👤 Jun Guo

AllergoOncology has emerged as an interdisciplinary field exploring the interaction between allergic diseases and cancer; however, the lack of stable in vivo models has limited mechanistic investigations. This study aimed to establish an experimental animal model to explore the impact of systemic allergic responses on tumor progression and to provide preliminary insights into the regulatory role of allergy in cancer development. An ovalbumin (OVA)-induced systemic allergy tumor-bearing mouse model (OVA-TM) was established by OVA sensitization followed by subcutaneous implantation of CT26 colon cancer cells. Tumor growth, immune responses, and behavioral changes were systematically evaluated. Tumor immune microenvironment alterations were assessed using immunological and histological analyses. Transcriptomic profiling and mass spectrometry imaging (MSI) were integrated to investigate immune-related metabolic alterations. Human tumor survival datasets were used to validate the prognostic relevance of differentially expressed genes (DEGs), and enrichment analyses of allergy- and cancer-associated genes were performed using humanized databases. OVA-induced systemic allergy significantly suppressed tumor growth and promoted immune cell infiltration, particularly CD3 This study establishes a practical in vivo model for AllergoOncology and demonstrates that systemic allergic responses can modulate tumor progression through immune activation, apoptosis, and inflammation-metabolism axis reprogramming, providing a foundation for future mechanistic and therapeutic studies. Show less

Research suggests that lipid levels may be associated with suicide risk. However, the specific relationship between Apolipoprotein B and suicidal ideation remains unclear. The aim of this study was to investigate the association between ApoB levels and suicidal ideation and to further explore the causal relationship using Mendelian randomization. A cross-sectional study of 6520 U.S. adults was conducted using the 2011-2016 National Health and Nutrition Examination Survey (NHANES) dataset. Multiple logistic regression, smoothed curve fitting, stratified analyses, and interaction tests were used to reveal the relationship between ApoB levels and suicidal ideation. MR analyses were conducted using inverse variance weighting (IVW), GSMR, Maximum likelihood method, and cML-MA-BIC MR method. Sensitivity analyses included MR-Egger intercept test, MR-PRESSO global test, and leave-one-out (LOO) analysis. Multivariate logistic regression analysis showed that serum ApoB levels were positively associated with suicidal ideation, and the association remained significant even after multiple covariates (P = 0.0463). Subgroup analyses showed that the risk of suicidal ideation was significantly increased in the highest tertile (T3) of the population compared to the lowest tertile (T1) of ApoB levels (OR = 1.48, 95% CI: 1.04-2.12, P = 0.0312). In addition, the association between ApoB and suicidal ideation was more significant in the smoking subgroup (P interaction = 0.034). However, MR analysis failed to confirm a significant causal effect of ApoB levels on suicidal ideation (P > 0.05), and these results were robust to sensitivity analyses. The present study found a significant positive association between serum ApoB levels and suicidal ideation, especially among smokers. MR analysis failed to provide causal evidence of ApoB on suicidal ideation. More research is needed to clarify the potential role of ApoB in the development of suicidal ideation. Show less

Rapid platelet inhibition is essential for effective management during emergency percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS). However, the oral dosage form of clopidogrel (CLP) commonly used in clinical practice shows a delayed onset due to gastrointestinal absorption, first-pass metabolism, and the requirement for hepatic cytochrome P450 (CYP450)-mediated bioactivation, which limits its applications in urgent scenarios and complicating post-PCI bleeding management. To address these challenges, we developed an intravenous micellar formulation (CLP/PM) using FDA-approved mPEG-PLA copolymers to promote rapid hepatic exposure and metabolic activation. By tuning the PLA chain length, micellar core density and PEG conformation were modulated, thereby influencing protein corona (PC) formation and liver-affinity interactions. Proteomic profiling revealed that micelles with intermediate PLA length selectively recruited liver-affinity apolipoproteins (ApoM, ApoH, ApoA1, and ApoB), which are known ligands of LDLR and SR-BI, while minimizing adsorption of inflammatory and opsonization proteins. The optimized CLP/PM (3.9 k) exhibited a hepatotropic-like PC that was associated with hepatocyte-enriched uptake in primary liver cell analyses. In vivo biodistribution showed rapid liver-level signal, and pharmacokinetic studies supported enhanced CYP450-mediated activation, achieving a higher C Show less

Dyslipidemia is common in patients with MASLD, but the frequency and significance of inherited disorders of dyslipidemia are unclear. We investigated the prevalence and significance of pathogenic variants associated with selected monogenic disorders of dyslipidemia in 3358 patients with well-characterised MASLD. We identified clinically relevant variants in APOB, MTTP, PCSK9, ANGPTL3, LDLR and LDLRAP1 genes which can cause hypobetalipoproteinemia (HBL) and familial hypercholesterolemia (FH). Using ClinVar annotations as initial variant selection, we identified 2027 variants in those 6 genes which are reported as 'pathogenic' or 'likely pathogenic' (P/LP). We first assessed for the presence of P/LP variants in the study cohort and then investigated the effect of carrying P/LP variants on liver histology, by comparing ~4 matched controls for each APOB and LDLR carrier. As interpretative analyses, we also looked at the difference between liver enzymes, lipid measures and outcomes between the carriers and matched controls. Twenty-two variants among these 2027 P/LP variants were present in 24 out of 3358 patients (12 ApoB, 10 LDLR, 1 ANGPTL3 and 1 MTTP variant carriers). Compared to controls, APOB carriers had higher steatosis grade (2.4 vs. 1.7, p-value 0.0028), higher NAFLD activity score (NAS) (4.9 vs. 3.8, p-value 0.04), and numerically higher but statistically not significant fibrosis stage (1.2 vs. 1.1, p-value 0.75) and ALT (87.4 vs. 58.1 U/L, p-value 0.06). Their LDL-c (51 vs. 147.8 mg/dL, p-value 6.1E-09) and triglycerides (91.5 vs. 160.6 mg/dL, p-value 2.8E-03) were significantly lower. Compared to controls, LDLR carriers had numerically higher steatosis grade, NAS, fibrosis stage and LDL-c levels, but these were not statistically different. Monogenic disorders of dyslipidemia are rarely present in patients with MASLD and are sometimes associated with worse liver histology. Testing for these conditions may be considered on a case-by-case basis. Show less

The therapeutic effects of different combination therapies containing cholesteryl ester transfer protein (CETP) inhibitors vary. Evidence from head-to-head comparisons is scarce and inconsistent. This study aimed to evaluate the impact of CETP inhibitor-based combination therapy on lipid levels and explore its adverse events (AEs). Randomized controlled trials (RCTs) were retrieved from PubMed, Embase, Cochrane Library, and Web of Science up to August 30, 2025. Thirteen RCTs were analyzed through STATA 14.0. This systematic review and network meta-analysis of 13 studies (9248 participants) evaluated CETP inhibitor-based combination therapies. For HDL-C elevation, obicetrapib + ezetimibe + statin ranked highest (SUCRA = 95.1%). Evacetrapib + statin achieved reduction in LDL-C (SUCRA = 94.3%). Obicetrapib + ezetimibe + statin excelled in reducing TC (SUCRA = 100.0%) and TG (SUCRA = 99.9%). Obicetrapib + statin was most effective for ApoAI increase (SUCRA = 100.0%), while obicetrapib + ezetimibe + statin best reduced ApoB (SUCRA = 100.0%). Regarding safety, obicetrapib + statin had the optimal profile for all grade AEs (SUCRA = 19.2%) and severe AEs (SUCRA = 22.5%), conversely, evacetrapib + statin had the worst profile (SUCRA = 83.1% and 66.3%, respectively). Our meta-analysis demonstrated that CETP inhibitor combination therapies offer distinct lipid-modulating benefits and safety profiles. The obicetrapib + ezetimibe + statin triple therapy showed superior comprehensive efficacy, while obicetrapib + statin exhibited the optimal safety. Evacetrapib + statin provided potent LDL-C reduction but had the poorest safety. These findings facilitate personalized treatment selection for dyslipidemia management. PROSPERO CRD420251145396 ( https://www.crd.york.ac.uk/prospero/ ). Show less

Patients on dialysis often suffer from carnitine deficiency due to reduced intake, reduced synthesis in the kidneys, and clearing through dialysis. Carnitine deficiency may lead to anemia, cardiomyopathy, hypotension, and so on. Several studies have shown that supplementing with L-carnitine can diminish the above symptoms in adult dialysis patients, but whether children can benefit from L-carnitine remains unclear. This study was performed to investigate the effect of L-carnitine in children with kidney failure undergoing dialysis. PubMed, Embase, The Cochrane Library, China National Knowledge Infrastructure (CNKI), WanFang Data, and VIP database were electronically searched from database inception to December 2023.  STUDY ELIGIBILITY CRITERIA: We included randomized controlled trials (RCTs), cohort studies, case-control studies, cross-section studies, and case series studies that evaluated the impact of L-carnitine on children. Patients aged less than 18 years with kidney failure undergoing dialysis.  STUDY APPRAISAL AND SYNTHESIS METHODS: We assessed the quality of studies using the RoB2 tool recommended by the Cochrane Handbook, the Newcastle-Ottawa Quality Assessment Scale (NOS), the checklist recommended by Agency for Healthcare Research and Quality (AHRQ), and the quality evaluation tool recommended by the National Institutes of Health (NIH). We conducted only descriptive analyses and did not perform meta-analysis due to significant differences in study types and limited data. A total of 194 patients were included in 9 studies, of which 3 were RCT studies; 2 were cohort studies, and 4 were case series studies. Due to limited data, we only conducted descriptive analysis rather than meta-analysis. For children undergoing hemodialysis, cohort study of high-quality showed that L-carnitine significantly improved hemoglobin (Hb) and reduced the required erythropoiesis-stimulating agent (ESA) dose; RCT study of moderate-quality indicated that L-carnitine did not influence serum lipid profiles except for reducing apolipoprotein B (ApoB). Cohort study of moderate-quality showed that L-carnitine improved cardiac function; RCT study of moderate-quality indicated that L-carnitine did not influence albumin, C-reactive protein (CRP), interleukin-6 (IL-6), and quality of life. For children undergoing peritoneal dialysis, only serum lipid profiles were analyzed. RCT and case series studies of moderate-quality indicated that L-carnitine did not influence serum lipid profiles except for reducing ApoB. The number of studies enrolled was limited, and their quality was not high. Our study found that children with kidney failure requiring dialysis could partially benefit from L-carnitine, including increased Hb, decreased ESA requirement, reduced ApoB, and improved cardiac function. Further RCTs of high quality are still needed to clarify this issue. This study provided more comprehensive and credible evidence for clinical use of L-carnitine in children. PROSPERO registration number CRD420250649553. Show less

Schizophrenia is frequently comorbid with dyslipidemia and hyperglycemia. However, whether metabolic-modifying agents aggravate schizophrenia progression remains unclear. We perform a drug-target genetic association study in two independent Han Chinese schizophrenia cohorts (N = 2,111/292 for discovery/validation). Leveraging metabolic genome-wide association studies, we generate genetic risk scores (GRSs) for lipid-modifying and hypoglycemic targets. Those with higher APOC3 (inhibited by volanesorsen/olezarsen) GRS exhibit attenuated triglycerides and improvement in negative symptoms assessed by Positive and Negative Syndrome Scale (PANSS) (β = 1.23, 95% confidence interval [CI]: 0.30-2.16). Higher GCK (activated by dorzagliatin) GRS is associated with decreased glucose and less improvement across PANSS total (β = -1.70, 95% CI: -2.91-0.50), positive, negative, general subscales. Causal associations of GCK are replicated in independent validation. The effects of APOC3 and GCK on negative symptom recovery are robust in hyperlipidemic/diabetic subgroups. Genetically proxied proteomics analysis provides further functional validation for the identified target-outcome associations. Our findings suggest volanesorsen/olezarsen as potential adjunctive candidates; dorzagliatin warrants prudence in schizophrenia with metabolic disturbance. Show less

Gene editing technologies have revolutionized therapeutic development, offering potentially curative and preventative strategies for cardiovascular disease (CVD), which remains a leading global cause of morbidity and mortality. This review provides an introduction to the state-of-the-art gene editing tools-including ZFNs, TALENs, CRISPR/Cas9 systems, base editors, and prime editors-and evaluates their application in lipid metabolic pathways central to CVD pathogenesis. Emphasis is placed on targets such as Show less

BackgroundTau pathology begins to accumulate in the medial temporal lobe in many individuals in middle age. Some individuals develop amyloid pathology, more advanced tau pathology (Braak stage), and higher levels of CA1 hippocampal tau pathology in the context of Alzheimer's disease. Others never develop significant amyloid pathology; in these cases, hippocampal tau pathology can be CA2-predominant and tends not to accumulate past intermediate stages. But factors associated with the early formation of these tau patterns is unclear.ObjectiveThe objective of this study is to examine demographic, genetic ( Show less

Atherosclerosis is the inflammatory consequence of lipid accumulation with plaque formation in the vascular intima and is a common condition to develop into various cardiovascular diseases. Current therapies do not always lead to satisfactory treatment outcomes. Enterolactone, a mammalian lignan produced by bacterial transformation from plant lignans, has a preventive effect against cardiovascular disease. However, its effect on atherosclerosis and the underlying mechanism of action remain unclear. To explore the therapeutic effect of ENL on atherosclerosis and elucidate the underlying mechanism. We established a model of atherosclerosis on ApoE-/- C57BL/6 mice by high fat diet. The aortic root was collected and sectioned to assess arterial plaque area, collagen fibrillar proliferation, and lipid content. RT-qPCR was used to determine the inflammatory response in the artery of mice. The serum from mice was isolated to measure lipid levels, and the fecal microbiota was analyzed by 16S rDNA. H In the animals, enterolactone significantly improved lipid metabolism, attenuated ferroptosis occurring in the intima, facilitated the antioxidant mechanisms, and promoted healing of the endothelial lesions, by interacting with Nrf2. Of great importance, enterolactone massively altered the gut microbiota toward a curative outcome by elevating the abundance of beneficial bacteria, such as the SCFA-producing taxa. Additionally, ENL suppresses lipid peroxidation and inflammatory activation in HUVECs by regulating the Keap1/Nrf2/GPX4 pathway, and knocking down Nrf2 attenuates the treatment effect of ENL. Enterolactone effectively resolves intimal inflammation and redresses atherosclerosis by ameliorating the gut microbiome and modulating lipid metabolism via the Keap1/Nrf2/GPX4 pathway. Show less

Dementia with Lewy bodies (DLB) frequently coexists with cerebrovascular injury and Alzheimer's-related pathology, yet accessible in vivo markers of these processes remain limited. The retinal microvasculature shares structural and physiological characteristics with cerebral small vessels and may provide a non-invasive window into neurovascular and neurodegenerative pathology. In this cross-sectional study, 32 individuals with DLB and 31 age-matched cognitively unimpaired controls (CU) underwent swept-source optical coherence tomography angiography (OCTA), brain MRI, and plasma biomarker assessment. Retinal vessel densities of the superficial vascular complex (SVC), deep vascular complex (DVC), and choriocapillaris (CC) were quantified. Plasma amyloid-β, phosphorylated tau-217 (p-tau217), and glial fibrillary acidic protein were measured. Cerebral small vessel disease (SVD) burden and white matter hyperintensity (WMH) volumes were derived from MRI. Associations with cognition and mediation by WMH burden were evaluated using generalized estimating equations and bootstrapped mediation analyses. Compared with CU, individuals with DLB exhibited significantly reduced SVC, DVC, and CC vessel densities (all p < 0.001). Lower retinal vessel densities were associated with higher plasma amyloid burden and elevated p-tau217, as well as greater SVD burden and periventricular WMH volume. APOE ε4 carriers demonstrated more pronounced retinal microvascular impairment, higher WMH burden, and elevated p-tau217 levels than non-carriers. Reduced SVC density was associated with worse global cognition, and this relationship was partially mediated by periventricular WMH volume. Retinal microvascular impairment measured by OCTA is closely linked to Alzheimer's-related plasma biomarkers, SVD, and cognitive decline in DLB. These findings support retinal OCTA as a scalable, non-invasive biomarker reflecting convergent neurodegenerative and vascular pathology in DLB. Show less

Klotho is a longevity-associated protein with established neuroprotective properties. However, it is unclear how plasma klotho levels relate to Alzheimer's disease (AD) pathologies and cognitive performance. In this study, we examined the associations between plasma klotho levels and plasma biomarkers, as well as amyloid beta (Aβ) positron emission tomography (PET), tau PET, neurodegeneration, and cognition, in 354 older adults. Stratified association, interaction, and mediation analyses were conducted to elucidate apolipoprotein E (APOE) ε4-dependent relationships and potential underlying pathways. Higher plasma klotho levels were associated with lower AD-related biomarkers and cognitive decline in APOE ε4 carriers. Plasma klotho and APOE ε4 exhibited significant or marginal interactions with less abnormal changes in plasma phosphorylated tau217, glial fibrillary acidic protein, neurofilament light chain, Aβ PET, and cognition. These AD-related biomarkers mediated the protective effect of plasma klotho on cognitive function in APOE ε4 carriers. This study suggests that plasma klotho is an APOE ε4-dependent protective factor, which may attenuate AD-related pathology and improve cognitive performance. Show less

Dichlorodiphenyltrichloroethane (DDT), a persistent organochlorine pesticide, continues to be used for malaria control under the Stockholm Convention. We investigated associations between exposure to DDT and its metabolite dichlorodiphenyldichloroethylene (DDE) and midlife cognitive function and brain structure among primarily Mexican-born Latina women in an agricultural community in California, USA. In the CHAMACOS Maternal Cognition Study, a prospective cohort study, we assessed global and domain-specific cognitive performance in 472 women. A subset of 95 women underwent T1-weighted brain MRI to measure cortical thickness. We evaluated associations between serum p,p'-DDT and p,p'-DDE concentrations-measured 12 years earlier-and cognitive Z scores and cortical thickness using linear regression. Bayesian hierarchical models accounted for co-exposure to other organochlorine pesticides. Apolipoprotein E (APOE) genotype was assessed as a potential modifier. Higher p,p'-DDT and p,p'-DDE concentrations were significantly associated with lower executive function scores (p,p'-DDT β=-0·10 [95% CI -0·18 to -0·02]; p,p'-DDE β=-0·09 [-0·19 to 0·00]; SDs per ten-fold increase in serum concentration). No associations were observed with other cognitive domains. Results were robust to adjustment for APOE genotype and organochlorine co-exposures. No effect modification by APOE ε4 status was found. Both exposures were associated with greater frontal lobe cortical thickness, particularly in the medial orbitofrontal and pars orbitalis regions. p,p'-DDT and p,p'-DDE exposure was associated with reduced executive function more than a decade later, and with altered frontal brain structure. These findings suggest potential long-term neurodevelopmental effects of legacy organochlorine exposure and warrant further investigation. US National Institutes of Health and US Environmental Protection Agency. Show less

Both Apolipoprotein E-ε4 (APOE-ε4) and astrocytic activation, as measured by glial fibrillary acidic protein (GFAP), play critical roles in Alzheimer's disease (AD). However, the influence of astrocytic activation on the relationship between APOE-ε4 and AD pathologies remains unclear. This study investigates the interrelationships among astrocytic activation, APOE-ε4, and AD pathophysiology in 529 participants who underwent plasma biomarker measurements, APOE genotyping, and cognitive testing. Additionally, 277, 284, and 104 underwent structural magnetic resonance imaging (MRI), amyloid-β (Aβ) positron emission tomography (PET), and tau PET, respectively. The associations of plasma GFAP, APOE-ε4, and AD-related biomarkers, as well as whether plasma GFAP mediates APOE-ε4-related effects on AD, were investigated. Higher plasma GFAP and APOE-ε4 were independently associated with more severe Aβ and tau aggregation, as well as cognitive decline. Mediation analyses showed a significant indirect effect of APOE-ε4 on plasma p-tau biomarkers (21.1%-24.9%), Aβ PET (16.4%), and cognition (19.6%), while the indirect effect on tau PET was trend-level (29.1%, p Show less

Vascular remodeling involves structural and functional vascular changes in response to injury, aging, and disease. A key pathological feature is vascular smooth muscle cells (VSMCs) phenotypic switching, which is accompanied by mitochondrial dysregulation. Metabolic reprogramming resembling the Warburg effect alongside mitochondrial oxidative damage collectively drive this pathological VSMC transdifferentiation. We hypothesized that targeting mitochondrial ROS could restore mitochondrial integrity and enhance oxidative phosphorylation (OXPHOS) to counteract both oxidative damage and metabolic reprogramming in cardiovascular diseases associated with vascular remodeling. We proposed that the uncharacterized membrane-associated protein FAM177A1 drives VSMC mitochondrial oxidative impairment and metabolic reprogramming, thereby promoting VSMC phenotypic switching and vascular dysfunction. We modeled vascular remodeling using global We identify FAM177A1 as a key mitochondrial regulator that drives VSMC switching through SIRT3-SOD2 axis disruption. Targeting FAM177A1 restores redox-metabolic homeostasis through scavenging ROS and improving OXPHOS, establishing it as a novel therapeutic target against vascular remodeling. Show less

Diabetic foot ulcers (DFU) are a major complication of diabetes, and its pathogenesis remains incompletely elucidated. Converging evidence indicates that oxidative stress and dysregulated mitochondrial polarization participate in DFU progression, nominating these processes as therapeutically actionable targets. This study integrates bulk and single-cell transcriptomic data with machine learning to reconstruct cross-scale, cell type-resolved molecular atlases and regulatory networks. Macrophages and fibroblasts emerged as communication hubs, dominating pathway enrichment and ligand-receptor programs such as macrophage migration inhibitory factor signaling pathway (MIF), ANNEXIN signaling pathway, and COMPLEMENT signaling pathway. Peptidylprolyl isomerase F (PPIF), which encodes cyclophilin D (CypD) and apolipoprotein E (APOE) were further prioritized as putative drivers within macrophages and fibroblasts, and a five-gene classifier was derived with robust performance (internal/external AUC = 0.833/0.933). Within DFU lesions, under the control of non-coding RNA circuitry, SOX5 may shape the inflammatory microenvironment, APOE may participate in lipid-metabolic remodeling, and PPIF (CypD) likely links reactive oxygen species (ROS) accumulation to a p53-dependent mitochondrial death pathway (necroptosis/apoptosis). Orthogonal validation showed significantly increased CypD in diabetic foot ulcer skin (DFUS) and diabetic foot ulcer tendon (DFUT) relative to diabetic foot skin (DFS) and DFT (Diabetic foot tendon), with up-regulated p53 and Cytc and down-regulated ApoE in DFUS; in primary foot-skin fibroblasts, a high-glucose plus tert-butyl hydroperoxide (HG+TBHP) model reproduced elevated ROS, loss of mitochondrial Δψm (mitochondrial membrane potential), growth restriction, and apoptosis, supporting a ROS-CypD/mPTP (mitochondrial permeability transition pore)-Δψm depolarization-p53/Cytc apoptosis axis. The delineated PPIF-centered regulatory network includes upstream transcription factors CEBPB/REL/SPI1 and a downstream ceRNA axis comprising miR-128-3p/miR-23a-3p-long non-coding RNA OIP5-AS1. Additionally, the significant role of polarization-specific reprogramming in regulating macrophage function highlights therapeutic strategies focused on metabolic reprogramming and inhibition of the PPIF/mPTP pathway. Collectively, a cell type-resolved molecular map of DFU is provided, healing-relevant cell populations and regulatory circuits are prioritized, and a translational, testable intervention framework is proposed. 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

The rupture of vulnerable plaques (VPs) serves as the pathophysiological foundation for the occurrence of acute coronary syndrome (ACS). The senescence of vascular smooth muscle cells (VSMCs) is pivotal in the formation and even rupture of VPs. Although previous studies have demonstrated that Sirt2 contributes to the attenuation of vascular aging, its specific mechanisms in VSMC senescence and vulnerable plaque formation remain poorly understood. This study aimed to explore the underlying mechanism of Sirt2 in the formation of vulnerable plaques. Male ApoE 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

Endothelial cell (EC) senescence is intimately linked to the development and progression of atherosclerosis. The FGFR2 (fibroblast growth factor receptor 2) signaling is crucial in regulating the phenotype of ECs. Recent studies have revealed that cell phenotype-specific alternative splicing of FGFR2 premRNA (precursor mRNA) results in the mutually exclusive inclusion of either exon IIIb or IIIc, leading to critical differences in receptor function. This study aimed to investigate the role of FGFR2 alternative splicing in EC senescence and atherosclerosis development, and to elucidate the underlying mechanisms. Clinical samples and animal models were used to assess the association between FGFR2-IIIc isoform expression and EC senescence as well as atherosclerotic plaque formation. The mechanisms underlying FGFR2-IIIc-induced EC senescence were elucidated through a combination of in vivo and in vitro investigations. In addition, genetically engineered mice with endothelial-specific overexpression or knockdown of FGFR2-IIIc were utilized to investigate the impact of FGFR2-IIIc on vascular endothelial senescence and the progression of atherosclerosis. Elevated expression of the FGFR2-IIIc isoform was detected in clinical samples and animal models of aging and atherosclerosis, where it correlated with both EC senescence and atherosclerotic plaque formation. Mechanistically, the alternative splicing-mediated switch from FGFR2-IIIb to FGFR2-IIIc established an FGF2-FGFR2-IIIc autocrine feedback loop, which drove ECs toward a senescence-associated secretory phenotype via the PKC (protein kinase C) ε/STAT3 (signal transducer and activator of transcription) pathway. Senescence-inducing stimuli promoted the binding of the splicing factor hnRNP H1 (heterogeneous nuclear ribonucleoprotein H1) to exon IIIb of the This study reveals that FGFR2 splicing mediated by hnRNP H1 promotes EC senescence and atherosclerosis via an FGF2-FGFR2-IIIc autocrine loop. These findings identify FGFR2-IIIc as a potential therapeutic target for age-related atherosclerosis. Show less

Atherosclerotic plaque rupture, driven by a vicious pathological cycle between endothelial-to-mesenchymal transition (EndMT) and chronic inflammation, represents a major therapeutic challenge in cardiovascular disease. Current clinical strategies, including statins and antiplatelet agents, fail to disrupt the EndMT-inflammation axis, while conventional TGF-β pathway inhibitors-critical for EndMT regulation-exhibit narrow therapeutic windows and systemic toxicity owing to the pleiotropic nature of TGF-β signaling. Here, we reported VRBPC, a VCAM-1-targeting, reactive oxygen species (ROS)-responsive baicalin-peptide conjugate that undergoes in situ self-assembly within atherosclerotic plaques to form a "molecular latch" that breaks the EndMT-inflammation loop. Upon VCAM-1-mediated endocytosis into activated endothelial cells, VRBPC responds to elevated ROS levels in the plaque microenvironment, triggering localized self-assembly that enhances baicalin retention and promotes its competitive binding to HSP90-a critical chaperone for TGF-β receptor stabilization. This mechanism inhibits Smad2/3 phosphorylation, reverses EndMT, and simultaneously suppresses inflammatory responses in macrophages. In vitro, VRBPC effectively restored endothelial phenotype, reduced aberrant migration, and diminished foam cell formation alongside pro-inflammatory cytokine secretion. In ApoE Show less

Atherosclerosis is respectively correlated with interleukin-6/interleukin-6 receptor (IL6/IL6R) mediated inflammation signaling and macrophages ferroptosis. Nonetheless, the underlying mechanism of IL6/IL6R signaling mediated macrophages ferroptosis in atherosclerosis remains unknown. This study aims to investigate whether IL6/IL6R signaling mediated macrophages ferroptosis through mitochondrial fragmentation and mitophagy impairment. Two human atherosclerotic transcriptomic datasets were used to conduct bioinformatic analysis. In vitro, counting kit-8 (CCK-8) assays, flow cytometry, immunofluorescence staining, malondialdehyde (MDA) and glutathione (GSH) assay kits were employed to evaluate reactive oxygen species (ROS) levels and macrophages ferroptosis. Transmission electron microscopy (TEM), laser confocal microscope and seahorse experiments were used to evaluate changes of mitochondrial morphology and mitochondrial function. Western blotting (WB) was used to quantify key markers of mitophagy and ferroptosis. In vivo, histological stainings and WB were used to determine the effects of IL6R deficiency on atherosclerosis, mitophagy and ferroptosis. Integrated bioinformatic analysis revealed that the IL6 expression could stratify early and advanced plaques. IL6 induced macrophages ferroptosis by increasing ROS and MDA levels, depleting GSH level, promoting lipid peroxidation and suppressing glutathione peroxidase 4 (GPX4) expression. Dynamin-related protein 1 (Drp1) mediated excessive mitochondrial fragmentation in IL6-induced macrophages, resulting in more shortened mitochondria, impaired oxidative phosphorylation (OXPHOS) and ROS accumulation. Activation of mitophagy, the process of mitochondrial fragmentation clearance, could increase GPX4 expression and attenuate the lipid peroxidation level in IL6 induced macrophages. Aggravation of ferroptosis further compromised mitophagy-related proteins expression. Targeting IL6R signaling attenuated atherosclerotic burden in ApoE [Image: see text] The online version contains supplementary material available at 10.1007/s10753-025-02359-5. Show less

Diabetes constitutes a risk factor for atherosclerotic calcification, which is highly associated with phenotypic switching in vascular smooth muscle cells (VSMCs). Protein cysteine S-nitrosylation plays a crucial role in multiple cardiovascular diseases. The objective of this study is to examine whether diabetic atherosclerotic calcification is regulated by S-nitrosylation of AMP-activated protein kinase (AMPK), a regulator of VSMC phenotype switching. The atherosclerotic plaque was induced by feeding Apoe In cultured VSMCs, high glucose (HG), but not high osmotic pressure, triggered nitrosative stress, reduced AMPKβ1 protein levels, increased AMPKβ1 S-nitrosylation and ubiquitination, and led to calcification. These effects were abolished by mutating AMPKβ1 at cysteine 173 or 223. Furthermore, mutations of AMPKβ1 at Cys173/223 to alanine restored AMPKβ1 protein levels and suppressed the AKT/Runx2 pathway in HG-treated VSMCs. In vivo, enforced expression of mutated AMPKβ1 (Cys173Ala plus Cys223Ala), but not overexpression of wild-type AMPKβ1, significantly prevented atherosclerotic calcification in diabetic Apoe Nitrosative stress contributes to atherosclerotic calcification in diabetes through AMPKβ S-nitrosylation. In perspective, it is advisable to consider inhibiting AMPKβ S-nitrosylation in diabetic patients with atherosclerosis. Show less

Lecanemab, an anti-amyloid beta (Aβ) protofibril antibody, was introduced in China in 2024, but its real-world performance remains unknown. In this prospective, multicenter study across 21 sites, 261 Alzheimer's disease patients (mild cognitive impairment to moderate dementia) received biweekly lecanemab (10 mg/kg). A matched Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort served as comparator. Cognitive tests, plasma biomarkers, and optional amyloid/tau positron emission tomography (PET) were assessed over 6 months. Lecanemab significantly attenuated cognitive decline versus ADNI. Plasma Aβ42, Aβ40, phosphorylated tau 217 (p‑tau217), glial fibrillary acidic protein (GFAP), and ratios showed robust changes; a p‑tau217 reduction correlated with amyloid PET clearance (mean -22.1 Centiloid; 29.2% turned amyloid-negative). Apolipoprotein E (APOE) ε4 non-carriers showed greater improvements. Infusion reactions occurred in 11.1% and amyloid-related imaging abnormalities in 9.2% (1.6% symptomatic), with no stage-related safety differences. Lecanemab was effective and well tolerated in real-world Chinese patients. Plasma p‑tau217 may serve as a sensitive, minimally invasive treatment-response biomarker. Show less

Following spinal cord injury (SCI), neuroinflammation driven by lipid-laden macrophage foam cells is a key pathology, yet how these cells manage their lipid homeostasis is unclear. We delineate a neuroprotective axis in which macrophages deploy apolipoprotein E (APOE) to transfer intracellular lipids to neighboring cells, especially fibroblasts. Genetic ablation of The online version contains supplementary material available at 10.1186/s12974-026-03756-9. Show less

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