting its interaction with β-site APP cleaving enzyme 1 (BACE1). Furthermore, SV2A overexpression altered the subcellular distribution of APP, shifting its localization away from the endosomal-lysosomal compartments. Collectively, our findings unveil SV2A as a critical regulator of APP metabolism and propose it as a promising therapeutic target for intervening in the early pathological progression of AD. Show less