👤 Lintong Xie

Angiogenesis is a critical pathological process in vascular dementia (VD), yet current therapeutic strategies targeting this mechanism remain limited. Identifying novel molecular pathways involved in angiogenesis holds significant promise for advancing both diagnostic and therapeutic approaches for VD. We first applied weighted gene coexpression network analysis (WGCNA) and differentially expressed gene (DEG) analysis, combined with phenotypic gene database mining, to identify angiogenesis-associated genes in VD. We then used the Least Absolute Shrinkage and Selection Operator (LASSO) regression to select key diagnostic genes. The diagnostic efficacy of these genes was evaluated using receiver operating characteristic (ROC) curve analysis, while their association with immune cell infiltration was assessed via xCell immunoinfiltration. Using single-nucleus RNA sequencing (snRNA-seq), we determined the cellular distribution of key genes and applied Gene Set Enrichment Analysis (GSEA) to analyze functional pathways in the differentially expressed cell clusters. Finally, we validated gene expression changes in the hippocampus of bilateral common carotid artery occlusion (BCCAO)-induced VD rats using quantitative polymerase chain reaction (qPCR) and Western blot (WB). Ultimately, we screened five key genes, namely, These five key genes might be used as angiogenesis diagnostic genes for VD and might be novel potential targets for diagnosis, treatment, and prevention. Show less

Cancer-associated fibroblasts (CAFs) are a critical component of the tumor microenvironment, being implicated in enhancing tumor growth and fostering drug resistance. Nonetheless, the mechanisms underlying their function in prostate cancer (PCa) remain incompletely understood, which is essential for devising effective therapeutic strategies. The main objective of this study was to explore the mechanisms by which CAFs mediate PCa growth and chemoresistance. We validated through data analysis and experimentation that CAFs significantly impact PCa cell proliferation and chemoresistance. Subsequently, we conducted a comprehensive proteomic analysis of the conditioned media from CAFs and PCa cells and identified angiopoietin-like protein 4 (ANGPTL4) as a key factor. We employed ELISA and multiplex immunofluorescence assays, all of which indicated that ANGPTL4 was primarily secreted by CAFs.Next, we conducted metabolomics analysis, GST pull-down assays, Co-IP, and other experiments to explore the specific molecular mechanisms of ANGPTL4 and its precise effects on PCa cells. Through drug screening, we identified Quercetin 3-O-(6'-galactopyranosyl)-β-D-galactopyranoside (QGGP) as an effective inhibitor of CAFs function. Finally, we thoroughly assessed the therapeutic potential of QGGP both as a monotherapy and in combination with docetaxel in PCa cells. We discovered that the extracrine factor ANGPTL4 is primarily expressed in CAFs in PCa. When ANGPTL4 binds to IQ motif-containing GTPase-activating protein 1 (IQGAP1) on the PCa cell membrane, it activates the Raf-MEK-ERK-PGC1α axis, promoting mitochondrial biogenesis and OXPHOS metabolism, and thereby facilitating PCa growth and chemoresistance. Furthermore, virtual and functional screening strategies identified QGGP as a specific inhibitor of IQGAP1 that promotes its degradation. Combined with docetaxel treatment, QGGP can reverse the effects of CAFs and improve the responsiveness of PCa to chemotherapy. This study uncovers a paracrine mechanism of chemoresistance in PCa and proposes that targeting the stroma could be a therapeutic choice. Show less

Smoking is harmful to health. Cigarette smoke (CS) contains a variety of toxic substances. Studies have found that nicotine, tar, polycyclic aromatic hydrocarbons, etc. in CS can pass through the blood-brain barrier and enter the brain to exert their effects. Moreover, some existing studies have pointed out that CS exposure is closely related to the accelerated pathology of Alzheimer's disease (AD). Transgenic mice with the five familial AD mutations (5xFAD), which are 1-month-old, were used for chronic CS exposure for 100 days. Subsequently, cognitive function and behavioral changes were evaluated through morris water maze and new object recognition tests. The acceleration of pathological changes due to CS exposure was assessed by HE, Tunel and Aβ immunohistochemical staining. Differential expression proteins and metabolites were screened through hippocampal proteomics and metabolomics analyses. Finally, the expression levels of key proteins were verified by Western blot. Compared with unexposed 5xFAD mice, the behavioral results of mice showed that FAD mice after CS exposure exhibited poorer cognitive abilities, with longer latencies in the Morris water maze, and decreased time spent and entries in the target quadrant. The results of pathological sections indicated that the total nuclei density in the DG and CA3 regions of the hippocampus of 5xFAD mice decreased significantly after chronic CS exposure, the number of TUNEL-positive cells increased, and the expression of Aβ42 increased. Multi - omics analysis revealed that CS exposure up - regulated the expression of 46 proteins and down - regulated the expression of 80 proteins in the hippocampus of 5xFAD mice, and caused changes in 92 metabolites. Analysis of the correlation between differential proteins and differential metabolites revealed six key cross-node proteins: Kng1, Hbb-b1, Fabp3, Apoa1, Ilk, and Apoa4. CS exposure may accelerate pathological changes and cognitive impairment in 5xFAD mice by affecting energy metabolism through the PPAR signaling pathway. Show less

Cardiovascular diseases from abnormal lipid metabolism significantly increase mortality in systemic lupus erythematosus (SLE). The causal link between dyslipidemia and SLE is unclear. Lipid metabolism in patients with SLE was evaluated based on clinical data from 511 patients with SLE and 706 healthy individuals. Bidirectional Mendelian randomization (MR) was employed to assess causal links between 179 plasma lipid metabolites, lipid-lowering drug targets, and SLE risk. Genetic instruments from GWAS and eQTL data were used to evaluate CETP and APOA4 effects. Peripheral blood CETP and apolipoprotein levels in SLE patients were validated via ELISA. SLE patients exhibited reduced HDL-C (P < 0.0001), APOA1 (P < 0.0001), and APOA4 (P < 0.0001), alongside elevated triglycerides (TG, P < 0.0001), APOC3, APOD, and APOF. MR identified three lipid metabolites-PC(18:2₂₀:4), TG(56:6), and TG(58:7)-as causal factors for SLE (P < 2.79E-5). CETP inhibition significantly reduced SLE risk via HDL-C modulation (OR = 0.72, P = 3.38E-08) and influenced LDL-C, TG, and apolipoproteins. Clinical validation confirmed elevated CETP and reduced APOA4 in SLE, correlating with disease activity. APOA4 activation showed protective effects, while PCSK9 inhibition lacked relevance. Bidirectional Mendelian randomization analyses confirmed dyslipidemia as a causal antecedent to SLE, with no evidence of reverse causation. A variety of MR analyses and clinical validation indicated that targeting HDL-C regulation offers significant advantages for managing dyslipidemia in patients with SLE, with CETP identified as the optimal pharmacological target. Show less

To systematically evaluate the causal effects of lipoproteins on ischemic stroke (IS) through a systematic review and meta-analysis of Mendelian randomization (MR) studies. A comprehensive literature search was conducted in PubMed, Embase, Cochrane Library, and Web of Science to identify MR studies investigating the relationship between lipoproteins and IS, covering all publications up to November 2024. Relevant data were extracted, followed by a quality assessment. Meta-analyses were performed using RevMan software, with evaluations of heterogeneity and publication bias. A total of 442 studies were evaluated, and 10 were included. Our meta-analysis showed a significant positive correlation between LDL and IS (OR 1.09, 95% CI 1.07-1.12; This meta-analysis provides evidence for a causal relationship between various lipoproteins and ischemic stroke. Most non-HDL lipoproteins (LDL, VLDL, apoB) are associated with an increased risk of IS, while HDL and apoA1 appear to confer a protective effect. The role of Lp(a) in IS remains inconclusive and warrants further investigation. https://www.crd.york.ac.uk/PROSPERO, CRD42024617825. Show less

Lipid overaccumulation in the liver predisposes ducks to metabolic disorders. The molecular mechanism of oleic acid (OA)-induced hepatic steatosis in ducks is not fully elucidated. A cellular model of steatosis was established by treating primary duck hepatocytes with OA. Transcriptome sequencing was performed to identify key signaling pathways and candidate genes. The role of Apolipoprotein A1 (APOA1) was investigated through overexpression and knockdown experiments. Intracellular triglycerides (TGs) were quantified commercially; lipid droplets were visualized by Oil Red O staining. Intracellular TG accumulation was induced by OA treatment in a dose-dependent manner. Through transcriptome analysis, 1045 differentially expressed genes (DEGs) were identified, with APOA1 being recognized as a key candidate within the peroxisome proliferator-activated receptor (PPAR) signaling pathway. The content of TGs and lipid droplets was increased by APOA1 overexpression, whereas these effects were suppressed by APOA1 knockdown. The expression of acetyl-CoA carboxylase alpha (ACACA) and fatty acid synthase (FASN) was upregulated by APOA1. Conversely, the expression of carnitine O-palmitoyltransferase 1 (CPT1), acyl-CoA oxidase 1 (ACOX1), and apolipoprotein B (APOB) was downregulated. This study demonstrates that OA upregulates APOA1, suggesting the involvement of the PPAR pathway and providing a theoretical basis for modulating hepatic fat deposition. Show less

Cardiovascular disease (CVD) remains the leading cause of death worldwide, according to global statistics from the WHO and GBD, with the incidence of acute coronary syndromes (ACS) continuing to rise annually. This study aims to develop a nomogram model to predict the risk in ACS patients with hypertension, providing clinicians with a tool for early diagnosis, personalized treatment, and prognostic evaluation. Data were collected from ACS patients at Huangshi Aikang Hospital between 2018 and 2023. Patient characteristics, including age, sex, hypertension history, initial blood test results, and cardiac doppler ultrasonography findings, were recorded. ACS diagnosis followed the 2019 revised Guidelines for the Diagnosis and Treatment of Acute ST-Segment Elevation Myocardial Infarction (STEMI) by the Chinese Society of Cardiology. The 2024 Revised Guidelines for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes from the Chinese Journal of Cardiovascular Diseases were used for NSTEMI and unstable angina (UA) diagnoses. Statistical analyses were performed using SPSS (version 27.0.1) and R software (version 4.3.2), with statistical significance at P < 0.05. A total of 980 ACS patients were included in the study. Among the three clinical subtypes, 592 patients (60.4%) had UA, which was the most prevalent. The hypertensive group comprised 682 ACS patients (69.59%), with a mean age of 64.93 ± 9.51 years. Significant differences between hypertensive and non-hypertensive groups were found in sex (P = 0.001), age (P < 0.001), clinical subtype (P < 0.001), and several clinical and laboratory parameters, including creatinine (Cr) (P < 0.001), left ventricular ejection fraction (LVEF) (P = 0.049), left ventricular posterior wall thickness (LVPW) (P = 0.003), CK-MB (P = 0.019), AST (P = 0.028), total cholesterol (TC) (P = 0.035), LDL-C (P = 0.007), and APOB (P = 0.005). Using LASSO regression, nine variables were selected for multivariate logistic regression analysis, leading to the construction of the nomogram model. The calibration curve, Hosmer-Lemeshow test, ROC curve, decision curve, and clinical impact curve all demonstrated the model's high quality. A high-quality predictive nomogram model for assessing the risk of ACS in patients with hypertension has been developed. This model can assist clinicians in early diagnosis, personalized treatment, and prognostic evaluation. Show less

Myocardial infarction (MI) is one of the most serious cardiovascular diseases in the world. Nevertheless, the majority of diagnostic procedures conducted subsequent to the illness do not provide any means to prevent several risks associated with MI. Blood and urine tests are frequently employed in clinical examinations to detect cardiovascular diseases at an early stage. Mendelian randomization (MR) is commonly employed to explore disease-trait relationships and uncover therapeutic targets. Our goal was to explore the genetic links between 35 blood and urine biomarkers and MI. Blood and urine biomarker MR correlations with MI risk were studied. In version R10, the UK Biobank and Finnish databases included blood and urine marker data and MI data (26,060 cases and 343,079 controls). We performed bidirectional 2-sample MR with 4 methods: inverse variance weighted, MR-Egger, weighted median, and weighted mode. Final causal associations were determined by inverse variance weighted. Sensitivity analyses (heterogeneity, pleiotropy) were conducted. MR-PRESSO and PhenoScanner were used to exclude invalid instruments. We used multivariate MR to filter the most important genes without including other positive genes. To identify positive gene pathways and gene networks that cause MI, we employed GeneMANIA for gene prediction. The findings revealed a positive genetic association between the 8 blood and urine biomarker levels and an elevated risk of MI. There are apolipoprotein B (APOB), glycated hemoglobin, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, sex hormone-binding globulin, triglycerides, and urate. Moreover, APOB, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol selectively affect MI through the rejection of other positive gene stems. Finally, APOB and numerous genes strongly impact MI development. APOB collaborates with related genes to regulate plasma lipoprotein particle levels, sterol homeostasis, organization, lipid homeostasis, and remodeling in MI. Our research further reveals the causal relationship between MI and blood/urine biomarkers, providing a new perspective for the prevention, diagnosis, and treatment of MI. Blood and urine marker tests can subsequently be conducted based on these results to detect MI and study the underlying mechanisms linking these metabolites to MI. Show less

Biochemical items play a significant role in clinical decision-making, so this study aims to evaluate the performance of different biochemical platforms. We collected 1,524 serum samples that were centrifuged, and plasma was analyzed for HDL-C, LDL-C, Apo A1, Apo B, PA, and Fs-CRP with the Mindray BS2000M and Roche Cobas 8000 platforms. The results were evaluated by a non-parametric two-related sample test, Passing-Bablok regression analysis, Weighted Least Square analysis (WLS), and Bland-Altman analysis according to CLSI EP09-A3, EP5-A2, and EP15-A3. Between the two systems, there were statistically significant differences in the average bias of LDL-C, Apo A1, Apo B, PA, and Fs-CRP ( These findings suggest that the two platforms have good correlation and consistency in high-concentration medical decision levels in HDL-C, LDL-C, Apo A1, Apo B, and Fs-CRP, and all levels of PA in the two platforms are interchangeable and can replace each other. Show less

To establish a short-term high-fat/high-cholesterol (HFHC) diet-induced Metabolic dysfunction-associated steatotic liver disease (MASLD) mouse model, and evaluate the effects of rapamycin (RaPa) and chloroquine (CQ) on this model to explore their therapeutic potential and side effects. An early MASLD mouse model was constructed via short-term HFHC diet feeding. Model mice were intraperitoneally injected with RaPa or CQ. Drug effects were analyzed on body weight, liver weight, lipid metabolism-related genes (APOB, FASN, PLIN2), inflammatory factors (IL-6, IL-10), and fibrosis markers (LOX, Col-1α-1, CCL2, TGFβ1, PDGFRβ, α-SMA) at mRNA and protein levels. RaPa ameliorated body weight and liver weight in early MASLD mice, downregulated FASN and PLIN2 expression, upregulated IL-10 mRNA levels, and alleviated hepatic steatosis, but induced metabolic disorders such as Insulin resistance and hyperlipidemia. In contrast, CQ promoted FASN and PLIN2 expression, exacerbated hepatic steatosis, reduced IL-10 mRNA levels, and upregulated fibrosis-related markers (LOX, TGFβ1, PDGFRβ, α-SMA) at both mRNA and protein levels, thereby driving MASLD progression to liver fibrosis. Notably, CQ improved metabolic abnormalities in model mice, including obesity, hyperlipidemia, and Insulin resistance. RaPa and CQ exhibit dual effects on early MASLD: RaPa alleviates hepatic steatosis but exacerbates metabolic disorders, whereas CQ improves metabolic abnormalities but accelerates liver fibrosis. This paradox highlights the need to balance metabolic regulation and liver injury prevention in MASLD treatment, providing critical experimental insights for targeted drug development. Show less

The common variant PNPLA3-I148M, globally, is the most significant genetic risk factor for fatty liver disease. However, it is unclear precisely how I148M drives disease risk. Using human hepatoma cells expressing endogenous I148M, we find that the variant impairs cellular secretion of apolipoprotein B (ApoB), the scaffolding protein of very-low-density lipoprotein (VLDL). This is not due to loss-of-function of wild-type PNPLA3. Expression of human I148M in primary hepatocytes and mice also hinders VLDL secretion. Lipidomic profiling reveals a shift from polyunsaturated phosphatidylcholine to polyunsaturated triglycerides in I148M cells, reducing membrane fluidity and, concomitantly, VLDL biogenesis. ApoB secretion is substantially rescued in I148M cells overexpressing ABHD5/CGI-58, an I148M-binding partner that normally activates ATGL/PNPLA2-mediated triglyceride lipolysis. Conversely, knocking down CGI-58 or PNPLA2 mimics I148M. We propose that I148M is a neomorph that exacerbates fatty liver risk by simultaneously impeding two major CGI-58-dependent pathways for liver triglyceride clearance: lipolysis and secretion. Show less

Lipid metabolism abnormalities and inflammation have been implicated in gallstone disease (GSD) development, but the causal relationships and potential mediation effects among lipid metabolites, inflammatory factors, and GSD remain unclear. The aim of this study is to explore the causal relationships among these 3 factors. This study employed 2-sample Mendelian Randomization (TSMR) and 2-step MR to investigate the causal relationships and potential mediation effects among 91 inflammatory factors, 6 lipid metabolism-related molecules (HDL-C, LDL-C, TG, total cholesterol, ApoA1, and ApoB), and GSD. We opted for 4 distinct MR analysis methods including inverse variance weighted method, weighted median method, MR-Egger regression method and MR-PRESSO analysis. Sensitivity analyses included MR-Egger intercept tests, Cochran's Q statistic, Steiger tests, and leave-one-out analyses. Product of coefficients method was used to estimate mediation proportion. TSMR analysis revealed that every 1-unit increase in low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB), the risk of GSD decreased by 16.5%, 10.2%, 8.4%, and 13.1%, respectively. Inflammatory factors such as Natural killer cell receptor 2B4 (CD244), Macrophage colony-stimulating factor 1 (CSF-1), and interleukin-18 receptor 1 (IL-18R1) were identified as risk factors for GSD, while Fibroblast growth factor 19 levels (FGF19), Interleukin-1-alpha levels (IL-1α), and Interleukin-8 levels (IL-8) were found to be protective. Mediation analysis through 2-step MR identified potential pathways involving ApoA1--IL-8--GSD (P = .084) and IL-1α--ApoB--GSD (P = .117). This study provides robust evidence of causal links between specific lipid metabolites and GSD, as well as suggestive causal associations for several inflammatory factors. However, mediation analysis did not support significant roles for lipids or inflammatory factors as mediators in GSD pathogenesis. Future research could be further pursued in areas such as drug target intervention and mechanistic studies. Show less

Primary Sjögren's Syndrome (pSS) is a chronic autoimmune condition affecting lacrimal and salivary glands. While previous studies suggest potential associations between dyslipidemia and autoimmune diseases, the causal relationship between lipid-lowering medications and pSS remains unclear. This study employed drug-targeted Mendelian randomization (MR) analysis to assess the impact of lipid-lowering drugs on pSS risk, focusing on genetic targets including HMGCR, PCSK9, NPC1L1, APOB, CETP, and LDLR. Data were sourced from the Global Lipids Genetics Consortium and UK Biobank. Significant single-nucleotide polymorphisms linked to LDL cholesterol were utilized as instrumental variables. Causal effects were estimated using Inverse Variance Weighted, Weighted Median, MR Egger, Simple Mode, and Weighted Mode methods. Robustness was ensured through heterogeneity and sensitivity analyses. The inhibition of HMGCR and CETP genes was found to be significantly associated with an increased risk of developing pSS (HMGCR: OR = 3.602, 95% CI [1.051, 12.344], p = 0.041; CETP: OR = 12.251, 95% CI [2.599, 57.743], p = 0.002). HMGCR and CETP may affect pSS risk via non-lipid pathways, suggesting distinct mechanisms among different lipid-lowering drug targets. This study provides compelling evidence suggesting that lipid-lowering drugs may contribute to the risk of pSS, thus offering new insights for clinical intervention strategies. Show less

Cardiac arrest (CA) prevention continues to be a substantial hurdle for global public health. Although dyslipidemia and 25-hydroxyvitamin D (25(OH)D) insufficiency are recognized contributing factors for cardiovascular disease (CVD), their causal relationship with CA risk is still uncertain. Here, we explored these correlations and pinpointed possible therapeutic targets for CA prevention though Mendelian randomization (MR). Both two-sample and multivariable MR analysis methods were conducted to assess how serum lipid traits and 25(OH)D influence the susceptibility to develop CA. Nine thousand nine hundred eighty-eight participants in total from the National Health and Nutrition Examination Survey (NHANES) engaged in validating the relationship between the concentrations of 25(OH)D and cardiovascular mortality in individuals with dyslipidemia. The integration of MR with expression quantitative trait locus (eQTL) analysis enabled the identification of druggable targets, and molecular docking was used to screen small molecules, which were subsequently validated in animal models. The MR results revealed that both elevated levels of low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (ApoB), as well as triglycerides (TGs), significantly contributed to an increased CA risk ( Show less

Patients with diabetic nephropathy (DN) often present with lipid profile abnormalities. While associations between these parameters and DN have been suggested, confounding factors obscure causal relationships. This study employed bidirectional Mendelian randomization (MR) to explore these links. Using genome-wide association study (GWAS) data, the primary analysis used the inverse-variance weighted (IVW) method, which was supported by MR-Egger regression and a weighted median estimator (WME). Sensitivity analyses, including heterogeneity, pleiotropy tests, leave-one-out, and reverse causality analyses, were conducted. The IVW model revealed the following: (1) causal relationships between triglycerides (TG) (OR: 1.5807, 95% CI: 1.2578-1.9865, P = 0.0001), high-density lipoprotein cholesterol (HDL-C) (OR: 0.7342, 95% CI: 0.5729-0.9409, P = 0.0146), and apolipoprotein A1 (ApoA1) (OR: 0.6506, 95% CI: 0.5190-0.8156, P = 0.0002) and DN; (2) causal relationships between TG (OR: 1.0607, 95% CI: 1.0143-1.1093, P = 0.0098), HDL-C (OR: 0.9453, 95% CI: 0.9053-1.9871, P = 0.0109), and apolipoprotein B (ApoB) (OR: 1.0672, 95% CI: 0.0070-1.1310, P = 0.0280) and the urinary albumin-creatinine ratio (UACR); (3) no causal relationship between total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), ApoB and DN, or between TC, LDL-C, ApoA1 and UACR; (4) none of the results showed reverse causality. TG is a risk factor for DN and UACR; HDL-C is protective for both; ApoA1 protects against DN; and ApoB is a risk factor for UACR. To further explore the underlying mechanisms between TG, HDL-C, ApoA1, ApoB, and their associations with DN and UACR, and to provide reference for the selection of lipid management and treatment strategies for clinical DN patients. This study demonstrated that causal relationships between TG, HDL-C, and ApoA1 with DN and between TG, HDL-C, and ApoB with the UACR. Show less

Neuromyelitis optica spectrum disorder (NMOSD) is a group of immune-mediated disorders that often lead to severe disability. The diagnosis and monitoring of NMOSD can be challenging, particularly in seronegative cases, highlighting the need for reliable biomarkers to enhance clinical management. This study aimed to identify serum lipid biomarkers for the diagnosis and monitoring of NMOSD and to assess their potential to improve clinical decision-making. We conducted a comprehensive serum proteomic analysis in a discovery cohort of NMOSD patients and controls to identify lipid-related proteins associated with NMOSD. Subsequently, we validated the candidate biomarkers in the retrospective cohort and developed diagnostic models using a random forest algorithm. The association between these lipid biomarkers and disease activity was further evaluated in longitudinal analysis. Our analysis identified a panel of serum lipid-related biomarkers that demonstrated significant differences between NMOSD patients and controls. The diagnostic models achieved the impressive accuracy of 72% for the full NMOSD spectrum, 72% for AQP4-IgG+ NMOSD, and 68% for double seronegative NMOSD. Importantly, these biomarkers showed a correlation with disease activity, with levels changing from relapse to remission. Additionally, a combination of these lipid biomarkers was found to predict relapse with the AUC of 0.861. A user-friendly smartphone application was developed to facilitate the straightforward "input-index, output-answer" screening process, enhancing both clinical decision-making and patient care. The diagnostic model based on the serum lipid-related indexes (TC, TG, LDL, HDL, ApoA1, and ApoB) may be the useful tool for NMOSD in diagnosis and monitoring of disease stage, thereby improving the treatment outcome for patients. Future studies should focus on integrating these biomarkers into routine clinical practice to realize their full potential in enhancing NMOSD management. Show less

Central obesity poses a significant health threat. Lutein-rich fruits and vegetables may help manage obesity. Limited evidence suggests that lutein exerts health effects by inhibiting advanced glycation end products (AGEs), but data on its effects in centrally obese individuals are sparse. Thus, we aimed to investigate the effects of lutein supplementation in subjects with central obesity. A double-blind, randomized controlled trial was conducted involving patients with central obesity. Anthropometric indices, dietary intake, metabolic parameters, carotenoid and AGEs levels were compared between those receiving a 32-week intervention of 10 mg d Show less

Low-density lipoprotein (LDL) is intricately associated with numerous clinical conditions, including dyslipidemia and metabolic-associated fatty liver disease (MAFLD), and its serum concentration is crucial for diagnostic purposes. However, the sensitive and accurate analysis of "intact" LDL is a significant difficulty, as conventional approaches typically focus solely on the detection of cholesterol or surface proteins of LDL. We developed a proximity ligation-induced DNAzyme motor that facilitates an outstanding amplification reaction for the precise and sensitive detection of LDL through the simultaneous recognition of the target ApoB and cholesterol. This technique facilitates the direct and accurate quantification of the concentration of "intact" LDL particles, as opposed to assessing the cholesterol content or ApoB protein inside LDL. The elevated amplification efficiency of the exponential amplification reaction, in conjunction with the trans-cleavage activity of the Cas14a1/crRNA complex, facilitates sensitive LDL detection with a low limit of detection of 6.12 mg/dL. The unique properties of the proposed method offer significant advantages in selectivity, stability, and sensitivity, rendering it extremely appropriate for diagnostics in MAFLD. Show less

This study aims to evaluate the relationship between apolipoproteins (ApoA1, ApoB, and the ApoB/A1 ratio) and the incidence of major adverse cardiovascular events (MACE) in patients with coronary artery disease (CAD) and impaired kidney function, assessing their potential role in secondary prevention. A prospective cohort of 1,640 patients with impaired kidney function who underwent percutaneous coronary intervention in China was analyzed. Patients were categorized based on the measurements of ApoA1, ApoB, and ApoB/A1 ratio. MACE, defined as a composite of all-cause mortality, cardiovascular death, nonfatal myocardial infarctions, strokes, and unplanned revascularizations, was tracked post-procedure, with statistical analyses including Kaplan-Meier survival curves and Cox regression models to identify associations with apolipoproteins. Subgroup analyses according to kidney function were conducted. During a median follow-up of 3.1 years, 324 MACE events were observed. Multivariable Cox regression analyses illustrated higher levels of ApoB and the ApoB/A1 ratio were significantly associated with increased MACE incidence (adjusted HR [95%CI] 1.668[1.044-2.666]; adjusted HR [95%CI] 2.231[1.409-3.533], respectively), while lower ApoA1 levels correlated with a higher risk (adjusted HR [95%CI] 0.505[0.326-0.782]). ROC curve analyses indicated comparable predictive performances to traditional risk factors like LDL cholesterol. Subgroup analysis revealed that the above association was not statistically significant in the moderate-to-severe renal impairment CAD patients (eGFR < 45 mL/min/1.73 m Our findings illustrate that apolipoproteins, specifically ApoA1 and ApoB, along with their ratio, are significant predictors of major adverse cardiovascular events in CAD patients with impaired kidney function. These results emphasize the need for incorporating apolipoprotein measurements in secondary prevention strategies for this high-risk population. Show less

Prior research has highlighted the significant roles of circulating retinol, retinol-binding protein 4 (RBP4), and apolipoprotein C (ApoC) in metabolic health. This study investigates the joint association of retinol and RBP4 with metabolic syndrome (MetS) and examines the potential mediating role of ApoCs in these relationships. This prospective study included 3,009 and 2,724 participants with baseline serum retinol and RBP4 data, respectively. Over a 9-year follow-up among 2,621 participants, 1,136, 127, 696, and 662 were categorized into MetS-free, recovered, incident MetS, and persistent MetS groups, respectively. Midway through the study, ApoC1-4 levels were measured in 2316 participants. Adjusted odds ratios (95% CIs) for the highest (vs. lowest) tertile of retinol and RBP4 levels were 3.63 (2.69-4.92) and 5.64 (4.05-7.92) for 9-year persistent MetS, respectively. The corresponding hazard ratios (95% CIs) were 1.67 (1.39-2.01) and 1.67(1.38, 2.03) for incident MetS, and 0.65 (0.41-1.03) and 0.44 (0.28, 0.70) for recovered MetS (all P-trends<.05). A synergistic association of retinol and RBP4 with MetS risk was observed for persistent MetS. Higher levels of retinol or RBP4 were associated with increased concentrations of ApoC1-4, which were linked to a greater risk of incident and persistent MetS. A newly developed composite score (ApoCS), derived from ApoC1-4 levels, explained 30.5% and 24.5% of the association between retinol or RBP4 and MetS, with ApoC2 and ApoC3 contributing predominantly to this connection. Our study identified notable positive correlations between serum retinol and RBP4 levels and MetS progression, explained by increases in circulating ApoC2 and ApoC3 within a Chinese cohort. Show less

Foam cells derived from macrophages and smooth muscle cells (SMCs) play a pivotal role in the progression of atherosclerosis. While phytosterols (PS) have demonstrated cholesterol-lowering and anti-inflammatory properties, their impact on foam cells remains elusive. Here, we investigated the effects of PS on foam cell formation, inflammatory responses, and lipid metabolism using both single-cell RNA sequencing (scRNA-seq) and functional assays. scRNA-seq of aortic tissue from Show less

Increasing evidence suggests that familial hypercholesterolemia (FHC) exacerbates myocardial infarction (MI). This study aimed to identify possible candidate biomarkers for patients with FHC and MI. The data were obtained from Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were screened using Limma, while module genes were identified through Weighted Gene Co-expression Network Analysis (WGCNA) in GSE48060. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis, protein-protein interaction (PPI) network and CIBERSORT methods were performed to explore the intersection genes. A receiver operating characteristic (ROC) curve were employed to evaluate the diagnostic effectiveness, with validation conducted using datasets GSE61144 and RT-qPCR. The FHC datasets included 656 DEGs, while there were 956 DEGs and 90 module genes in MI datasets. There were 49 overlapping DEGs between FHC and MI, which were associated with immune functions. Additionally, immune infiltration analysis revealed disturbances in immune cell populations. There were 13 candiate hub genes were screen after PPI network analysis. Show less

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with limited therapeutic options, thus necessitating novel strategies targeting upstream fibrogenic drivers; the exact impact of apolipoprotein E (apoE) on IPF and its therapeutic potential remain unexplored. This study aims to identify novel therapeutic targets for pulmonary fibrosis and elucidate the mechanism by which plasma apoE alleviates this condition. We conducted an integrated meta-analysis of seven plasma cohorts and two-sample Mendelian randomization to assess apoE's association with IPF risk. CRISPR-engineered APOE-deficient canines and Apoe Plasma apoE was identified as a robust protective factor against IPF, with genetically elevated levels correlating with improved pulmonary function, and its deficiency in plasma showed potential diagnostic value for IPF. APOE-deficient canines developed spontaneous pulmonary fibrosis, and Apoe Plasma apoE is a causal guardian against pulmonary fibrogenesis, inhibiting TGF-β/Smad signaling through dual receptor (LRP1/PLAU) engagement. Cross-species validation and mechanistic elucidation position RGX-104, a small-molecule LXR agonist, as a potential therapeutic candidate for clinical translation in IPF. Show less

CD11c+ microglia are a functionally specialized subpopulation of microglia that play a crucial role in the pathophysiological processes of various central nervous system diseases. This review synthesizes compelling evidence that CD11c+ microglia exhibit unique transcriptomic and phagocytic characteristics. These characteristics distinguish them from homeostatic microglia and support their specialized functions. During development, CD11c+ microglia are crucial for the maturation of oligodendrocytes and the integrity of white matter, particularly in regions such as the corpus callosum and cerebellum. In preclinical models of neurodegenerative diseases (such as Alzheimer's disease and amyotrophic lateral sclerosis) and central nervous system injuries (such as stroke and spinal cord injury), they are consistently associated with neuroprotective phenotypes. CD11c+ microglia exhibit enhanced phagocytic capacity near amyloid plaques and damaged neurons, helping to clear pathological protein aggregates and cell debris, thereby reducing neurotoxicity and promoting a repair environment. The current consensus is that specific microenvironmental cues, particularly hazard signaling molecules (DAMPs) and cytokines (such as interferon-γ), are the main drivers of the differentiation and activation of CD11c+ microglia. Among these, the TREM2-APOE signaling axis is a key and widely accepted regulatory pathway for their survival, proliferation, and functional status. The plasticity of CD11c+ microglia is regulated by multiple signaling pathways, including CSF1R, SIRPα-CD47, IFN-γ, and the complement cascade. Emerging therapeutic strategies aim to regulate their activities through gene targeting, metabolic intervention, and immune regulation using TREM2 agonists, CSF1R inhibitors, or nanopharmacological methods. However, challenges remain in defining specific CD11c+ biomarkers, understanding environment-dependent functions, and achieving targeted delivery. Future prospects depend on clearly addressing individual developmental issues, deciphering the molecular switches that control phenotypic plasticity, and developing highly specific therapeutic strategies to leverage their beneficial functions, thereby paving the way for new intervention methods for neurological diseases. Show less

Prostate cancer (PCa) remains a leading cause of cancer-related mortality in men, with challenges in diagnosis and treatment due to tumor heterogeneity. This study identifies palmitoylation-related signature genes as potential diagnostic and therapeutic targets. Integrating GEO datasets, six differentially expressed genes (DEGs) linked to palmitoylation were identified. Machine learning algorithms (LASSO, RF, SVM) selected three core genes: TRPM4, LAMB3, and APOE. A diagnostic model based on these genes achieved an AUC of 0.929, demonstrating robust accuracy in distinguishing PCa from normal tissues. Functional analysis revealed roles in lipid metabolism and immune modulation, with ssGSEA highlighting correlations between key genes and immune cell infiltration. Experimental validation showed that LAMB3 overexpression suppressed PCa cell proliferation, migration, and invasion, while knockdown enhanced these processes. Molecular docking identified diethylstilbestrol as a potential therapeutic agent targeting LAMB3 and APOE. These findings emphasize the clinical relevance of palmitoylation-related genes in PCa diagnosis and therapy, offering novel biomarkers and insights for personalized treatment strategies. Show less

Cardiac hypertrophy as one of the major predisposing factors for chronic heart failure lacks effective interventions. It has been shown that protein ubiquitination plays an important role in cardiac hypertrophy. SMURF2 (SMAD-specific E3 ubiquitin ligase 2) is an important member of NEDD4 (neuronal precursor cell expressed developmentally downregulated 4) family of HECT E3 ubiquitin ligases. In this study we investigated the regulatory role of SMURF2 in cardiac hypertrophy. Experiment models were established in mice by transverse aortic constriction (TAC) in vivo, as well as in neonatal rat cardiomyocytes (NRCMs) by treatment with angiotensin II (Ang II, 1 μM) in vitro. We showed that the expression levels of SMURF2 were significantly elevated in cardiac tissues from patients with cardiac hypertrophy and the two experiment models. In NRCMs, SMURF2 knockdown or treatment with a specific SMURF2 inhibitor heclin (8 μM) significantly inhibited Ang II-induced cardiomyocyte hypertrophy, evidenced by reduced mRNA levels of Anp, Bnp and β-Mhc as well as cell surface. Prophylactic or therapeutic administration of heclin (10 mg·kg Show less

Biomolecular condensates, membrane-less assemblies formed by phase separation, are implicated in neurodegenerative disease, but their role in Alzheimer's disease (AD) remains unclear. Here, we report that in the brain of AD patients and animal models, an elevation of poly(C)-binding protein 2 (PCBP2) correlates with biomolecular condensation that involves phase separation. These condensates sequester large numbers of mitochondrial and mRNA-binding proteins, leading to the outside impairment of mitochondrial morphology and function, and BACE1 mRNA decay relative to amyloid deposition. We then identify a small molecule CN-0928 that inhibits the condensates by reducing PCBP2 protein level and mitigates AD pathology and cognitive decline, in which CN-0928 binding to a target protein integrator complex subunit 1 (INTS1) allows to regulate PCBP2 expression. Our findings place PCBP2 condensates as a key player that cooperates the seemingly disparate but important pathways, and show pharmacological modulation of PCBP2 as an effective approach for treating AD. Show less