👤 Xingwei Wu

To observe the effect of moxibustion on the lipid metabolism, aortic arch and mitochondrial structure, PTEN-induced kinase 1 (PINK1)/Parkin signaling pathway, and the expressions of apoptosis-related proteins in atherosclerotic (AS) mice, so as to explore its potential mechanisms underlying prevention and treatment of AS. Ten C57BL/6J mice were fed with normal chow and used as the control group. Thirty ApoE Compared with the control group, the contents of serum TC, TG and LDL-C, expression levels of PINK1, Parkin, Bax and Caspase3 protein, and the immunoactivity of Parkin and Cyt C were significantly increased ( Moxibustion can improve the lipid metabolism level, relieve pathological injury of the thoracic aorta, restore mitochondrial structure and function in ApoE Show less

Cerebrospinal fluid amyloid beta 42, total tau, and phosphorylated tau 181 are well accepted markers of Alzheimer's disease. These biomarkers better reflect disease pathogenesis compared to clinical diagnosis. Here, we perform a genome wide association study meta-analysis including 18,948 individuals of European ancestry and identify 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicate the association of biomarkers with APOE, CR1, GMNC/CCDC50 and C16orf95/MAP1LC3B. Novel loci include BIN1 for amyloid beta and GNA12, MS4A6A, SLCO1A2 with both total tau and phosphorylated tau 181, as well as additional loci on chr. 8, near ANGPT1 and chr. 9 near SMARCA2. We also demonstrate that these variants have significant association with Alzheimer's disease risk, disease progression and/or brain amyloidosis. The associated genes are implicated in lipid metabolism independent of APOE, coupled with autophagy and brain volume regulation driven by total tau and phosphorylated tau 181 dysregulation. 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 frequently complicated by vascular co-morbidities. However, the specific mechanistic pathways by which vascular lesions interact with genetic susceptibility to accelerate cognitive decline remain unclear. This study investigated whether cerebral amyloid angiopathy (CAA) and cortical microinfarcts mediate the impact of AD pathology on cognition and evaluated the modifying role of APOE genotype. We conducted a retrospective clinico-pathological study using the National Alzheimer's Coordinating Center (NACC) database. The cohort included autopsy-confirmed participants aged 50 and older. Structural Equation Modeling (SEM) was employed to quantify the pathways linking AD pathology (Thal phase) to CAA severity, microinfarcts, and cognitive performance (CDR-Sum of Boxes). We further assessed the cumulative burden of pathology by comparing "Pure AD" cases against those with a "Triple Hit" of AD, CAA, and microvascular injury. SEM analysis identified a significant statistical mediation pathway wherein parenchymal amyloid is strongly associated with CAA, which correlates with an increased risk of microinfarcts and subsequent cognitive dysfunction. We observed a significant gene-pathology interaction: APOE ε4 carriers demonstrated a steeper trajectory of cognitive decline for a given severity of CAA compared to non-carriers. Furthermore, the "Triple Hit" group exhibited significantly worse cognitive impairment than the "Pure AD" group (P < 0.001), independent of age and education. Vascular pathology is a critical mediator of cognitive failure in AD, particularly in APOE ε4 carriers. The concurrent "Triple Hit" of proteinopathy and vasculopathy is associated with a profound failure of cognitive reserve, likely reflecting a more advanced global disease state. These findings highlight the urgent need to target vascular resilience as a disease-modifying strategy in Alzheimer's disease. Show less

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by hepatic steatosis with cardiometabolic disorders. Due to the complicated pathophysiological processes, current therapeutic strategies for MASLD remain limited. Previous studies revealed that miR-320 was a regulator of systemic lipid metabolism with multi-targets. However, whether treatments against miR-320 would be benefit to MASLD was unclear. Mice with MASLD were induced by high-fat diet (HFD) treatment. Tough Decoy or sponge against miR-320 was delivered by recombinant adeno-associated virus (serotype 8) vectors in vivo. Hepatic steatosis and plasma lipids were assessed by histopathology, biochemical assays and LC-MS. Moreover, LC-MS, Western blotting, real-time PCR, immunofluorescence and luciferase reporter were performed to investigate the underlying mechanisms. Knockdown of miR-320 attenuated HFD-induced MASLD by alleviating hepatic lipid accumulation and hyperlipidemia. Mechanistically, palmitic acid (PA) combined with oleic acid (OA) treatment promoted the translocation of miR-320 from the cytoplasm into the nucleus of hepatocytes. Especially, increased nuclear miR-320 activated the transcription of APOE by targeting its promoter, which in turn aggravated triglyceride accumulation and secretion in hepatocytes. Our study revealed that treatments against miR-320 attenuated hepatic steatosis and hyperlipidemia simultaneously, which might be a potential strategy of MASLD. Show less

Progressive supranuclear palsy (PSP) is a heterogeneous neurodegenerative disease characterised by the accumulation of misfolded 4-repeat tau within neurones and glial cells. There are limited longitudinal data on pathologically confirmed PSP patients with phenotypes other than classic Richardson's syndrome (RS) and the pathomechanisms responsible for the broad variability in clinical phenotype and progression are not well understood. An unresolved question in this context is whether distinct spatiotemporal patterns of tau pathology propagation exist within the clinicopathological spectrum of PSP. We included 241 consecutive, pathologically confirmed patients with PSP from the Queen Square Brain Bank for Neurological Disorders (2010-2022). Phenotyping was performed based on clinical features present within the first 3 years from symptom onset according to the Movement Disorder Society (MDS) criteria, and specific clinical features and disease milestones were recorded. Genotyping was performed using Illumina NeuroBooster and NeuroChip arrays and MAPT haplotype, APOE genotype, TRIM11 rs564309 and SLC2A13 rs2242367 single nucleotide polymorphism data were collated. Tissue sections from eight brain regions, mounted on glass slides, were immunostained for hyperphosphorylated tau and digitised using whole-slide scanning. Forty-one anatomical regions of interest were manually segmented, and total tau pathology burden was quantified using an automated, machine learning-based algorithm. The associations between survival and both clinicogenetic features and regional tau pathology burden were modelled using Cox regression and generalised linear models, respectively and the Subtype and Stage Inference (SuStaIn) algorithm was used to identify subgroups with distinct progression patterns. We have identified: (i) several clinical predictors of survival in PSP and the relationship between regional tau pathology burden and survival; (ii) novel anatomical reference standards for the expected distribution of tau pathology across MDS-defined PSP phenotypes, including region-specific white matter involvement in patients with corticobasal syndrome and speech/language variants; (iii) associations potentially linking biological sex, MAPT haplotype and TDP-43 co-pathology to clinical phenotype and regional tau pathology burden; (iv) patterns of covariance in regional tau pathology implicating inter-regional connectivity in tau spreading; and (v) three distinct spatiotemporal patterns of tau pathology progression: one characterised by initial involvement of subcortical grey matter followed by rostral spread to cortical regions and two characterised by early, simultaneous involvement of subcortical grey matter and cortical regions. Taken together, these results indicate that PSP clinicopathological heterogeneity is mediated by propagation of tau pathology along anatomically connected networks and via intrinsic regional susceptibility mechanisms, possibly influenced by sex, genetic factors and co-pathology. Show less

Macrophages play central roles in the initiation and growth of atherosclerosis (AS). This study aimed to investigate the role of ENC1 in macrophage oxidative stress during AS and its mechanism. An animal model of AS was constructed by feeding ApoE KO mice with a high-cholesterol diet, and an in vitro AS model was induced on mouse macrophages RAW 264.7 using oxLDL. Macrophage-specific adeno-associated viruses containing the F4/80 promoter were used to interfere with RBM47 and ENC1 expression in vivo, and lentiviral infection of RAW 264.7 was applied in vitro. RBM47 improved the stability of ENC1 by binding to the AU-rich elements, which curbed NRF2 synthesis and nuclear translocation. Exogenous inhibition of ENC1 or RBM47 suppressed aortic oxidative stress in mice with AS, reduced lipid and cholesterol uptake, and strengthened cellular scavenging activity against oxidative stress in RAW 264.7 cells. The NRF2 inhibitor ML385 reversed the above benefits from the knockdown of ENC1 in RAW 264.7 cells, and combined overexpression of ENC1 reversed these benefits from the knockdown of RBM47 in vitro and in vivo. This study provides new evidence that ENC1 is a contributor to AS progression, and targeting ENC1 in macrophages may serve as a potential therapy. Show less

Effective real-time monitoring and tracking of lipid droplets (LDs) are essential for the precise diagnosis of atherosclerotic plaques and the assessment of pathological progression. However, viable strategies for 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

BuYang HuanWu Decoction (BYHW), a classical herbal formula first documented in Yilin Gaicuo (1830), is officially listed in the Chinese Pharmacopoeia for the treatment of stroke and sequelae attributed to "qi deficiency and blood stasis." Vertebral artery stenosis (VAS) is a leading cause of posterior circulation ischemic stroke-a condition for which BYHW has been traditionally prescribed. However, the molecular mechanism underlying its therapeutic effects against VAS remains poorly understood. This study aimed to systematically predict the therapeutic targets of BYHW against VAS using network pharmacology and to experimentally validate its core mechanism of action, with a focus on the AGE-RAGE/NF-κB signaling axis. Potential targets of BYHW and VAS-related genes were retrieved from TCMSP and DisGeNET databases for network construction and enrichment analysis. Key predictions were validated in vitro using ox-LDL/AGEs-stimulated human umbilical vein endothelial cells (HUVECs) and RAW 264.7 macrophages, and in vivo using ApoE Network analysis identified 62 common targets and six core hubs (IL-6, IL-10, FOS, MAPK1, AKT1, and CTNNB1), with the AGE-RAGE signaling pathway being the most significantly enriched. In vitro, BYHWE inhibited ox-LDL/AGEs-induced endothelial inflammation, oxidative stress, and macrophage foam cell formation by suppressing the AGE-RAGE/NF-κB axis. In vivo, BYHWE administration (2 g/kg/day for 4 weeks) significantly attenuated atherosclerotic plaque burden by 34.7% and reduced macrophage infiltration in ApoE This study provides the first evidence that BYHW alleviates VAS through multi-target modulation of the AGE-RAGE/NF-κB pathway, thereby protecting endothelial function and stabilizing plaques. These findings offer a mechanistic explanation for its traditional use in stroke-related disorders and support its therapeutic potential for atherosclerotic vertebral artery stenosis. Show less

Functional decline may be an early indicator of dementia. This study examined the trajectories of frailty, grip strength, and gait speed over the 11 years prior to dementia, compared to matched individuals without dementia. A total of 1092 dementia cases were matched on age, sex and education to 4368 controls from a cohort of community-dwelling older adults recruited in Australia and the USA, aged 65 years or above at recruitment. Frailty was characterised by a deficit-accumulation index involving 67 items. Hand grip strength and gait speed were measured regularly by physical examination. Linear mixed-effects models estimated the backward trajectories of frailty, grip strength and gait speed before dementia, compared to controls. Secondary analyses were stratified by sex and ApoE ε4 carrier status. Higher frailty burden, with a steeper increase over time, was found in the years before dementia, compared to controls (P-interaction < .001). Hand grip strength and gait speed declined more rapidly in dementia cases than in controls (P-interaction < .001 for both). Differences between cases and controls became consistently significant four to six years prior to dementia (P-contrast < .001). An earlier divergence across all three measures was observed for females, and to a lesser extent in ApoE ε4 non-carriers. Functional decline occurs within the decade before dementia onset, with gait speed being the earliest indicator. These findings support the utility of functional measures as early markers of dementia risk, with potential implications for targeted monitoring and preventative strategies. Show less

Atherosclerosis is a chronic inflammatory disease characterized by lipid-driven immune dysregulation. Argininosuccinate synthase 1 (ASS1) has been implicated in macrophage inflammation, yet its precise mechanistic role in foam cell-mediated vascular injury during atherosclerosis remains unclear. This study investigates whether ASS1 promotes disease progression via the NLRP3/IL-33/ST2 axis. An Ox-LDL treatment significantly upregulated ASS1 expression in U937-derived foam cells. ASS1 overexpression enhanced intracellular ROS production, NLRP3 inflammasome activation, STAT3 phosphorylation, and IL-33 secretion. These effects were reversed by ASS1 knockdown. Rescue experiments demonstrated that STAT3 is required for ASS1-mediated NLRP3 activation and IL-33 upregulation. ASS1 altered IL-33 receptor ST2 signaling by increasing the soluble decoy isoform (sST2) and decreasing the membrane-bound signaling isoform (ST2L). In co-culture, ASS1-overexpressing foam cells promoted HUVEC apoptosis (via mitochondrial pathway) and HAVSMC proliferation, migration, and dedifferentiation. NLRP3 overexpression alone mimicked the pro-inflammatory effects of ASS1 and reversed the anti-inflammatory effects of ASS1 knockdown. ASS1 drives atherosclerosis by activating the STAT3/NLRP3 inflammasome axis, shifting the IL-33/ST2 balance toward a pro-inflammatory state, and amplifying foam cell-mediated endothelial injury and smooth muscle cell dysfunction. Targeting ASS1 may offer a novel therapeutic strategy for inflammatory vascular disease. 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

Individuals with prediabetes or diabetes face elevated dementia risk, yet robust prediction tools and mechanistic insights remain limited. This study aimed to develop and validate a protein-based risk score for dementia prediction in this high-risk population while elucidating underlying biological pathways and therapeutic targets. Utilising data from 10 433 UK Biobank participants with prediabetes or diabetes and proteomic profiling (2911 plasma proteins measured), we developed a dementia protein risk score in a training set ( In the training set, 23 out of 2911 proteins were selected. In the testing set, compared with the basic model (age and sex, C-index: 0.78; 95% confidence interval [CI] 0.74-0.82), the dementia protein risk score (C-index: 0.84; 95% CI 0.81-0.88) significantly improved the performance in predicting incident dementia (C-index increase: 0.06; 95% CI 0.02-0.12), while cardiovascular risk factors, ageing and dementia incidence risk factors (C-index: 0.80; 95% CI 0.76-0.83) and apolipoprotein E (APOE; age and sex included, C-index: 0.81; 95% CI 0.77-0.85) had no significant improvement. Six key proteins (glial fibrillary acidic protein [GFAP], neurofilament light polypeptide [NEFL], Brevican core protein [BCAN], protein MENT [MENT], APOE and growth/differentiation factor 15 [GDF15]) captured the most predictive power. Pathway analyses implicated extracellular matrix remodelling and cholesterol metabolism, whereas Mendelian randomisation identified causal roles for APOE, haematopoietic prostaglandin D synthase (HPGDS), BAG family molecular chaperone regulator 3 (BAG3) and GDF15. Nine proteins were prioritised as druggable targets, including HPGDS, with existing Food and Drug Administration-approved drugs. This study establishes a highly accurate protein-based risk score for dementia prediction (including 6-23 proteins) in individuals with prediabetes or diabetes, uncovering actionable biological pathways and therapeutic targets. The findings enable precision risk stratification and accelerate translational opportunities for dementia prevention in this population. Show less

Dementia in Lewy body diseases (LBD) is common and arises through heterogeneous and incompletely understood pathways. Evidence suggests contributions from genetic factors, including APOE ε4 genotype, co-pathology including concomitant Alzheimer's disease pathology and hypoperfusion related to orthostatic hypotension. However, the relative impact of these factors remains unclear. To address this, we analysed 399 post-mortem brains from LBD cases comprising Parkinson's disease, Parkinson's disease dementia and dementia with Lewy bodies, and controls, integrating APOE genotype, clinical data and assessment of ischaemic pathology alongside large-scale digital pathology quantification. We established an image analysis pipeline utilising machine learning to enable automated, standardised measurement of α-synuclein, amyloid-β, and phosphorylated tau burden across multiple brain regions. Quantitative pathology strongly correlated with semi-quantitative ratings and outperformed conventional staging in predicting dementia. Across multiple analytical approaches, APOE ε3 and ε4 carriers showed distinct dementia risk profiles. APOE ε3 carriers developed dementia at lower quantitative α-synuclein and amyloid-β thresholds than ε4 carriers, although overall dementia risk was dominated by ε4 genotype, consistent with ε4 both promoting greater pathology accumulation and modifying the threshold for dementia onset. Orthostatic hypotension and ischaemic pathology increased dementia risk only in ε3 carriers with low Lewy and Alzheimer's proteinopathy burden, while male sex further modulated dementia risk for this subgroup. The Subtype and Stage Inference (SuStaIn) algorithm identified four trajectories of Lewy pathology progression. Two corresponded to recognised patterns, one brainstem-first and the other with early amygdala and concomitant brainstem involvement. Two further patterns showed early cortical involvement, one with early cingulate cortex involvement together with brainstem pathology and the other starting in neocortex before limbic and brainstem involvement. Co-pathology progression modelling identified subtypes with early predominance of amyloid-β, phosphorylated tau, or α-synuclein, and showed that Lewy subtypes follow two propagation trajectories in opposite directions. Together, these findings demonstrate that integrating quantitative pathology with genotype and clinical data reveals distinct yet overlapping pathways to dementia in LBD, refining disease progression models and providing a basis for genotype- and pathology-informed patient stratification in therapeutic trials. Show less

Yiqi Huoxue Granule (YQHX), a traditional Chinese medicine (TCM) formulation, is extensively utilized for the treatment of atherosclerotic diseases. However, its active constituents and molecular mechanisms remain unclear. We utilized a systematic methodology to identify bioavailable compounds in vivo and predict and validate the principal targets and pathways responsible for their anti-atherosclerotic actions. Serum pharmacochemistry utilizing UPLC-Q-Exactive Orbitrap-MS was employed to identify the bioavailable compounds of YQHX. An integrated methodology combining network pharmacology and molecular docking was implemented to predict its potential targets and mechanisms against atherosclerosis, which were subsequently verified experimentally in apolipoprotein E-deficient (ApoE We identified 36 absorbable compounds in the serum of rats following YQHX administration, and 252 potential therapeutic targets were predicted. Protein-protein interaction analysis identified 10 hub targets, which are IL-6, TNF, EGFR, TP53, AKT, STAT3, SRC, CTNNB1, TLR4, and MMP-9. Enrichment analyses indicated that these targets are primarily involved in lipid metabolism and inflammatory responses, with significant enrichment in the PI3K-Akt and SRC signaling pathways. Molecular docking revealed strong binding affinities between the proteins EGFR, SRC, and AKT and their respective compounds. In ApoE This study systematically identified the bioactive compounds of YQHX and demonstrated its multi-target anti-atherosclerotic effect, which involved the enhancement of lipid metabolism and suppression of inflammation, mediated, at least in part, by the inhibition of the SRC/AKT signaling pathway. Show less

Apolipoprotein E (ApoE) serves as a critical molecular nexus between Alzheimer's disease (AD) and atherosclerosis, two age-associated inflammatory disorders that share vascular pathology, amyloid-beta (Aβ) deposition, and lipid dysregulation. Atractylenolide I (AI), a promising therapeutic candidate derived from Show less

Atherosclerosis is a common vascular disease that poses a serious threat to global health. However, the mechanism underlying the pathogenesis and progression of atherosclerosis remains elusive. We analysed the expression of deubiquitinating enzymes in human atherosclerotic lesions and found that USP25 was significantly downregulated. The role of USP25 in atherosclerosis was validated in mouse models with an ApoE USP25 was predominantly expressed in macrophages in atherosclerotic lesions, and ablation of macrophagic USP25 significantly exacerbated atherosclerosis in ApoE This study elucidated the function and molecular mechanism of USP25 in atherosclerosis, identifying USP25 as a beneficial regulator for this disease. This work was supported by the Natural Science Foundation of Zhejiang Province (LZ24H090003 to X.W. and LTGY23H090001 to W.W.), the National Natural Science Foundation of China (82150710557 and 82293642 to W.S.; 81971143 to X.W., and 82271347 to G.W.), and Wenzhou Municipal Science and Technology Bureau (Y2021094 to J.H.). Show less

To investigate the distribution of the apolipoprotein E (ApoE) and solute carrier organic anion transporter family member 1B1 (SLCO1B1) polymorphisms in dyslipidemia patients and their impact on statin efficacy and safety. A retrospective analysis was conducted on dyslipidemic inpatients (April 2024-March 2025) who received statin therapy and genetic testing for SLCO1B1 (rs4149056) and ApoE (rs429358 and rs7412), to analyze the association of genotypes with lipid levels and safety indicators. The final analysis included 238 hospitalized patients with dyslipidemia (156 males and 82 females) who met the inclusion criteria. The study population had a mean age of 60.61 ± 0.91 years (mean ± SEM). The allele frequencies for both ApoE and SLCO1B1 polymorphisms were in Hardy-Weinberg equilibrium (P > 0.05). Analysis of statin efficacy revealed a significant association between ApoE genotype and atorvastatin response: E3 carriers demonstrated higher low-density lipoprotein cholesterol levels posttreatment compared to E2 carriers (2.85 ± 1.00 mmol/l vs. 2.28 ± 0.96 mmol/l, P = 0.026). However, no such association was found in patients administered rosuvastatin. For safety outcomes, comparisons of creatine kinase and alanine aminotransferase levels between carriers of the SLCO1B1 TC and TT genotypes showed no statistically significant differences. APOE polymorphisms influence statin efficacy. The E2 genotype is associated with better atorvastatin efficacy in lipid management. At low-to-moderate doses, the SLCO1B1 TC genotype did not increase safety risk, supporting its clinical safety. Show less

Diabetes mellitus (DM) is hypothesized to increase the risk of Alzheimer's disease (AD). However, existing studies have yielded conflicting results, with some demonstrating a significant association between DM and AD risk while others have not. Therefore, this meta-analysis aimed to systematically evaluate the association between DM and AD risk. Comprehensive searches were conducted in PubMed, Web of Science, and Embase databases to identify cohort or case-control studies investigating the association between DM and AD risk. All eligible studies published before October 2025 were included. The Newcastle-Ottawa Scale (NOS) was used to assess the risk of bias. Hazard ratio (HR) and 95% confidence interval (CI) were pooled as the effect size for meta-analysis. Heterogeneity among studies was evaluated using Cochran's A total of 11 studies involving 3,393,545 participants were included. A meta-analysis revealed that DM was significantly associated with an increased risk of AD (HR = 1.36, 95% CI (1.19, 1.55), This meta-analysis provides compelling evidence that DM is an independent risk factor for AD, offering important implications for clinical practice and future research. However, due to the methodological limitations of this study, the results should be interpreted with caution. Large-scale, high-quality prospective cohort studies are needed to fully investigate the relationship between DM and AD risk. https://www.crd.york.ac.uk/prospero/, identifier CRD420251159844. 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

Elucidating effective components and mechanisms of traditional Chinese medicine (TCM) formulas remains a critical challenge for modernization. ErShiWei RouDouKou Pills (ESWRDK), a Tibetan formula with cardiovascular potential, lacks systematic exploration of its anti-atherosclerotic (AS) material basis and mechanisms. A novel six-stage cascade focused strategy integrating three-dimensional filtering mode, qualitative characterization, multi-component quantification, anti-AS efficacy, multi-lipidomics and bioactive compounds evaluation was proposed, advancing TCM research by holistic and multi-layered approach. UHPLC-MS combined with mass defect-ion intensity filtering (MD-ITF), DPIs, Nl and FBMN employed for profiling. Nine characteristic components were quantitated. A 12-week high-fat diet was fed to ApoE Firstly, the MD-ITF method and structural classification was established for complicated matrix. Secondly, 426 chemical components including 74 low-abundance were characterized. Thirdly, 9 characteristic components were quantified, and content distribution were profiled. Fourthly, ESWRDK reduced lipids, inflammation, and aortic plaques in AS mice. Fifthly, a total of 38, 23 and 48 differential biomarkers were identified predominantly linked to glycerophospholipids (GP) metabolism. WB confirmed ESWRDK downregulated hepatic PLA2, upregulated p-AMPK/AMPK and PPAR-α, and suppressed SREBP-1, orchestrating and mitigating lipid dysregulation. Finally, dehydrodiisoeugenol and agarotetrol bound PLA2, formed stable 1:1 static quenchingand inhibited PLA2 activity in vitro. A novel six-stage cascade-focused strategy was successfully established to elucidate ESWRDK's anti-AS mechanisms, offering feasible paradigm for advancing modernization of TCM. Show less

Atherosclerosis (AS) is a chronic inflammatory disease driven significantly by metabolic reprogramming (MR). However, the core MR-related genes and their specific functions in AS remain incompletely understood, thus creating an urgent need for reliable diagnostic and therapeutic biomarkers. Two AS-related microarray datasets (GSE100927 and GSE28829) were integrated and normalized. Differential expression analysis identified differentially expressed genes (DEGs), which were intersected with an MR-related gene set to obtain MR-related DEGs (MRDEGs). Functional enrichment analyses-including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses-were conducted. Subsequently, weighted gene co-expression network analysis (WGCNA) was combined with multiple machine learning algorithms to screen for hub genes. These candidate genes were further validated using an external dataset (GSE43292) and evaluated via receiver operating characteristic (ROC) curve analysis. Additionally, a multi-gene diagnostic model was constructed and assessed using both nomogram and SHAP analysis. Single-gene Gene Set Enrichment Analysis (GSEA) elucidated the biological functions of core genes. Immune infiltration and single-cell analyses investigated microenvironment remodeling. Moreover, transcription factor (TF) prediction via hTFtarget, integrated with transcriptome sequencing of human umbilical vein endothelial cells (HUVECs), identify upstream regulators. Finally, Experimental validation was performed in ApoE We identified 57 MRDEGs and selected four core genes-LYN, FABP5, MMP9, and ANPEP-which demonstrated high diagnostic value. The multi-gene model showed strong clinical predictive performance. GSEA further revealed significant involvement of these genes in immune-inflammatory pathways. Immune infiltration and single-cell analyses confirmed substantial immune microenvironment remodeling and altered cell-cell communication. EGR1 was identified as a key upstream transcription factor. Ultimately, Experimental validation in ApoE This study identifies LYN, FABP5, MMP9, and ANPEP as core MR-related genes in AS, clarifies their roles in immune microenvironment regulation, and confirms their value as diagnostic biomarkers, thereby providing new insights for precise diagnosis and targeted therapy of AS. Show less

This study established a hyperlipidemia model by feeding Sprague-Dawley rats a high-fat diet for 8 weeks. The rats were randomly assigned to the following groups: model group, atorvastatin calcium group(4.8 mg·kg~(-1)), low-, medium-, and high-dose Tanyu Tongzhi Optimization Decoction(TYTZD) groups(3.6, 7.2, and 14.4 g·kg~(-1)), and a normal diet control group. After 4 weeks of continuous administration, hematoxylin-eosin(HE) and oil red O staining were used to observe liver pathological changes and lipid infiltration. Automatic biochemical analyzer were performed to assess blood lipid profiles, coagulation function, and liver function. Transcriptomic and proteomic analyses were employed to identify differentially expressed genes(DEGs) and proteins(DEPs), followed by enrichment analysis. The MCODE algorithm was applied to classify DEGs and DEPs into modules, and network separation index(S₍AB)) was calculated to assess module separation, enabling construction of a gene-protein co-expression network for core target screening. The diagnostic accuracy of core targets was evaluated by area under the receiver operating characteristic(ROC) curve(AUC), and ELISA was used to measure core target expression. Western blot detected the expression of core pathway-related proteins in liver tissue. RESULTS:: demonstrated that TYTZD significantly improved dyslipidemia, coagulation dysfunction, liver injury, hepatic pathology, and lipid infiltration in hyperlipidemic rats. Transcriptomic analysis identified 571 DEGs significantly reversed by TYTZD, mainly enriched in inflammatory signaling pathways such as Toll-like receptor 4(TLR4)/nuclear factor-κB(NF-κB). Proteomic analysis identified 102 reversed DEPs, mainly involved in cholesterol metabolism pathways. Integrated analysis identified core targets including TLR4, tumor necrosis factor-α(TNF-α), integrin subunit alpha M(ITGAM), Toll-like receptor 2(TLR2), matrix metalloproteinase 9(MMP9), interleukin-1β(IL-1β), apolipoprotein E(APOE), and apolipoprotein C2(APOC2), all with AUC values greater than 0.70. ELISA showed that TYTZD intervention significantly downregulated MMP9, TNF-α, IL-1β, TLR2, ITGAM, and TLR4, and upregulated APOC2 and APOE. Western blot indicated that TYTZD reduced TLR4, p-NF-κB, and IL-1β protein expression in liver tissue. In conclusion, TYTZD may exert anti-hyperlipidemic effects through regulation of core targets such as ITGAM, TLR4, and APOC2, and by modulating the TLR4/NF-κB signaling pathway to intervene in inflammatory responses and cholesterol metabolism, thereby achieving multi-target, multi-pathway therapeutic effects against hyperlipidemia. Show less

Alzheimer's disease pathology (ADP) and Lewy body pathology (LBP) are traditionally associated with distinct cognitive profiles. However, growing evidence highlights the role of behavioral and psychological symptoms of dementia (BPSD) in shaping clinical presentations. The combined influence of cognitive and behavioral symptoms across neuropathologically confirmed ADP, LBP, and mixed AD-LBP has not been systematically examined. This study aimed to identify clinically meaningful subtypes by jointly analyzing cognitive performance and BPSD profiles in individuals with autopsy-confirmed dementia pathology. This retrospective longitudinal cohort study used data from the National Alzheimer Coordinating Center (NACC), collected across multiple U.S. Alzheimer's Disease Research Centers. Participants had a Clinical Dementia Rating (CDR) Global score ≤1 at baseline and autopsy-confirmed ADP, LBP, or mixed AD-LBP. Cognitive outcomes included standardized tests of memory, executive function, and language. BPSD were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q), which captures ten symptom domains: agitation, apathy, depression, delusions, disinhibition, auditory and visual hallucinations, irritability, personality change, and REM sleep behavior disorder. Cluster analysis was applied to identify subtypes based on combined cognitive and BPSD data. The study included 1,028 participants (mean age at baseline 76.4 years; 47.6% female): 521 with ADP, 96 with LBP, and 411 with mixed AD-LBP. A three-cluster clinical subtype (CS) solution best fit the data. The most symptomatic group (CS-3) had the youngest age at first visit (mean 72.1 years), the highest BPSD burden, and the fastest cognitive and functional decline across ADP and AD-LBP groups. CS-1 and CS-2 exhibited milder early cognitive impairment and lower BPSD burden. Within ADP and AD-LBP, CS-2 showed slower progression than CS-1, fewer APOE ε4 carriers (41% vs. 58%), and better memory scores, despite reporting a higher frequency of agitation. These findings reveal distinct clinical subtypes that cut across traditional pathological boundaries, emphasizing the need to incorporate both cognitive and behavioral features into early dementia characterization. This multidimensional approach can improve guide personalized prognosis and care planning and enhance clinical trial design by considering disease heterogeneity. The study supports integrated clinical profiling as important factor in robust evaluation of dementia outcomes. Show less