👤 Jiangkun Yu

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

To explore the correlation between different traditional Chinese medicine (TCM) constitution types and apolipoprotein B (ApoB) in patients with hyperuricemia (HUA) and to investigate the relationships between TCM constitutions, uric acid levels, and various cardiovascular risk factors. A cross-sectional study involving 683 patients diagnosed with HUA was conducted. Patients' TCM constitutions were classified using the standardise "Classification and Determination of TCM Constitution" questionnaire. Serum uric acid (UA), lipid profiles, ApoB, and homocysteine (Hcy) levels were measured. Among 683 HUA patients, phlegm-dampness (22.99% ) and damp-heat constitution (20.06% ) were the most common TCM constitution types. UA, ApoB, and Hcy levels in patients with phlegm-damp constitution were significantly higher than those in other constitutions (P< 0.05). UA levels were negatively correlated with HDL-C (r=-0.472, P= 0.027) and positively correlated with ApoB (r= 0.618, P= 0.012) and Hcy (r= 0.492, P= 0.018). Phlegm-damp and damp-heat constitutions are the most common TCM constitution types in HUA patients and are associated with higher levels of UA, ApoB, and Hcy. These constitutional types are independently associated with increased cardiovascular risk. 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 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

To construct a nomogram for predicting metabolic syndrome (MetS) in women with polycystic ovary syndrome. In this retrospective study, we analyzed clinical and biochemical data from 859 Chinese women diagnosed with PCOS. Univariable logistic regression and forward stepwise logistic regression were employed to identify independent predictors of MetS. A predictive nomogram was developed that integrates age, acne status, body mass index (BMI), fasting insulin levels (FINS), and the ApoB/ApoA ratio. The model's discriminative performance, calibration accuracy, and clinical utility were assessed using the area under the receiver operating characteristic curve (AUC), calibration curves accompanied by Brier scores, Hosmer - Lemeshow tests, decision curve analysis (DCA), and clinical impact curves (CIC). Internal validation was conducted through bootstrap resampling over 1,000 iterations. The nomogram exhibited strong discriminative capability with an AUC of 0.874 (95% CI: 0.850-0.899), surpassing BMI alone which had an AUC of 0.824 ( The proposed nomogram accurately predicts MetS risk in PCOS patients, supporting early identification and individualized management. 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-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

Cholesterol is an essential molecule for tumor cell growth and proliferation, and dysregulated cholesterol metabolism has been widely implicated in cancer pathogenesis. However, the specific role and underlying molecular mechanisms of cholesterol metabolism alterations in diffuse large B-cell lymphoma (DLBCL) remain poorly understood. We retrospectively analyzed clinical data from 200 DLBCL patients and 185 healthy controls, focusing on lipid and lipoprotein levels, including triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), and apolipoprotein E (ApoE). Univariate and multivariate Cox proportional hazard models were used to evaluate the prognostic value of these markers, and Kaplan-Meier analysis assessed their associations with overall survival (OS). Bioinformatics analysis predicted associations between lipid markers and cholesterol metabolism. Cellular experiments further investigated the expression of cholesterol metabolism-related proteins and the effect of the cholesterol-depleting agent Methyl-β-cyclodextrin (MβCD) on DLBCL cells. We confirmed significant alterations in metabolic markers (such as TC and ApoA1) between the healthy control group and patients, which were significantly associated with patient prognosis and overall OS. Bioinformatics analysis revealed a strong correlation between these markers and elevated CD36 expression. In addition, DLBCL cells exhibited increased expression of cholesterol uptake and synthesis proteins (CD36, SREBP2, and HMGCR) and decreased expression of efflux proteins (APOA1, NR1H2 and ABCG1), consistent with cholesterol metabolic reprogramming. Treatment with MβCD disrupted CD36 expression and cholesterol metabolism, leading to reduced DLBCL cell survival. These findings underscore the pivotal role of cholesterol metabolic reprogramming in DLBCL progression. CD36 and related metabolic markers represent promising therapeutic targets, opening novel avenues for the treatment of this malignancy. Show less

This study aims to evaluate the association between mean arterial pressure (MAP) and anthropometric, metabolic, and endocrine parameters in Chinese infertile women with polycystic ovary syndrome (PCOS). A total of 1,000 PCOS subjects were enrolled in the clinical trial project of Acupuncture and Clomiphene in the treatment of PCOS infertility patients (PCOSAct). Of these, 998 patients were selected for this study. Linear trends and regression analyses were conducted to evaluate the association between MAP and anthropometric, metabolic, and endocrine parameters. Logistic regression was employed to estimate the association between MAP and risk of insulin resistance (IR), nonalcoholic fatty liver disease (NAFLD) and hyperlipidemia. The receiver operating characteristics (ROC) curve was used to determine the predictive value of the MAP for IR, NAFLD and hyperlipidemia. Linear trends revealed that the MAP was positively associated with age, height, body weight, body mass index (BMI), waist circumference (WC), hip circumference (HC), waist-to-hip ratio (WHR), systolic blood pressure (SBP) and diastolic blood pressure (DBP), hirsutism score, and acanthosis nigricans score, fasting blood glucose (FBG), fasting insulin (FINS), the homeostatic model assessment for insulin resistance (HOMA-IR), low-density lipoprotein (LDL), triglycerides (TG), total cholesterol (TC), apolipoprotein B (ApoB), ApoB/apolipoprotein A1 (ApoA1) ratio, total testosterone (TT), and free androgen index (FAI), as well as the prevalence of IR, metabolic syndrome (MetS), NAFLD, and hyperlipidemia. Conversely, MAP was negatively correlated with the quantitative insulin sensitivity check index (QUICKI), high-density lipoprotein (HDL), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), the LH/follicle stimulating hormone (FSH) ratio, and anti-Müllerian hormone (AMH). After adjusting for age and BMI, a significant linear relationship was observed between MAP and WC, WHR, hirsutism score, FBG, LDL, TG, TC, ApoB, and ApoB/ApoA1 ratio. Logistic regression analysis demonstrated that participants in the highest quartile (Q4) of MAP had no significantly higher odds ratios (OR) for IR, NAFLD and hyperlipidemia after adjusting for confounding factors. The ROC curve analysis indicated that the AUC Elevated MAP is associated with dysregulation of glucose and lipid metabolism and alterations in endocrine hormone levels. It may thus serve as a promising screening approach for IR-related conditions in patients with PCOS. 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

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

The role of lipid markers in acute coronary syndrome remains incompletely understood, particularly for novel indices such as the Castelli risk indices (CRI-I, CRI-II) and cholesterol index (CHOINDEX). This study aims to elucidate the relationship between novel lipid markers and plaque rupture. In this single-center retrospective study, 649 patients with acute coronary syndrome undergoing optical coherence tomography were stratified into plaque rupture (n = 130) and non-rupture (n = 519) groups. Lipid indices included the following: CRI-I - total cholesterol/high-density lipoprotein cholesterol (HDL-C), CRI-II - low-density lipoprotein cholesterol (LDL-C)/HDL-C, and CHOINDEX - LDL-C/HDL-C. Multivariable logistic regression identified independent predictors of plaque rupture. Model performance was assessed using area under the curve and integrated discrimination improvement. The plaque rupture group had higher proportions of males (89.2% vs. 80%; P = 0.01) and smokers (57.7% vs. 44.9%; P = 0.009), with elevated LDL-C mean 3.14 vs. 2.83 mmol/l), apolipoprotein B (APOB; 1.03 vs. 0.85 g/l), CRI-I (4.75 vs. 3.91), CRI-II (3.11 vs. 2.45), and CHOINDEX (1.97 vs. 1.65; all P <0.01). Multivariable analysis identified CRI-I (odds ratio [OR], 1.57), CRI-II (OR, 2.09), CHOINDEX (OR, 0.40), and APOB (OR, 5.50) as independent predictors. The combined model (traditional factors + novel indices) showed superior discrimination (area under the curve = 0.775 vs. 0.622; integrated discrimination improvement = 0.059; P <0.001). The combined assessment of CRI-II, CRI-I, CHOINDEX, and APOB, in conjunction with traditional cardiovascular risk factors, exhibits robust diagnostic efficacy for plaque rupture. Show less

To investigate the relationship between serum lipid levels and the risk of Chronic obstructive pulmonary disease (COPD) in the UK Biobank. We performed this prospective study in 381,938 adults without COPD from UK Biobank. Serum high-density cholesterol (HDL-C), low-density cholesterol (LDL-C), total cholesterol (TC), triglyceride (TG), apolipoprotein A (ApoA) and apolipoprotein B (ApoB) were measured and classified into quintiles. Restricted cubic spline (RCS) analysis was applied to visualize the dose-response relationship between lipids and COPD risk and Cox proportional hazard models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). We documented 10,443 incident COPD cases. Nonlinear relationships were found between HDL-C, LDL-C, TC, ApoA, ApoB and COPD risk with RCS analysis (P values for non-linearity < 0.05). Accordingly, multivariable-adjusted regression analysis indicated abnormal HDL-C and ApoA, and low LDL-C, TC and ApoB were associated with increased risk of COPD. Compared to intermediate quintile (Q3) group, both high or low HDL-C and ApoA were associated with risk of COPD. Corresponding HRs (95% CIs) were 1.15 (1.08-1.22), 1.16 (1.09-1.23) in Q1 group and 1.08 (1.01-1.16), 1.07 (1.00-1.14) in Q5 group. For LDL-C, TC and ApoB, there were more than 29% higher risk was observed in Q1 group with HRs (95% CIs) of 1.34 (1.27-1.42), 1.38 (1.30-1.46) and 1.29 (1.21-1.37), while HRs (95% CIs) were 0.88 (0.83-0.94), 0.92 (0.86-0.98) and 0.90 (0.84-0.95) in Q5 groups. We also observed the interactions between specific lipids and age at recruitment, sex and smoking status with stratified analysis. Our study provides the first evidence demonstrating the associations between six major serum lipids and COPD risk, revealing multiple nonlinear relationships. There were U-shaped associations between serum HDL-C, ApoA and COPD risk, and L-shaped associations between LDL-C, TC, ApoB and COPD risk. Show less

To investigate the relation of glycemic and lipid metabolism with brain structure and cognitive function in people with diabetes, so as to improve cognitive function in these individuals. Based on the UK Biobank, 26,394 patients, who were diagnosed with diabetes by doctors between 2006 and 2010, were included in the study. The demographic information, clinical data of glycemic and lipid metabolism and cognitive function (brain MRI and cognitive function scores) were collected. Multiple linear regression and non-restricted cubic spline analyses were used to investigate the relations of glycemic and lipid metabolism with brain structure and cognitive function. In this study, the mean age of people with diabetes (containing 39 % females) was 59.58 ± 7.21 years. Higher random blood glucose (β = -0.116, p < 0.001) and glycosylated hemoglobin (HbA1c) (β = -0.062, p = 0.051) were associated with a smaller brain volume. Higher HbA1c (β = 0.036, p < 0.001; β = 0.023, p = 0.021) was related with worse cognitive function. Further analysis showed that HbA1c < 6.5 % had a protective effect on cognitive function, and HbA1c = 6.5 %∼8.5 % and >8.5 % was unrelated and negatively related with cognitive function, respectively. Different types of lipids had varying effects on cognitive function. Higher total cholesterol (TC) (β = 0.125, p = 0.008), low density lipoprotein-cholesterol (LDL-C) (β = 0.086, p = 0.025), and ApoB (β = 0.092, p = 0.026) were associated with more significant brain structural abnormalities. Conversely, triglyceride (TG) = 0.75∼8.0 mmol/L was positively correlated with cognitive function (β = -0.036, p < 0.001; β = -0.044, p < 0.001; β = 0.058, p = 0.001), and higher ApoA (β = -0.032, p < 0.001; β = -0.033, p < 0.001; β = 0.047, p = 0.004) was associated with better cognitive function. The age-stratified analysis revealed that the impact of lipids on cognitive function was age-dependent. TC and LDL-C were related to brain structural abnormalities in the 55-60 age group, while TG had a stronger protective effect on cognitive function in older adults, particularly those aged 65-70 years. In people with diabetes, higher HbA1c (>8.5 %), as well as elevated TC, LDL-C, and ApoB, are associated with worse brain structure and cognitive function. Conversely, HbA1c < 6.5 % and elevated TG within the range of 0.75∼8.0 mmol/L have a protective effect on cognitive function, and the later exhibited more evident impact in older adults. To prevent or delay the onset of dementia in people with diabetes, it may be necessary to intensify glycemic control, targeting an HbA1c level of <6.5 %. Additionally, the age-specific lipid-lowering strategies shall be considered, with more flexible triglyceride-lowering goals for elderly patients. Show less

The association between low-density lipoprotein (LDL) cholesterol and increased mortality risk has been well-documented, yet apolipoprotein B (apoB) is regarded as a more precise risk indicator. However, a comprehensive analysis integrating both markers in relation to mortality risk remains unreported. This study aimed to investigate the relationship between LDL cholesterol levels and mortality across varying apoB concentrations within the general population. Data from 15,380 participants in the 2005-2016 National Health and Nutrition Examination Survey (NHANES) were utilized to construct Cox regression models and apply restricted cubic splines, assessing the association between LDL cholesterol and mortality across distinct apoB stratifications. The study cohort had a median (IQR) age of 46.0 (32.0, 60.0) years, with 7949 (51.8%) males. During a median follow-up of 101.0 months (IQR: 67-137), 1771 (8.8%) all-cause mortality events were observed; 443 (2.1%) deaths were attributed to cardiovascular diseases, while 109 (0.5%) resulted from cerebrovascular diseases. Low apoB and LDL-cholesterol levels were independently linked to an elevated risk of all-cause and cardiovascular mortality. Compared with participants having apoB <90 mg/dL and LDL-cholesterol levels between 100-129 mg/dL, those with LDL-cholesterol <70 mg/dL (HR, 1.81; 95%CI: 1.39-2.36) and 70-99 mg/dL (HR, 1.28; 95%CI: 1.01-1.62) demonstrated a higher risk of all-cause mortality. Additionally, reduced apoB levels contributed to an increased risk of cardiovascular mortality among individuals with low LDL-cholesterol levels. Low apoB and LDL-cholesterol levels were associated with heightened all-cause and cardiovascular mortality risk in the general population. Conversely, high apoB and low LDL-cholesterol levels did not correlate with increased mortality risk. Show less

Breast cancer is the second most common cancer worldwide. Chemotherapy often causes dyslipidemia and obesity in breast cancer patients. Monitoring lipid profiles and body mass index (BMI) is crucial to evaluate chemotherapy's metabolic side effects, identify interventions to mitigate them, and understand health risks linked to weight changes during treatment. Shenling Baizhu Powder (SLBZP), a traditional Chinese medicine (TCM), treats spleen-stomach ailments by boosting spleen function, enhancing qi, and reducing dampness. SLBZP has potential benefits in managing chemotherapy-induced dyslipidemia and improving overall metabolic health in cancer patients. This study retrospectively examined the effects of SLBZP on blood lipid levels and BMI in breast cancer patients undergoing adjuvant chemotherapy. This study reviewed the medical records of patients who were diagnosed with breast cancer at the Breast Surgery Department of Zhejiang Provincial Hospital of Traditional Chinese Medicine from January 2022 to December 2023. Based on the inclusion criteria, a total of 180 eligible patients were included and divided into an observational group (which received SLBZP) and a control group (which did not receive SLBZP) during chemotherapy. Patients' clinical data, including age at diagnosis, menopausal status, tumor location, smoking and drinking habits, tumor molecular type, tumor node metastasis (TNM) stage, chemotherapy drugs, targeted therapy, lipid levels, and BMI before and after chemotherapy, were collected. Statistical analyses were conducted using SPSS 25.0. After chemotherapy, the control group showed significant increases in total cholesterol (TC) (P=0.03), triglyceride (TG) (P=0.001), low-density lipoprotein cholesterol (LDL-C) (P=0.02), and apolipoprotein B (ApoB) (P=0.01) levels. In the observational group, the TC, TG, and LDL-C levels remained stable (P>0.05), but the high-density lipoprotein cholesterol (HDL-C) (P=0.001) and apolipoprotein A1 (ApoA1) (P<0.001) levels significantly decreased, and BMI (P=0.02) significantly increased. The subgroup analysis revealed that the taxane followed by anthracycline subgroup showed significant increases in BMI (P=0.007) and significant decreases in the HDL-C (P=0.007) and ApoA1 (P<0.001) levels, while the taxane subgroup showed a significant decrease in the HDL-C level post-chemotherapy (P=0.003). In the control group, the TG (P=0.002) and LDL-C (P=0.02) levels were significantly elevated in the taxane followed by anthracycline subgroup post-chemotherapy. No significant changes were observed in BMI or the other lipid indexes in the remaining chemotherapy drug regime subgroups (P>0.05). Chemotherapy increased the TC, TG, LDL-C, and ApoB levels in breast cancer patients, but SLBZP mitigated dyslipidemia. The patients who received SLBZP also showed increased BMI post-chemotherapy, which was likely due to reduced gastrointestinal side effects. Taxane-based chemotherapy drugs had greater effects on blood lipids and BMI, while anthracycline-based drugs did not significantly affect blood lipids and BMI. Show less

To investigate the impact of the Panax notoginseng saponin extract on hyperlipidaemic mice. We developed a hyperlipidemia model in mouse through the administration of a high-fat diet. We conducted weekly measurements of body weight, serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C) and highdensity lipoprotein cholesterol (HDL-C). Additionally, serum levels of Apolipoprotein A (APOA) and Apolipoprotein B (APOB) were determined post-feeding. We assessed pathological liver tissue damage in mice, as well as examined malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity in liver tissue. Immunohistochemical analysis was conducted to detect the expression levels of heme oxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) proteins within liver tissues. Administration of Panax notoginseng saponin extract led to a reduction in body weight, liver index, and histopathological scores among mice. Additionally, there was a significant reduction in TC, TG and LDL-C levels, accompanied by an increase in HDL-C levels. Additionally, an increase in hepatic SOD activity and a decrease in MDA content were observed in the liver homogenates of mice. Furthermore, the expression levels of HO-1 and Nrf2 proteins were upregulated in liver tissue. These findings suggest that Panax notoginseng saponin extracts may ameliorate high-fat diet-induced hyperlipidemia. 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

The research on Apolipoprotein A-1 (ApoA-1), Apolipoprotein B/Apolipoprotein A-1 (ApoB/ApoA-1) ratio, and preterm birth was limited to the first and second trimesters. No studies have been conducted in the third trimester, and thus this study aimed to investigate the association between ApoA-1, ApoB/ApoA-1 ratio, and preterm birth in patients with gestational diabetes mellitus (GDM) in the third trimester. This study collected the data of single pregnant women of age at pregnancy 16-49 years with GDM who were in the third trimester and gave birth in the Obstetrics department, Hangzhou Linping District Women & Children Hospital from December 1, 2023, to April 20, 2024. The patients were divided into preterm birth group and term birth group according to whether they had preterm birth or not. The restricted cubic spline analysis was used to explore whether there was a linear relationship between ApoA-1, ApoB/ApoA-1 ratio, and preterm birth. The relationship between ApoA-1, ApoB/ApoA-1 ratio, and preterm birth in patients with GDM was explored using trend analysis. The receiver operating characteristic and Decision Curve Analysis were conducted to evaluate the predictive efficacy and clinical benefits of ApoA-1, ApoB/ApoA-1 ratio in predicting preterm birth in patients with GDM. There was a linear relationship between ApoA-1, ApoB/ApoA-1 ratio, and preterm birth. The higher the ApoA-1 level, the lower the risk of preterm birth; the higher the ApoB/ApoA-1 ratio, the higher the risk of preterm birth. ApoA-1, ApoB/ApoA-1 ratio in pregnant women with GDM in the third trimester were associated with preterm birth. Show less

Ovarian cancer presents a significant treatment challenge due to its insidious nature and high malignancy. As autophagy is a vital cellular process for maintaining homeostasis, targeting the autophagic pathway has emerged as an avenue for cancer therapy. In the present study, we identify apolipoprotein B100 (ApoB100), a key modulator of lipid metabolism, as a potential prognostic biomarker of ovarian cancer. ApoB100 functioned as a tumor suppressor in ovarian cancer, and the knockdown of ApoB100 promoted ovarian cancer progression in vivo. Moreover, ApoB100 blocked autophagic flux, which was dependent on interfering with the lipid accumulation/endoplasmic reticulum (ER) stress axis. The effects of LFG-500, a novel synthetic flavonoid, on ApoB100 induction were confirmed using proteomics and lipidomics analyses. Herein, LFG-500 induced lipid accumulation and ER stress and subsequently blocked autophagy by upregulating ApoB100. Moreover, data from in vivo experiments further demonstrated that ApoB100, as well as the induction of the lipid/ER stress axis and subsequent blockade of autophagy, were responsible for the anti-tumor effects of LFG-500 on ovarian cancer. Hence, our findings support that ApoB100 is a feasible target of ovarian cancer associated with lipid-regulated autophagy and provide evidence for using LFG-500 for ovarian cancer treatment. Show less

SORT1 (sortilin 1), a member of the the Vps10 (vacuolar protein sorting 10) family, is involved in hepatic lipid metabolism by regulating very low-density lipoprotein (VLDL) secretion and facilitating the lysosomal degradation of CES1 (carboxylesterase 1), crucial for triglyceride (TG) breakdown in the liver. This study explores whether SORT1 is targeted for degradation by chaperone-mediated autophagy (CMA), a selective protein degradation pathway that directs proteins containing KFERQ-like motifs to lysosomes via LAMP2A (lysosomal-associated membrane protein 2A). Silencing LAMP2A or HSPA8/Hsc70 with siRNA increased cytosolic SORT1 protein levels. Leupeptin treatment induced lysosomal accumulation of SORT1, unaffected by si Show less

Type 1 diabetes is a chronic, autoimmune disease characterized by the destruction of insulin-producing β-cells in the pancreas. Early detection can facilitate timely intervention, potentially delaying or preventing disease onset. Circulating proteins reflect dysregulated biological processes and offer insights into early disease mechanisms. Here, we construct a genome-wide pQTL map of 1985 proteins in 695 newborn babies (median age 2 days) at increased genetic risk of developing Type 1 diabetes. We identify 535 pQTLs (352 cis-pQTLs, 183 trans-pQTLs), 62 of which characteristic of newborns. We show colocalization of pQTLs for CTRB1, APOBR, IL7R, CPA1, and PNLIPRP1 with Type 1 diabetes GWAS signals, and Mendelian randomization causally implicates each of these five proteins in the aetiology of Type 1 diabetes. Our study illustrates the utility of newborn molecular profiles for discovering potential drug targets for childhood diseases of significant concern. Show less

Apolipoprotein C-III (APOC3) plays a crucial role in triglyceride metabolism, and its high expression leads to hypertriglyceridemia, which can contribute to an increased risk of cardiovascular disease and, when severely increased, can lead to acute pancreatitis. Loss-of-function variants in APOC3 are linked to lower triglyceride levels and reduced incidence of coronary artery disease. APOC3 mRNA, primarily synthesized by hepatocytes, is an ideal target for GalNAc-conjugated RNA-targeted therapies such as the antisense oligonucleotide (ASO) oleszarsen and small-interference RNA (siRNA) plozasiran. Herein, we systematically evaluate siRNA chemical modifications or multiple siRNAs to identify a long-acting APOC3 siRNA with a minimal number of 2'-F nucleotides. Using a series of structure-activity relationship (SAR) studies, we explored the effects of various oligonucleotide chemical modification scaffolds on siRNA potency, efficacy, and durability. These efforts led to the identification of an APOC3 targeting siRNA containing a novel chemical scaffold with robust activity and an extended duration of action in preclinical models. Additionally, selectivity and tolerability assessments in human cells, rodents, and nonhuman primates showed excellent safety and tolerability. A comparative analysis of the lead APOC3 siRNA with a surrogate of a clinical-stage APOC3 siRNA drug suggests the potential for similar or better potency and efficacy combined with less frequent dosing, potentially reducing the treatment burden on patients with hypertriglyceridemia. Show less

Heart failure with preserved ejection fraction (HFpEF) is becoming increasingly prevalent, yet clinical practice lacks specific biomarkers, early diagnostic tools, and reliable risk assessment methods. Given the growing burden of HFpEF, identifying novel diagnostic markers is crucial. This study investigates the diagnostic potential of apolipoprotein C3 (ApoC3) in HFpEF and its correlation with ventricular structure. We analyzed data from HFpEF patients admitted to the Kunshan Branch of Gusu College of Nanjing Medical University and the First People's Hospital of Kunshan (March-December 2023). Controls included HFrEF+HFmrEF patients and healthy individuals. Enzyme-linked immunosorbent assay (ELISA) was used to detect the concentration of ApoC3 in all collected cases. The receiver operating characteristic (ROC) curve was plotted to evaluate the diagnostic performance of ApoC3 alone and combined with the fibrinogen-to-albumin ratio (FAR) in plasma, and the relative wall thickness (RWT) in echocardiography for HFpEF. After exclusions, 80 HFpEF patients (39 male, 41 female), 41 HFrEF+HFmrEF patients (27 male, 14 female), and 79 healthy controls (53 male, 26 female) were included. ApoC3 levels were significantly higher in HFpEF (63136.03±12,113.07 ng/mL) than in HFrEF+HFmrEF (55580.84±13,685.35 ng/mL) and controls (53090.31±5893.25 ng/mL, P<0.001). ROC analysis demonstrated that ApoC3 alone (AUC=0.836) and the combined index (ApoC3+FAR+RWT, AUC=0.891) effectively distinguished HFpEF. Both also aided in differentiating HFpEF from HFrEF+HFmrEF (AUC=0.702 vs 0.823). ApoC3 is a promising biomarker for HFpEF diagnosis, and the combined index (ApoC3+FAR+RWT) enhances diagnostic accuracy. These findings may improve early detection and clinical management of HFpEF. Show less

Abnormal lipid accumulation is an important cause of metabolic dysfunction-associated fatty liver disease (MAFLD) progression and can induce several stress responses within cells. This study is the first to explore the role and molecular mechanism of stress granules (SGs) in MAFLD. A gene knock-down model of G3BP1, a core SG molecule in mice and HepG2 cells, was constructed to explore the role of SGs in MAFLD induced in vivo by a high-fat diet or in vitro by palmitic acid (PA). Methods included metabolic phenotyping; western blotting; qPCR; and immunofluorescence, haematoxylin/eosin and masson staining. The downstream molecules of G3BP1 and its specific molecular mechanism were screened using RNA sequencing (RNA-seq). G3BP1 and TIA1 expression were upregulated in high-fat diet-fed mouse liver tissues and PA-induced HepG2 cells, and the two molecules showed significantly increased colocalisation. G3BP1 knock-down slightly increased TIA1 expression in the livers of obese mice but not in lean mice. G3BP1 deficiency aggravated liver lipid deposition and insulin resistance in obese mice, and this phenotype was confirmed in vitro in PA-induced hepatocytes. RNA-seq demonstrated that G3BP1 slowed down MAFLD progression by inhibiting APOC3, possibly through a mechanistic suppression of APOC3 entry into the nucleus. This study reveals for the first time a protective role for SGs in MAFLD. Specifically, knocking down the core G3BP1 molecule in SGs aggravated the progression of fatty acid-induced MAFLD through a mechanism that may involve the nuclear entry of APOC3. These findings provide a new therapeutic direction for MAFLD. Show less

The Tibetan sheep is a typical hypoxia-tolerant mammal, which lives on the plateau, at an altitude of between 2500 and 5000 m above sea level; the study of its hypoxic adaptation mechanism provides a reference for exploring the hypoxic adaptation mechanism of other animals. To grope for the genetic mechanism of adaptation to the hypoxic environment at the transcriptional level in Tibetan sheep testicular tissue, and to identify candidate genes and key pathways related to sheep adaptation, histological observation of testicular tissues from two sheep breeds was carried out using haematoxylin-eosin (HE) conventional staining. A total of 103 differentially expressed genes (DEGs) were authenticated in high altitude Tibetan sheep (ZYH) and low altitude Tibetan sheep (ZYM) by RNA sequencing technology (RNA-Seq), which included 50 up-regulated genes and 53 down-regulated genes. Functional analyses revealed several terms and pathways that were closely related to testis adaptation to the plateau. Several genes (including GGT5, AGTR2, EDN1, LPAR3, CYP2C19, IGFBP3, APOC3 and PKC1) were remarkably enriched in several pathways and terms, which may impact the Plateau adaptability of sheep by adjusting its reproductive activity and sexual maturation, and protecting Sertoli cells, various spermatocytes, and spermatogenesis processes. The results make a reasonable case for a better understanding of the molecular mechanisms of adaptation to altitude in sheep. Show less

Clustered regularly interspaced short palindromic repeats-Cas13 effectors are used for RNA editing but the adeno-associated virus (AAV) packaging limitations because of their big sizes hinder their therapeutic application. Here we report the identification of the Cas13j family, with LepCas13j (529 aa) and ChiCas13j (424 aa) being the smallest and most highly efficient variants for RNA interference. The miniaturized Cas13j proteins enable the development of compact RNA base editors. Chi-RESCUE-S, by fusing dChiCas13j with hADAR2dd, demonstrates high efficiency and specificity in A-to-G and C-to-U conversions. Importantly, this system is compatible with single-AAV packaging without the need for protein sequence truncation. It successfully corrected pathogenic mutations, such as APOC3 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

As a novel member of the interleukin(IL)-1 family, IL-38 has shown therapeutic effects in various chronic inflammatory diseases. However, its role and underlying mechanisms in cardiovascular diseases, particularly atherosclerosis, remain unclear. This study aimed to explore the effects of IL-38 on atherosclerosis progression and its mechanisms in regulating macrophage function during the atherosclerotic process. To evaluate the therapeutic potential of IL-38 in atherosclerosis, we performed histopathological examinations and biochemical analyses in vivo. In vitro, we used primary bone marrow-derived macrophages (BMDMs) stimulated with oxidized low-density lipoprotein (ox-LDL) to assess the anti-inflammatory effects of IL-38 and quantified its impact on ox-LDL-induced macrophage polarization. To further elucidate the specific mechanisms by which IL-38 regulates macrophage function, we conducted mRNA sequencing and validated downstream regulatory signaling pathways. IL-38 exhibited therapeutic potential in atherosclerosis by reducing atherosclerotic plaque formation, modulating plaque composition, suppressing the production of proinflammatory cytokines within plaques, and potentially regulating macrophage cholesterol metabolism. Moreover, IL-38 exerted significant anti-inflammatory effects on macrophages both in vivo and in vitro. Notably, it inhibited the polarization of macrophages toward the proinflammatory M1-like phenotype in both settings. Additionally, IL-38 impeded the phosphorylation and nuclear translocation of p65 in BMDMs and reduced ox-LDL-induced macrophage apoptosis. IL-38 holds therapeutic potential for atherosclerosis, as it alleviates disease progression, inhibits macrophage polarization toward the M1-like phenotype, suppresses nuclear factor-κB (NF-κB) signaling activation, and reduces macrophage apoptosis. This study provides new insights into the anti-inflammatory mechanisms by which IL-38 mitigates atherosclerosis. Show less

Atherosclerosis (AS) is the leading cause of global mortality and morbidity. Despite the elevated expression of sodium-hydrogen exchanger 1 (NHE1) and olfactory receptor 2 (Olfr2) in plaque macrophages, their interactions within the AS context remain poorly understood. In this study, ApoE Show less