Genome-wide association studies (GWAS) have identified nearly 100 loci associated with metabolic dysfunction-associated steatotic liver disease (MASLD), but the molecular functions of these variant al Show more
Genome-wide association studies (GWAS) have identified nearly 100 loci associated with metabolic dysfunction-associated steatotic liver disease (MASLD), but the molecular functions of these variant alleles remain elusive, particularly when they occur in non-coding regions. Here we profiled the chromatin accessibility landscape of liver nuclei from MASLD individuals, and demonstrated these accessible genomic sites were bound by cell type-specific transcription factors (TFs) and enriched for MASLD risk variants, highlighting lineage- and disease state-specific regulation. Using a massively parallel reporter assay (MPRA), we identified hundreds of differential activity variants (DAVs) that operate in a cell type-specific manner or in a stimulus-dependent context by disrupting liver pathogenesis-associated transcriptional regulatory network. Integrative analyses combining liver eQTLs, chromatin looping, and single-cell CRISPRi screening linked these DAVs to functional target genes. Notably, we demonstrated that DAVs located near Show less
To investigate the association between polymorphisms of the A case-control study was conducted, enrolling 100 HTG patients and 100 age-matched controls with normal triglyceride levels from the physica Show more
To investigate the association between polymorphisms of the A case-control study was conducted, enrolling 100 HTG patients and 100 age-matched controls with normal triglyceride levels from the physical examination cohort at Guangzhou 11th People's Hospital (January-December 2023) The observation group showed significant differences in genotype frequencies of Show less
Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease with no effective pharmacological treatments. The causal role of triglycerides (TGs) in AAA development remains unclear and contr Show more
Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease with no effective pharmacological treatments. The causal role of triglycerides (TGs) in AAA development remains unclear and controversial. Mendelian randomization was applied to assess causal relationships between lipoproteins, circulating proteins, metabolites, and the risk of AAA. To test the hypothesis that elevated plasma TG levels accelerate AAA development, we used Mendelian randomization analyses integrating genetic, proteomic, and metabolomic data identified causal relationships between elevated TG-rich lipoproteins, TG metabolism-related proteins/metabolites, and AAA risk. In the angiotensin II infusion AAA model, most These findings identify hypertriglyceridemia as a key contributor to AAA pathogenesis and suggest that targeting TG-rich lipoproteins may be a promising therapeutic strategy for AAA. Show less
Cholesterol (CH) plays a crucial role in enhancing the membrane stability of drug delivery systems (DDS). However, its association with conditions such as hyperlipidemia often leads to criticism, over Show more
Cholesterol (CH) plays a crucial role in enhancing the membrane stability of drug delivery systems (DDS). However, its association with conditions such as hyperlipidemia often leads to criticism, overshadowing its influence on the biological effects of formulations. In this study, we reevaluated the delivery effect of CH using widely applied lipid microspheres (LM) as a model DDS. We conducted comprehensive investigations into the impact of CH on the distribution, cell uptake, and protein corona (PC) of LM at sites of cardiovascular inflammatory injury. The results demonstrated that moderate CH promoted the accumulation of LM at inflamed cardiac and vascular sites without exacerbating damage while partially mitigating pathological damage. Then, the slow cellular uptake rate observed for CH@LM contributed to a prolonged duration of drug efficacy. Network pharmacology and molecular docking analyses revealed that CH depended on LM and exerted its biological effects by modulating peroxisome proliferator-activated receptor gamma (PPAR-γ) expression in vascular endothelial cells and estrogen receptor alpha (ERα) protein levels in myocardial cells, thereby enhancing LM uptake at cardiovascular inflammation sites. Proteomics analysis unveiled a serum adsorption pattern for CH@LM under inflammatory conditions showing significant adsorption with CH metabolism-related apolipoprotein family members such as apolipoprotein A-V (Apoa5); this may be a major contributing factor to their prolonged circulation Show less
Cholesteryl ester transfer protein (CETP) mediates the exchange of triglycerides (TG) from apolipoprotein B (ApoB)-containing lipoproteins to high-density lipoproteins (HDL) and the reciprocal exchang Show more
Cholesteryl ester transfer protein (CETP) mediates the exchange of triglycerides (TG) from apolipoprotein B (ApoB)-containing lipoproteins to high-density lipoproteins (HDL) and the reciprocal exchange of cholesterol (C) from HDL to ApoB-containing lipoproteins. CETP inhibition increases HDL-C and decreases low-density lipoprotein cholesterol (LDL-C) while modestly decreasing TG. Considering that CETP inhibitors block removal of TG from TG-rich lipoproteins (TRL), it is interesting that CETP inhibition decreases TG concentrations. TG levels are largely regulated by lipoprotein lipase (LPL), the enzyme primarily responsible for hydrolyzing TG. The angiopoietin-like 3/8 complex (ANGPTL3/8) is the most potent circulating LPL inhibitor, while the TG-lowering apolipoprotein A5 (ApoA5) acts by suppressing ANGPTL3/8-mediated LPL inhibition. To better understand CETP biology, we studied the effects of CETP overexpression and CETP inhibition on the levels of ANGPTL3/8 and ApoA5 in circulation using dedicated immunoassays. CETP-overexpressing transgenic mice had increased TG and normal ANGPTL3/8 levels but manifested dramatically reduced ApoA5 concentrations. Administration of the CETP inhibitor evacetrapib had no effect on ANGPTL3/8 levels in CETP-overexpressing mice or in humans. However, evacetrapib administration increased ApoA5 concentrations in both species. In human subjects, evacetrapib treatment increased circulating ApoA5 levels in the late-stage ACCELERATE and ACCENTUATE studies by 160.1% and 204.7%, respectively. Our results uncover a previously unrecognized link between CETP and ApoA5 by showing that CETP overexpression reduces ApoA5 levels while CETP inhibition increases ApoA5 concentrations. Show less
This pioneering genome-wide association study examined surrogate markers for insulin resistance (IR) in 147,880 Taiwanese individuals using data from the Taiwan Biobank. The study focused on two IR su Show more
This pioneering genome-wide association study examined surrogate markers for insulin resistance (IR) in 147,880 Taiwanese individuals using data from the Taiwan Biobank. The study focused on two IR surrogate markers: the triglyceride to high-density lipoprotein cholesterol (TG:HDL-C) ratio and the TyG index (the product of fasting plasma glucose and triglycerides). We identified genome-wide significance loci within four gene clusters: GCKR, MLXIPL, APOA5, and APOC1, uncovering 197 genes associated with IR. Transcriptome-wide association analysis revealed significant associations between these clusters and TyG, primarily in adipose tissue. Gene ontology analysis highlighted pathways related to Alzheimer's disease, glucose homeostasis, insulin resistance, and lipoprotein dynamics. The study identified sex-specific genes associated with TyG. Polygenic risk score analysis linked both IR markers to gout and hyperlipidemia. Our findings elucidate the complex relationships between IR surrogate markers, genetic predisposition, and disease phenotypes in the Taiwanese population, contributing valuable insights to the field of metabolic research. Show less
The current study aimed to clarify the roles of apolipoprotein A5 (ApoA5) and milk fat globule-epidermal growth factor 8 (Mfge8) in regulating myocardial lipid deposition and the regulatory relationsh Show more
The current study aimed to clarify the roles of apolipoprotein A5 (ApoA5) and milk fat globule-epidermal growth factor 8 (Mfge8) in regulating myocardial lipid deposition and the regulatory relationship between them. The serum levels of ApoA5 and Mfge8 in obese and healthy people were compared, and the obesity mouse model induced by the high-fat diet (HFD) was established. In addition, primary cardiomyocytes were purified and identified from the hearts of suckling mice. The 0.8 mmol/L sodium palmitate treatment was used to establish the lipid deposition cardiomyocyte model Show less
Pancreatic cancer (PC), characterized by the absence of effective biomarkers and therapies, remains highly fatal. Data regarding the correlations between PC risk and individual plasma proteome known f Show more
Pancreatic cancer (PC), characterized by the absence of effective biomarkers and therapies, remains highly fatal. Data regarding the correlations between PC risk and individual plasma proteome known for minimally invasive biomarkers are scarce. Here, we analyzed 1,345 human plasma proteins using proteome-wide association studies, identifying 78 proteins significantly associated with PC risk. Of these, four proteins (ROR1, FN1, APOA5, and ABO) showed the most substantial causal link to PC, confirmed through Mendelian randomization and colocalization analyses. Data from two clinical cohorts further demonstrated that FN1 and ABO were notably overexpressed in both blood and tumor samples from PC patients, compared to healthy controls or para-tumor tissues. Additionally, elevated FN1 and ABO levels correlated with shorter median survival in patients. Multiple drugs targeting FN1 or ROR1 are available or in clinical trials. These findings suggest that plasma protein FN1 associated with PC holds potential as both prognostic biomarkers and therapeutic targets. Show less
To investigate the effect of tannic acid (TA) on the growth, disease resistance, and intestinal health of Chinese soft-shelled turtles, individual turtles were fed with 0 g/kg (CG), 0.5 g/kg, 1 g/kg, Show more
To investigate the effect of tannic acid (TA) on the growth, disease resistance, and intestinal health of Chinese soft-shelled turtles, individual turtles were fed with 0 g/kg (CG), 0.5 g/kg, 1 g/kg, 2 g/kg, and 4 g/kg TA diets for 98 days. Afterwards, the turtles' disease resistance was tested using Show less
Yaozhong Liu, Huilun Wang, Minzhi Yu+19 more · 2025 · medRxiv : the preprint server for health sciences · Cold Spring Harbor Laboratory · added 2026-04-24
Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease without effective medications. This study integrated genetic, proteomic, and metabolomic data to identify causation between incre Show more
Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease without effective medications. This study integrated genetic, proteomic, and metabolomic data to identify causation between increased triglyceride (TG)-rich lipoproteins and AAA risk. Three hypertriglyceridemia mouse models were employed to test the hypothesis that increased plasma TG concentrations accelerate AAA development and rupture. In the angiotensin II-infusion AAA model, most 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 Show more
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
Ischemic stroke is frequently associated with symptomatic intracranial atherosclerotic stenosis (sICAS), is a leading cause of global disability and mortality. Current guidelines recommend dual antipl Show more
Ischemic stroke is frequently associated with symptomatic intracranial atherosclerotic stenosis (sICAS), is a leading cause of global disability and mortality. Current guidelines recommend dual antiplatelet and intensive statin therapies. Proprotein convertase subtilisin 9/kexin type 9 (PCSK9) inhibitors have emerged as a potent lipid-lowering therapy, potentially influenced by genetic variations, particularly in the CYP2C19 gene. This study at Xuzhou Central Hospital from January 2021 to December 2023 included 151 patients divided into a statin group (n = 73) and a PCSK9 inhibitor (PCSK9i) group (n = 78). It evaluated lipid profiles, inflammatory markers, neurological function, and clinical outcomes over a 180-day follow-up period, with additional analysis stratified by CYP2C19 genotype. The PCSK9i group demonstrated significant improvements in lipid parameters compared to the statin group, including greater reductions in low-density lipoprotein cholesterol (LDL-C) (p = 0.008), total cholesterol (TC) (p < 0.001), and triacylglycerols (TAG) (p = 0.041), along with apolipoprotein A1 (ApoA1) and apolipoprotein B (ApoB) (both p < 0.001). Inflammatory markers, particularly interleukin-6 (IL-6), significantly reduced in the PCSK9i group (p < 0.001). In the PCSK9i group, CYP2C19 rapid metabolizers achieved greater reductions in LDL-C (p = 0.021), ApoB (p = 0.003), and IL-6 levels (p = 0.041) compared to slow metabolizers. Post-treatment modified Rankin Scale (mRS) scores were significantly lower in rapid metabolizers compared to slow metabolizers (p = 0.018), though clinical events occurred infrequently in both subgroups. This study demonstrates that PCSK9 inhibitor therapy combined with statins provides enhanced lipid-lowering and anti-inflammatory effects compared to statin monotherapy in sICAS patients. While the CYP2C19 genotype may influence specific treatment responses, particularly lipid parameters, its impact on clinical outcomes requires further investigation. Show less
Diabetes mellitus and dyslipidemia are major risk factors for atherosclerosis. Hypoechoic plaques, which indicate vulnerable or unstable plaques, may rupture and lead to ischemic stroke, cognitive imp Show more
Diabetes mellitus and dyslipidemia are major risk factors for atherosclerosis. Hypoechoic plaques, which indicate vulnerable or unstable plaques, may rupture and lead to ischemic stroke, cognitive impairment, increased adverse cardiac events, and even death. This study aimed to investigate the correlation between plasma lipid levels and the characteristics of atherosclerotic plaques in adult patients with type 2 diabetes mellitus. A retrospective analysis was conducted on adult patients with type 2 mellitus who were hospitalized in the Department of Endocrinology at Affiliated Hospital of Hebei University between January 2017 and December 2021.Patients were categorized into two groups based on arterial ultrasound results. Statistical analyses were performed to compare plasma lipid levels and plaque characteristics across the groups. 1) Statistically significant differences were observed among the two groups in terms of gender, hypertension, age, duration of diabetes mellitus, plaque location, triglycerides (TG),total cholesterol (TC), Apolipoprotein A1 (Apo A1),very-low-density lipoprotein (VLDL), VLDL/apolipoprotein B(ApoB), high-density lipoprotein cholesterol (HDL)/ApoA1 ( In clinical practice, the characteristics of atherosclerotic plaques and lipid profiles should be jointly evaluated to guide targeted treatment and effectively reduce the risk of atherosclerotic cardiovascular disease. 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 m Show more
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
Pentadecanoic acid (PEA), an odd-chain fatty acid derived from diet by the gut microbiome, has garnered increasing attention for its systemic health-promoting properties. Its potential role in bladder Show more
Pentadecanoic acid (PEA), an odd-chain fatty acid derived from diet by the gut microbiome, has garnered increasing attention for its systemic health-promoting properties. Its potential role in bladder cancer (BC) occurrence and invasion, however, remains unclear. Large-scale cohorts' analyses were performed to assess the association between dietary PEA and BC occurrence and invasion. In vitro and in vivo experiments, including EJ and T24 BC cell assays and a BBN-induced mouse model, were conducted to experimentally assess the impact of PEA on BC. Serum proteomics, gut microbiome, and targeted fecal lipidomics analyses were employed to explore the underlying mechanisms. Dietary PEA was negatively associated with BC occurrence and invasion in cohort analyses. PEA suppressed EJ and T24 BC cell migration, invasion, and proliferation, while inhibiting BC development in a BBN-induced mouse model. In vivo serum proteomics identified differentially expressed lipid-related proteins (e.g., Apoe and Apob) following PEA treatment, implicating its modulation of lipid metabolism pathways. Considering the essential role of the gut-bladder axis, the gut microbiome analysis exhibited that PEA markedly altered bacteria (e.g., g_Alistipes) and fungi (e.g., o_Erysiphales, g_Teberdinia, and g_Gibberella), with concomitant lipid metabolism changes. Furthermore, targeted fecal lipidomics demonstrated the shifts in key lipids, such as phosphatidylethanolamines (PE) involved in essential lipid clusters, suggesting regulation by gut microbiome linked to BC development. Collectively, our findings demonstrate that PEA mitigates BC by reshaping the gut microbiome and modulating lipid metabolism, providing new insights into its molecular and therapeutic potential. 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 cen Show more
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
By various assessments, the previous study has unequivocally concluded functional apoB and MTTP (microsomal triglyceride transfer protein) for VLDL production in chicken ovaries. The present study sou Show more
By various assessments, the previous study has unequivocally concluded functional apoB and MTTP (microsomal triglyceride transfer protein) for VLDL production in chicken ovaries. The present study sought to use whole tissue culture to define the role of VLDL secretion by small yellow follicles (SYFs) along their development under normal and heat stress (HS) conditions. Under thermoneutral conditions (39 °C), chicken SYFs increased MTTP activity, apoB expression and VLDL secretion, while underwent cell apoptosis along the time course. Despite relieved ER stress and protein ubiquitinylation, inhibition of VLDL secretion by Lomitapide and Mipomersen greatly increased triglyceride accumulation, impaired estradiol production and cell proliferation, and accelerated cell apoptosis in accordance with upregulated caspase 3/7 activity, JNK activation, protein carbonylation, and MDA accumulation. Exposure to HS at 44 °C boosted cell apoptosis in a duration-dependent manner. Acute HS for 3 h enhanced VLDL secretion, impaired estradiol production and cell proliferation, and promoted IL-1b production, oxidative damages, and cell apoptosis, whereas except MDA content and cell proliferation, the detrimental effects were halted after 13 h recovery. Lomitapide and Mipomersen augmented lipid accumulation, oxidative stress, inflammatory response, and exacerbated transient impairment of estradiol secretion and cell proliferation in SYFs under 3 h HS and after recovery, but failed to rescue cell viability despite relieved ER and proteostatic stress. In conclusion, routine secretion of VLDL by SYFs serves as an intrinsic mechanism to sustain cell viability and functions to support the whole program required for follicle development, while under HS, this mechanism provisionally rescues steroidogenesis and cell proliferation. Show less
Postmenopausal women are at elevated risk for osteoporosis and dysregulated lipid metabolism. While the relationship between conventional lipid markers and bone mineral density (BMD) remains controver Show more
Postmenopausal women are at elevated risk for osteoporosis and dysregulated lipid metabolism. While the relationship between conventional lipid markers and bone mineral density (BMD) remains controversial, the association between apolipoprotein B-100 (ApoB-100) (an established independent predictor of atherosclerosis) and bone metabolism in postmenopausal women remains poorly understood. This study investigated the relationship between ApoB-100 and lumbar BMD in postmenopausal women, with specific focus on potential inflammatory and platelet-mediated pathways. We conducted a cross-sectional study of 1,429 postmenopausal women who underwent health screening at the First Affiliated Hospital of Xinxiang Medical University between January 2022 and December 2024. ApoB-100 levels were measured by immunoturbidimetry, and lumbar BMD was assessed using low-dose chest CT imaging. Participants were stratified into tertiles based on ApoB-100 levels. We employed univariate and multivariate regression analyses to evaluate the relationship between lumbar BMD and ApoB-100. Generalized additive models with smooth curve fitting were used to characterize the linear relationship. Subgroup analyses assessed the consistency of associations across different populations, while mediation models quantified the intermediary roles of the neutrophil-to-lymphocyte ratio (NLR) and platelet count. After multivariate adjustment, ApoB-100 demonstrated a significant independent negative correlation with lumbar BMD (β=-6.37, 95%CI: -9.26 to -3.49). This association was more pronounced in women younger than 60 years (β=-10.18, 95%CI: -13.94 to -6.42), those with BMI≥28kg/m² (β=-10.73, 95%CI: -15.31 to -0.86), and those without hypertension (β=-7.3, 95%CI: -10.42 to -4.19). Mediation analysis revealed that NLR accounted for 8.17% of the negative association between ApoB-100 and lumbar BMD, while platelet count showed a suppressive indirect association (20.60%). ApoB-100 exhibits an independent negative association with lumbar BMD in postmenopausal women, partially mediated through inflammatory and platelet pathways. These findings support the potential utility of ApoB-100 as a biomarker for osteoporosis risk assessment in postmenopausal women, particularly within specific high-risk subgroups. Show less
Little is known about the importance of blood lipids for risk of myocardial infarction (MI) in Chinese vs. European populations. We compared the associations with MI of apolioprotein B (ApoB) vs. low- Show more
Little is known about the importance of blood lipids for risk of myocardial infarction (MI) in Chinese vs. European populations. We compared the associations with MI of apolioprotein B (ApoB) vs. low-density lipoprotein cholesterol (LDL-C) and remnant-cholesterol (remnant-C) vs. triglycerides in the China Kadoorie Biobank (CKB) and UK Biobank (UKB). Plasma levels of LDL-C, high-density lipoprotein-cholesterol (HDL-C), apolipoprotein B (ApoB), apolipoprotein A1 (ApoA1), non-HDL-C, remnant-C, LDL-C/ApoB, and HDL-C/ApoA1 ratios were measured in a nested case-control study of MI (948 cases, 6101 controls) in CKB and a prospective study (5344 cases in 279 989 participants) in UKB. Associations of lipids with MI were assessed using logistic regression in CKB and Cox regression in UKB after adjustment for confounders and correction for regression dilution. The mean levels of LDL-C were about 30% lower in CKB than in UKB [2.3 (0.6) vs. 3.7 (0.8) mmol/L], but mean levels of HDL-C were comparable [1.3 (0.3) vs. 1.5 (0.4) mmol/L], as were those for triglycerides [1.8 (1.1) vs. 1.7 (1.1) mmol/L]. While the rate ratios (RRs) of MI for 1 SD higher usual levels of LDL-C in Chinese were about half those in Europeans (1.27; 1.13-1.44 vs. 1.55; 1.49-1.61), the corresponding RRs for ApoB or non-HDL with MI were comparable between Chinese and Europeans. The findings reinforce current guidelines for primary prevention of atherosclerotic cardiovascular disease (ASCVD) in China that advocate initiation of statin treatment in individuals at high-risk of ASCVD rather than high levels of LDL-C. Show less
Among individuals diagnosed with type 2 diabetes mellitus (T2DM), an abnormal accumulation of visceral fat heightens the cardiovascular risk (CVR), and the major reason for death for these people is a Show more
Among individuals diagnosed with type 2 diabetes mellitus (T2DM), an abnormal accumulation of visceral fat heightens the cardiovascular risk (CVR), and the major reason for death for these people is atherosclerotic cardiovascular disease (ASCVD). This study aimed to gain further insights into the longitudinal relationship between CVR and visceral fat area (VFA) in patients with T2DM, and to compare the predictive performance of additional abdominal obesity measures and VFA for changes in CVR. This prospective cohort study included 316 patients with T2DM who were followed up for more than one year, and VFA was measured by the bioimpedance method. This study investigated the prospective association between a VFA percentage change (∆VFA, %) and CVR, and evaluated the potential nonlinear relationships between ∆VFA (%) and the increase 10-year ASCVD risk. Furthermore, the area under the pooled curve (AUC) was contrasted for both ∆VFA (%) and other abdominal obesity indices. The excessive VFA loss group showed lower low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), total cholesterol (TC), triglyceride-glucose index, LDL-C/HDL-C, brachial-ankle pulse wave velocity, 10-year ASCVD risk, atherogenic index of plasma, TC/HDL-C, and apolipoproteins B/apolipoproteins A-1 than the VFA gain group (all β [Formula: see text] 0, HR [Formula: see text] 1, all P [Formula: see text] 0.05) after covariate controlling. VFA reduction of more than 14.82% led to a reduction in the stated risk. Moreover, ∆VFA (%) demonstrated superior predictive value for changes in ASCVD risk, with an AUC of 0.585 (95% CI: 0.513-0.656), compared to other obesity indices. Excessive VFA reduction improved 10-year ASCVD risk in patients diagnosed with T2DM. VFA was a more effective predictor of 10-year ASCVD risk changes than other abdominal obesity measures. This investigation has been registered with the Chinese Clinical Trial Registry (ChiCTR2400086569). Show less
A comprehensive understanding of protein corona (PC) composition is critical for engineering nanoparticles (NPs) with optimal safety and therapeutic performance, because the PC governs NP pharmacokine Show more
A comprehensive understanding of protein corona (PC) composition is critical for engineering nanoparticles (NPs) with optimal safety and therapeutic performance, because the PC governs NP pharmacokinetics, biodistribution, and cellular interactions. Yet systematic analyses are hampered by the absence of standardized, richly annotated data sets. Here, we introduce the Protein Corona Database (PC-DB), which compiles data from 83 studies (2000-2024) and integrates 817 NP formulations with quantitative profiles of 2497 adsorbed proteins. The PC-DB exposes pronounced heterogeneity in NP materials (metal 28.8%, silica 22.8%, lipid-based 14.8%), surface modifications, sizes (1-1400 nm), and ζ-potentials (-70 to +70 mV). Subsequent meta-analysis shows that silica, polystyrene, and lipid-based NPs smaller than 100 nm with moderately negative to neutral ζ-potentials preferentially bind the lipoproteins APOE and APOB-100, which are linked to receptor-mediated uptake and enhanced delivery efficiency. In contrast, metal and metal-oxide NPs carrying highly negative surface charge enrich complement component C3, indicating a greater likelihood of immune recognition and clearance. Interpretable machine learning models (LightGBM and XGBoost; ROC-AUC > 0.85) confirm NP size, ζ-potential, and incubation time as the most influential predictors of protein adsorption. These results delineate how physicochemical parameters dictate PC composition and illustrate the power of predictive modeling to guide rational NP design. 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, infla Show more
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
Cirrhosis and hepatocellular carcinoma (HCC) are long-term complications of chronic liver disease (CLD). In this large multi-ancestry genome-wide association study of all-cause cirrhosis (35,481 cases Show more
Cirrhosis and hepatocellular carcinoma (HCC) are long-term complications of chronic liver disease (CLD). In this large multi-ancestry genome-wide association study of all-cause cirrhosis (35,481 cases, 2.36M controls) and HCC (6,680 cases, 1.76M controls), we identified 27 loci associated with cirrhosis (10 novel) and 11 with HCC (three novel). Three novel cirrhosis loci were replicated in independent cohorts (e.g. Show less
As inflammatory processes may be involved in the pathogenesis of diabetic distal sensorimotor polyneuropathy (DSPN), the first aim of the present study was to determine the clinical characteristics of Show more
As inflammatory processes may be involved in the pathogenesis of diabetic distal sensorimotor polyneuropathy (DSPN), the first aim of the present study was to determine the clinical characteristics of type 2 diabetes mellitus (T2DM) with distal sensorimotor polyneuorpathy (DSPN). Next goal was to investigate inflammatory biomarkers, insulin-like growth factor- 1 and lipid profile in these patients. Finally, we aimed to compare the renal function in these patients. In a cross-sectional study, we included 160 patients diagnosed with T2DM. The control group was included 22 non-diabetic healthy subjects (HC). The patients with diabetes were divided into four groups, absent (n = 74), mild (n = 38), moderate (n = 24), and severe (n = 24) using a nomogram based on the MNSI features for a DSPN severity grading probability. Patients with moderate and severe DSPN were a little older and had longer duration of diabetes compared to patients with absent and mild DSPNS (p < 0.05). Serum levels of interferon-gamma (INF-γ), interleukin (IL)-1β, IL-4, IL- 6 levels in patients with severe DSPN were significantly higher than HC, absent, mild and moderate of DSPN (p < 0.05). The circulating levels of insulin-like growth factor-1 (IGF-1) were significantly lower in patients with severe DSPN (p < 0.05) compared to absent, mild and moderate of DSPN and HC. Diabetic patients with moderate DSPN showed increased circulating levels of TC, LDL-C, APOB (p < 0.05) compared to HC and patients with absent, mild and severe DSPN. Moreover, APO-A1/APOB was significantly lower in patients with diabetes compared to HC. In addition, patients with severe DSPN showed increased Cystatin C (p < 0.05) compared to HC and absent, mild, and moderate DSPN. Multivariate ordered logistic regression analysis showed that the levels of IL-6 (OR = 3.166, 95%CI 1.461-6.860, p = 0.003, IL-1β(OR = 1.148, 95%CI 1.070-2.232; p = 0.000), TC (OR = 1.174, 95%CI 1.011-1.364; p = 0.035), LDL-C (OR = 1.246, 95%CI 1.098-3.618; p = 0.003), Cystatin C (OR = 1.867, 95%CI 1.245-3.434; p = 0.004), ages (OR = 1.043, 95%CI 1.009-1.078; p = 0.012), and duration of diabetes (OR = 1.157, 95%CI 1.049-1.277; p = 0.004) were positively associated with increasing the odds ration of DSPN in T2DM. Conversely, the level of IGF-1 (OR = 0.922, 95%CI 0.961-0.982; p = 0.000) and ratio of APO-A1/APOB (OR = 0.212, 95%CI 0.078-0.567; p = 0.002) were significantly associated with decreasing the odds ratio of DSPN in T2DM. The levels of inflammatory biomarkers such as INF-γ, IL-1β, IL-4, IL- 6 were increased in patients with severe DSPN in T2DM. Ages, duration of diabetes as well as high circulating levels of IL-6, IL-1β, TC, LDL-C and Cystatin C were positively associated with DSPN in T2DM. Conversely, the level of IGF-1 and the ratio of APOA1/APOB were independent protective factors for DSPN in T2DM. Our results emphasize the importance of addressing issues related to inflammatory biomarkers, lipids and early impaired renal function in T2DM with DSPN, as these may be of potential relevance for deteriorating DSPN. Show less
Thrombosis is a life-threatening complication in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. This study aims to conduct a statistical analysis of the incidence of blood clo Show more
Thrombosis is a life-threatening complication in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. This study aims to conduct a statistical analysis of the incidence of blood clots and lipid concentrations, and to examine the networks of oxylipins in hospitalised patients with SARS-CoV-2. Serum samples of 1731 hospitalised patients with SARS-COV-2 were used to measure six lipid parameters: total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A (apoA), and apolipoprotein B (apoB). Additionally, the lipid profiles and oxidative lipidomics characteristics were examined via liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-MS/MS) in SARS-COV-2-positive patients with and without thrombosis. The mortality rate in the SARS-COV-2 thrombosis group was significantly higher at 29.6% compared to the SARS-COV-2 non-thrombosis group at 12.1% (P < 0.0001). The levels of the lipid parameters were closely associated with both thrombosis and SARS-COV-2 severity. Patients with SARS-COV-2 admitted to the hospital exhibited significant changes in oxidative lipid metabolites, specifically in the arachidonic acid (ARA) and docosahexaenoic acid (DHA) classes, compared with those in the control group. Among the thrombus group, 28 oxidative lipid metabolites were found to be differentially expressed compared to the non-thrombus group, and with the most notable variations observed in 20-hydroxyPGF2α and 14(15)-EpETE. Enrichment analysis using KEGG revealed that differential oxidized lipid metabolites mainly concentrated in the ARA and serotonergic synapses metabolism signaling pathway. Our findings indicate a close association between lipid mediators and both SARS-COV-2 and thrombi. Specifically, ARA and serotonergic synapses metabolism signaling pathway may be an important pathogenic factor for thrombosis caused by SARS-COV-2. Furthermore, 20-hydroxyPGF2α and 14(15)-EpETE show promise as potential biomarkers for SARS-CoV-2-induced thrombosis. Show less
Calcific aortic valve stenosis (CAVS) is steadily rising worldwide with no effective pharmacological agents available. Observational studies implicated dyslipidaemia as a risk factor for CAVS. Whether Show more
Calcific aortic valve stenosis (CAVS) is steadily rising worldwide with no effective pharmacological agents available. Observational studies implicated dyslipidaemia as a risk factor for CAVS. Whether dyslipidaemia is causative for CAVS and the therapeutic potential of different lipid-modifying drug targets for CAVS treatment remains unclear. We appraised the relationship of genetically-proxied lipid traits and 12 lipid-modifying drug targets with CAVS risk using Mendelian randomization (MR). Genetic variants associated with lipid traits and variants in genes encoding lipid-modifying drug targets were retrieved from GLGC. Summary-level data for CAVS were obtained from the TARGET consortium and FinnGen. Validation analyses were performed using genetic instruments retrieved from liver-derived gene expression and circulation plasma levels of targets. Colocalisation and mediation analyses were performed to evaluate the robustness of our findings and explore potential mediators (i.e., lipoprotein a (Lp(a)), body mass index, apolipoprotein B (ApoB)). The MR analyses supported that total cholesterol and LDL-cholesterol level were independent causal risk factors. The drug-target MR analysis suggested that genetic mimicry of PCSK9 inhibition should reduce CAVS risk (OR = 0.63, 95% CI = 0.56-0.70), which was corroborated by colocalisation analysis. Secondary analyses supported a genetically proxied effect of liver-specific PCSK9 expression (OR = 0.94 per SD reduction in PCSK9 expression, 95% CI = 0.88-1.00) and circulating plasma levels of PCSK9 (OR = 0.86 per SD reduction in PCSK9 protein, 95% CI = 0.83-0.88) on CAVS risk. ApoB and Lp(a) mediated 55.9% and 4.5%, respectively, of the total effect of PCSK9 on CAVS risk. Multiple sensitivity analyses supported this observation. Our study supports total cholesterol, LDL-cholesterol as a causal factor for CAVS, and genetically proxied inhibition of PCSK9 may reduced its risk. Show less
In Traditional Chinese Medicine (TCM), dampness is a pathogenic factor arising from impaired production and transportation of bodily fluids. While Fuling Zexie decoction (FLZXD) has demonstrated thera Show more
In Traditional Chinese Medicine (TCM), dampness is a pathogenic factor arising from impaired production and transportation of bodily fluids. While Fuling Zexie decoction (FLZXD) has demonstrated therapeutic efficacy in dampness constitution (DC) treatment, the material basis underlying its constitutional modulatory effects remains unclear. This study proposes objective indicators for the differentiation and therapeutic evaluation of DC and elucidates the material basis of FLZXD in DC treatment. Serum exosome proteomic profiling was conducted across two independent cohorts to identify DC-related indicators and assess the therapeutic efficacy of FLZXD in DC-associated hyperlipidemia (DC-hyperlipidemia). The bioactive compounds of FLZXD were prioritized through a comprehensive analysis of patent documentation and network pharmacology, with subsequent validation of DC-related targets using enzyme-linked immunosorbent assay (ELISA). Proteomic analysis of serum exosomes revealed signatures that differentiate individuals with a balanced constitution (BC) from those with DC. The differentially expressed proteins (DEPs) were enriched predominantly in pathways related to the complement cascade and cardiovascular diseases. FLZXD demonstrated therapeutic efficacy against DC-hyperlipidemia, as evidenced by the reversal of DEPs expression following treatment, which was supported by the patentable findings and network pharmacology analysis. Through experimental validation and pharmacological evidence, the active herbs of FLZXD (Fuling, Zexie and Baizhu, collectively referred to as FZB) were identified, and a total of 73 putative therapeutic targets involved in the dampness-resolving effects of FZB were revealed. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment further confirmed that FLZXD exerts its anti-dampness effects primarily through regulation of the complement and coagulation cascades. Among eight candidate indicators specifically associated with DC, four proteins were validated via ELISA, indicating potential utility for the differentiation of DC. The sensitivity (%), specificity (%), fold change (FC), p-value, and area under the curve (AUC) for each indicator were as follows: apolipoprotein B-100 (APOB) (100.00, 80.00, 0.63, 0.0051, 0.94), complement factor H-related protein 1 (CFHR1) (90.00, 100.00, 0.55, 0.0001, 0.98), alpha-1-acid glycoprotein 1 (ORM1) (100.00, 80.00, 0.71, 0.0043, 0.92), and pigment epithelium-derived factor (SERPINF1) (90.00, 70.00, 0.66, 0.0002, 0.87). The integrative approach, combining proteomic profiling, network pharmacology analysis, and clinical validation, establishes an integrative approach for research on TCM constitutions. This approach provides (1) molecular insights into the differentiation of DC, (2) a foundation for mechanism-based, targeted therapeutic strategies, and (3) enhanced patient stratification to support personalized treatment approaches. Show less