👤 Jian Huang

Coronary heart disease (CHD) is driven by endothelial dysfunction and chronic vascular inflammation. hsa-miR-2110 (miR-2110) has been associated with adverse cardiovascular outcomes, but its mechanistic role in CHD remains unclear. In this study, miR-2110 expression was quantified in peripheral blood from CHD patients and healthy controls. Functional effects were assessed in EA.hy926 endothelial cells following lentiviral overexpression of miR-2110. The target gene Show less

Oxidised 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (oxPAPC), dendritic cells (DCs), and long non-coding RNAs (lncRNAs) play crucial roles in atherosclerosis (AS). This study aimed to determine whether oxPAPC-induced DC-derived lncRNAs contribute to AS and to elucidate the underlying regulatory mechanisms. DCs were treated with increasing oxPAPC concentrations to assess transcriptomic changes. RNA sequencing was used to identify differential expression of lncRNAs. ChIP-Seq and RNA pull-down assays were used to assess direct binding between lncRNA CYP1B1-AS1 and NFATC2. The association between CYP1B1-AS1 and CYP1B1 was assessed using Pearson's correlation analysis. Elevated serum oxPAPC levels were confirmed in patients with coronary heart disease. In vitro, sustained oxPAPC stimulation activated the TLR4-MD2 pathway in DCs. CYP1B1-AS1 was identified as the key oxPAPC-induced DC-derived lncRNA, with Gm33055 as its murine homologue. RNA sequencing revealed oxPAPC-driven alterations in DC chemotaxis, differentiation, and lymphocyte activation. Analysis of human atherosclerotic plaque-derived DCs showed significant CYP1B1-AS1 upregulation. Gm33055 enhanced Cyp1b1 expression in murine DCs. Mechanistically, oxPAPC promoted NFATC2 nuclear translocation. NFATC2 binds to the CYP1B1-AS1 promoter, whereas CYP1B1-AS1 directly interacts with NFATC2, forming a positive regulatory loop. Adoptive transfer of m-CYP1B1-AS1-expressing DCs into Apoe Show less

Apolipoprotein E (APOE) and proprotein convertase subtilisin/kexin type 9 (PCSK9) are both lipid proteins and related to immunity/inflammation. We hypothesized that PCSK9 impacts on Alzheimer's disease (AD) risk in an We used the Framingham Heart Study (FHS) Offspring cohort (Gen 2), with data on plasma PCSK9 protein concentration, as the baseline exposure for 1,704 study subjects. Using Cox regression models, the outcomes were incidents of AD or all-cause dementia. Using another FHS dataset with 3,048 individuals with genetic data, we examined the association between PCSK9 genotypes and the incidence of AD/dementia, stratifying the analysis based on Higher plasma PCSK9 protein levels were associated with a lower risk of AD (HR [95%CI]: 0.74 [0.58, 0.94]; Our study suggests that high blood PCSK9 levels are protective against AD risk in Show less

Periodontitis is linked to dyslipidaemia, but the mechanism still requires further investigation. This study aimed to investigate the periodontitis-dyslipidaemia interplay, comparing the impact of periodontitis-associated versus healthy salivary microbiota on systemic lipid metabolism in mice via the oral-gut axis. NHANES analysis established epidemiological link. ApoE-/- mice received salivary microbiota from periodontally healthy (A-PH) or severe periodontitis (A-SP) donors. Serum lipids and gut microbiota were assessed; correlations between microbial shifts and lipid changes were evaluated. NHANES confirmed significant association between self-reported physician-diagnosed bone loss around teeth and hypercholesterolemia (OR=1.266). A-SP mice exhibited higher TC, LDL and non-HDL compared with A-PH group. Gut dysbiosis featured increased proinflammatory genera ( Collectively, building upon the NHANES link, our findings demonstrate that the salivary microbiome from periodontitis patients, compared to that from healthy individuals, disrupts systemic lipid metabolism and induces gut dysbiosis in mice. The correlation between specific gut microbial shifts and atherogenic lipid profiles provides experimental support for the mediating role of the oral‒gut axis in linking periodontitis to hyperlipidaemia. Show less

COG133, a peptide fragment derived from apolipoprotein E (ApoE) corresponding to residues 133-149, has demonstrated significant anti-inflammatory and neuroprotective activity. However, its precise anti-inflammatory mechanisms and its potential to ameliorate depression-like behaviors remain incompletely understood. This study investigated the effects of COG133 in mouse models of depression induced by lipopolysaccharide (LPS), chronic social defeat stress (CSDS), and corticosterone (CORT), as well as in LPS-stimulated BV-2 microglial cells. We found that COG133 treatment significantly alleviated depression-like phenotypes and suppressed hippocampal neuroinflammation by inhibiting microglial overactivation. Using RNA sequencing (RNA-seq) and biochemical validation, we identified the MKK3/6-p38-ATF2 signaling axis as a central mechanism underlying the anti-inflammatory effects of COG133. Pharmacological modulation of p38 MAPK further confirmed that this pathway is essential for COG133-mediated behavioral and cellular recovery. Together, these findings identify COG133 as a promising peptide candidate for the treatment of depression through modulation of the p38 MAPK-mediated neuroinflammation axis. Show less

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

Atherosclerosis is a leading cause of worldwide cardiovascular morbidity and mortality, and endothelial ferroptosis has emerged as a key mechanism in driving vascular injury. This study aimed to investigate whether quercetin (QCT), a natural dietary flavonoid with potent anti-oxidant activity, protects against atherosclerosis-associated endothelial dysfunction by modulating ferroptosis. In order to test this, ApoE[Formula: see text] mice fed a high-fat diet were treated with QCT or ferrostatin-1, and their aortic plaque burden, stability, and macrophage infiltration were then assessed. To evaluate ferroptosis, human umbilical vein endothelial cells (HUVECs) were exposed to oxidized low-density lipoprotein (Ox-LDL), with or without QCT, and their reactive oxygen species (ROS), Fe[Formula: see text] accumulation, and heme oxygenase-1 (HMOX-1) expression were measured. While functional assays examined endothelial barrier integrity and monocyte adhesion, gene modulation studies explored the role of phosphofurin acidic cluster sorting protein 2 (PACS2). QCT treatment markedly reduced plaque area, necrotic core size, and macrophage infiltration while enhancing plaque stability. Show less

Atherosclerosis is a lipid-driven chronic inflammatory process, in which the functional status of macrophages significantly influences its initiation, progression, and eventual outcomes. Tartrate-Resistant Acid Phosphatase 5 (ACP5) has been shown to be highly expressed in various cancers and serves as a serum biomarker for extensive bone metastasis and poor prognosis. However, its role and underlying mechanisms in atherosclerosis remain largely unknown. In this study, we found that high-fat diet-fed Apoe Show less

Branched-chain amino acids (BCAAs) have been associated with cognitive function, with conflicting evidence suggesting both potential benefits and risks in neurodegenerative diseases such as Alzheimer’s disease (AD) and mild cognitive impairment (MCI), highlighting the need for further investigation. This study aimed to explore the relationship between total BCAAs, cognitive function, and brain structure, specifically examining hippocampal volumes and their potential mediating effects in individuals with AD, MCI, and cognitively normal (CN) individuals. Cognitive function was assessed using the CDR-SB scale, total BCAAs were measured in serum through NMR metabolomics, and hippocampal volumes were evaluated using voxel-based morphometry (VBM). This study found that elevated total BCAAs were initially associated with increased hippocampal volumes in MCI, though this relationship became non-significant after adjusting for confounding factors such as age, gender, education, and ApoE ɛ4 status. Increased hippocampal volumes, however, remained consistently linked to better cognitive function in both MCI and AD, regardless of adjustments. Importantly, mediation analysis revealed indirect effects of elevated total BCAAs on improved cognitive function via increased hippocampal volumes, with being significant only in MCI before controlling for confounders; however, this mediation relationship disappeared after adjusting for age, gender, education, and ApoE ɛ4 status. These findings suggested that BCAAs may be associated indirectly with improved cognitive function, with increased hippocampal volume acting as a key mediator, particularly in MCI. However, the effects of BCAAs were sensitive to confounding factors such as age, gender, education, and APOE-ɛ4 status, which we accounted for in our analyses; however, other unmeasured factors such as dietary intake may also affect the observed associations, underscoring the importance of considering these variables in future studies. Show less

Atherosclerotic vascular diseases remain the leading cause of death despite the use of lipid-lowering drugs. The development of more efficacious therapies targeting endothelial inflammation and endothelial-to-mesenchymal transition (EndMT) is an essential endeavor, aiming for better treatment outcomes. The increased mutation frequency of the The results of liquid chromatography-mass spectrometry, immunostaining, RNA sequencing, and Western blot in mouse and human arteries with atherosclerotic plaques identified TBK1 as one of the key mediators of EndMT and atherogenesis. Its role was then investigated in endothelium-specific TBK1 knockdown An increased expression of TBK1 was observed by liquid chromatography-mass spectrometry analysis in the aortas of The interaction between activated TBK1 and PAK1IP1 inhibits the binding of PAK1IP1 to PAK1, which, in turn, increases the phosphorylation of PAK1 and ERK1/2 in endothelial cells. This process drives EndMT. Endothelium-specific TBK1 knockdown or GSK8612 treatment inhibits EndMT and plaque formation. Safe TBK1 inhibitors could be developed into effective agents for the treatment of atherosclerotic vascular disease. Show less

Glioblastoma (GBM) remains one of the most intractable malignancies owing to the dual challenges of the blood brain barrier (BBB) and profound immunosuppression. Here, we present a nanobomb (OMV-ApoE@ALF) that integrates heterologous production of the aromatic polyketide albofungin (ALF) with programmable outer membrane vesicles (OMVs) displaying ApoE peptides for GBM immunotherapy. OMV-ApoE@ALF efficiently crossed the BBB, accumulated in tumors, and functioned as a lysosomal nanobomb to boost pyroptosis and activate cGAS-STING pathway, thereby promoting dendritic cell maturation, T-cell infiltration, and durable antitumor immunity. Mechanistically, OMV-ApoE@ALF delivered ALF into lysosomes, inducing lysosomal disruption, reactive oxygen species (ROS) production, and subsequent mitochondrial damage. Crucially, this lysosomal rupture also suppressed protective autophagy of tumor cells themselves, thereby reinforcing the cascade activation between caspase-3/GSDME-dependent pyroptosis and cGAS-STING signaling pathway. This lysosomal disruption-nanobomb represents a new strategy for advancing GBM immunotherapy. Show less

Cognitive dysfunction affects over 50 million individuals worldwide, with Alzheimer's disease (AD) representing two-thirds of cases. We identified Human proteomic analysis revealed eQTL mapping identified Show less

Toll-like receptor 9 (TLR9), expressed in both microglia and neurons of the CNS, represents a promising therapeutic target for Alzheimer's disease (AD). While either microglial or neuronal TLR9 activation exerts neuroprotective effects that ameliorate AD pathology and preserve cognitive function, CpG oligodeoxynucleotides (ODNs), the synthetic agonists, cannot cross the blood-brain barrier (BBB). To overcome this, we developed tNCpG, an apolipoprotein E (ApoE)-functionalized polymersome nanocarrier for brain-targeted delivery of CpG ODNs. APP/PS1 transgenic mice, which overexpress human mutant APP/PS1 and are widely used in AD mouse models for preclinical studies, were administered tNCpG intravenously biweekly for 3 months, starting at 4 months of age. tNCpG achieved efficient brain delivery while specifically targeting microglia and neurons. tNCpG treatment enhanced microglial recruitment to and phagocytosis of Aβ plaques, suppressed Aβ production while promoting its degradation, and improved BBB integrity and Aβ efflux. Collectively, these effects significantly reduced cerebral Aβ burden, neuroinflammation, and neurodegeneration, leading to the rescue of cognitive deficits. Our study establishes targeted TLR9 activation via tNCpG as a disease-modifying therapeutic strategy for AD. Show less

Apolipoprotein E (APOE) ε4 is the strongest genetic risk factor for Alzheimer's disease (AD). However, it is known that other pathways independent of APOE also play a role in AD. Disentangling APOE-dependent and independent effects is instrumental for understanding the biology of AD. We conducted an APOE-stratified multi-omic analysis in multiple large datasets to identify AD-associated plasma proteins and metabolites. More than 64% of the identified proteins were not found in non-APOE stratified studies, and 17% of the proteins showed APOE-specific trends. Mitochondrial dysfunction was associated in AD independently of APOE and was accompanied by disruptions in glucose and lipid metabolism and cell death and increased in inflammatory signaling activation. Lipid upregulation was found in AD cases when compared with controls with the same APOE genotype, indicating that additional factors beyond APOE affect lipid regulation and AD risk. These findings may be informative in guiding the development of effective medications for AD. Show less

Diabetic atherosclerosis (DA), characterized by disordered glucose and lipid metabolism, represents a significant metabolic vascular complication. Tangzhiqing (TZQ) has traditionally been used to treat diabetes and its complications. However, its material basis and mechanism for DA remain require further investigation. This research aimed to systematically elucidate the pharmacological material basis and underlying mechanism of the traditional Chinese medicine TZQ in diabetic atherosclerosis model mice. This study established UPLC-MS/MS and UPLC-Q-TOF/MS methods to detect composition and content of TZQ in vivo and in vitro, with pharmacokinetic analysis determining plasma concentration changes of representative components. DA model was induced by western diet and streptozotocin injection in ApoE 118 compounds were identified from TZQ. It contains categories such as organic acids, quinones, flavonoids, alkaloids, and terpenoids. Among them, 39 compounds were absorbed into bloodstream. Pharmacokinetic analysis demonstrated that 18 compounds were effectively absorbed into plasma with appropriate bioavailability. Pharmacodynamic results demonstrated that TZQ significantly alleviated hyperglycemia, hyperlipidemia, and aortic pathology in DA mice. Metabolomics and network pharmacology suggested the anti-DA effects were associated with bile acid metabolism. Targeted analysis confirmed TZQ restored high-fat-diet-induced bile acid metabolic imbalance. 16S rRNA sequencing revealed TZQ modulated gut microbiota dysbiosis, specifically regulating bile acid metabolism-related genera (e.g., Desulfovibrio, Bacteroides, Lactobacillus). The WB results showed that TZQ enhanced the expression of FXR, SHP and CYP7A1 in liver. Molecular docking proved that the bioactive compounds of TZQ exhibits favorable affinity for both FXR and CYP7A1. The study provided a comprehensive detection of in vitro and in vivo constituents and pharmacokinetic profile of TZQ, establishing a foundation for further exploration of its pharmacologically active components. TZQ alleviated DA by regulating the gut microbiota and bile acid metabolism. These results created a new perspective for the management of DA. Show less

BackgroundCognitive impairment is increasingly prevalent in younger populations. The interplay between environmental exposures like noise and genetic susceptibility in dementia etiology remains unclear. This study investigated the combined effects of work-related cumulative noise exposure (WCNE) and genetic polymorphisms on cognitive performance.ObjectiveTo examine the relationships among WCNE, genetic factors (APOE rs429358/rs7412 and PS-1 rs165932), and lower cognitive performance (LCP), and to analyze the potential interaction.MethodsThis study included 523 workers from a health surveillance cohort in western China. WCNE was assessed for each participant. Genotyping was performed for APOE (rs429358/rs7412) and PS-1 (rs165932) polymorphisms. Cognitive function was evaluated via Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). The individual and combined effects of WCNE and genetic factors on LCP were analyzed.ResultsAPOE rs429358/rs7412 were not significantly associated with LCP. The PS-1 rs165932T allele (PS-1T) was associated with LCP (p < 0.05). The adjusted odds ratios (aORs) for LCP (evaluated by MMSE and MoCA) in the PS-1T group were 2.443 (95% CI: 1.149-5.195) and 2.065 (95% CI: 1.091-3.906), respectively. Age and WCNE had an interaction effect on the LCP for both MMSE and MoCA (p < 0.05), while PS-1T had an effect modification on the relationship between WCNE and LCP (p < 0.05).ConclusionsThese findings highlight the urgent need to identify and mitigate noise exposure risks in vulnerable populations. These findings also provide evidence for further mechanistic studies exploring how noise, aging, and genetic susceptibility contribute to cognitive impairment through underlying biological mechanisms. Show less

Vascular graft fibrosis can cause a decrease in cellular infiltration and capillary ingrowth in vascular walls. It can also lead to vascular stiffening. As such, there are still no vascular grafts that can be used in blood vessels where their diameters are less than 6 mm in patients. Although various approaches have been evaluated to mitigate implant-associated fibrosis, effective treatments remain quite limited. In this study, we demonstrated that Apolipoprotein E (APOE) significantly increased during vascular regeneration after graft implantation Show less

Monocyte adhesion to vascular endothelial cells is a critical step in the pathogenesis of atherosclerosis. While unconventional myosins are known to participate in various cellular activities, their specific role in monocyte-endothelium adhesion remains unclear.In the present study, we investigated the effects of Myosin IF (Myo1f), a class I unconventional myosin, on atherosclerosis and its underlying mechanisms. A high-cholesterol diet was administered to apolipoprotein E-KO (Apoe Myo1f expression was found to be significantly increased in PBMCs of patients with coronary artery disease. Moreover, Myo1f-deficient mice exhibited a notable reduction in atherosclerotic plaque area and lipid deposition compared to Apoe Our data indicate that Myo1f regulates monocyte adhesion and contributes to the pathogenesis of atherosclerosis by recruiting EPLINα, which stabilizes F-actin. This stabilization enhances MRTFA nuclear translocation, thereby promoting ITGB2 transcription. Show less

Previous studies have shown that plasma amyloid-beta oligomers (AβOs), the toxic form of amyloid-beta (Aβ), are a critical issue in the development or worsening of Alzheimer's disease (AD) and can be regarded as a blood marker for screening in dementia. We examined plasma AβOs with their related biomarkers in a case-control study to clarify these issues. A total of 16 patients diagnosed with Alzheimer's dementia (AD) and 16 cognitively normal controls (NCs) were recruited to compare their plasma biomarkers, AβO, Aβ Show less

The longissimus dorsi muscle and backfat are important components of pork and complement each other in physiological function, significantly influencing key traits such as growth performance, carcass traits, and meat quality. While the transcriptomic atlas across different tissues in pigs has been widely studied, the underlying epigenetic regulatory mechanisms remain to be explored. In this study, we collected muscle and adipose tissues from hybrid offspring of lean-type (Western commercial pigs) and fat-type (Chinese indigenous pigs) pigs ( Transcriptome sequencing identified 2,908 differentially expressed genes, which are primarily involved in collagen fibril organization, skeletal muscle contraction, and muscle organ development. Whole-genome DNA methylation sequencing identified 2,787 differentially methylated genes in the promoter region. Through integrative analysis, we found 571 genes that were shared, 390 of which showed a significant negative correlation between gene expression and promoter DNA methylation. These genes are mainly involved in cholesterol metabolism, PPAR signaling pathway, cytoskeleton in muscle cell, and calcium ion signaling pathways. Notably, we discovered that the differential expression of genes such as These results suggest that DNA methylation plays an extensive and subtle regulatory role in tissue-specific gene expression, thereby facilitating different tissues to execute their specific physiological functions. This study further enriches our understanding of the integrative mechanisms between epigenetic regulation and transcriptomics in pigs and provides important theoretical foundations for precision molecular breeding. The online version contains supplementary material available at 10.1186/s12864-026-12559-4. Show less

Advanced age impairs bone fracture healing; the underlying mechanism of this phenomenon remains unknown. We determined that apolipoprotein E (ApoE) increases with age and causes poor fracture healing. After deletion of hepatic ApoE expression (ΔApoE), 24-month-old ΔApoE mice displayed a 95% reduction in circulating ApoE levels and significantly improved fracture healing. ApoE treatment of aged BMSCs inhibited osteoblast differentiation in tissue culture models; RNA-seq, Western blot, immunofluorescence, and RT-PCR analyses indicated that the Wnt/β-catenin pathway is the target of this inhibition. Indeed, we showed that ApoE had no effect on cultures with stabilized β-catenin levels. Next, we determined that Lrp4 serves as the osteoblast cell surface receptor to ApoE, as expression of Lrp4 is required in ApoE-based inhibition of Wnt/β-catenin signaling and osteoblast differentiation. Importantly, we validated this ApoE-Lrp4-Wnt/β-catenin molecular mechanism in human osteoblast differentiation. Finally, we identified an ApoE-neutralizing antibody (NAb) and used it to treat aged, wildtype mice 3 days after fracture surgery resulting in fracture calluses with 35% more bone deposition. Our work here identifies novel liver-to-bone cross-talk and a noninvasive, translatable therapeutic intervention for aged bone regeneration. Show less

C-reactive protein (CRP) is a key marker of systemic inflammation that affects blood vessel endothelial function, including in the brain. Since endothelial dysfunction is linked to Alzheimer's disease (AD), we investigated whether elevated CRP level interacts with genetic pathways in brain endothelial cells to influence AD risk. Using AD genome-wide association study (GWAS) data, we developed multiple polygenic risk scores (PRSs) including single nucleotide polymorphisms (SNPs) in genes expressed in brain endothelial cells, excluding the APOE region, that are involved in inflammation, synaptic transmission, and other pathways. Analysis across three independent cohorts revealed that individuals with low inflammatory PRSs (<50%) and elevated blood CRP level were associated with an increased risk of AD; in contrast, those with high inflammatory PRSs (≥50%) did not exhibit this CRP-related AD risk increase. Further examination of individuals with a low inflammatory PRS showed that elevated CRP was associated with lower cerebrospinal fluid (CSF) Aβ42 level and temporal lobe atrophy. Among individuals with a high inflammatory PRS, elevated CRP level was negatively correlated with CSF pTau181 and brain tauopathy, suggesting a potential protective mechanism against tau pathology. Key inflammatory PRS genes, which were impacted by circulating CRP for AD, included APP, IL6ST, and FN1, are involved in amyloid pathology, wound healing, and coagulation. Our findings highlight two distinct genetic-dose dependent backgrounds: "vulnerable" (<50% inflammatory PRS) and "resilient" (≥50% inflammatory PRS), and support a Genome-Internal Environment (G×IE) interaction model, linking peripheral inflammation to AD risk. Show less

The genetic basis of sporadic early-onset Alzheimer's disease (EOAD) remains largely unknown, prompting evaluation of late-onset Alzheimer's disease (LOAD) polygenic risk in EOAD. A LOAD polygenic score (PGS) was calculated in the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) and Alzheimer's Disease Neuroimaging Initiative (ADNI) study and tested for associations with AD risk, cognitive performance, and imaging and fluid biomarkers. Though PGS was elevated in LOAD and EOAD, it was not a significant predictor of EOAD adjusting for APOE ε4 carrier status and was not associated with age of EOAD onset (p = 0.106) or with cognitive performance (p = 0.417). In LEADS, greater LOAD PGS was associated with differences in neuroimaging and fluid biomarkers, including elevated synaptosomal-associated protein 25 (SNAP-25) (p = 2.3 × 10 While LOAD polygenic risk contributed minimally to EOAD onset and cognitive dysfunction, PGS association with fluid biomarkers in LEADS suggests a role for LOAD polygenic risk in EOAD pathophysiology. LOAD PGSs were elevated in both LOAD and EOAD compared to controls; however, LOAD PGS did not significantly predict EOAD risk, age at onset, or cognitive performance independent of APOE ε4 in the LEADS. Higher LOAD PGS was associated with lower amyloid PET Centiloids (less brain amyloid deposition) as well as lower CSF biomarker Aβ42 in LEADS (proxy marker suggesting higher brain amyloid deposition) in LEADS; these contradictory findings support the need for larger studies to further investigate whether LOAD PGS is associated with increased amyloid deposition in EOAD. Higher LOAD PGS was also associated with higher levels of CSF synaptosomal-associated protein 25 (SNAP-25), a key component of the SNARE complex, suggesting that LOAD genetic factors may contribute to dysregulation of synaptic transmission and/or pathological protein aggregation in EOAD. Show less

Gynostemma pentaphyllum (GP) is known as the "elixir of life" in Guizhou Province, China, as it has been widely consumed by the elderly. Numerous studies have shown that gypenosides (GPS) extracted from GP are involved in lipid metabolism. Apolipoprotein E (ApoE) is a polymorphic protein with multiple biological functions, such as regulating lipid transport and iron metabolism. The deficiency of ApoE can lead to disorders in both lipid and iron metabolism. Therefore, ApoE knockout (ApoE We randomly divided C57BL/6 mice were randomly divided into blank group (WT), apolipoprotein E knockout group (ApoE KO/ApoE The results demonstrate that gypenosides reduce ApoE deficiency-induced iron accumulation by downregulating TfR1 (a cellular iron import protein) and upregulating Fpn1 (an iron export protein). In the spleen of ApoE Gypenosides can reduce tissue iron accumulation in the liver and spleen of ApoE-deficient mice, suggesting that, based on its function in regulating lipid metabolism, gypenosides also possess the potential ability to regulate iron metabolism. Show less

Lecanemab is an anti-Aβ antibody approved in China for mild cognitive impairment (MCI) and mild dementia. Real-world application requires comprehensive assessment beyond MMSE scores, considering factors like ARIA risk. This single-center, real-world study aims to evaluate its efficacy in an expanded population, observe biomarker changes, and assess its safety profile in clinical practice. We recruited adults aged 40-90 with early AD from the PUMCH Dementia Cohort. A total of 42 patients received lecanemab treatment, of whom 29 completed the 6-month treatment evaluation. Participants had confirmed amyloid and tau pathology and met clinical criteria (CDR ≤ 1, CDR-SB ≤ 8and MMSE ≥ 18). Comprehensive assessments included neuropsychological testing, CSF and plasma biomarkers (Lumipulse G1200), multi-sequence 3T MRI (volumetric and ALPS index analysis), and amyloid/tau PET imaging (Centiloid quantification). All were monitored for adverse reactions. Matched control groups (matched for sex, age, APOE genotype, disease severity, and baseline therapy) were established for comparison of longitudinally changes in cognitive function, daily living ability and structure MRI. Treatment was effective even for patients with lower MMSE scores but still classified as having mild dementia by CDR. A significant median Centiloid reduction of 30.9 was observed, with a 24.1% amyloid PET negativity rate after six months. While scores on cognitive and functional scales (CDR-SB, ADL) significantly worsened, indicating disease progression, the rate of progression was significantly slower compared to the control group. Structural MRI showed significant volume reduction in multiple brain regions and increased ventricular volume post-treatment, with no statistically significant change in the ALPS value. The rate of brain volume reduction is faster than that in the control group. Plasma biomarker dynamics (Aβ This study confirms the clinical efficacy, biomarker changes, and safety profile of lecanemab treatment over a 6-month period, demonstrating its positive therapeutic value and a favorable safety profile in the Chinese population with AD. Show less

Apigenin is a bioactive flavonoid and widely found in herbs, fruits, and vegetables. Accumulated evidences have demonstrated the protective potential of apigenin on cardiovascular diseases, but its role in atherosclerosis remains unclear. Here, we aim to investigate the therapeutic effects of apigenin on atherosclerosis in vivo and explore the potential mechanism. ApoE Apigenin obviously reduced lesion areas in both en-face aortas and aortic root in HFD fed ApoE Apigenin alleviated atherosclerosis development by inhibiting macrophage foam cell formation via PPARγ-LXRα-ABCA1/ABCG1 pathway. Show less

The agreement between plasma Aβ42/40 and Aβ positron emission tomography (PET) is approximately 75 %, with ∼85 % of discrepancies due to positive plasma but negative PET results. It is unclear whether this reflects Aβ changes in plasma before PET-detectable. To assess the influence of Aβ42/40 positivity on risk of progression to Aβ PET positivity, and feasibility of using plasma Aβ42/40 tests to enrich a primary prevention trial. A prospective longitudinal cohort study. Participants of Australian Imaging, Biomarkers and Lifestyle study (AIBL), Alzheimer's Disease Neuroimaging Initiative (ADNI), and Open Access Series of Imaging Studies 3 (OASIS3). 507 cognitively unimpaired adults at baseline, with a baseline Aβ PET < 20 Centiloid (CL) and available longitudinal Aβ PET data. Baseline Aβ PET and plasma Aβ42/40 measurement by mass-spectrometry, followed by 1-6 additional Aβ PET scans every 1.5-3 years. Those < 5 CL were classified as PET- and 5-20 CL as PET At baseline, 283 were Plasma-/PET-, 97 Plasma+/PET-, 76 Plasma-/PET Cognitively unimpaired individuals with abnormal Aβ42/40 are at increased risk for future Aβ PET positivity. In the 5-20 CL subgroup, baseline CL is the main driver of this risk. Combining blood-based pre-screening with PET imaging may help efficiently enrich primary prevention trials. Show less

Impaired synaptic plasticity underlies cognitive impairment as a core pathological substrate. While aerobic exercise represents a significant non-pharmacological intervention for enhancing synaptic plasticity, its precise molecular mechanisms remain incompletely defined. This study investigated whether aerobic exercise ameliorates synaptic plasticity and synaptic loss in Apolipoprotein E homozygous knockout (APOE Show less

Cancer cachexia involves severe skeletal muscle and adipose tissue loss. The role of Apolipoprotein E (ApoE) in adipose remodeling remains unclear. This study investigated ApoE's function in cancer cachexia. We found cachectic patients had decreased plasma ApoE but elevated expression in subcutaneous adipose. In vitro, ApoE knockdown in adipocytes downregulated both lipogenesis and lipolysis genes. In vivo, ApoE Show less

Hemodynamic abnormalities within atherosclerotic plaque regions, particularly localized high shear stress and endothelial dysfunction, present novel targets for intervention by drug delivery systems. In this study, we designed a polysaccharide-based carrier (HF-AF) from fucoidan, featuring a dynamic supramolecular structure. A dynamic supramolecular network was established within this carrier via dynamic supramolecular interactions between hydroxypropyl-β-cyclodextrin and adamantane-methylamine. The anti-inflammatory compound tilianin, formulated into nanocrystals (Til NCs), was then encapsulated to create a shear-responsive nanosystem (HF-AF@Til NCs). The system's primary therapeutic strategy is its response to pathological hemodynamic forces: upon encountering high shear stress at a stenosis, the supramolecular network undergoes dissociation, triggering a mechanically-gated release of the encapsulated Til NCs. This shear-triggered function is complemented by the natural P-selectin affinity of the fucoidan backbone, which facilitates the anchoring of the nanocarrier at the inflamed lesion site. This sophisticated "anchor-and-release" mechanism enables superior drug accumulation precisely at plaque sites. In ApoE Show less