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The disruption of key mechanisms involved in amyloid beta (Aβ) clearance during the early stages of dementia may contribute to the progression of cognitive decline toward irreversible brain damage. In this study, we investigated multiple immune-related pathways implicated in the management and clearance of Aβ within circulating extracellular vesicles (cEVs) and serum from individuals with subjective cognitive decline (SCD) who later progressed to mild cognitive impairment (MCI). A cytokine panel and the levels of Aβ In SCD patients, the concentrations of Aβ Our findings support the potential value of integrating serum M-CSF levels with RAVLT performance and cEVs Aβ Show less

The choroid plexus (CP), known for producing cerebrospinal fluid, is increasingly implicated in the pathogenesis of Alzheimer's disease (AD). Neuroimaging studies document structural CP alterations in aging and AD. One such alteration, calcium deposition, increases with age and is typically considered benign, though the mechanism and clinical significance of CP calcification remain uncertain. Given established association between peripheral vascular calcification and cardiovascular risk, we hypothesized that the volume of calcium within CP would correlate with systemic cardiovascular health. Based on prior findings of APOEε4-specific associations between CP calcium and neurodegeneration, participants were stratified by APOEε4 status, a strong genetic risk factor for AD also implicated in cardiovascular disease. In this retrospective analysis of 105 adults (mean age 58.9 years; 39 APOEε4+), we examined whether CP calcium correlates with cardiovascular risk in cognitively normal adults. CP calcium was quantified using a previously validated MRI-CT method. Spearman correlations assessed the association of CP calcium and Framingham Cardiovascular Risk Score (FCRS), as well as individual cardiovascular risk factors. Overall, CP calcium was not associated with FCRS. Among APOEε4- subjects, CP calcium correlated positively with FCRS ( Show less

Blood-based biomarkers are increasingly used to characterize Alzheimer's disease (AD)-related pathology, yet substantial heterogeneity exists in how biomarker burden relates to cognitive performance. Grip strength, a marker of frailty and functional reserve, may modify this relationship. We conducted a cross-sectional analysis of 348 participants from the Aging Adult Brain Connectome (AABC) study. Global cognition was assessed using the Preclinical Alzheimer Cognitive Composite (PACC). Plasma biomarkers included phosphorylated tau-217 (pTau Show less

This study evaluates plasma-based proteomic profiles for predicting amyloid positivity in adults with Down syndrome (DS) and examines the impact of apolipoprotein E ε4 (APOE ε4) on test performance. Cross-sectional data from 290 adults with DS were analyzed using single molecule array (SIMOA) technology to measure plasma amyloid beta (Aβ)42, Aβ40, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau phosphorylated at threonine 181, and total tau. Amyloid burden was quantified using Pittsburgh Compound B and (18)F-florbetapir Aβ positron emission tomography. Support vector machine analyses were conducted with biomarkers as predictors and age, sex, and APOE ε4 carrier status as covariates. Age, GFAP, and NfL contributed the most to the model performance. The proteomic profile achieved an area under the curve (AUC) of 96% in models with and without APOE ε4. These findings suggest that plasma proteomic biomarkers can effectively identify amyloid positivity in adults with DS and may support clinical triage, monitoring, and selection for clinical trials, independent of APOE ε4 status. Show less

Genetic polymorphisms in cardiovascular disease (CVD) susceptibility across different ethnic groups is highly imperetive. Therefore, it is of interest to investigate the role of genetic polymorphisms in cardiovascular disease (CVD) susceptibility across different ethnic groups. Participants were tested for variations in LDLR, APOE and LPL genes and their association with cardiovascular risk factors such as cholesterol levels and blood pressure was examined. Data shows ethnic differences in the prevalence of these polymorphisms, suggesting that genetic factors contribute to CVD risk in a population-specific manner. Thus, we show the need for personalized cardiovascular risk assessment strategies. The ethnic-specific distribution of genetic polymorphisms (LDLR, APOE and LPL) linked to cardiovascular disease susceptibility, highlighting the need for personalized cardiovascular risk assessment strategies based on genetic and ethnic factors is highlighted. Show less

Disruption of brain glucose and lipid metabolism contributes to Alzheimer's disease (AD) and often emerges before clinical symptoms. Women are at elevated AD risk due to menopause-associated estrogen decline, which impairs mitochondrial function and glucose metabolism. Women's risk of AD is further elevated by the APOE4 allele, the strongest genetic risk factor for late-onset AD. To investigate the impact of APOE3/3 mice exhibited dynamic regulation of brain metabolic systems that supported postmenopausal bioenergetic demand. In contrast, APOE3/4 and APOE4/4 mice displayed accelerated and altered metabolic shifts, resulting in postmenopausal amino acid depletion, reduced tricarboxylic acid (TCA) cycle intermediates, lipid accumulation, and alterations in brain lipid composition. A single APOE4 allele was sufficient to impair metabolic adaptation, while APOE4 homozygosity resulted in greater severity of deficits. Outcomes of these analyses revealed that APOE4 accelerated menopause-related metabolic decline and compromised bioenergetic adaptation, providing a mechanistic basis for increased AD susceptibility and earlier onset in APOE4-positive women. Show less

While the apolipoprotein E (APOE) ε4 allele is a major risk factor for Alzheimer's disease (AD), the role of translocase of outer mitochondrial membrane 40 (TOMM40)-an adjacent gene involved in mitochondrial protein import-is not known. Human brain tissue, human induced pluripotent stem cell-derived neurons (iNeurons), and mice were used for study of gene expression, cholesterol metabolism, mitochondrial function, and animal cognition. Human brain transcriptomics showed reduced TOMM40 expression that correlated with cholesterol regulatory gene expression, amyloid burden, and clinical AD diagnosis. In human iNeurons, TOMM40 knockdown (KD) disrupted mitochondria-endoplasmic reticulum contact sites (MERCs), causing mitochondrial dysfunction and promoting reactive oxygen species that led to activation of liver X receptor beta (NR1H2), upregulation of APOE and low-density lipoprotein receptor (LDLR), and increased cellular cholesterol and amyloid beta (Aβ)42 independent of APOE ε4. Consistently, Tomm40 KD in mice induced increased brain cholesterol, Aβ42 content, and impaired memory. TOMM40 is a novel mediator of AD pathology through dual effects on MERCs that regulate cholesterol homeostasis and mitochondrial function. Show less

Anti-amyloid-β (Aβ) therapies are reshaping Alzheimer's disease (AD) management. Understanding changes in real-world patterns of diagnostic testing and infusion chair usage is essential for optimizing access to care. Retrospective analysis of Mayo Clinic enterprise electronic health records (Jan 2019-Mar 2025) assessed trends in AD-relevant brain imaging, fluid biomarkers, apolipoprotein E (APOE) testing, and lecanemab infusions. Rates of amyloid-beta (Aβ) positivity by sex and age, APOE genotype frequencies, and lecanemab treatment initiation and discontinuation were evaluated. Following national insurance coverage changes, lecanemab infusions grew by 110 infusions per quarter to 605 in Q1 2025. Aβ positron emission tomography scans increased (+22/quarter), cerebrospinal fluid biomarker orders declined (-25/quarter), and plasma p-tau The adoption of anti-Aβ therapies coincided with a rapid shift in diagnostic workflows. Show less

Alzheimer's disease (AD) heterogeneity complicates early detection and trial design. Scalable predictors may aid risk stratification. We assessed whether scalable baseline plasma biomarkers and neuropsychological measures predict 5‑year cognitive and functional decline in cognitively unimpaired older adults. We analyzed 866 amyloid-positive participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial and 343 amyloid-negative individuals from the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. Decline was defined as a ≥0.5 increase in Clinical Dementia Rating-Global Score over 240 weeks. The separate and joint value of demographics, apolipoprotein E ( The p-tau217 and PACC significantly improved prediction. Full models achieved areas under the curve (AUCs) of 0.78-0.80 across cohorts. Additional plasma biomarkers offered modest AUC gains (1%-3%). The p-tau217 and PACC enhanced prediction of preclinical decline, supporting their utility in early identification and trial enrichment in AD. Show less

To determine whether long-term residential air pollution [AP; ozone (O₃) and fine particulate matter (PM₂.₅)] is associated with (1) incident mild cognitive impairment (MCI) or Alzheimer’s disease (AD), (2) biomarkers of core and AD-relevant pathology, and (3) whether these relationships are moderated by APOE4+/- (carrier/non-carrier of one or both ε4 alleles) status or mediated by neuroinflammation. Sample included 795 participants (Mage 68.7 ± 7.9; 68% female) from the Wisconsin Alzheimer’s Disease Research Center and Wisconsin Registry for Alzheimer’s Prevention parent studies, both enriched for AD risk at enrollment based on parental AD history. Residential zip code and 2009–2021 EPA-based annual AP reports were used to estimate individual exposure. Cox proportional hazards models assessed MCI/AD risk. Linear regressions examined the relationships between AP exposure and biomarkers of core and AD-relevant pathology, with and without APOE4 + stratification. Causal mediation analysis examined whether markers of inflammation mediated the AP-AD pathology relationships. Neither O₃ nor PM₂.₅ exposure predicted MCI/AD incidence nor core AD pathology (Ps > 0.05). Higher PM₂.₅ was associated with higher CSF GFAP levels ( 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

Calcific aortic valve disease (CAVD), the most common human valve disease on a global scale, ranks and persists as an unaddressed clinical challenge. This is primarily attributed to the absence of efficacious pharmacological approaches. The Nuclear Receptor Subfamily 4 Group A Member 1 (NR4A1), intricately associated with the pathogenesis of multiple cardiovascular diseases, has emerged as a pivotal target for the diagnosis and treatment of numerous ailments. However, the specific molecular mechanisms and the functional significance of NR4A1 in the pathogenesis of CAVD are yet to be comprehensively elucidated. By performing in-depth analyses on human aortic valve tissues and carrying out functional investigations using primary valvular interstitial cells (VICs), we were able to demonstrate that NR4A1 significantly facilitated cellular proliferation and intensifies the osteogenic differentiation process of VICs. Evidently, this is reflected in the elevated expression of key osteogenic markers, namely runt-related transcription factor 2 (RUNX2) and alkaline phosphatase (ALP). Mechanistically, the pro-calcific effects were achieved via NR4A1-dependent modulation of the cell cycle regulatory protein Cyclin D2 (CCND2). Significantly, Show less

The olfactory system is an early target in Alzheimer's disease (AD), yet regional glial pathology interactions remain poorly defined. We examined how glial activation and pathological burden differ between the olfactory cortex (OC) and olfactory bulb (OB) across disease stages. Post mortem OC and OB samples from cognitively normal (CN), mild cognitive impairment, and AD cases were analyzed using immunohistochemistry and immunofluorescence for amyloid beta (Aβ), phosphorylated tau (pTau), Iba1 (microglia), GFAP (astrocyte), and apolipoprotein E (apoE). Both regions showed stage-dependent increases in Aβ and pTau, with regionally distinct glial responses. ApoE signal varied with clinical stage rather than genotype. Co-expression analyses revealed astrocyte-linked networks in the OC and microglia-linked relationships in the OB. Findings demonstrate spatially heterogenous glial pathology architectures in the human olfactory system, supporting its role as an early and regionally diverse site of AD vulnerability. Show less

Although clinical trials have suggested a lower incidence of adverse events associated with Lecanemab in Asian populations compared to global cohorts, longitudinal real-world data across broader clinical indications are necessary to confirm these findings in routine practice. This study aimed to provide real-world evidence regarding the safety profile of Lecanemab in Japanese patients in a clinical setting. A real-world observational study with a follow-up period of up to 18 months. A single center in Japan. We included 120 Japanese patients who received Lecanemab between December 2023 and November 2025 and underwent at least one brain MRI before the fifth infusion. Safety outcomes included amyloid-related imaging abnormalities (ARIA), infusion-related reactions (IRRs), and treatment discontinuation. The mean age was 74.2 ± 7.9 years, and 89 (74%) were female. The majority of patients (88%) had a baseline CDR global score of 0.5. During follow-up, 81 patients completed the 12-month assessment. ARIA occurred in 24 patients (20%); ARIA-E with or without ARIA-H occurred in 5 patients (4%), and isolated ARIA-H occurred in 19 patients (16%). Crucially, no patients experienced symptomatic ARIA. All patients with ARIA-E who had available APOE data were ε4 carriers. Patients with ARIA had significantly lower baseline MMSE scores (p = 0.04), alongside non-significant trends toward higher plasma GFAP levels (p = 0.11) and higher deep white matter Fazekas scores (p = 0.05). IRRs occurred in 34 patients (28%), all of which were mild. Treatment was discontinued in 19 patients (16%), mainly due to disease progression (n = 8). In this Japanese AD cohort, Lecanemab demonstrated a manageable safety profile in a real-world setting. In exploratory analyses, potential trends toward a higher frequency of ARIA were observed in patients with lower MMSE scores, higher plasma GFAP levels, and higher Fazekas scores, underscoring the importance of individualized risk assessment prior to therapy. 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

Cutaneous squamous cell carcinoma (cSCC) involves complex immune interactions. This study aimed to identify a T cell-related gene signature to characterize the immune landscape and aid in molecular diagnosis. We integrated single-cell RNA sequencing (scRNA-seq) and five bulk microarray datasets, utilizing an independent RNA-seq cohort for external validation. Feature genes were identified from the intersection of scRNA-seq-defined T cell-related genes (TRGs) and bulk differentially expressed genes using machine learning. A diagnostic nomogram was constructed, and its performance was assessed via ROC curves. In addition, immune infiltration, immunofluorescence staining, drug interactions, and clinical expression (qRT-PCR) were evaluated. Screening yielded 28 T cell-related DEGs enriched in extracellular matrix functions. machine learning selected a core signature: APOE, CYBA, and S100A2. The diagnostic model demonstrated high diagnostic performance in the studied cohorts (AUC > 0.9) across training and external validation cohorts. Clinically, qRT-PCR supported significant upregulation of CYBA and S100A2. APOE exhibited distinct immunomodulatory connectivity, correlating positively with Th17 cells and negatively with Tregs, whereas CYBA and S100A2 were associated with Treg infiltration. Immunofluorescence results revealed significantly elevated levels of S100A2 and Foxp3 in cSCC tissues compared to the control group. Pharmacogenetic analysis highlights the association of these genes, particularly the APOE gene, with drug response. This T cell-associated signature highlights the potential link between molecular diagnosis and immune characterization. Specifically, CYBA and S100A2 are identified as promising diagnostic candidate signatures, while APOE may reflect immunomodulatory heterogeneity. These findings offer insights for developing diagnostic strategies and targeted immunotherapies in cSCC. Show less

Alzheimer's disease (AD) is one of the most pressing public health challenges in an aging world. However, effective therapeutic strategies are still lacking. Imbalance in lipid homeostasis is a key driver of AD. Given the established link between dysregulated lipid metabolism and amyloid-beta (Aβ) aggregation, we investigated whether chicoric acid (CA), a dietary polyphenol with reported lipid-modulating properties, could mitigate Aβ pathology by modulating lipid metabolism in 5xFAD transgenic mice. In the brain, we found that CA upregulated the expression of liver X receptor Beta (LXR-β) and ATP-binding cassette transporter A1 (ABCA1) in 5xFAD mice. Through this pathway, it promoted apolipoprotein E (ApoE) lipidation and enhanced the expression of Aβ-clearance proteins (IDE and LRP1). Notably, in the periphery, CA reshaped the gut microbiota in 5xFAD mice, which reduced serum neurotoxic bile acid levels and preserved the integrity of the peripheral Aβ clearance system. Together, our study first demonstrated that CA globally regulated lipid homeostasis to alleviate Aβ pathology by coordinating cerebral cholesterol efflux with peripheral bile acid metabolism. The findings facilitated exploring active compounds from traditional Chinese medicine that may reduce Aβ deposition by targeting lipid metabolism pathways. Show less

Social isolation (SI) is an established risk factor for Alzheimer's disease (AD) and cognitive decline. However, its stage-specific effects across the AD continuum, particularly at subjective cognitive decline (SCD) and mild cognitive impairment (MCI) stages, remain unquantified in Chinese populations. The sex-specific effects of SI on cognitive decline remain incompletely characterized. The apolipoprotein E ( To investigate social connection characteristics and gene distribution in individuals with SCD or MCI, examine their cross-sectional associations with cognitive function, and explore gender differences in SCD or MCI risk/prevention. A community-based sample of 164 SCD and 84 MCI patients (July 2021-Dec 2024) was assessed. Demographic, social connectivity, LSNS-6 scores showed weak-to-moderate correlations with Montreal Cognitive Assessment ( SI may exacerbate cognitive dysfunction in adults with SCD or MCI. Women leverage social connectivity into significantly greater neuroprotective gains compared to men. ChiCTR2300073429. https://www.chictr.org.cn/bin/project/edit?pid=200381. Show less

Rheumatoid arthritis (RA) is a chronic inflammatory joint disorder in which macrophages play crucial roles. Given macrophage heterogeneity, novel biomarkers are needed for timely diagnosis and severity assessment. This study aimed to identify macrophage-specific hub genes in RA and investigate their biological functions. Bulk and single-cell RNA-seq datasets were downloaded from the Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) in RA synovial macrophages were identified from the GSE97779 dataset using the Limma R package. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to determine the biological processes and pathways associated with the DEGs, followed by Gene Set Enrichment Analysis (GSEA) for further validation. Hub genes were identified using the STRING database and Cytoscape. Based on the single‑cell dataset GSE192504, cell clusters were annotated with Seurat to determine macrophage‑specific hub genes, whose associated biological processes were explored via gene set variation analysis (GSVA). Further sub‑clustering revealed distinct macrophage subtypes. Finally, immunofluorescence staining was performed to identify molecular markers of macrophage subtypes, while RT-qPCR and ELISA were used to validate the mRNA and protein expression of macrophage-specific hub genes in in vitro experiments. We identified 334 DEGs enriched in immune-related pathways. Ten hub genes ( Show less

In our previous study, we identified Niemann-Pick C1 like intracellular cholesterol transporter 1 (NPC1L1) as a key contributor in lipid oxidative stress during atherosclerosis (AS) progression. However, the regulation mode of its expression and the specific approaches by which it functions in lipid oxidative stress are still unclear. HUVECs and macrophages were treated with oxidized low-density lipoprotein (ox-LDL) to induce endothelial cell injury. First, the effects of the RNA binding proteins IGF2BP1 and poly (A) binding protein cytoplasmic 1 (PABPC1) on the stability of NPC1L1 mRNA was evaluated. The interaction between NPC1L1 and cytochrome P450 family 11 subfamily A member 1 (CYP11A1) was analyzed using Co-IP, and the co-localization of the two was detected using immunofluorescence. Combined with qPCR, Western blotting, CCK8, ferroptosis-related index and mitophagy-related index determination were performed to evaluate the expression of CYP11A1 in ox-LDL-treated HUVECs and its role of ferroptosis and mitophagy. Subsequently, pcDNA-NPC1L1 or CYP11A1 siRNA were individually or altogether transfected into ox-LDL-treated HUVECs to verify the involvement of CYP11A1 in NPC1L1-mediated ferroptosis and mitochondrial oxidative stress. Finally, ApoE-/- mice were fed with high-fat diet to establish an AS model in vivo and sh-NPC1L1 and/or Ad-CYP11A1 were injected via tail vein to verify the therapeutic effect of NPC1L1 knockdown on AS and reversal effect of CYP11A1. Either knockdown of IGF2BP1 or PABPC1 reduced NPC1L1 mRNA stability. Mechanistically, NPC1L1 interacted with CYP11A1 and promoted CYP11A1 protein expression. CYP11A1 was upregulated in ox-LDL-treated HUVECs and overexpression of CYP11A1 induced ferroptosis by activating excessive mitophagy, and knockdown of CYP11A1 reversed the promotion of NPC1L1 on mitophagy and ferroptosis in ox-LDL treated HUVECs. In vivo, injection of the sh-NPC1L1 lentiviral vector inhibited AS progression, while injection of the LV-CYP11A1 lentiviral vector attenuated the protective effect of sh-NPC1L1 on AS. PABPC1 and IGF2BP1 synergistically stabilized NPC1L1 mRNA, and NPC1L1 interacted with CYP11A1 to induce endothelial mitophagy and ferroptosis during AS. Show less

Psoriasis vulgaris (PV) is a chronic inflammatory skin disease increasingly recognized as a systemic disorder with potential cognitive implications. Amyloid beta (Aβ) and apolipoprotein E (APOE) are key proteins involved in Alzheimer's disease (AD) and neurodegeneration. This study investigated the relationship between PV, cognitive function, and serum levels of Aβ and APOE4. This case-control study was conducted on 80 participants: 50 PV patients and 30 age- and sex-matched controls. Clinical assessments included Psoriasis Area and Severity Index (PASI). Depression severity was assessed with Beck Depression Inventory-II (BDI-II), while cognitive function was evaluated using Montreal Cognitive Assessment (MoCA). Serum APOE4 and Aβ levels were measured using ELISA. Patients with PV exhibited significantly higher levels of APOE4 (1125.5 ± 232.1 ng/ml vs. 821.8 ± 266 ng/ml, P<0.001) and Aβ (21.4 ± 2.2 ng/ml vs. 18.7 ± 1.4 ng/ml, P<0.001) compared to controls. ROC analysis identified APOE4 (AUC=0.80, P<0.001) and Aβ (AUC=0.86, P<0.001) as significant predictors of PV. MoCA scores were significantly lower in PV patients (median=22 vs. 28, P<0.001), particularly in those with severe disease. APOE4 and Aβ levels negatively correlated with cognitive function (r= -0.418, P=0.003), and (r= -0.399, P=0.004) respectively. PV is associated with elevated Aβ and APOE4 levels, potentially linking chronic inflammation to neurodegeneration. The observed cognitive dysfunction in PV individuals underscores the importance of integrating neurological assessments into routine clinical evaluations. Show less

According to existing research findings, dihydroartemisinin effectively regulates bone metabolism balance, while ferroptosis is closely related to the occurrence of steroid-induced osteonecrosis of the femoral head. As the exact biological mechanism among the three is still unclear, Mendelian randomization, computer-aided drug design, and transcriptomics sequencing were used to explore the specific mechanism of action. The study validated the specific signaling pathways through which dihydroartemisinin may treat steroid-induced osteonecrosis of the femoral head using animal experiments and transcriptomics sequencing. Data were obtained from public databases for Mendelian randomization analysis, and a two-sample Mendelian randomization was used to determine the intermediary role of core pathway-related targets. Computer-aided drug design was employed to assess the binding affinity between dihydroartemisinin and core targets. Transcriptome sequencing determined that dihydroartemisinin may treat steroid-induced osteonecrosis of the femoral head by regulating ferroptosis. We obtained 564 ferroptosis-related targets that met the analysis criteria and 1812 plasma proteins from the UK Biobank, and analyzed finngen_R11_OSTEON_DRUGS in the Finnish database as outcome. The results showed that there were two quantitative trait loci that had a causal relationship with ferroptosis targets. There were 110 protein quantitative trait loci causally associated with plasma proteins from the UK Biobank, and none of these loci had an inverse causal relationship with SONFH. Through mediation analysis, 7 mediating pathways were identified, yielding eight targets including ZP3, CCL17, APOE, C7ORF50, SPINK4, SPINK2, FTMT, and PRDX6. Computer-aided drug design revealed that CCL17 and PRDX6 exhibited the best docking effects. The study determined that CCL17 and PRDX6 have a significant causal relationship with SONFH. It also clarified the specific mechanism by which DHA may regulate ferroptosis to treat SONFH, which will provide a reference for the discussion of the prevention and treatment mechanisms of SONFH. Show less

Although traditional rehabilitation training can partially improve motor function in patients with post-stroke motor disorders, its impact on neural plasticity remains limited. Transcutaneous auricular vagus nerve stimulation (taVNS), a non-invasive method targeting the auricular branch of the vagus nerve, represents a promising neuromodulatory approach. This prospective study aimed to assess the therapeutic effects of taVNS on functional recovery in this population. A total of 147 patients with post-stroke motor disorders were consecutively enrolled between February 2023 and November 2024. After excluding 8 dropouts, 139 patients were randomly assigned via a random number table to either an electrical stimulation group (taVNS group) or a rehabilitation group (conventional training). The taVNS group initially included 73 patients, with 3 dropouts yielding a final sample of 70. The rehabilitation group initially included 74 patients, with 5 dropouts resulting in 69 participants. All participants underwent comprehensive assessments at baseline and following a 4-week intervention period. Outcome measures encompassed neuroelectrophysiological parameters (motor evoked potential latency and amplitude), clinical functional evaluations (Action Research Arm Test, Fugl-Meyer Assessment for Upper Extremity, Modified Barthel Index), serum biomarker levels (brain-derived neurotrophic factor, S100 calcium-binding protein β), and systematic documentation of adverse events. Based on post-treatment Fugl-Meyer Assessment-Upper Extremity (FMA-UE) scores, patients were further categorized into improvement and non-improvement subgroups for additional comparative analysis. Pearson correlation analysis was utilized to examine potential relationships between functional scores, neurophysiological data, and biomarker concentrations. Baseline characteristics were comparable between groups ( taVNS is an effective and safe adjunctive therapy for post-stroke motor recovery. It enhances neuroelectrophysiological function, improves motor and daily living abilities, and favorably modulates biomarkers of neural injury and repair. The consistent correlations among functional, neurophysiological, and biochemical outcomes highlight an integrated recovery pathway, supporting the integration of taVNS into standard neurorehabilitation protocols. Show less

β-amyloid (Aβ) inhibition significantly attenuates the early-stage Alzheimer's disease (AD) progression, but the improvement in cognitive function remains limited by neuroinflammation. Here, we developed a bioinspired neuroenhancer that concurrently targets both Aβ aggregation and neuroinflammation. Rutin and small interfering RNA targeting beta-site amyloid precursor protein cleaving enzyme 1 (siBACE1) were co-loaded into the calcium phosphate core, which was further coated with lipid bilayers and Angiopep-2/rabies virus glycoprotein 29 peptides to form the multifunctional neuroenhancer (RB@LCP-AR). RB@LCP-AR not only releases siBACE1 to silence BACE1 expression and block Aβ production from the cleavage of amyloid precursor protein, but also releases Rutin to suppress the Aβ aggregation. Moreover, the released Rutin of RB@LCP-AR directly alleviates Aβ-induced mitochondria dysfunction and intracellular ROS production in neuronal cells. Notably, the targeting of RB@LCP-AR to neurons and the inhibition of Aβ reduce the microgliosis and astrogliosis, further alleviating neuroinflammation and synapse loss. Consequently, AD mice receiving RB@LCP-AR treatment efficiently recovered their memory and cognition. Our study thus provides a coordinated targeting of Aβ and neuroinflammation inhibition, holding considerable potential to promote the recovery of memory and cognition in AD. Show less

Pathological progression in sporadic Alzheimer's disease (sAD) initiates with an early rise in soluble amyloid-β (Aβ), preceding plaque formation and neurodegeneration. However, the molecular event triggering this initial accumulation remains unknown. We report that phosphoglycerate dehydrogenase (PHGDH), a consistent biomarker of prodromal sAD, drives Aβ production through a previously unrecognized RNA-binding function. Specifically, PHGDH binds the 3'UTR of Show less

Amyloid-β (Aβ) plays a critical role in Alzheimer's disease (AD) and its accumulation in the brain is pivotal to disease progression and precedes memory and neuronal loss. Besides the severely handicapping brain symptoms, AD patients display early gastro-intestinal (GI) manifestations such as upper and lower GI dysmotility, in particular constipation. Although there is increasing evidence of Aβ accumulation in the gut, its pathogenic effects on enteric nervous system (ENS) connectivity and gut function as well as underlying pathophysiological mechanisms are poorly understood. Furthermore, studies have reported a gut to brain transmission of Aβ that causes memory deficits in mice. Therefore, identifying therapeutics which can reduce Aβ accumulation in the gut at an early stage of the disease could have the advantage of slowing or even reversing disease progression before severe alterations or irreversible damages at both intestinal and brain levels. Hence, in this study, we investigated the capacity of the short-fatty acid butyrate to restore Aβ-driven alteration of ENS connectivity and gut-brain functions in the SAMP8 mouse model of AD. Here we show that SAMP8 mice display a gut amyloid pathology, an alteration of ENS connectivity and gut defects prior to memory decline. BACE1, an Aβ-producing enzyme, expression and activity are increased whereas neprilysin, an Aβ-degrading enzyme, is decreased in the gut of SAMP8 mice, indicating a rise in the Amyloid Precursor Protein (APP) holoprotein processing and a reduction of Aβ clearance which promote an amyloidosis. In primary ENS cultures, Aβ causes a degradation of synaptic-associated proteins EphB2 and synaptophysin, leading to an alteration of ENS connectivity. In wild-type mice, intra-colon delivery of Aβ alters ENS connectivity and causes subsequent GI symptoms, recapitulating the phenotype of the SAMP8 mouse model of aging and AD. Moreover, Aβ impairs ENS connectivity in human induced pluripotent stem cell (iPSC)-derived intestinal organoids and explant cultures of human colon, indicating that Aβ causes ENS lesions in models of the human gut. Butyrate, a short-chain fatty acid derived from bacterial metabolism, reduces Aβ secretion and preserves enteric neuronal connectivity in vitro and in vivo, and blocks Aβ accumulation in the gut, brain and plasma in SAMP8 mice. In addition, butyrate ameliorates neuroinflammation and prevents gut dysfunction and memory deficit. Collectively, these findings suggest that Aβ promotes gut symptoms through alteration of ENS connectivity and butyrate counteracts these impairments with an amelioration of neuroinflammation and memory function in AD model. Show less

Small dense low-density lipoprotein (sdLDL) is a highly atherogenic LDL subclass associated with cardiovascular disease (CVD). While type 1 diabetes confers increased cardiovascular risk despite adequate glycemic control, the role of sdLDL and its regulators remains unclear. In this cross-sectional observational study, plasma from 69 individuals with long-standing type 1 diabetes and 24 healthy controls was analyzed. sdLDL-cholesterol (sdLDL-C) concentration, sdLDL-C/LDL-cholesterol ratio, LDL size and subclasses were assessed using homogeneous assays, NMR spectroscopy, and gradient gel electrophoresis. Apolipoprotein C3 (ApoC3), hepatic lipase (HL), endothelial lipase (EL), and cholesteryl ester transfer protein (CETP) activity were measured by immunoturbidimetric, ELISA and functional assays. Despite adequate glycemic control (mean HbA1c 7.6% [60 mmol/mol]) and near-normal lipid levels, individuals with type 1 diabetes had significantly higher sdLDL-C (0.56 ± 0.28 mmol/L vs 0.43 ± 0.26 mmol/L), increased sdLDL-C/LDL-cholesterol ratio (0.20 ± 0.08 vs 0.12 ± 0.06) and smaller LDL particle size (26.32 ± 1.08 nm vs 26.81 ± 0.68 nm) compared with controls. ApoC3 and HL mass/activity were significantly increased (8.67 ± 3.22 mg/dL vs 6.53 ± 2.42; 46.60 ± 16.12 ng/mL vs 15.45 ± 7.40 ng/mL and 1.03 ± 0.24 U/mL vs 0.89 ± 0.23 U/mL; respectively), CETP activity significantly reduced (808.8 ± 197.0 pmol/mL/h vs 929.7 ± 149.6 pmol/mL/h), and endothelial lipase levels unchanged. sdLDL-C positively correlated with ApoC3 (r = 0.7517) and inversely with CETP activity (r = -0.2682). Long-standing type 1 diabetes with adequate glycemic control is associated with an atherogenic sdLDL profile despite near-normal conventional lipid levels. This first multi-method characterization study of sdLDL in type 1 diabetes highlights the contribution of ApoC3, CETP and HL to sdLDL-C enrichment and suggests that direct assessment of sdLDL may improve cardiovascular risk stratification. Show less

Neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis (ALS), represent a growing global health challenge characterized by progressive neuronal loss and a lack of definitive disease-modifying treatments. This review explores the emerging potential of targeting non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and exosomal RNAs, to modulate pathogenic molecular pathways and address the underlying molecular origins of neurodegeneration. We evaluate the integration of advanced computational techniques for RNA structure prediction and gene regulatory network analysis, alongside chemical engineering strategies-such as Locked Nucleic Acids (LNAs) and phosphorothioate modifications-aimed at enhancing the stability and specificity of RNA-based molecules. Furthermore, we analyze cutting-edge delivery and editing technologies, including nanotechnology-driven solutions for precise neuronal targeting and the CRISPR/Cas13 system for direct ncRNA manipulation.The findings indicate that while challenges in delivery efficiency and long-term efficacy persist, the synergy of chemical engineering and computational modeling significantly improves the therapeutic profile of ncRNAs, with exosomal pathways offering a novel route for intercellular signaling modulation and biomarker discovery. Therapeutic interventions directed at specific clinical targets, such as miR-34a and BACE1-AS, demonstrate the capacity to influence protein aggregation and neuroinflammatory cascades. Although ncRNA-based therapies are currently in nascent stages, ongoing technological advancements in RNA editing and nanotechnology offer a transformative framework that could redefine the future of ND treatment and successfully halt disease progression rather than merely managing symptoms. Show less

Prostate cancer (PCa) cells are known to heavily depend on lipids to support their growth. We hypothesized that hyperlipidemic factors, for which inhibitors are already available and used to treat cardiovascular disease, would be dysregulated in metastatic PCa (mPCa). The goal of this case-control study, including 35 men per group, was to compare the levels of PCSK9, ANGPTL3, Apo CIII, leptin, and the lipid profile in patients with mPCa versus localized Gleason 8/9 PCa (lPCa) and patients at risk of developing PCa (controls). Protein levels were assessed using ELISAs, while lipids were measured using the Roche Cobas analytical platform. The following circulating analytes were higher in mPCa: triglycerides (in mmol/L; controls 1.7 ± 1.2, lPCa 1.5 ± 0.7, mPCa 2.3 ± 1.2, In this cohort of men, whole-body lipid metabolic rewiring is a feature restricted to the metastatic phase of prostate cancer, suggesting it may play a significant role in the progression toward more aggressive cancer forms. Given the availability of drugs targeting ANGPTL3 and Apo CIII, the therapeutic potential of these drugs should be evaluated in metastatic PCa. Show less