👤 Yu-Wen Cheng

The effects of lipid traits on colorectal cancer (CRC) risk and the extent to which obesity may modify these effects remain unclear. To examine the associations between lipid traits and CRC risk using an observational study and Mendelian randomization (MR) analyses, and the role of weight status in the potential associations. In the Guangzhou Biobank Cohort Study (GBCS), lipid profiles were measured during 2003-2008, and CRC events were identified through record linkage with the cancer registry. MR analyses assessed the causal effects of lipid traits on CRC using a genome-wide association study meta-analysis of 185,616 Europeans. Among 28,576 GBCS participants followed until 2020, 599 CRC events occurred. Participants in the highest quartile of apolipoprotein B (apoB) had a higher CRC risk (hazard ratio [HR] 1.43, 95% CI 1.02-2.01). This association remained in those with overweight/obesity (HR 2.21, 95% CI 1.28-3.83). MR analyses supported a detrimental effect of apoB on CRC (odds ratio 1.12 per 1 SD, 95% CI 1.02-1.22). MR analyses also showed positive associations for total cholesterol and the apoB/apolipoprotein A-I ratio, which were not significant in the observational study. Higher apoB levels were associated with an increased CRC risk in both observational and MR analyses, suggesting a potential role of apoB in CRC prevention, especially among participants with overweight/obesity. However, the limitations of single-time lipid measurements and the use of different ancestries across study designs indicate the need for further research to confirm the robustness and generalizability of the findings. Show less

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

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

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

Atherosclerotic cardiovascular disease remains the leading cause of global mortality, with hypercholesterolemia serving as a critical driver of atherogenesis. Although current lipid-lowering therapies substantially improve circulating lipid profiles, strategies that provide more durable, safe, and efficient control of lipid metabolism are still needed. Epigenome editing offers a promising approach for long-lasting repression of disease-modifying genes without altering the underlying DNA sequence. Here, we develop CRISPRoff platforms delivered by adeno-associated virus or lipid nanoparticle to epigenetically silence hepatic Hmgcr or Pcsk9 in vivo. In both C57BL/6J wild-type and ApoE 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

Alzheimer's disease (AD) is an irreversible neurodegenerative disease defined by its molecular hallmarks - amyloid beta peptide plaques and neurofibrillary Tau tangles. Despite significant progress that has been made in uncovering a large number of genetic risk factors through extensive genomic sequencing and genetic studies, the molecular mechanisms driving AD-associated pathology and cognitive decline remain poorly understood. Therefore, alongside the identification of more risk genes, it is also paramount to study how these genes function and influence each other within the cellular pathways and overall molecular networks in AD-relevant brain cell types. However, current human protein-protein interactome datasets were all generated in either yeast or generic human cell lines. Consequently, many important neuronal interactions, especially neuron-specific ones, have yet been discovered. To address this critical gap, we developed a highly scalable, high-quality interactome mapping pipeline in human excitatory neurons derived from induced pluripotent stem cells (iPSC), and generated a comprehensive, neuron-specific interactome map, named ADNeuronNet, for key AD risk genes. ADNeuronNet consists of 1,767 high-confidence interactions among 1,189 proteins and is the only dataset enriched with neuron-specific genes when compared to known protein interactions, including previous large-scale interactome maps, for the same baits in the literature. Within ADNeuronNet, we identified 1,375 novel interactions, many of which are likely neuron specific. For example, we identified a neuron-specific interactor, RIN2, for major AD risk factor BIN1 and confirmed RIN2's function in recruiting BIN1 to RAB5 positive early endosomes, a process that has been well-associated with AD etiology. Additionally, we performed quantitative interaction perturbation analyses on AD risk genes with AD-associated mutations or isoforms and identified significant changes in 99 protein interactions among 11 different protein variants. Finally, we found that subunits from the anaphase-promoting complex/cyclosome (APC/C), another novel BIN1 interactors identified by ADNeuronNet, mediated modulation of Tau-aggregation in neurons via regulation of APOE expression, uncovering a previously unrecognized BIN1-APC/C-APOE regulatory axis in AD pathobiology. In summary, these findings illustrate how our neuron-specific ADNeuronNet can be leveraged to uncover new risk gene candidates and cellular pathways that help advance our understanding of molecular mechanisms underlying AD etiology. Show less

Decline in pulmonary function (PF) and respiratory muscle strength (RMS) is influenced by environmental and genetic factors and is inconsistently linked to cognitive outcomes. This study explores the associations between PF, RMS, and cognitive function among community-dwelling older adults in China, analyzing interactions with APOE Ɛ4 and the mediating effect of serum total bilirubin. About 1,081 Hubei Memory and Aging Cohort (HMACS) participants underwent PF (PEF, FEV1 and FVC), RMS (MIP and MEP) assessment, cognitive tests, APOE genotyping, and bilirubin measurement. Multivariate logistic regression and general linear regression were used to analyze associations. Among 1,081 participants (mean age 70.52 ± 5.55 years), 26.1% had cognitive impairment. Lower PF and RMS scores were associated with cognitive impairment. Higher comprehensive PF (c-PF) and RMS indices protected against cognitive impairment (eg, c-PF: OR = 0.482-0.609, PF (especially PEF) and RMS (especially MEP) indices are significantly associated with cognitive function and impairment in older adults, independent of APOE Ɛ4 status. These findings provide biomarkers for assessing cognitive health risk and a basis for interventions targeting PF and RMS to preserve cognitive function. Show less

Our previous study demonstrated that a 6-month combined physical and cognitive training program improved mismatch negativity (MMN)—an event-related potential reflecting the brain’s automatic detection of environmental changes—in older adults with subjective cognitive decline (SCD). However, not all individuals benefited equally from the intervention. Identifying baseline predictors of intervention outcomes could enable the prediction of individual responsiveness and support the development of personalized, stratified intervention strategies to promote brain health in this at-risk population. This study aimed to identify baseline predictors of response to a 6-month combined cognitive and physical training program among older adults with SCD. We conducted a secondary analysis of a cluster-randomized trial involving 33 older adults with SCD who participated in twice-weekly integrated training sessions. MMN was assessed for the analytic sample ( Regression analysis indicated that APOE ε4 non-carriers showed significantly greater improvement in MMN amplitude (β = ‒0.449, APOE ε4 carrier status and baseline physical activity levels may be associated with the effectiveness of multidomain interventions in older adults with SCD. The online version contains supplementary material available at 10.1186/s12877-026-07270-8. Show less

Vitiligo pathogenesis involves progressive melanocyte loss and keratinocyte dysfunction, which are driven primarily by oxidative stress resulting from excessive ROS accumulation. We engineered a temporally controlled hydrogel microneedle system that integrates ginseng-derived exosomes (G-Exos) with biomimetic polydopamine nanoparticles (PDA@PEGs) to concurrently target the pathogenic triad of vitiligo, including oxidative stress, inflammation, and melanocyte deficiency. This system employs methacrylated hyaluronic acid (HAMA) hydrogel microneedles for rapid PDA@PEG release while utilizing glyceryl monostearate micelles to achieve matrix metalloproteinase-9 (MMP-9)-responsive G-Exo release at inflammatory foci, enabling intelligent spatiotemporal control. Functionally, G-Exos help restore redox homeostasis and suppress inflammation through bioactive constituents, thereby protecting melanocytes and enhancing keratinocyte proliferation. Moreover, PDA@PEG promotes repigmentation through the dual mechanisms of exogenous melanin deposition and endogenous melanogenesis stimulation. In murine models, this strategy achieves significant repigmentation within 3 weeks by activating follicular stem cells, upregulating melanogenic markers (Tyr/Mc1r), increasing antioxidant defense (ApoE), and suppressing inflammatory signaling (IL-17). This natural-biomimetic hybrid design leverages biocompatible materials to co-target multiple pathological axes, offering a novel self-adaptive approach for microenvironmental rehabilitation in vitiligo. 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

The presence of a blood-brain barrier (BBB) prevents the delivery of most drugs to the brain. This characteristic limitation poses a major challenge to effective pharmacological treatment for numerous neurodegenerative diseases, particularly Alzheimer's disease. Delivering small interfering RNA (siRNA) via nanoparticles represents a highly promising approach for treating Alzheimer's disease. Nevertheless, developing a safe and efficient siRNA delivery system remains challenging. To enhance brain targeting and therapeutic efficacy, we developed an siRNA nanocarrier system based on PAH-AM-PEG-ApoE (PAPA) nanoparticles (PAPA/siRNA NPs), which facilitates BBB penetration. In this study, an siRNA nanocarrier delivery system modified with ApoE peptide (PAPA/siRNA NPs) developed by our research team was employed to simultaneously encapsulate BACE1-siRNA and GSK3β-siRNA. The PAPA/siRNA NPs were prepared through self-assembly and electrostatic binding. The particle size distribution profile and zeta potential of the PAPA/siRNA NPs were analysed with dynamic light scattering, while its morphology was examined with transmission electron microscopy. For in vitro assessments, flow cytometry, confocal laser scanning microscopy, PCR, and Western blotting were employed to evaluate the cellular uptake, gene silencing capacity, and endosomal escape. The biodistribution was investigated by in vivo imaging technology, and the therapeutic effect on AD was verified in AD model mice. The prepared PAPA/siRNA NPs exhibited a regular spherical appearance with a uniform particle size distribution profile. In in vitro cell experiments, the PAPA/siRNA NPs demonstrated excellent cellular uptake ability and efficient endosomal escape. Meanwhile, the dual-loaded siRNA nanocarrier delivery system effectively inhibited the expression of GSK3β and BACE1 genes. In vivo experimental results showed that the siRNA could successfully cross the BBB and deliver to the brain. It not only significantly prolonged the half-life of siRNA but also greatly reduced the generation of pathological β-amyloid and phosphorylated microtubule-associated protein tau, showing excellent therapeutic effects in the treatment of AD. In this study, we successfully constructed a brain-targeted siRNA nanocarrier delivery system for double-gene knockdown. This system can efficiently overcome the obstacle of the BBB, markedly alleviating cognitive and memory deficits in AD mice. It paves the way for novel strategies in the clinical treatment of AD and is expected to bring new breakthroughs and changes to the conquest of this disease. Show less

The poor efficacy of chemotherapy for glioma is mainly due to the difficulty of drug penetration through the blood-brain barrier (BBB), as well as the difficulty of drug concentration in the tumor tissue to reach the effective therapeutic level. The emerging tumor-targeted delivery technology can facilitate the precise enrichment of drugs in the tumor site. Apolipoprotein E (ApoE(159-167) 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

Atherosclerosis is attributable to a series of diabetes-related complications. CAV1 (caveolin 1)-mediated low-density lipoprotein (LDL) particle transcytosis across endothelial cells (ECs) is the initial step of atherosclerosis. MAP1LC3/LC3-interacting regions in the intramembrane domain (IMD) of CAV1 were buried in the caveolae and were not accessible for LC3B interaction, protecting CAV1 from autophagic degradation. However, the CSD domain of CAV1, exposed in the cytosol, directly interacted with a CBM domain of LC3B and inhibited autophagy. Therefore, the peptide IMD-CBM was constructed to induce the selective autophagic degradation of CAV1 and suppress LDL transcytosis in diabetic atherosclerosis. EC-specific expression of IMD-CBM was achieved using adenovirus. IMD-CBM directly interacted with CAV1 and LC3B in ECs, leading to the selective autophagic degradation of CAV1, activation of autophagy, and subsequent inhibition of LDL transcytosis. IMD-CBM promoted the autophagic degradation of CAV1 and consequently reduced the area of atherosclerotic plaques in 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

Immune checkpoint inhibitors (ICIs) have prolonged cancer survival but exacerbated atherosclerotic cardiovascular disease (ASCVD). This research aims to interrogate the underlying mechanism of ICIs-related atherosclerotic progression and the potential protective effect of Red Yeast Rice (RYR) on it. A tumor-bearing atherosclerotic (TB-AS) mouse model was established by subcutaneously injecting MC38 cells in male ApoE Show less

The apolipoprotein E ε4 (APOE ε4) allele is a major genetic risk factor for Alzheimer's disease, but its relevance to cognition in intracranial atherosclerosis (ICAS) remains unclear. We investigated the association between APOE ε4 and cognition in ICAS. Baseline data from a multicenter cohort were analyzed. Patients with radiologically confirmed ICAS underwent APOE genotyping, plasma biomarker assays, magnetic resonance imaging assessment of cerebral small vessel disease (CSVD) and brain atrophy, and standardized cognitive testing. Among 409 patients (mean age 60 years, 55% male), 16% carried APOE ε4. Carriers showed more frequent cognitive impairment (63% vs 48%), greater stenosis burden, and lower plasma amyloid beta (Aβ)42/40 ratios, whereas other Alzheimer's biomarkers, CSVD burden, and atrophy scores showed no difference. After adjustment, APOE ε4remained associated with cognitive impairment (odds ratio [OR] 1.86). The association was pronounced in women (OR 4.43) but absent in men. APOE ε4 is linked to cognitive impairment in ICAS, particularly in women, through mechanisms beyond Alzheimer's pathology. In patients with ICAS, cognitive impairment was more prevalent in carriers than in non-carriers. Carriers showed greater stenosis burden and lower plasma Aβ42/40 ratios. After full adjustment (stroke, CSVD, and AD biomarkers), APOE ε4 remained associated with cognitive impairment. Female carriers had substantially higher odds of cognitive impairment. Show less

Lobar intracerebral haemorrhage (ICH) is associated with cerebral amyloid angiopathy (CAA) pathology. Uncertainty remains about the mechanisms leading from CAA to ICH. We investigated the distribution and characteristics of CAA, and its clinical and neuropathological associations. Participants underwent research autopsy in the Lothian IntraCerebral Haemorrhage, Pathology, Imaging and Neurological Outcome (LINCHPIN) study. Neuropathologists rated tissue for CAA using standardised consensus criteria, as well as non-amyloid small vessel disease, Thal phase, and Braak stage. We compared the presence, distribution, and severity of CAA among different brain regions, and in the lobe or hemisphere affected by lobar ICH to corresponding contralateral regions. We evaluated the diagnostic accuracy of Vonsattel CAA grade on a post-mortem cortical specimen (simulating surgical biopsy) versus the reference standard of moderate-to-severe parenchymal CAA at autopsy. Among 162 participants, parenchymal CAA, meningeal CAA, and CAA-associated vasculopathy were diffusely distributed among all cerebral lobes irrespective of the ICH location, but capillary CAA showed an occipital predominance. In lobar ICH, all CAA measures did not differ between the ICH lobe or hemisphere and the contralateral unaffected region. CAA measures did not increase with age, but they were higher in carriers of APOE ε2 or ε4 alleles and in individuals with higher Thal phase or Braak stage. Using a rule-out category of Vonsattel grade ≥ 1 to diagnose CAA on a simulated cortical biopsy achieved 100% sensitivity (95%CI 93.4-100), and a rule-in category of Vonsattel grade ≥ 2 had 79.5% specificity (95%CI 63.5-90.7) versus the reference standard. The distribution and severity of parenchymal CAA, meningeal CAA, and CAA-associated vasculopathy are diffuse regardless of ICH location, indicating the need to better understand the factors underlying bleeding in CAA-affected vessels. Show less

Atherosclerosis is considered as a major contributor for cardiovascular disease with high morbidity and mortality globally. However, the cross-talk between efferocytosis and inflammation in atherosclerosis remains elusive. ApoE (apolipoprotein E) YY1 and NEDD4L were upregulated, but MerTK was downregulated in the arteries of ApoE Our findings demonstrated that YY1 positively regulated NEDD4L to modulate MerTK-mediated efferocytosis and activate NLRP3-mediated inflammation and pyroptosis, thus exacerbating atherosclerosis. Show less

Perirenal fat deposition significantly impacts sheep carcass quality and economic efficiency. To elucidate the underlying genetic regulation, we performed a genome-wide association study (GWAS) on 556 Hu sheep and a comparative transcriptome analysis on 24 Hu sheep (12 with high- and 12 with low-perirenal fat deposition), all with accurate phenotypic records. Furthermore, hub genes and tissue-specific genes (TSGs) were discerned through weighted gene co-expression network analysis (WGCNA) and by leveraging RNA-Seq data from 12 tissues, respectively. qRT-PCR is used to validate the accuracy of RNA-Seq data. GWAS identified significant SNPs near genes including SETD4, TIMP2, SOCS3, and DNAH17. Comparative transcriptome analysis of HPF and LPF groups identified 2072 differentially expressed genes (DEGs), which were significantly associated with lipid storage (LPL), fatty acid homeostasis (APOE, GOT1), and biosynthesis (ACACA). A total of 2333 differential alternative splicing events were identified in 1169 genes, with skipped exons (SE, 30.65 %) being the most common. GO analysis of these SEs showed links to RNA splicing and lipid metabolism, with genes like BSCL2, DGAT1, PLIN5, and PNPLA2 involved in lipid droplet organization and triglyceride storage. WGCNA revealed key modules that were positively and negatively correlated with perirenal fat deposition, emphasizing hub genes (SAR1B, THRSP, ACSS2, KIF5B) associated with lipid droplet organization and metabolism. The integrated analysis of GWAS and RNA-seq identified TIMP2, SOCS3, and DNAH17 as potential key genes involved in regulating perirenal fat deposition in sheep. An association analysis of 372 Hu sheep populations identified significant links (P < 0.05) between perirenal fat deposition traits and mutations in the TIMP2 (g.9759169 G > A) and DNAH17 (g.9494469C > T) genes. Crucially, tissue-specific gene analysis across 12 tissues identified 448 perirenal fat TSGs, of which 75 were also differentially expressed genes (e.g., LPL, THRSP, LEP, ADRB3). In conclusion, our multi-omics study identified key genes influencing perirenal fat deposition in sheep. Notably, mutations in TIMP2 and DNAH17 could serve as candidate markers for enhancing carcass quality through marker-assisted selection. Show less

Atherosclerosis (AS), a major cardiovascular disease driver, can be caused by high levels of serum cholesterol. Eggs are the main source for dietary cholesterol, and although epidemiological studies reported no association between egg intakes and cardiovascular diseases, dietary cholesterol intake is still restricted for individuals with dyslipidemia. This study evaluated the effects of egg yolk lipids isolated from low-cholesterol (LC) and normal eggs (NC) on the progression of AS using the ApoE Show less

Aging is a "multidimensional engine" of biological dysfunction that can fundamentally reshape the pathology of Alzheimer's disease (AD), This review systematically elaborates on how aging synergistically promotes the core pathologies of AD: aging upregulates the activity of β-secretase 1 (BACE1)/γ-secretase, impairs the clearance function of glial cells and meningeal lymphatic drainage, and accelerates Aβ deposition; the imbalance of kinases/phosphatases, dysfunction of molecular chaperones, and aging exosome-mediated propagation of Tau "seeds" facilitate Tau pathology; hyperreactivity of microglia and the transformation of astrocytes to the A1 phenotype form a senescence-associated secretory phenotype (SASP) → neuroinflammation vicious cycle; downregulation of synaptic proteins and disintegration of the default mode network lead to cognitive decline. Recent studies have identified that the impaired transition of aging microglia to the disease-associated microglia (DAM) phenotype, peripheral-central aging signal transmission loops (the gut-brain axis, immune-brain axis, and metabolic-brain axis), as well as circadian rhythm/vascular metabolic dysregulation, have emerged as novel intervention targets. Precision strategies targeting aging mechanisms-such as senescent cell clearance, SASP inhibition, epigenetic reprogramming, and biomarker-guided early intervention-provide a new paradigm for blocking the progression of AD. Show less

Nutrient competition between tumor and immune cells is a hallmark of the glioblastoma (GBM) microenvironment, yet the mechanisms underlying amino acid metabolic reprogramming and immune evasion remain incompletely understood. Here, we demonstrate that GBM cells outcompete NK cells for branched-chain amino acid (BCAA), leading to BCAA depletion, suppression of NK and CD8 Show less

N-carbamylglutamate (NCG) is an activator of arginine biosynthesis, but its specific role in crustaceans remains poorly understood. This study aimed to investigate the effects of NCG on arginine biosynthesis capacity, metabolism, digestion, and the gene expression of the mTOR signaling pathway in Eriocheir sinensis. In Experiment 1, hepatopancreas was cultured in vitro with NCG medium (0, 65, 75, and 85 mg/L NCG). In Experiment 2, crabs were fed either regular feed or NCG feed (content: 302.96 ± 4.07 mg/kg) for 14 days. In Experiment 1, NCG significantly upregulated pyrroline-5-carboxylate synthase (p5cs) gene expression (P < 0.05), an enzyme that is related to arginine biosynthesis. Similarly, dietary NCG upregulated p5cs expression and significantly increased the activities of carbamoyl-phosphate synthase-1 (CPS-1) and P5CS in the hepatopancreas and intestine (P < 0.05). Metabolomics analysis indicated that NCG altered the metabolic profile of the hepatopancreas, promoting cholesterol metabolism, and arginine and proline metabolism. In the intestine, trypsin and α-amylase activities were significantly elevated (P < 0.05). NCG also altered the composition of intestinal microflora, with an increase in Proteobacteria and in the ratio of Firmicutes to Bacteroidota. Additionally, NCG increased the content of signaling molecule nitric oxide (NO) and upregulated the expression of genes in the mTOR signaling pathway (P < 0.05). In conclusion, NCG supplementation enhanced arginine biosynthesis capacity, stimulated intestinal enzymatic activities, and upregulated mTOR signaling pathway gene expression in Eriocheir sinensis, indicating the potential for improved metabolism and digestion. Show less

Pharmacological preconditioning of mesenchymal stem cells (MSCs) is a promising strategy to enhance their therapeutic efficacy for end-stage liver disease; however, maximizing this benefit remains a major clinical challenge. Senkyunolide H (SNH), a small-molecule compound derived from Angelica sinensis, exhibits anti-inflammatory, antioxidant, and anti-apoptotic properties. Nevertheless, its capacity to optimize MSCs-based therapy for liver disease has not been fully elucidated. Here, we demonstrate that SNH preconditioning significantly enhances the therapeutic efficacy of bone marrow mesenchymal stem cells (BMSCs) in a murine model of liver cirrhosis. Specifically, SNH-pretreated BMSCs markedly alleviated hepatocellular injury, promoted hepatocyte proliferation, and attenuated collagen deposition. Mechanistically, SNH augments the therapeutic potency of BMSCs by partly binding to macrophage erythroblast attacher (MAEA), a subunit of the E3 ubiquitin ligase complex. This interaction stabilizes MAEA, which in turn facilitates the ubiquitination and proteasomal degradation of dual specificity phosphatase 6 (DUSP6), thereby activating ERK/STAT3 signaling and upregulating the secretion of hepatocyte growth factor (HGF). Collectively, our findings highlight SNH preconditioning as a robust approach to enhance the paracrine function and therapeutic potential of BMSCs, and identify MAEA as a novel therapeutic target for BMSCs-based interventions in liver cirrhosis. Show less

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and the leading cause of cancer-related deaths. Immune checkpoint inhibitors (ICIs) of programmed death-1 (PD-1)/programmed death ligand-1 signaling induce tumor regression in some patients with NSCLC, but most patients with NSCLC exhibit resistance to ICIs therapy. NSCLC shapes the potent tumor immunosuppressive microenvironment (TIME) that underlies tumor immune tolerance and acquired resistance. Therefore, elucidating the cellular and molecular mechanisms by which NSCLC establishes and sustains the TIME is essential for developing novel strategies to overcome immune resistance and enhance the clinical benefit of ICIs. The correlation between sterile alpha motif domain and histidine-aspartate domain-containing protein 1 (SAMHD1) expression and ICIs was analyzed via immunohistochemistry. Cell migration assay was performed to assess the effect of SAMHD1 on macrophage recruitment. Multicolor flow cytometry was performed to analyze the effect of SAMHD1 knockdown on the tumor microenvironment. SAMHD1 regulation of the dual specificity phosphatase 6-extracellular regulated protein kinases 1/2 (DUSP6-ERK1/2) pathway was verified by RNA sequencing and western blotting. Here, we identify the SAMHD1 as a potential therapeutic target and a major determinant of poor response to ICIs in patients with NSCLC. Tumors with high SAMHD1 expression show resistance to anti-PD-1 antibody (αPD-1) treatment, whereas tumors with low SAMHD1 expression are highly sensitive. SAMHD1-dependent resistance to αPD-1 is characterized by increased tumor-associated macrophages (TAMs) infiltration and reduced CD8+T cell numbers. Mechanistically, SAMHD1 regulates the expression of macrophage-associated chemokines by influencing the activation of the DUSP6-ERK1/2 pathway, which contributes to TAMs aggregation within NSCLC tumors to shape an immunosuppressive microenvironment. The HIV accessory protein viral protein-x (VPX) specifically degrades SAMHD1 to promote HIV replication. Similarly, the vpx-engineered oncolytic adenovirus (oAd-vpx) targets SAMDH1 degradation to enhance oncolytic adenovirus replication and weaken the hostile immune microenvironment shaped by TAMs, thereby triggering a CD8+T-cell-dependent antitumor immune response. The combination of oAd-vpx and αPD-1 inhibits tumor growth and enhances sensitivity to ICIs in both mouse and human NSCLC. This research identifies a key mechanism of SAMHD1-driven immunosuppression and highlights its important role in oncolytic adenovirus therapy. This study provides a theoretical basis for targeting SAMHD1 as a drug therapy strategy in patients with NSCLC. Show less

This study aimed to identify blood pressure-associated metabolites and explore their underlying pathways using multiomics data from 1188 Chinese participants. Serum metabolite levels were profiled using untargeted and widely targeted metabolomic technologies. The associations of metabolites as well as ratios with blood pressure were assessed using generalized linear models (GLM). Targeted metabolomics was used to replicate a subset of metabolites. Genome-wide association studies (GWAS) were performed on all metabolites identified. Potential causality was examined using two-sample Mendelian randomization (MR) analyses, with partial validation against GWAS results from an independent cohort. This study identified 10 blood pressure-associated metabolites supported by GLM and MR analyses. Cortisol demonstrated the strongest association with blood pressure, with l-glutamic acid and its ratios identified as key drivers. Multiomics integration revealed that a genetic variant near the omega-3 metabolism genes ( Show less

Cancer-associated fibroblasts (CAFs) are key components of the tumor microenvironment (TME) that contribute to tumor progression and therapeutic resistance in non-small cell lung cancer (NSCLC). However, effective strategies targeting CAF regulation remain limited. Here, we investigated the effects of the plant-derived compound 20(S)-Ginsenoside Rg3 on CAFs using an integrated network pharmacology and experimental validation approach. Network pharmacology analysis identified 107 overlapping targets between Rg3 and NSCLC. PPI network analysis highlighted EGFR, JUN, TP53, and STAT3 as key hub genes. KEGG enrichment analysis indicated that these targets were significantly enriched in the IL-17 and MAPK signaling pathways. These genes and pathways have been associated with fibroblast activation and tumor stromal remodeling, suggesting a potential role of Rg3 in regulating CAF-related processes within the tumor microenvironment. Functional experiments demonstrated that Rg3 inhibited CAF proliferation, colony formation and migration, while inducing apoptosis and mitochondrial dysfunction. Mechanistically, Rg3 upregulated IL-17RD and suppressed FGFR1-MAP2K4-JNK-c-Jun signaling. Furthermore, co-culture experiments revealed that Rg3-treated CAFs exhibited reduced pro-tumorigenic effects on NSCLC cells, indicating impaired tumor-stroma communication. Collectively, these findings demonstrate that 20(S)-Ginsenoside Rg3 suppresses CAF activation and function associated with the IL-17RD-FGF-MAP2K4-JNK-c-Jun signaling pathway, highlighting its potential as a tumor microenvironment-targeted therapeutic agent in NSCLC. The online version contains supplementary material available at 10.1007/s10616-026-00957-1. Show less