Atherosclerosis (AS) is the leading cause of global mortality and morbidity. Despite the elevated expression of sodium-hydrogen exchanger 1 (NHE1) and olfactory receptor 2 (Olfr2) in plaque macrophage Show more
Atherosclerosis (AS) is the leading cause of global mortality and morbidity. Despite the elevated expression of sodium-hydrogen exchanger 1 (NHE1) and olfactory receptor 2 (Olfr2) in plaque macrophages, their interactions within the AS context remain poorly understood. In this study, ApoE Show less
Atherosclerosis (AS) remains a leading cause of cardiovascular morbidity and mortality, characterized by intricate interactions between immune dysregulation and lipid metabolism abnormalities-identify Show more
Atherosclerosis (AS) remains a leading cause of cardiovascular morbidity and mortality, characterized by intricate interactions between immune dysregulation and lipid metabolism abnormalities-identifying key mediators in its pathogenesis is critical for improving diagnostics and therapies. This study focuses on Transmembrane Protein 106A (TMEM106A) to clarify its role and clinical relevance in AS progression. Public transcriptomic datasets (GSE43292, GSE100927, GSE28829) were analyzed to assess TMEM106A expression and diagnostic value; single-cell RNA-seq data (GSE159677) defined its cellular localization. Immune infiltration (ssGSEA, Cibersort, xCell) and CellChat (intercellular communication) analyses explored its immune associations. TMEM106A was significantly upregulated in AS samples across datasets, with strong diagnostic efficacy (AUC 0.80-0.95). Single-cell analysis confirmed its specific enrichment in macrophages, with functional links to immune-related pathways. TMEM106A promoted macrophage infiltration, foam cell formation, oxidative stress, and inflammatory responses, while regulating PLCB2 in chemokine signaling; silencing TMEM106A alleviated these pro-atherosclerotic effects. TMEM106A contributes to AS progression by modulating macrophage-mediated immune responses and chemokine signaling, as validated in experimental models. These findings support its potential as a clinically relevant biomarker and promising therapeutic target for AS intervention. Show less
Telomere length (TL), a biomarker of biological aging, but its association with Alzheimer's disease (AD) remains unclear. We estimated TL in whole-genome sequencing data from 35,014 Alzheimer's Diseas Show more
Telomere length (TL), a biomarker of biological aging, but its association with Alzheimer's disease (AD) remains unclear. We estimated TL in whole-genome sequencing data from 35,014 Alzheimer's Disease Sequencing Project participants using TelSeq, which after quality control yielded a dataset including 6,973 persons of European ancestry (EA), 4,188 African Americans (AA), 4,005 Caribbean Hispanics (CH), and 4,170 Native American Hispanics (NAH). TL was log-transformed, adjusted for age and blood cell counts, and z-scaled. Scaled TL was dichotomized into long and short groups according to the median. An AD GWAS for the interaction of TL with variants having a minor allele count >20 was performed in each ancestry group using logistic regression models including SNP and TL main effects and a SNP×TL interaction term. AD risk was associated with shorter TL (β = -0.18, We identified variants that significantly impact AD risk through their interaction with TL, suggesting that TL maintenance pathways may be central to AD pathogenesis. Show less
Atherosclerosis is a chronic inflammatory disease driven by dysregulated lipid metabolism and macrophage dysfunction. However, the role of An adenovirus encoding These findings demonstrate that The on Show more
Atherosclerosis is a chronic inflammatory disease driven by dysregulated lipid metabolism and macrophage dysfunction. However, the role of An adenovirus encoding These findings demonstrate that The online version contains supplementary material available at 10.1186/s12944-025-02805-1. Show less
Cholesterol plays a crucial role in regulating synaptic membrane fluidity and ion channels. Due to the blood-brain barrier, cholesterol in the brain is primarily self-synthesized by astrocytes. Howeve Show more
Cholesterol plays a crucial role in regulating synaptic membrane fluidity and ion channels. Due to the blood-brain barrier, cholesterol in the brain is primarily self-synthesized by astrocytes. However, limited research has been conducted on the effects of polystyrene nanoplastic (PS-NPs) on intracranial cholesterol metabolic pathways. In this study, we exposed whole-brain organoids (WBOs) to PS-NPs and identified significant changes in endoplasmic reticulum stress and cholesterol biosynthesis pathways through whole-transcriptome sequencing. To investigate potential mechanisms of altered cholesterol pathways, we constructed a Transwell neuronal-astrocyte co-culture model. Results demonstrated that PS-NPs induced significant endoplasmic reticulum stress in astrocytes, specifically manifested by elevated levels of ATF4 and CHOP, along with increased autophagy indicated by the elevated LC3-II/I ratio. PS-NPs significantly inhibited the AKT/ACLY pathway of cholesterol biosynthesis, leading to marked reductions in acetyl-CoA and cholesterol within astrocytes (P < 0.05). In addition, PS-NPs led to a significant reduction of apolipoprotein APOE, which hindered cholesterol transport and ultimately inhibited synaptin (SYN) formation. In summary, PS-NPs induce endoplasmic reticulum stress and autophagy in astrocytes, impair cholesterol de novo synthesis and apolipoprotein-mediated transport, ultimately inhibiting neuronal synaptogenesis. Furthermore, specific inhibition of ERs restored cholesterol synthesis in astrocytes and neuronal synapses. This study demonstrates that PS-NPs produce neurotoxic effects by affecting cholesterol homeostasis in the brain. Show less
Endothelial cells (ECs) senescence has emerged as a critical factor in the pathogenesis of atherosclerosis, contributing to vascular aging and plaque formation. However, the molecular mechanisms under Show more
Endothelial cells (ECs) senescence has emerged as a critical factor in the pathogenesis of atherosclerosis, contributing to vascular aging and plaque formation. However, the molecular mechanisms underlying endothelial senescence in atherosclerosis remain poorly understood. Single-cell RNA sequencing (scRNA-seq) data from atherosclerotic core plaques and adjacent normal tissues were analyzed using the Seurat package to identify cell subpopulations and senescence markers. RNA-seq data from early and late atherosclerotic plaques were used for differential gene expression analysis. Subsequently, the candidate gene was identified and validated in the atherosclerotic plaques of Single-cell analysis revealed elevated levels of senescence markers in ECs within atherosclerotic plaques. Combined with bulk RNA-seq analysis, This study highlights the critical role of endothelial senescence in atherosclerosis and identifies Show less
Atherosclerosis (AS), a chronic inflammatory condition of the vasculature, is a major contributor to cardiovascular morbidity. Yaoshi Tongyuan Tablet (YTT) is a food-medicine homology (FMH) formulatio Show more
Atherosclerosis (AS), a chronic inflammatory condition of the vasculature, is a major contributor to cardiovascular morbidity. Yaoshi Tongyuan Tablet (YTT) is a food-medicine homology (FMH) formulation containing A combination of network pharmacology, ultra-performance liquid chromatography coupled with Q Exactive Orbitrap mass spectrometry (UPLC-QE-MS), and molecular docking was employed to predict potential bioactive compounds and their molecular targets. ApoE Integrated analyses revealed kaempferol, isorhamnetin, and quercetin as central bioactive molecules acting on AKT1, a key node within the PI3K/Akt signaling cascade. YTT ameliorates atherosclerosis by counteracting dyslipidemia and inflammation, primarily through modulation of the PI3K/Akt/NF-κB pathway. This study offers novel integrative insights into the anti-atherogenic properties of YTT and pinpoint crucial bioactive constituents worthy of further pharmacological investigation. Show less
Metabolic reprogramming is a hallmark of cancer; however, the mechanisms driving metabolic heterogeneity across diverse cell types in the tumor microenvironment remain poorly understood. Most existing Show more
Metabolic reprogramming is a hallmark of cancer; however, the mechanisms driving metabolic heterogeneity across diverse cell types in the tumor microenvironment remain poorly understood. Most existing methods predict metabolic states at the pathway level but rarely map reaction-level alterations to their upstream regulators, thereby constraining both interpretability and translational relevance. We developed MetroSCREEN, a reference-guided computational framework that infers reaction-level metabolic flux propensity and nominates upstream regulators from bulk and single-cell transcriptomes. MetroSCREEN uses a fast enrichment-based procedure to quantify reaction-level metabolic activity. To characterize metabolic regulons, it integrates intrinsic gene-regulatory signals with extrinsic cell-cell interaction cues, then applies a robust multi-evidence ranking scheme to combine these information sources, and finally employs a constraint-based causal discovery module to infer regulatory directionality. MetroSCREEN accurately predicts reaction-level metabolic activities and their upstream regulators, as demonstrated using paired transcriptomic-metabolomic datasets from the cancer cell lines. We further validated predicted regulators with in-house single-cell CRISPR screens in PC9 cells targeting metabolic regulators. Applying MetroSCREEN to a pan-cancer single-cell atlas of more than 700,000 fibroblasts and myeloid cells across 36 cancer types, we identified ZNF281 and STAT1 as key regulators of collagen metabolism, which is elevated in extracellular-matrix-associated fibroblasts and macrophages at tumor margins. By contrast, APOE and KLF7 regulate sphingolipid metabolism and antigen presentation in macrophages. Leveraging extensive tumor profiles, MetroSCREEN also delineates metabolic subtypes and regulators associated with patient survival and response to immunotherapy. MetroSCREEN is a robust and scalable approach for characterizing metabolic heterogeneity and pinpointing metabolic regulators at single-cell resolution, unveiling novel antitumor targets for future metabolic interventions. The source codes of MetroSCREEN is available at the Github site https://github.com/wanglabtongji/MetroSCREEN . Show less
Atherosclerosis (AS) is a vascular disorder characterized by lipid accumulation and chronic inflammation, with pathogenesis closely linked to genetic factors and immune regulatory mechanisms. This stu Show more
Atherosclerosis (AS) is a vascular disorder characterized by lipid accumulation and chronic inflammation, with pathogenesis closely linked to genetic factors and immune regulatory mechanisms. This study comprehensively identified ASassociated genes by integrating data from the Gene Expression Omnibus (GEO) database and expression quantitative trait locus (eQTL) analyses, complemented by Mendelian randomization (MR) analysis, followed by experimental validation of their functional roles. Results indicated significant upregulation of CLEC5A and ISG20 in patients with AS, with MR analysis revealing positive causal relationships between both genes and AS risk (CLEC5A: OR = 1.001, P = 0.047; ISG20: OR = 1.001, P = 0.030), while HOXA2 showed a negative causal association. Functional enrichment analysis highlighted CLEC5A and ISG20's involvement in immune responses, inflammatory pathways, and lipid metabolism regulation. Experimental validation in oxidized low-density lipoprotein (ox-LDL)-stimulated macrophages and apolipoprotein E-deficient (ApoE This study represents the first to elucidate the molecular mechanism by which ISG20 promotes AS progression through macrophage lipid accumulation and inflammatory responses, positioning it as a potential novel therapeutic target for AS. Show less
Extensive research has demonstrated that gut microbiota and its metabolites-including short-chain fatty acids, trimethylamine N-oxide (TMAO), and bile acids-play a crucial role in the pathophysiology Show more
Extensive research has demonstrated that gut microbiota and its metabolites-including short-chain fatty acids, trimethylamine N-oxide (TMAO), and bile acids-play a crucial role in the pathophysiology of coronary artery disease (CAD).The bidirectional interaction between the gut microbiota and the cardiovascular system significantly influences host metabolic and inflammatory homeostasis. As a result, targeted modulation of the gut microbiota emerges as a promising adjunctive therapeutic strategy for CAD, offering potential benefits with minimal side effects. This study aims to elucidate the therapeutic mechanisms of the clinically validated Chinese medicine formula HJ11 in mitigating coronary heart disease (CHD), with a particular focus on its regulation of the heart-gut axis and associated atherosclerotic processes. This study established an ApoE-/- mouse model of atherosclerosis and treated with HJ11 via gavage.We investigated the effects of HJ11 on the gut microenvironment in these atherosclerotic mice. Gut microbial composition and faecal metabolite profiles were analyzed using 16S rDNA sequencing and metabolomics. Additionally, an in vitro model of atherosclerosis was used to examine whether HJ11 exerts anti-inflammatory effects by modulating the TLR4/MYD88/IκB-α signaling pathway. HJ11 exerted protective effects on coronary atherosclerosis by reducing systemic serum lipid levels and inhibiting plaque formation, vascular inflammation, and collagen deposition, while also alleviating aortic injury. It suppressed endothelial inflammation and inhibited the proliferation of vascular smooth muscle cells. In the gut, HJ11 alleviated intestinal structural damage and enhanced barrier integrity. Notably, it promoted the function of Akkermansia, a beneficial bacterium known to influence TLR4 expression. Finally, in an in vitro atherosclerosis model, HJ11 decoction inhibited cell proliferation and migration by inactivating the TLR4/MYD88/IκB-α signaling pathway-an effect that was abolished by TLR4 overexpression. Show less
Macrophage-like phenotype switching of vascular smooth muscle cells (VSMCs) is a crucial mechanism driving atherogenesis. Inhibition of a phenotype switch to macrophage-like cells is a promising strat Show more
Macrophage-like phenotype switching of vascular smooth muscle cells (VSMCs) is a crucial mechanism driving atherogenesis. Inhibition of a phenotype switch to macrophage-like cells is a promising strategy to prevent atherosclerosis (AS), and targeted nanotherapeutics represent one approach for implementing this strategy. To this end, we designed immunosuppressive oligodeoxynucleotide A151 functionalized selenium nanoparticles with a spearhead LacNAc (LN-A151-SeNPs) that target macrophage-like VSMCs. Nano characterization showed that the uniformity and stability of nanoparticles were optimized by modification with LacNAc and A151, resulting in an average diameter of 88.90 ± 1.45 nm, Zeta potentials of -21.1 ± 1.5 mV, a A151:Se molar ratio of 1:60 and mass ratio of 1.68:1. The effects of LN-A151-SeNPs on inhibiting VSMCs phenotype switching and attenuation of AS were investigated using [Image: see text] The online version contains supplementary material available at 10.1186/s12951-025-03925-7. Show less
Temozolomide (TMZ) is a first-class clinical drug for patients with pancreatic neuroendocrine tumors (pNETs). However, the therapeutic effects of TMZ are limited because of the chemoresistance of pNET Show more
Temozolomide (TMZ) is a first-class clinical drug for patients with pancreatic neuroendocrine tumors (pNETs). However, the therapeutic effects of TMZ are limited because of the chemoresistance of pNET cells, which has not been fully elucidated. Here, we demonstrate that the reprogramming of lipid metabolism regulates TMZ resistance in patients with pNETs. Via integrated multiomics sequencing, apolipoprotein E (APOE), which is a critical lipid carrier, was identified to be highly increased in the tissue and blood plasma of patients in the TMZ treatment group compared with those in the control group. Further mechanistic studies revealed that TMZ treatment promotes the expression and secretion of APOE, which binds to its surface receptor known as scavenger receptor class B member 1 (SCARB1), thus leading to increased uptake of exogenous lipids to remodel cellular lipid metabolism and activation of the homologous recombination repair (HRR) pathway to repair DNA damage via the β-catenin-BRCA1/2 axis. The interruption of APOE-mediated lipid uptake via a SCARB1 inhibitor named as block lipid transport-1 (BLT-1), suppressed TMZ-induced HRR activation and sensitized tumor cells to TMZ treatment in preclinical models, including PDCs, PDOs, and PDXs. In addition, APOE expression levels were shown to be positively correlated with BRCA1/2 expression in clinical specimens and online databases. This study reveals a new functional role of APOE that leads to chemoresistance in patient treatment. Our findings suggest the potential of combined administration of BLT-1 to overcome TMZ chemoresistance and improve treatments for patients with pNETs. Show less
Many patients are suffering from atherosclerosis without typical risk factors, which can cause severe cardiovascular complications. Trimethylamine N-oxide (TMAO), derived from gut microbes, is a key u Show more
Many patients are suffering from atherosclerosis without typical risk factors, which can cause severe cardiovascular complications. Trimethylamine N-oxide (TMAO), derived from gut microbes, is a key unconventional contributor to the development of atherosclerosis. Here we present a strategy performed by orally administered nano-functionalized probiotics (PDMF@LGG) to inhibit TMAO through the gut microbiota-trimethylamine (TMA)-TMAO axis. PDMF@LGG, composed of polydopamine-coated Lacticaseibacillus rhamnosus GG and nanoparticles based on a reactive oxygen species (ROS)-responsive polymeric prodrug of fluoromethylcholine (FMC), can promote the retention of probiotics and nanoparticles in the intestine to persistently scavenge elevated ROS and release drugs. This process suppresses TMA production and absorption, lowering plasma TMAO levels. The therapeutic effects on male ApoE Show less
New methods estimate amyloid positivity onset age (EAOA) from amyloid positron emission tomography (PET). We explore the genetics of EAOA to identify molecular factors underlying the earliest Alzheime Show more
New methods estimate amyloid positivity onset age (EAOA) from amyloid positron emission tomography (PET). We explore the genetics of EAOA to identify molecular factors underlying the earliest Alzheimer's disease (AD) changes. Harmonized amyloid PET data from 4216 participants were used in genome-wide survival, tissue-specific gene expression, and genetic covariance analyses of EAOA. Variants in apolipoprotein E (APOE), ABCA7, and RASGEF1C associated with earlier EAOA. APOE ε4/ε4 and ε3/ε4 converted 6.3 and 5 years earlier than ε3/ε3, respectively. ε2 was protective against earlier EAOA. rs4147929, an expression quantitative trait locus for ABCA7, associated with a 4 year earlier EAOA. This variant was associated with lower brain expression of ABCA7, which was associated with increased amyloid pathology at autopsy. Multiple immune-related diseases shared genetic covariance with EAOA. APOE, ABCA7, and RASGEF1C associated with earlier EAOA, with supporting evidence from tissue-specific expression analyses, offering insights into intervenable targets at early stages of AD. Novel methods estimate how long ago a patient converted to amyloid positivity. Estimating this amyloid clock allows us to determine the onset of the earliest Alzheimer's disease changes. We evaluated what genes influence when someone converts to amyloid positivity. Apolipoprotein E (APOE), ABCA7, and RASGEF1C associated with earlier age of amyloid positivity. Genetic results were supported by tissue-specific expression analyses. Show less
Molecular QTL studies quantify whether genetic variants affect molecular traits, but non-linear effects including distributional patterns, variance, and interactions provide mechanistic insights beyon Show more
Molecular QTL studies quantify whether genetic variants affect molecular traits, but non-linear effects including distributional patterns, variance, and interactions provide mechanistic insights beyond mean-level associations. Methods for detecting distributional effects have been developed for eQTL analysis, yet applications have focused on method demonstrations rather than large-scale biological discovery. We comprehensively mapped quantile, variance, and interaction QTLs across 34 data-set from 22 molecular contexts in >2,300 human brain donors, revealing that 48.7% of quantile QTLs (qQTLs) exhibit context-dependent regulation invisible to linear models, with enrichment at phenotypic extremes and in cell-type-specific regulatory elements, chromatin accessibility regions, and long-range chromosomal contacts. qQTL variants explained additional trait heritability beyond linear QTLs for brain-related traits. At Alzheimer's disease (AD) risk loci, qQTL analysis revealed complex regulatory architecture including variance effects at Show less
Acupuncture has been proposed as a therapeutic intervention for stroke recovery, yet the underlying molecular mechanisms remain poorly understood. In this study, we used a mouse model of hemorrhagic s Show more
Acupuncture has been proposed as a therapeutic intervention for stroke recovery, yet the underlying molecular mechanisms remain poorly understood. In this study, we used a mouse model of hemorrhagic stroke induced by autologous blood injection to investigate the effects of acupuncture on post-stroke recovery at the cellular and molecular levels, utilizing single-cell RNA sequencing. Our findings revealed that acupuncture modulates the gene expression of microglia, astrocytes, and oligodendrocytes, three major glial cell types, which may contribute to the improvement of stroke-induced phenotypes. Notably, we identified a potential role of the APOE-TREM2 signaling axis, with ligand-binding interactions enhancing microglia activation and promoting their neuroprotective functions. These findings also suggested that acupuncture may promote microglia-astrocyte interactions, leading to enhanced neuroinflammation resolution and tissue repair. Our study provided new insights into the cellular mechanisms underlying acupuncture's therapeutic effects in stroke recovery and highlighted the potential of targeting glial cell-mediated pathways, including APOE-TREM2, as a strategy for improving post-stroke rehabilitation. Show less
Atherosclerosis (AS), a chronic inflammatory disease linked to oxidative stress and lipid imbalance, remains a major cardiovascular threat. Traditional herbs Salvia miltiorrhiza and Carthamus tinctori Show more
Atherosclerosis (AS), a chronic inflammatory disease linked to oxidative stress and lipid imbalance, remains a major cardiovascular threat. Traditional herbs Salvia miltiorrhiza and Carthamus tinctorius exhibit multi-target anti-AS potential, yet their compositional complexity limits clinical translation. This study aimed to systematically identify core anti-AS components from these herbs and enhance their anti-AS efficacy via machine learning-aided screening and nanotechnology-driven codelivery. We initially pioneered a machine learning-aided hybrid strategy integrating network pharmacology and quantitative activity relationship (QSAR) modeling to identify four core anti-AS polyphenols (i.e., salvianic acid A, salvianolic acid B, protocatechuic acid, and hydroxysafflor yellow A). Subsequently, a quaternary metal-phenolic network (SSPH-MPN) was engineered for plaque-targeted codelivery, optimized via the median-effect principle for achieving a synergistic effect based on ROS scavenging efficacy. The optimized SSPH-MPN was characterized by a series of studies, including molecular dynamics simulations, UV, DLS, TEM, FTIR, XPS, and ICP-MS. The anti-AS effect of the optimized SSPH-MPN was evaluated by monitoring oxidative status (ROS levels, antioxidant enzymes SOD, GSH-Px, MDA, T-AOC), inflammatory markers (IL-1β, IL-6, TNF-α), lipid metabolism (DiI-oxLDL uptake, cholesterol efflux, blood lipid levels, lipid accumulation), and plaque areas. The results demonstrated that the optimized SSPH-MPN showed great efficiency in inhibiting lipid uptake and accumulation, and mediating cholesterol efflux in RAW 264.7 cells, and exhibited improved lipid metabolism, attenuated oxidative stress and inflammation, thus acquired diminished plaque area in apoE Show less
Tao Geng, Mengwei Feng, Kaiyan Wang+11 more · 2025 · FASEB journal : official publication of the Federation of American Societies for Experimental Biology · added 2026-04-24
The uptake of modified lipoproteins by macrophages to form foam cells is a crucial step in atherosclerosis (AS) development. N7-methylguanosine (m7G) is frequently methylated internally in eukaryotic Show more
The uptake of modified lipoproteins by macrophages to form foam cells is a crucial step in atherosclerosis (AS) development. N7-methylguanosine (m7G) is frequently methylated internally in eukaryotic RNA transcripts and plays a crucial role in various processes. This study aimed to investigate the m7G RNA methylation profile in AS. We employed high-throughput sequencing to analyze the m7G methylome in foam cells induced by ox-LDL, using an in vitro AS model. Then, m7G-seq, RNA-seq, bioinformatic analysis, cell biological analyses, followed by qRT-PCR were performed. Additionally, the roles of SCARB2 and RASSF8 were investigated in an in vivo AS mouse model, and cells with SCARB2/RASSF8 overexpression/knockdown. In vitro and in vivo oil red O staining confirmed the successful establishment of the atherosclerotic foam cell and mouse models. We identified 1197 m7G peaks and 430 differentially expressed mRNAs during foam cell formation. Bioinformatics analyses revealed different m7G peaks associated with the gonadotropin-releasing hormone (GnRH) signaling pathway, cytoskeleton-dependent intracellular transport, and mitochondrial organization, regulating the processes of macrophage foaminess. Moreover, 28 key differentially expressed methylated genes were identified. m7G methyltransferases (WDR4, METTL1, WBSCR22) were upregulated in the AS cell model, and m7G modification genes (SCARB2 and RASSF8) associated with pathological processes were confirmed. Immunofluorescence staining showed that RASSF8 and SCARB2 were both expressed in AS mice plaque tissues. Finally, RASSF8/SCARB2 overexpression could promote apoptosis and lipid accumulation of ox-LDL-induced RAW264.7 cells. An m7G transcriptome-wide map of AS in vitro was created, and the differentially m7G methylated genes SCARB2 and RASSF8 may be crucial in macrophage foaminess. Our findings offer novel insights into the underlying mechanisms and potential treatments for AS. Show less
The entorhinal cortex (ERC) is implicated in early progression of Alzheimer's disease (AD). Here we investigated the impact of established biological risk factors for AD, including
Mitochondria play an essential role in regulating various physiological functions including bioenergetics, calcium homeostasis, redox signaling, and lipid metabolism and also are involved in the patho Show more
Mitochondria play an essential role in regulating various physiological functions including bioenergetics, calcium homeostasis, redox signaling, and lipid metabolism and also are involved in the pathogenesis of cardiovascular diseases. However, the relationship between mitochondrial calcium homeostasis in vascular smooth muscle cells (VSMCs) and atherosclerosis remains poorly understood. Here, we demonstrate that cholesterol induces mitochondrial calcium overload and lipid accumulation in VSMCs, which is resulted from dysregulation of mitochondrial calcium uniporter (MCU), as evidenced by genetic and pharmacologic inhibition of MCU. Furthermore, MCU inhibitors alleviate Western diet-induced atherosclerosis in ApoE-/- mice. Mechanistically, high-fat and high-cholesterol diets induce the contact between mitochondria and the endoplasmic reticulum (ER) in VSMCs as indicated by transmission electron microscopy, proximity ligation assay and immunofluorescence staining, which increases the formation of mitochondria-associated membranes (MAMs), leading to Ca2 + release from the ER into the mitochondria and thus elevating Ca2 + in the mitochondria. Using mitochondrial calcium uptake 1 (MICU1) mutant and Ca2 + detection assay, we confirmed that this increased Ca2 + binds to MICU1, a blocker of MCU, to impair its ability to block MCU, thus enabling the MCU to remain open and resulting in mitochondrial calcium overload. Further, mitochondrial calcium overload dysregulates fatty acid β-oxidation by modulating medium-chain acyl-CoA dehydrogenase (ACADM), thereby leading to lipid deposition. The inhibition of MCU alleviates the pathological changes elecited by cholesterol. Our findings unveil the previously unrecognized role of MAM-MICU1-MCU axis in cholesterol-induced mitochondrial calcium overload and atherosclerosis, indicating that MCU represents a promising therapeutic target for the treatment of atherosclerosis. Show less
Pancreatic ductal adenocarcinoma (PAAD) metastasis is driven by complex tumor-microenvironment interactions. Here, we integrated single-cell and bulk transcriptomic analyses of 104,855 cells from 10 p Show more
Pancreatic ductal adenocarcinoma (PAAD) metastasis is driven by complex tumor-microenvironment interactions. Here, we integrated single-cell and bulk transcriptomic analyses of 104,855 cells from 10 patients to delineate the cellular and molecular landscape of primary versus metastatic PAAD. We identified metastasis-associated epithelial (LMO7⁺, TOP2A⁺, PIGR⁺), fibroblast (IGKC⁺, RGS5⁺), and M2-like macrophage (APOE⁺, CD14⁺, FOLR2⁺, SPP1⁺) subpopulations, validated via bulk deconvolution. Functional analyses revealed upregulated Wnt signaling, epithelial-mesenchymal transition, and angiogenesis in metastatic epithelial and fibroblast compartments. Intercellular communication analysis highlighted SPP1-mediated macrophage-epithelial/fibroblast crosstalk involving key receptor-ligand pairs, contributing to immune suppression and metastatic niche formation. Integrating gene expression and cell proportions, we developed a prognostic model with high predictive accuracy (C-index > 0.85), stratifying patients into risk groups with distinct immune landscapes. Furthermore, PTK6 was identified as a driver of PAAD proliferation, migration, and invasion. Collectively, our study elucidates TME-driven mechanisms of PAAD metastasis, identifies prognostic and therapeutic targets, and provides a framework for precision intervention. Show less
Subjective cognitive decline (SCD) serves as an initial symptom of preclinical Alzheimer's disease (AD). The accumulation of amyloid-beta (Aβ) is acknowledged as a critical risk factor for the eventua Show more
Subjective cognitive decline (SCD) serves as an initial symptom of preclinical Alzheimer's disease (AD). The accumulation of amyloid-beta (Aβ) is acknowledged as a critical risk factor for the eventual progression to mild cognitive impairment or dementia in individuals with SCD, highlighting the necessity for early detection and intervention. Previous studies have identified the retina and choriocapillaris as potential biomarkers for AD; however, these investigations have not thoroughly examined large and medium-sized choroidal vessels. Ultra-wide swept-source optical coherence tomography angiography (SS-OCTA), an innovative noninvasive imaging modality, facilitates rapid and precise quantitative assessment of retinal and choroidal boundaries and vasculature through dynamic scanning, encompassing large and medium-sized choroidal vessels. This study aims to characterize the outer retinal and choroidal vasculature and structure in individuals with SCD, examine the correlation between altered choroidal vasculature parameters and amyloid burden, and the presence of the apolipoprotein E (APOE) ε4 allele in SCD participants, to identify potential ocular biomarkers for high-risk SCD screening. In this study, 57 individuals with SCD and 45 matched normal controls were enrolled. Ultra-wide SS-OCTA was employed to assess the thickness of the outer retina and choroid and the blood flow within the choriocapillaris and large, medium-sized choroidal vessels. Show less
We test the hypothesis that high levels of neuroplasticity in the context of Alzheimer's disease (AD) risk factors are involved in AD pathogenesis by investigating interactions between cerebrospinal f Show more
We test the hypothesis that high levels of neuroplasticity in the context of Alzheimer's disease (AD) risk factors are involved in AD pathogenesis by investigating interactions between cerebrospinal fluid (CSF) levels of growth-associated protein-43 (GAP-43) and AD risk factors (female sex, cerebrovascular risk, mild cognitive impairment, apolipoprotein E [APOE] ε4 genotype, amyloid positivity) on CSF biomarkers of AD pathology (amyloid beta 42/40[Aβ42/40], phosphorylated tau (p-tau)) and neurodegeneration (tau). Baseline GAP-43 levels in 161 non-demented older adults were related to cross-sectional and longitudinal (mean follow-up = 4 years) CSF biomarkers of AD, adjusting for covariates, with GAP-43 x AD risk factor interaction terms. Higher GAP-43 was cross-sectionally related to all AD biomarkers (p-values < 0.0001) and predicted longitudinal reductions in Aβ42 (p < 0.0001). Associations were stronger in AD risk groups. We found strong support linking increased levels of neuroplasticity in the context of AD risk factors to the pathological cascade of AD over a 4-year mean follow-up period. Cerebrospinal fluid growth-associated protein-43 (GAP-43) is associated with Alzheimer's disease (AD) biomarkers cross-sectionally and longitudinally. GAP-43 interacts with AD risk factors to predict AD biomarkers. Increased neuroplastic activity may play a role in AD pathogenesis. Show less
This study aims to compare the protein expression profiles of plasma-derived exosomes in patients with sudden sensorineural hearing loss (SSNHL) and normal hearing control groups to identify exosome p Show more
This study aims to compare the protein expression profiles of plasma-derived exosomes in patients with sudden sensorineural hearing loss (SSNHL) and normal hearing control groups to identify exosome proteins that may be associated with SSNHL or serve as biomarkers for SSNHL. Researchers collected peripheral venous blood from SSNHL patients and healthy controls for exosome isolation. The isolated exosomes were identified through nanoparticle tracking analysis, transmission electron microscopy observation, and Western blotting, followed by total protein extraction for proteomic sequencing. Differential expression proteins (DEPs) were screened using the threshold criteria of Researchers isolated exosomes from plasma and identified them through particle size analysis, morphological observation, and expression of exosome marker proteins. Comparative studies with healthy individuals revealed 363 DEPs in SSNHL. Additionally, 515 DEPs were identified in mild sudden deafness (MilSSNHL) and healthy controls, 982 in moderate cases (ModSSNHL) and healthy controls, and 1,161 in profound cases (ProSSNHL) and healthy controls. These proteins are involved in signaling pathways enriched by DEPs. Validation experiments demonstrated that the expression levels of these proteins consistently matched their sequencing results, ensuring high reliability. Furthermore, these candidate proteins show significant diagnostic potential for SSNHL. The four extracellular proteins identified in this study, including RPS2, RPL19, ACO2 and APOE, may be closely related to the occurrence and development of SSNHL or serve as biomarkers for the diagnosis and staging of SSNHL. Show less
Accumulating evidence has demonstrated that nucleic acid-based therapies are promising for atherosclerosis. However, nearly all nucleic acid delivery systems developed for atherosclerosis necessitate Show more
Accumulating evidence has demonstrated that nucleic acid-based therapies are promising for atherosclerosis. However, nearly all nucleic acid delivery systems developed for atherosclerosis necessitate injection, which results in rapid elimination and poor patient compliance. Consequently, oral delivery strategies capable of targeting atherosclerotic plaques are imperative for nucleic acid therapeutics. Herein we report the development of yeast-derived capsules (YCs) packaging an antisense oligonucleotide (AM33) targeting microRNA-33 (miR-33) for the oral treatment of atherosclerosis. YCs provide stability for AM33, preventing its premature release in the gastrointestinal tract. AM33-containing YCs, defined as YAM33, showed high transfection in macrophages, thus promoting cholesterol efflux and inhibiting foam cell formation by regulating the target genes/proteins of miR-33. Orally delivered YAM33 effectively accumulated within atherosclerotic plaques in Show less
Atherosclerosis serves as the core pathological basis of cardiovascular, cerebrovascular, and peripheral arterial diseases, posing a serious threat to human health. However, current mainstream treatme Show more
Atherosclerosis serves as the core pathological basis of cardiovascular, cerebrovascular, and peripheral arterial diseases, posing a serious threat to human health. However, current mainstream treatments such as statin drugs and stent implantation are associated with significant side effects or limited efficacy, highlighting the urgent need for new therapeutic strategies. Pulsed electromagnetic fields (PEMFs), due to their noninvasive nature and anti-inflammatory properties, show potential in the treatment of atherosclerosis. This study utilized ApoE-/- mice, ApoE-/-NLRP3-/- knockout mice, human umbilical vein endothelial cells (HUVECs), human aortic endothelial cells (HAECs), and human plasma samples for experiments, revealing significant endothelial cell (EC) inflammation and pyroptosis during the progression of atherosclerosis. PEMFs were found to effectively inhibit the activation of the NLRP3 inflammasome, reduce plaque formation, and delay the progression of atherosclerosis. Proteomic analysis of plasma from atherosclerosis patients further indicated elevated expression levels of proteins related to inflammation and pyroptosis, with particularly notable changes in membrane proteins. Mechanistic studies demonstrated that PEMFs improve mitochondrial dysfunction in ECs by regulating membrane tension and the mechanosensitive tension-mediated transient receptor potential vanilloid 4 (TRPV4) channels, thereby reducing pyroptosis. This discovery not only reveals a novel mechanobiological pathway but also provides a solid theoretical foundation for the development of PEMF-based therapies for atherosclerosis. Schematic diagram of the mechanism by which PEMFs treat atherosclerosis (created in BioRender). Wei, B. (2025) https://BioRender.com/undefined ). Show less
Sparstolonin B (SSNB) and Curcumin (Cur), from a pair of compatible herbs, were previously identified as anti-inflammation and T helper 17 (Th17) modulation reagents. However, their compatible roles i Show more
Sparstolonin B (SSNB) and Curcumin (Cur), from a pair of compatible herbs, were previously identified as anti-inflammation and T helper 17 (Th17) modulation reagents. However, their compatible roles in atherosclerosis (AS) and underlying mechanisms remain uninvestigated. In vivo, the apoE The gene-disease interaction and hub gene network reveals Th17-associated genes in the pathogenesis of atherosclerosis. In vitro, SSNB and Cur reduced oxLDL-induced BMDC activation by downregulating CD36. SSNB showed stronger inhibition to inflammatory activation of DC, while Cur more intensively suppressed co-stimulatory molecules. For the Th17/Treg bias in co-culture of BMDC and CD4 Our findings reveal, for the first time, that SSNB and Cur alleviate AS by modulating Th17-stromal cell interactions, with the IL-17RA-TAK1-NF-κB pathway as a related mediator. Notably, SSNB and Cur exhibit distinct anti-atherogenic roles. SSNB primarily targets TLR4/CD36 to inhibit DC activation, Th17 differentiation, VSMC inflammation and mainly inhibited TAK1 phosphorylation, while Cur more significant inhibited macrophage inflammation, and more directly inhibited NF-κB P65 phosphorylation. This study will be valuable for developing novel and precise adjuvant therapies for AS. Show less
Rupture of vulnerable atherosclerotic plaques is a major cause of acute cardiovascular events. Vascular smooth muscle cell (VSMC) senescence promotes plaque vulnerability by impairing fibrous cap inte Show more
Rupture of vulnerable atherosclerotic plaques is a major cause of acute cardiovascular events. Vascular smooth muscle cell (VSMC) senescence promotes plaque vulnerability by impairing fibrous cap integrity. Although melatonin exhibits atheroprotective potential, its capacity to stabilize plaques by targeting VSMC senescence along with the underlying mechanisms, remains unclear. In this study, a vulnerable plaque model was established in ApoE Show less
Histone deacetylase 3 (HDAC3) is an epigenetic modifying enzyme closely linked to the development of atherosclerosis. Endothelial inflammation is a critical factor in atherosclerosis. However, the rol Show more
Histone deacetylase 3 (HDAC3) is an epigenetic modifying enzyme closely linked to the development of atherosclerosis. Endothelial inflammation is a critical factor in atherosclerosis. However, the role of HDAC3 in mediating epigenetic modifications and regulating endothelial inflammation in atherosclerosis remains unclear. This study aims to investigate the impact of HDAC3 on endothelial inflammation and its contribution to atherosclerosis. Firstly, single-cell transcriptomic analysis identified elevated expression of HDAC3 and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) in inflammatory endothelial cells of atherosclerotic plaques in symptomatic patients. Endothelial-specific knockout HDAC3 in an apolipoprotein E knockout (ApoE Show less