👤 Zhongping Yu

Air pollution is linked to dementia, but evidence from low-exposure settings is limited. We examined sex-specific associations between long-term exposure to fine particulate matter ≤2.5 µm in diameter (PM2.5) and dementia risk in older adults living in Australia. In 16,145 dementia-free Aspirin in Reducing Events in the Elderly (ASPREE) participants (≥70 years; median follow-up 10.3 years), Cox models assessed associations between 1-year mean PM2.5 (continuous and guideline-based categories) and incident dementia, adjusting for demographic, lifestyle, environmental, and genetic factors. Subgroup analyses by sex, apolipoprotein E genotype (APOE), and age were conducted. Overall associations were null, but with a trend for increased risk at exposures >10 versus ≤5 µg/m Findings suggest a threshold of >10 µg/m Show less

Cardiovascular disease (CVD) risk is elevated among people living with HIV (PLWH), particularly those receiving antiretroviral therapy (ART). This study aimed to examine associations between single-nucleotide polymorphisms (SNPs) in lipoprotein-related genes and CVD risk among PLWH undergoing ART. Blood samples from 337 PLWH at Chung Shan Medical University Hospital were analyzed, including 238 individuals who switched ART and 99 who continued their regimen. Genotyping of four SNPs-namely, ATP binding cassette B1 ( The cohort was predominantly male 95.6% (322/337), with a mean age of 34.6 years. Metabolic abnormalities were common, and 16.0% (54/337) of participants on ART were classified as high-risk for CVD. Among the SNPs analyzed, SNPs in Show less

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized primarily by deterioration in memory, cognition, and learning ability. Its etiology is complex and influenced by multiple factors, including genetics and environment. With advancing research into mitochondrial function and mechanisms, impaired mitophagy has been proposed as a significant mechanism contributing to AD. The ApoE ε4 allele, a high-risk genetic factor for AD, may play a key role in disease pathogenesis by inducing mitophagy dysfunction and apoptosis. From the perspective of APOE gene polymorphisms, this study investigates abnormal changes in mitochondrial function and autophagy in humanized APOE4 mice primary astrocytes under oxidative stress, as well as the regulatory effect of curcumin (Cur) on mitophagy and oxidative stress-induced apoptosis, thereby exploring its potential to ameliorate AD through targeting mitophagy. Mitochondrial function analysis revealed that APOE4 expression reduced the antioxidant capacity and respiratory function of primary astrocytes, leading to mitochondrial membrane damage, intracellular reactive oxygen species (ROS) accumulation, and decreased ATP production. Curcumin effectively protected mitochondrial integrity, reduced the number of damaged mitochondria, improved overall mitochondrial function, and helped maintain mitochondrial homeostasis involving in PINK1/Parkin pathway. Regarding autophagy and apoptosis, curcumin was shown to restore autophagic flux, mitigate autophagy disruption caused by oxidative stress, and reverse early-stage apoptosis. Show less

Alzheimer's disease (AD) is characterized by amyloid plaques that form complex microenvironments in the brain. However, the molecular composition of these plaques and their temporal regulation are not well defined. Here, we developed a sensitive workflow for quantitative proteomic profiling of single plaques using refined laser capture microdissection and data-independent acquisition mass spectrometry (LCM-DIA-MS). From >200 plaques and control regions in AD mouse models (5xFAD and APP-KI) and human brains, we quantified >7,000 proteins, revealing stage-dependent, cell-type-related remodeling of the amyloid proteome (amyloidome). Temporal profiling uncovered early immune and lysosomal activation followed by engagement of RNA processing and synaptic pathways. Cross-model and cross-species analyses determined a conserved amyloidome including APOE, MDK, PTN, and HTRA1, validated by co-localization in imaging analysis. Network analysis highlighted modules in lipid transport, vesicle organization, and autophagy. These findings establish amyloid plaques as conserved, dynamic multicellular hubs that link amyloid accumulation to downstream cellular events. Show less

Abdominal aortic aneurysm (AAA) refers to a disease where the abdominal aorta progressively dilates to 3.0 cm or more, making it prone to rupture. The etiologic and pathophysiological mechanisms underlying the formation and development of AAA are not yet fully understood. A preliminary investigation was conducted into the effects of Kruppel-like factor 5 (KLF5) regulation of the nuclear factor erythroid-2-related factor 2/heme oxygenase 1 (NRF2/HO-1) signalling pathway on ferroptosis in AAA vascular smooth muscle cells (VSMCs). ApoE KLF5 expression was downregulated in abdominal aorta tissues from AAA mice. KLF5 overexpression ameliorated inflammatory response by reducing phenotypic switching in VSMCs and inhibited ferroptosis and vascular calcification by reducing oxidative stress. Induction of ferroptosis partially reversed the ameliorative effect of KLF5 on vascular calcification in VSMCs. KLF5 exerted antioxidant effects by increasing NRF2 nuclear translocation and upregulating HO-1. Inhibition of the NRF2/HO-1 pathway partially reversed KLF5 regulation of phenotypic switching and vascular calcification in VSMCs. KLF5 may exert a protective effect by inhibiting ferroptosis and calcium deposition in VSMCs in AAA through regulation of the NRF2/HO-1 signalling pathway. Show less

Atherosclerosis (AS), a chronic inflammatory process driven largely by macrophage-mediated plaque formation, remains poorly understood in mitochondrial-macrophage crosstalk. While CYBA polymorphisms correlate with cardiovascular risk, the functional role of CYBA in connecting mitochondrial dysfunction to macrophage phenotypic alteration and functional modulation remains largely unknown. In this study, we integrated multi-omics profiling of AS immune microenvironments with mitochondrial-associated gene sets. Machine learning and single-cell RNA sequencing identified CYBA as a key oxidative stress regulator. CYBA expression was significantly upregulated both in oxidized low-density lipoprotein (ox-LDL)-stimulated THP-1 macrophages and in atherosclerotic lesions, with immunofluorescence confirming macrophage enrichment. Show less

The apolipoprotein E ε4 (APOE ε4) allele is a major genetic risk factor for Alzheimer's disease, but its relevance to cognition in intracranial atherosclerosis (ICAS) remains unclear. We investigated the association between APOE ε4 and cognition in ICAS. Baseline data from a multicenter cohort were analyzed. Patients with radiologically confirmed ICAS underwent APOE genotyping, plasma biomarker assays, magnetic resonance imaging assessment of cerebral small vessel disease (CSVD) and brain atrophy, and standardized cognitive testing. Among 409 patients (mean age 60 years, 55% male), 16% carried APOE ε4. Carriers showed more frequent cognitive impairment (63% vs 48%), greater stenosis burden, and lower plasma amyloid beta (Aβ)42/40 ratios, whereas other Alzheimer's biomarkers, CSVD burden, and atrophy scores showed no difference. After adjustment, APOE ε4remained associated with cognitive impairment (odds ratio [OR] 1.86). The association was pronounced in women (OR 4.43) but absent in men. APOE ε4 is linked to cognitive impairment in ICAS, particularly in women, through mechanisms beyond Alzheimer's pathology. In patients with ICAS, cognitive impairment was more prevalent in carriers than in non-carriers. Carriers showed greater stenosis burden and lower plasma Aβ42/40 ratios. After full adjustment (stroke, CSVD, and AD biomarkers), APOE ε4 remained associated with cognitive impairment. Female carriers had substantially higher odds of cognitive impairment. Show less

Oscillatory shear stress (OSS), resulting from disturbed blood flow, is implicated in atherosclerotic plaque formation by incompletely understood mechanisms. This study aims to elucidate the involvement of death-associated protein kinase (DAPK) 2 in OSS-induced endothelial cell (EC) activation and atherosclerosis. Publicly available resources, including genome-wide microarray, RNA sequencing, and single-cell RNA sequencing, were utilized to identify key OSS-sensitive regulatory factors. Techniques such as mass spectrometry, immunoprecipitation, proximity ligation assay, and RNA sequencing were employed to identify pyruvate kinase M2 (PKM2) as the binding protein of DAPK2 and determine the specific site of PKM2 phosphorylation by DAPK2. To assess the role of Dapk2 in vivo, EC-specific DAPK2 expression was elevated in OSS-exposed regions of human and murine arteries. Mechanistically, Krüppel-like factor 2 (KLF2) suppressed DAPK2-driven phosphorylation of PKM2 at threonine 45 orchestrates endothelial inflammatory responses to disturbed flow, identifying a novel mechanistic axis and potential therapeutic target in atherosclerosis. Show less

Atherosclerosis (AS) is the main pathological basis of atherosclerosis-related cardiovascular and cerebrovascular diseases. The phenotypic conversion and death mechanisms of vascular smooth muscle cells (VSMCs) are crucial during its development. This study reveals the molecular mechanisms of the C1qbp-DLAT axis and the U2AF2 (U2 Small Nuclear RNA Auxiliary Factor 2)-NEAT1 network in regulating cuproptosis in AS. In this study, an ApoE The study revealed elevated copper ion levels and dysregulated cuproptosis-related genes in an AS model. U2AF2 stabilized C1qbp mRNA, enhancing C1qbp protein expression, which promoted DLAT oligomerization to regulate cuproptosis. LncRNA NEAT1 facilitated this process by scaffolding U2AF2-C1qbp mRNA interaction. Targeted inhibition of U2AF2 significantly improved AS pathological characteristics, reduced lipid deposition, collagen deposition and macrophage infiltration within the plaque, increased smooth muscle cell content and lowered serum levels of total cholesterol (TC), total triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C). This study revealed the role of the U2AF2-C1qbp-copper death regulatory axis in the development of AS, providing new targets and a theoretical basis for the treatment of AS. Targeted inhibition of U2AF2 may become an effective strategy to delay progression of AS. Show less

Aerobic exercise reduces cardiovascular events in atherosclerosis, but the causal roles of microRNAs (miRNAs) in mediating exercise-induced vascular smooth muscle cell (VSMC) phenotypic switching and plaque stabilization remains unclear. This study investigated whether aerobic exercise stabilizes atherosclerotic plaques by reprogramming VSMC miRNA expression, focusing on the miR-15a-5p/Semaphorin-3A (Sema3A) axis. High-fat diet-fed ApoE Exercise reduced plaque vulnerability, increased collagen content, reduced lipid content, and attenuated macrophage infiltration. Integrative miRNA profiling revealed that miR-15a-5p was markedly upregulated in atherosclerotic aortas but significantly suppressed by exercise locally and in circulation. In human carotid plaques, miR-15a-5p levels positively correlated with the plaque vulnerability index. Mechanistically, miR-15a-5p directly targeted the 3'-UTR of Sema3A, repressing its expression. VSMC-specific miR-15a-5p overexpression in vivo downregulated contractile markers, accelerated phenotypic switching, and destabilized plaques, such traits resembled those in cells from sedentary mice. Aerobic exercise stabilizes plaques by downregulating miR-15a-5p, relieving Sema3A repression and preserving the contractile VSMC phenotype. The miR-15a-5p/Sema3A signaling axis mediates exercise-induced atheroprotection. Notably, elevated miR-15a-5p levels in human carotid plaques correlate positively with plaque vulnerability, supporting its potential as an atherosclerotic therapeutic target. Show less

Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have revolutionized cancer therapy, yet primary and acquired resistance remain major clinical obstacles. Dysregulated angiogenesis fuels the development of an immunosuppressive tumor microenvironment, while crosstalk between immunity and angiogenesis further propels tumor immune evasion and treatment resistance. The present study aimed to establish a penpulimab-resistant model, delineate anti-PD-1 resistance traits via single-cell RNA sequencing, and unravel the precise mechanisms through which anlotinib-an anti-angiogenic agent-mitigates penpulimab resistance. These findings offer insights to guide clinical management of immune-pretreated patients. Single-cell sequencing analyses demonstrated that anlotinib reverses penpulimab resistance by reprogramming the tumor immune microenvironment, thereby boosting PD-1 blockade efficacy via modulation of immune infiltration and tumor signaling pathways. Identifying Apoe⁺ M2 macrophages, Srgn⁺ M1 macrophages, and Cxcl2⁺ T cells provides key cellular and molecular targets for developing clinically actionable immunotherapies. Taken together, this work validates the preclinical potential of anlotinib combined with immunotherapy for immunotherapy-resistant tumors. Show less

To assess the association between hepatitis C virus (HCV) infection and cognitive impairment among seniors in Taiwan, building on our previous findings from a cross-sectional study. Retrospective cohort study. Taiwan Biobank. 326 participants with positive serum anti-HCV and a control group of 8753 with negative HCV free of cognitive impairment were assessed by the Mini-Mental State Examination at baseline. The association between HCV infection and cognitive impairment was evaluated using Cox proportional hazard models. The analysis was adjusted for age, sex, education, BMI, hypertension, cirrhosis, depression, estimated glomerular filtration rate, APOE genotype, and recruitment periods. Anti-HCV positive patients showed a significantly higher incidence of cognitive impairment compared to anti-HCV negative individuals (14.28 vs. 7.21 per 1000 person-years, P = 0.004). After adjusting for covariates, HCV infection was significantly associated with an increased risk of developing cognitive impairment (adjusted HR [aHR]: 1.80, 95% confidence interval [CI]: 1.12-2.90). Subgroup analyses for individuals diagnosed prior to the public direct-acting antivirals reimbursement in 2017 and with high antibody titres (sample/cutoff ratio ≥ 5), the elevated risk of cognitive impairment remained statistically significant, with aHRs of 1.69 (95% CI: 1.04-2.75) and 1.81 (95% CI: 1.11-2.96) respectively. Additionally, HCV patients carrying the APOE ɛ4 allele had a marginally higher risk (aHR: 2.60, 95% CI: 0.96-7.08, P = 0.06). In Taiwan, our findings strengthen evidence that individuals above the age of 60 with HCV infections are at a greater risk of developing cognitive impairment than their counterparts, who were HCV negative. Show less

This study utilized a novel Proximity Barcoding Assay to perform high-resolution proteomic profiling of individual plasma extracellular vesicles from 85 patients with advanced high-grade serous ovarian carcinoma (OC) and 95 healthy controls (HC). Single-EV analysis identified 119 differentially expressed proteins and 17 distinct EV subpopulations. Cluster 7 (enriched in integrins ITGB3, ITGB1, and ITGA6) was significantly elevated in OC plasma (4.47% in HC vs. 14.79-15.82% in OC). Machine learning (SVM-RFE, LASSO, Random Forest) identified a diagnostic panel (ITGA6, ITGB2, ILK) achieving exceptional accuracy in distinguishing OC from HC (AUC = 0.999 training; 1.000 validation). Furthermore, risk models incorporating specific protein signatures effectively stratified patients by platinum sensitivity/resistance (9-protein panel: ILK, CDCP1, CD86, CLDN4, CLEC1B, CDHR5, CLDN11, JAM2, FOLH1), lymph node metastasis status (7-protein panel: APOE, CD28, CLDN4, FOLH1, ITGAL, JAML, ULBP3), and post-surgical residual disease burden (4-protein panel: CD44, CLMP, ITGA4, AMIGO1), with Cluster 13 (ITGB1-high) also significantly associated with residual disease. This work demonstrates the power of single-EV proteomics combined with machine learning for non-invasive diagnosis and clinical outcome assessment in advanced ovarian cancer, though the absence of early-stage patients limits its applicability for early detection. Show less

To investigate the effects of SLCO1B1, apolipoprotein E (APOE) and ABCG2 gene polymorphisms on the lipid-modulating efficacy of rosuvastatin. Systematic searches were conducted in PubMed, Cochrane Library, Embase, Web of Science, PharmGKB, CNKI, VIP, and Wanfang databases (from database establishment to 1 March 2025). Studies on the correlation between SLCO1B1, APOE, ABCG2 gene polymorphisms and the lipid-modulating efficacy of rosuvastatin were collected, and meta-analysis was performed using RevMan 5.4 software. A total of 16 studies involving 6167 patients were included, covering APOE (p.C130R/rs429358, p.R176C/rs741), SLCO1B1 (p.V174A/rs4149056, p.N130D/rs2306283), and ABCG2 (p.Q141K/rs2231142) genes. The results showed that SLCO1B1 [AG+GG vs. AA, mean difference = -4.36, 95% confidence interval (CI): -7.92 to -0.80, P = 0.02], APOE (E2 vs. E3, mean difference = -5.58, 95% CI: -8.04 to -2.51, P < 0.00001] and ABCG2 (CA+AA vs. CC, mean difference = -7.07, 95% CI: -9.47 to -4.68, P < 0.00001) genotypes all significantly affected statin-induced low-density lipoprotein cholesterol (LDL-C) reduction; patients with ABCG2 CA+AA genotype had statistically significant differences in total cholesterol level changes (mean difference = -7.15, 95% CI: -8.78 to -5.53) and triglyceride level changes (mean difference = -7.37, 95% CI: -10.91 to -3.83) (both P < 0.05). The lipid-lowering efficacy of rosuvastatin (especially the reduction of LDL-C level) is significantly affected by the polymorphisms of SLCO1B1 (c.388A>G), ApoE (c.388T>C, c.526C>T) and ABCG2 (c.421C>A) genes. Show less

High levels of circulating interleukin (IL)-16 are associated with a reduced incidence of cardiovascular events. The disruption of atherosclerotic plaques commonly causes myocardial infarction and stroke. In this study, we investigated the effects of IL-16 on phenotypic modification of plaques. Mice with deficiencies in IL-16 and apolipoprotein E (IL16 IL-16 deficiency increased the necrotic core and reduced fibrous cap thickness in the plaques. IL-16 deletion accelerated the degradation of intraplaque collagen and elastin, increased matrixmetalloproteinase activity, and reduced TIMP-3 expression. Transplantation of wild-type IL-16 bone marrow into IL-16 knockout mice successfully attenuated the plaque instability caused by IL16 deficiency. Furthermore, hematopoietic-derived IL-16 activated the CD4/JAK2/STAT6 pathway and increased the binding of STAT6 to the coactivator cAMP-response element-binding protein (CBP)/p300 at the TIMP-3 promoter in smooth muscle cells (SMCs). Consequently, acetylation of STAT6 and histone H3 increased more than 2-fold, which caused a 2.2-fold upregulation of TIMP-3. Moreover, the anti-atherosclerotic effects of IL-16 on plaque stability were abrogated by the SMC-specific deletion of CD4, and the plaque vulnerability caused by IL-16 defects was reversed by SMC-specific overexpression of TIMP-3. IL-16/CD4/JAK2/STAT6 upregulates TIMP-3 expression in SMCs to remodel the intraplaque extracellular matrix toward a stable phenotype. Our findings suggest that IL-16 is a novel factor in vascular remodeling and atherosclerotic plaque phenotype modulation and is a potential target for intervention in the later stages of atherosclerosis. Show less

The ability to precisely control the interactions between nanoparticles and biomolecules is crucial for advancing their biomedical applications, yet existing strategies often lack dynamic responsiveness. Herein, we demonstrate that terahertz (THz) waves can serve as a novel, noninvasive tool to actively modulate the adsorption of proteins onto graphene oxide (GO). Through all-atom molecular dynamics simulations, we investigate the effects of THz waves at two characteristic frequencies (19.2 THz and 35.5 THz) on the adsorption of human serum albumin (HSA) and apolipoprotein E (ApoE). Our results reveal a frequency-dependent regulatory effect. Irradiation at 19.2 THz significantly enhances the adsorption of both HSA and ApoE onto GO. This enhancement is primarily attributed to the resonance with the hydrogen-bonding network of hydration water, which disrupts the hydration shell surrounding the proteins and weakens their shielding effect. In contrast, a 35.5 THz wave, which resonates with the hydroxyl groups on GO, exerts distinct effects on the two proteins: it enhances ApoE adsorption by increasing the hydrophobicity of GO, while it leaves HSA adsorption unchanged. This differential effect is attributed to a concomitant increase in the structural rigidity of HSA upon irradiation, counteracting the enhanced adsorption drive. Overall, this study establishes THz waves as a potent physical stimulus for dynamically tuning bionano interactions, which provide a foundation for developing innovative strategies in biosensing, drug delivery, and precision medicine. Show less

Anti-inflammatory colchicine therapy has emerged as a new era for atherosclerotic cardiovascular diseases. However, the therapeutic benefit of colchicine has not been clearly defined. Herein, we present a double coordination-driven approach to fabricate a stable metal-organic nano-assembly of colchicine (COL-TA-Zn) by uniting the tropolone ring of colchicine (COL), phenolic groups of tannic acid (TA), and Zn Show less

Health and financial literacy decline in aging, but it is unclear why. In this study, we hypothesized that older people who are carriers of the APOE ε4 allele exhibit a steeper decline in literacy over time. Participants were 851 community-dwelling older adults without dementia at analytic baseline (188 ε4 carriers and 663 noncarriers). Literacy was assessed at baseline and each year thereafter for up to 14 years. In a linear mixed-effects model adjusted for age, gender, and education, ε4 was associated with a lower starting level of literacy (b = -3.60, SE b = 1.00, p < 0.001) and, critically, a roughly 40% steeper decline in literacy over time (b = -0.41, SE b = 0.14, p = 0.004). The association between ε4 and literacy decline persisted after adjusting for global cognition at baseline (b = -0.35, SE b = 0.14, p = 0.012) and among a subgroup of participants with no cognitive impairment at baseline (b = -0.34, SE b = 0.14, p = 0.016). ε4 contributes to literacy decline among older adults, presumably due in part to the accumulation of neuropathologies associated with ε4. We discuss the potential clinical implications of ε4-related literacy decline. Show less

Vascular senescence is a fundamental driver of age-related cardiovascular diseases, yet the epigenetic mechanisms controlling this process remain poorly understood. This study investigated the role and underlying mechanisms of lysine acetyltransferase 8 (KAT8), a key histone acetyltransferase, in maintaining endothelial cell homeostasis and preventing vascular senescence. We found that KAT8 expression is consistently downregulated in human aged vessels, senescent rats and mice, and cellular models of aging. Using CRISPR-Cas9-based loss-of-function and gain-of-function approaches in endothelial cells, C57BL/6J mice, and ApoE Show less

Atherosclerosis is a chronic inflammatory disease marked by lipid accumulation and immune cell infiltration in arterial walls. Macrophages contribute by internalizing oxidized low-density lipoprotein, forming foam cells, and driving inflammation. The ubiquitin-proteasome system regulates immune and inflammatory responses in atherosclerosis. This study investigated the protective role of TRIM31 (tripartite motif-containing 31), an E3 ubiquitin ligase, in macrophage lipid metabolism and inflammation through selective regulation of LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1). Transcriptomic profiling, macrophage-specific TRIM31 was selectively upregulated in macrophages under oxidized low-density lipoprotein stimulation and in atherosclerosis plaques. Trim31 deficiency exacerbated plaque burden, foam cell formation, and inflammatory signaling (n=8 per group). Single-cell analysis revealed enrichment of lipid transport and inflammatory pathways in Trim31-deficient plaques. LOX-1 was identified as a key TRIM31 substrate. TRIM31 promoted K48-linked ubiquitination of LOX-1 at lysine 12, facilitating its degradation. The atheroprotective effects of Trim31 were abolished in TRIM31, an inducible, macrophage-enriched protective factor in atherosclerosis, restricts foam cell formation and inflammation by targeting LOX-1 for proteasomal degradation. These findings position TRIM31 as a promising therapeutic target for macrophage-driven atherogenesis. Show less

Purinergic receptor P2X7 has been considered as a potential new target for detecting and treating high-risk plaque. Nanobodies are the smallest antibody fragments with high antigen binding ability and specificity, which are well-suited for radionuclide imaging. The present study aimed to develop a novel P2X7-targeted nanobody SPECT tracer and to investigate its potential for identification of atherosclerotic plaque (AP). The anti-P2X7 nanobody 1c81 was site-specifically conjugated with [ Show less

Pro-inflammatory macrophage function is linked to an increase in mitochondrial fission. Melatonin has a positive impact on atherosclerosis and has a significant effect on the control of mitochondrial fission and fusion. Nevertheless, it is still unclear how melatonin contributes to slowing the advancement of atherosclerosis. The ApoE The study found that melatonin treatment decreased the area of atherosclerotic plaque, decreased lipid deposition, suppressed inflammatory cytokine levels, inhibited macrophage pro-inflammatory differentiation, inhibited mitochondrial fragmentation, increased the level of Sirt3, and decreased Drp1 expression in atherosclerosis (AS) mice. However, Sirt3 inhibition abolished the protective affects of melatonin in AS mice. Melatonin therapy upregulated Sirt3 expression in RAW264.7 cells subjected to ox-LDL, blocked Drp1-mediated mitochondrial fission, and reduced inflammatory cytokine levels. On the other hand, melatonin's inhibitory effects on Drp1 expression and mitochondrial fission were lessened by Sirt3 inhibition. Additionally, DRP1 siRNA knockdown inhibited mitochondrial fission and pro-inflammatory differentiation of macrophages induced by ox-LDL. Melatonin inhibits the growth of atherosclerosis and the pro-inflammatory differentiation of macrophages by blocking the Sirt3-Drp1 pathway, which prevents mitochondria from fission. Melatonin's suppression of mitochondrial fission may be a viable strategy for postponing cardiovascular problems in atherosclerosis patients. Show less

Aging and age-related diseases share convergent pathways at the proteome level. Here, using plasma proteomics and machine learning, we developed organismal and ten organ-specific aging clocks in the UK Biobank (n = 43,616) and validated their high accuracy in cohorts from China (n = 3,977) and the USA (n = 800; cross-cohort r = 0.98 and 0.93). Accelerated organ aging predicted disease onset, progression and mortality beyond clinical and genetic risk factors, with brain aging being most strongly linked to mortality. Organ aging reflected both genetic and environmental determinants: brain aging was associated with lifestyle, the GABBR1 and ECM1 genes, and brain structure. Distinct organ-specific pathogenic pathways were identified, with the brain and artery clocks linking synaptic loss, vascular dysfunction and glial activation to cognitive decline and dementia. The brain aging clock further stratified Alzheimer's disease risk across APOE haplotypes, and a super-youthful brain appears to confer resilience to APOE4. Together, proteomic organ aging clocks provide a biologically interpretable framework for tracking aging and disease risk across diverse populations. Show less

To identify plasma proteins associated with glaucoma and assess the translational potential of key proteins as both biomarkers and therapeutic targets. Genome-wide association study data were obtained from the UK Biobank Pharma Proteomics Project, FinnGen, and the Million Veteran Program. We used a four-stage analytical framework: Stage 1 applied Mendelian randomization and Bayesian colocalization to evaluate associations between 2923 plasma proteins and glaucoma; Stage 2 used summary-based Mendelian randomization to explore transcriptomic and epigenomic associations of the identified proteins with glaucoma risk; Stage 3 involved a prospective association analysis of protein levels and incident glaucoma in the UK Biobank cohort, including 40,170 glaucoma-free participants; and Stage 4 systematically evaluated the druggability of the prioritized protein targets. We identified 26 plasma proteins with putative causal associations with glaucoma, six of which were novel: COL24A1, KAZALD1, EBAG9, CSNK1D, AZI2, and AXIN1. COL24A1 (odds ratio [OR] = 0.85; 95% confidence interval [CI], 0.80-0.90; PFDR < 0.001; PP.H4 = 0.95) and EFEMP1 (OR = 0.88; 95% CI, 0.83-0.92; PFDR < 0.001; PP.H4 = 0.98) emerged as the most compelling candidates. To further elucidate the regulatory mechanisms, multiomics analyses indicated that epigenetic modifications and alternative splicing events affecting these genes were associated with elevated glaucoma risk. Notably, EFEMP1 was significantly associated with glaucoma incidence in the prospective cohort analysis (fully adjusted Cox model: hazard ratio = 1.61; 95% CI, 1.29-2.00; PFDR = 0.002), demonstrating strong predictive performance (C-index = 0.811, area under the curve = 0.806) and representing a promising therapeutic target. Our findings provide new insights into the proteomic basis of glaucoma and highlight promising opportunities for developing targeted therapies. Show less

AXIN1 (axis inhibition protein 1), as a rate-limiting component of canonical Wingless-type mouse mammary tumor virus integration site (Wnt)/β-catenin signaling pathway, may influence midbrain dopaminergic neurons. A recent genome-wide association study identified AXIN1 as a candidate gene for Parkinson's disease (PD). Our study aimed to investigate the potential relevance of AXIN1 single nucleotide polymorphisms (rs13337493 and rs9921222) in the risk, clinical characteristics, and pathology of PD. Data were collected from the Northern Han Chinese and Parkinson's Progression Markers Initiative (PPMI) cohorts. Associations between AXIN1 variants, PD-related biomarkers, and clinical manifestations were analyzed. Both loci were identified as risk factors in the Northern Han Chinese population, and the A allele of rs13337493 [odds ratio (OR) 1.320, 95% confidence interval (CI) 1.052, 1.653, P Our findings support a gatekeeper role for AXIN1; its polymorphisms contribute to increased PD susceptibility and accelerated motor progression, yet may also trigger a compensatory presynaptic response, as evidenced by elevated CSF DOPA levels, to counteract neurodegeneration. Future studies should include larger sample sizes, more diverse ethnic populations, and protein-level investigations. Show less

It is known that insulin stimulates skeletal muscle glucose uptake via the InsR-IRS-PI3K pathway. The signaling downstream of PI3K is divided into the Akt-AS160-Rabs branch and the Rac1-actin cytoskeleton branches. These two signaling branches jointly mediate the effect of insulin to promote GLUT4 transporters to transport glucose into the cell. The scaffolding protein Axin1 plays a crucial role in maintaining glucose homeostasis and TNKS, a member of the PARP family, is involved in insulin-stimulated GLUT4 translocation. However, the specific roles of Axin1 and TNKS and their relationship are elusive in insulin-stimulated skeletal muscle cell glucose uptake. Here, we showed that insulin up-regulated the protein levels of Axin1 and TNKS in an Akt-dependent manner in C2C12 skeletal muscle cells. Knockdown of Axin1 inhibited insulin-stimulated GLUT4myc translocation in C2C12-GLUT4myc myotubes. Both over-expression Axin1 and TNKS activity inhibitor XAV939 enhanced insulin-stimulated GLUT4myc translocation. XAV939 up-regulated Axin1 and TNKS protein levels. Knockdown or over-expression of Axin1 down- or up-regulated the protein level of TNKS, respectively. Axin1 interacted with TNKS which was enhanced by insulin. Knockdown of Axin1 inhibited insulin-induced the phosphorylation of the Rac1 target protein PAK. Over-expression of Axin1 and XAV939 increased insulin-phosphorylated PAK. Up- and down-regulation of Axin1 and XAV939 had no effects on the phosphorylation of Akt and AS160. Insulin increased the Rac1-GEF Tiam1 protein levels. Knockdown of Tiam1 diminished insulin-stimulated PAK phosphorylation and GLUT4myc translocation. Knockdown of Axin1 inhibited insulin-induced Tiam1 expression, while over-expression of Axin1 and XAV939 had the opposite effect. In summary, our results suggest that an Akt-Axin1/TNKS-Tiam1-Rac1 signaling pathway mediates insulin-stimulated GLUT4 translocation in skeletal muscle cells. Show less

Alzheimer's disease (AD), a chronic and progressive neurodegenerative disease, is the most common cause of dementia. An important pathological basis for AD lesions is the excessive generation and deposition of β-amyloid (Aβ) caused by increased expression of the β-secretase, known as the β-site amyloid precursor protein cleaving enzyme 1 (BACE1). Effective suppression of the BACE1 overexpression has become a key AD treatment. Nuclear factor of activated T cells (NFAT) is a key transcription factor that regulates the expression of BACE1 in AD lesions, while Calcineurin (CaN) is a key regulatory protein that affects the transcription function of NFAT. Several lines of evidence have indicated that FK506 may promote the Aβ degradation via upregulation of the matrix metalloproteinase-9 (MMP-9) expression, which is associated with reduction of Aβ plaque deposition in the cerebral cortex and hippocampus. In this study, behavioral, histological, and biochemical methods were used to investigate the key role and molecular mechanisms of CaN inhibitor FK506 in cognitive dysfunction, regulation of BACE1 expression, and Aβ production in APPswe/PS1dE9 transgenic mice. Results The results indicate that FK506 inhibits NFAT1 levels in the cerebral cortex and hippocampus, thereby reducing the expression of BACE1 and mediating APP processing towards non-amyloidosis pathways, significantly reducing Aβ overproduction, which in turn saved cognitive deficits in APPswe/PS1dE9 transgenic mice. In addition, FK506 treatment had no significant effect on the expression of a disintegrin and metalloprotease (ADAM10) in α - secretase. FK506 rescues cognitive deficits in APPswe/PS1dE9 mice by reducing Aβ production and deposition in the brain. Show less

Nutrient competition between tumor and immune cells is a hallmark of the glioblastoma (GBM) microenvironment, yet the mechanisms underlying amino acid metabolic reprogramming and immune evasion remain incompletely understood. Here, we demonstrate that GBM cells outcompete NK cells for branched-chain amino acid (BCAA), leading to BCAA depletion, suppression of NK and CD8 Show less

Papillary thyroid carcinoma (PTC) is the most common form of thyroid cancer, with the majority of cases driven by genetic alterations that activate the MAPK signaling pathway. The BRAF V600E mutation is the most frequent alteration, while BRAF fusions are relatively rare but increasingly recognized as oncogenic drivers. These fusions typically involve the loss of BRAF's autoinhibitory N-terminal domain, leading to constitutive MAPK pathway activation. Here, we report a novel SORBS2::BRAF fusion in a case of PTC, further expanding the spectrum of BRAF alterations in thyroid cancer. A 32-year-old male was incidentally found to have a left thyroid nodule during a routine physical examination. Follow-up examinations revealed changes in the nodule's characteristics, prompting fine-needle aspiration biopsy, which identified atypical follicular epithelial cells suggestive of papillary thyroid carcinoma. Histopathological examination confirmed the diagnosis, and next-generation sequencing (NGS) revealed a novel in-frame fusion between SORBS2 exon 18 and BRAF exon 9. The resulting fusion protein retains the BRAF kinase domain while replacing its autoinhibitory domains with those of SORBS2. RT-PCR and Sanger sequencing confirmed the presence of the SORBS2::BRAF fusion. Quantitative PCR profiling of MAPK transcriptional output genes (DUSP6, CCND1, ETV4, c-Myc, and c-FOS) revealed marked upregulation in the tumor versus adjacent normal tissue, providing functional evidence for pathway activation. The SORBS2::BRAF fusion has not been previously reported in PTC or any other tumor type. Given the deletion of BRAF's inhibitory domain, this fusion likely acts as a tumor driver through constitutive activation of the MAPK pathway. This case underscores the importance of molecular diagnostics in identifying rare genetic alterations and highlights the need for further research into targeted therapies for BRAF fusion-driven cancers. The discovery of this novel fusion expands our understanding of the molecular landscape of PTC and provides a foundation for future therapeutic development. Show less