👤 Aiguo Ma

Obesity is a heritable disease, but its genetic basis is incompletely understood. Canine population history facilitates trait mapping. We performed a canine genome-wide association study for body condition score-a measure of obesity-in 241 Labrador retrievers. Using a cross-species approach, we showed that canine obesity genes are also associated with rare and common forms of obesity in humans. The lead canine association was within the gene DENN domain containing 1B ( Show less

Infantile hemangioma (IH) is a common benign vascular tumor in infants, often requiring intervention due to potential functional impairment and cosmetic concerns. Propranolol, a nonselective β-adrenergic receptor blocker, is the first-line therapy for IH, yet its mechanisms remain incompletely elucidated. This prospective study investigated the systemic angiogenic protein profile changes in response to propranolol in 14 treatment-naïve IH infants compared to 14 healthy controls using antibody array analysis. We identified twenty-six angiogenic proteins significantly downregulated in pretreatment IH patients compared to healthy controls. After 3 months of propranolol treatment, six proteins including HB-EGF, TGFα, ANGPTL4, Follistatin, Tie-1 and PLGF were significantly upregulated. Bioinformatic enrichment analysis revealed that these proteins are involved in key biological processes and signaling pathways, including epithelial cell proliferation, angiogenesis regulation, VEGF signaling, ERBB-EGFR axis, Ras-MAPK, and PI3K-Akt pathways. These results suggest that propranolol treatment is associated with a rebalancing of dysregulated angiogenic proteins in IH, through modulating both pro- and anti-angiogenic factors to rebalance vascular homeostasis. Our study provides novel insights into the systems-level pharmacological actions of propranolol and proposes potential biomarkers for treatment response evaluation. Show less

Gallbladder cancer (GBC) is a biliary tract cancer with a poor prognosis. Consistent evidence suggests that fasting has extensive antitumor effects in various cancers and influences levels of poly (rC)-binding protein 2 (PCBP2). However, whether fasting and PCBP2 are involved in GBC remains unknown. We assessed the expression of PCBP2 in GBC tumor tissues and cells. Knockdown and overexpression of PCBP2, combined with in vitro and in vivo assays using fasting mimic medium or diets, were conducted to provide functional significance. The effect of PCBP2 on glycolysis was assessed by glucose uptake, lactate production, oxygen consumption rate, and limiting glycolytic-associated enzymes (PDK1, PKM2, and HK-2). We found that fasting could inhibit glycolysis and cell migration/invasion in GBC cells and that fasting mimic diets could significantly inhibit GBC cell proliferation in a mouse xenograft model. PBCP2 was upregulated in GBC tumor tissues and cells. Moreover, PCBP2 is a key downstream target of fasting, and fasting decreases PCBP2 expression in GBC cells. PCBP2 knockdown inhibits GBC cell proliferation, migration/invasion, and glycolysis, whereas PCBP2 overexpression has the opposite effect. Through co-immunoprecipitation, we identified a physical connection between PCBP2 and the angiopoietin-like protein ANGPTL4. PCBP2 can negatively regulate the expression of ANGPTL4. Hence, fasting inhibits cell proliferation, migration/invasion, and glycolysis through PCBP2/ANGPTL4 signaling. We conclude that PCBP2 is a target of fasting and is involved in cell migration/invasion and glycolysis through the negative regulation of ANGPTL4 in GBC. PCBP2 represents a potential therapeutic target for GBC. Show less

The adipocyte-rich tumor microenvironment (TME) is recognized as a key factor in promoting cancer progression. A distinct characteristic of peritumoral adipocytes is their reduced lipid content and the acquisition of a proinflammatory phenotype. However, the underlying mechanisms by which adipocytes rewire metabolism and boost tumor progression in triple-negative breast cancer (TNBC) remain poorly understood. We utilized transcriptomic analysis, bioinformatic analysis, metabolic flux analysis, protein-protein docking, gene and protein expression profiling, in vivo metastasis analysis and breast cancer specimens to explore how adipocytes reprogram tumor metabolism and progression in TNBC. Our findings reveal that Angiopoietin-like 4 (ANGPTL4) exhibits significantly higher expression levels in adipocyte-rich tumor circumstance compared to the symbiotic environment lacking of adipocyte. Furthermore, ANGPTL4 expression in tumor cells is essential for adipocyte-driven glycolysis and metastasis. Interleukin 6 (IL-6), enriched in cancer-associated adipocytes, and lipolysis-derived free fatty acids (FFAs) released from adipocytes, amplify ANGPTL4-mediated glycolysis and metastasis through activation of STAT3 and PPARα pathways in TNBC cells. Additionally, ANGPTL4 interacts with transcription factor KLF4 and enhances KLF4 activity, which further drives glycolysis and metastasis, whereas KLF4 knockdown attenuates migration and glycolysis in TNBC cells. Importantly, Elevated ANGPTL4 and KLF4 expression was observed in metastatic breast cancer specimens compared to non-metastatic cases and was positively correlated with poor prognosis. Collectively, our results uncover a complex metabolic interaction between adipocytes and TNBC cells that promotes tumor aggressiveness. ANGPTL4 emerges as a key mediator in this process, making it a promising therapeutic target to inhibit TNBC progression. Show less

Hyperlipidemia is a common metabolic disorder and a risk factor for cardiovascular disease. The traditional medicine herb, Hippophae rhamnoides L., known as sea buckthorn, has anti-obesity and lipid-lowering effects, while Silybum marianum (L.) Gaertn, known as milk thistle, has hepatoprotective properties and exhibits antioxidant effects. To evaluate the effect of sea buckthorn and milk thistle solid beverage (H-S solid beverage) in alleviating hyperlipidemia in rats and explore the underlying mechanisms by analyzing plasma and liver metabolomics, lipidomics, and liver transcriptomics. A hyperlipidemic rat model was established after 2 weeks of high-fat diet (HFD) feeding in Sprague Dawley rats. The administered doses of H-S solid beverage were 0.30 g/kg/d, 0.15 g/kg/d and 0.075 g/kg/d. Serum biochemical parameter detection, histopathological section analysis, untargeted plasma and liver metabolomics, lipidomics, and liver transcriptomics were performed to determine the therapeutic effects of H-S solid beverage and predict the related pathways in rats with hyperlipidemia. Changes in genes and proteins related to lipid metabolism were detected using real-time quantitative polymerase chain reaction and western blotting. Eighty-nine components were identified in H-S solid beverage using ultra-performance liquid chromatography coupled with quadrupole time of flight mass spectrometry, with flavonoids being the major constituents. The H-S solid beverage significantly reduced body weight, liver index, body fat percentage, lipid accumulation, and liver injury in HFD-fed rats. Fatty acids (FA), bile acid, phosphatidyl ethanolamine, phosphatidylcholine, triglyceride, cholesterol ester, diglyceride and phosphatidylinositol levels were significantly altered in the liver and plasma. Moreover, the transcriptomic analysis suggested that H-S solid beverage significantly altered the hepatic gene expression of cholesterol synthesis (Pdk4, Hmgcs1, and Dhcr24), lipogenesis (Scd, Angptl4, and Angptl8), and FA β-oxidation (Cpt1α, Pparδ, Acsl, Pgc-1α, and Pla2g2d). The solid beverage of sea buckthorn and milk thistle was firstly demonstrated to ameliorate HFD-induced hyperlipidemia. The lipid-lowering and hepatoprotective effects of H-S solid beverage significantly regulated cholesterol synthesis and de novo lipogenesis, as well as FA β-oxidation. In summary, this study highlights the potential of H-S solid beverages for the treatment of hyperlipidemia. Show less

Meniscus degeneration contributes to knee arthritis progression, but the cellular and molecular mechanisms of meniscus aging remain poorly understood. We aimed to characterize age-related changes in the rat meniscus using single-cell RNA sequencing (scRNA-seq) and identify key pathogenic cell populations and pathways. Meniscal tissues from young (12 weeks) and aged (24 months) rats were processed for histology, flow cytometry, and scRNA-seq. Bioinformatics tools, including Seurat, Monocle 2, and CellChat, were used to analyze cellular composition, pseudotime trajectories, and intercellular communication. Senescence-related features and signaling pathways were evaluated. Knee joint of aged rats exhibited higher Osteoarthritis Research Society International (OARSI) scores and synovial inflammation. scRNA-seq revealed three major chondrocyte subpopulations: Sox9 + stable chondrocytes, Fndc1 + fibrochondrocytes, and Atf3 + senescent chondrocytes. Aging caused a significant increase in Atf3 + senescent chondrocytes, characterized by the expression of senescence markers (Cdkn1a/Cdkn2a) and activation of inflammatory pathways such as tumor necrosis factor (TNF) and nuclear factor-κB (NF-κB). These cells were predominantly located at the endpoint of differentiation trajectories. CellChat analysis identified the ANGPTL4-SDC4 axis as a key signaling pathway mediated by Atf3 + cells. Immunostaining confirmed elevated Angiopoietin-Like Protein 4 (ANGPTL4) expression in aged menisci. We identified Atf3 + senescent chondrocytes as a key pathogenic population in the aging meniscus, driving degeneration via the ANGPTL4 pathway. Targeting Atf3 + cells or ANGPTL4 signaling may offer new therapeutic strategies for age-related meniscus degeneration and arthritis. Show less

The escalating prevalence of diabetes-depression comorbidity (DDC) necessitates novel therapies targeting shared pathophysiological pathways, which needs to decipher the underlying molecular mechanisms. This study elucidates the therapeutic potential of chrysophanol, a natural anthraquinone, in streptozotocin (STZ) and chronic unpredictable mild stress (CUMS)-induced DDC rat model. Behavioral assessments, biochemical profiling, and integrated multi-omics analyses (RNA-seq and proteomics) were employed to decipher underlying mechanisms. Successful model establishment was confirmed by prolonged immobility time in the tail suspension test (p < 0.01) and reduced general health scores. Chrysophanol treatment restored serum brain-derived neurotrophic factor (BDNF) levels (p < 0.01) and ameliorated dyslipidemia (total cholesterol: p < 0.05). RNA-seq results revealed that chrysophanol regulated expression of hundreds of genes, which were enriched in synaptic vesicle cycling (downregulation of Sh3gl2, Camk5), CNS myelination, and axonal ensheathment pathways. Proteomic profile demonstrated the suppression of neurodegenerative markers and activation of axonal regeneration pathways. Notably, chrysophanol downregulated synaptic proteins associated with leukocyte chemotaxis (Pla2g7, Mdk) and glutamatergic synapses (Itpr2, Slc1a1) while upregulated axonal development, regeneration, and PPARγ signaling proteins (Apoa4, Apoa1, Apod), suggesting anti-inflammatory effects and disease-modifying potential through synaptic/axonal regulation. Integrated multi-omics identified overlapping targets linked to neuronal repair (Ankrd27) and iron metabolism (Fth1). These findings suggest chrysophanol as a multitarget agent alleviating DDC via synergistic restoration of neuroplasticity, suppression of neuroinflammation, and rebalancing of metabolic homeostasis, implying a mechanistic foundation for developing chrysophanol-based therapies of diabetes-associated neuropsychiatric disorders. Show less

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons in the spinal cord, brainstem, and motor cortex. This study investigates the effects of simvastatin on the G93A-copper/zinc superoxide dismutase (G93ASOD1) transgenic mouse model of ALS. The experiment included three groups: C57BL/6 wild-type mice, C57BL/6J SOD1G93A mice treated with PBS (SOD1G93A + PBS), and C57BL/6J SOD1G93A mice treated with simvastatin (SOD1G93A + simvastatin). The primary endpoints were survival rates, body weight changes, performance in pole climbing and suspension tests, and neurological deficit scores. Pathological changes were assessed using hematoxylin and eosin staining, transmission electron microscopy, Nissl staining, and Masson staining. Proteomic and metabolomic analyses were performed to identify differentially expressed proteins (DEPs) and metabolites. Quantitative real-time polymerase chain reaction and western blotting were used to measure gene expression. Although there were no significant differences in survival rates, body weight, pole climbing, and suspension test performance, or neurological deficit scores between the SOD1G93A + simvastatin and SOD1G93A + PBS groups, simvastatin treatment improved axonal organization within the spinal cord, increased the number of neurons, and reduced cytoplasmic swelling and gastrocnemius fibrosis. A total of 47 DEPs and 13 differential metabolites were identified between the SOD1G93A + PBS and SOD1G93A + simvastatin groups. Notably, the expression levels of Apoa4 and Alb were elevated in the SOD1G93A + simvastatin group compared to the SOD1G93A + PBS group. Our results suggest that simvastatin may have potential therapeutic effects in ALS, likely involving the modulation of Apoa4 and Alb expression. Show less

Patients with chronic kidney disease frequently exhibit abnormalities in their lipid metabolism. Confounding factors in observational studies often obscure the causal relationship between these 2 diseases. This study investigated the causal relationships between genetically predicted levels of 6 key lipid parameters (total cholesterol (TC), triglycerides (TG), HDL-C, low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1 (ApoA1), and apolipoprotein B (ApoB)) and circulating kidney injury molecule 1 (KIM-1) levels, using a comprehensive bidirectional Mendelian randomization (MR) analysis. Using genome-wide association study data, the primary analysis used the inverse-variance weighted (IVW) method, supported by MR-Egger regression and a weighted median estimator. Sensitivity analyses including heterogeneity, pleiotropy tests, leave-one-out, and reverse causality analyses were conducted. The IVW model revealed the following: TG (odds ratio (OR): 1.1843, 95% confidence interval (CI): 1.1178-1.2547, P = 9.5894e-09), TC (OR: 1.1096, 95% CI: 1.0178-1.2095, P = .0182), and ApoA1 (OR: 1.1820, 95% CI: 1.0741-1.3007, P = .0007) were found to have significant causal relationships with KIM-1, a biomarker of kidney tubular injury, and may be risk factors for renal tubular injury; No significant causal associations were observed between high-density lipoprotein cholesterol (HDL-C), (P = .2929), LDL-C (P = .2178), ApoB (P = .1836), and KIM-1; Horizontal pleiotropy was detected for ApoA1 (P = .0208). However, sensitivity analyses confirmed the robustness of the results after the removal of outliers; significant heterogeneity was observed across all lipid parameters (Cochran Q P < .05), which necessitated the use of random-effects IVW models; and reverse causality analyses (MR-Egger intercept P > .05, Steiger filtering) confirmed no evidence of reverse causation between lipid profiles and KIM-1. TG, HDL-C, and ApoA1 levels may be risk factors for renal tubular injury. However, no significant causal relationships were observed between HDL-C, LDL-C, and ApoB levels and renal tubular injury. To further explore the underlying mechanisms of the associations between TG, HDL-C, ApoA1, and KIM-1 and to inform lipid management strategies in tubulopathy-related conditions. Show less

Dyslipidemia and oxidative stress are key components in the pathophysiology of gestational diabetes mellitus (GDM), yet the contribution of genetic factors to these metabolic disturbances remains unclear. This study aimed to investigate the relationship between two lipid-related genetic polymorphisms, apolipoprotein C1 (apoC1) gene -317H1/H2 (rs1568822) and rs4420638, with GDM risk and lipid profiles and oxidative stress markers in Chinese populations. The apoC1 -317H1/H2 and rs4420638 polymorphisms were genotyped in 734 GDM patients and 1,102 control subjects. Genetic association with GDM risk and related traits were also analyzed. The distribution of genotype and allele in both polymorphisms were similar between the two groups. However, the combined H1H1/AG+GG genotype was significantly more frequent in women with GDM than in the control group. GDM patients who carried H1H1/AG+GG genotype were 1.97-fold increased risk to develop GDM (95% CI: 1.140-3.414, ApoC1 gene polymorphisms associate with GDM risk and affect the lipid profile. The combined H1H1/AG+GG genotype of the apoC1 gene polymorphisms appears to augment the propensity to develop GDM, while the rs4420638 polymorphism links to adverse lipid components in the patients. Further genetic studies to add information beyond the traditional risk factors in GDM and to identify risk genotypes will help in early prediction and identification of at-risk patients. Show less

Gout is a chronic inflammatory condition increasingly recognized as a risk factor for cardiovascular events (CVE). Early identification of high-risk individuals is crucial for targeted prevention and management. However, conventional risk stratification approaches often fall short in accuracy and clinical utility. This study aimed to develop and validate a robust, interpretable machine learning (ML)-based model for predicting CVE in patients with gout. This retrospective cohort study included 686 hospitalized gout patients at Xiyuan Hospital (Beijing, China) between January 1, 2013, and December 31, 2023. We applied Synthetic Minority Oversampling Technique (SMOTE) combined with random undersampling of the majority class. Then, patients were randomly divided into training (70%) and testing (30%) sets. A comprehensive set of clinical and biochemical variables (n = 39) was collected. Feature selection was performed using Boruta algorithms and Lasso to identify the most predictive variables. Multiple ML algorithms-including Decision Tree Learner, LightGBM Learner, K Nearest Neighbors Learner, CatBoost Learner, Gradient Boosting Desicion Tree Learner-were implemented to construct predictive models. SHAP values were used to assess model interpretability, and robustness was evaluated through 10-fold bootstrap resampling with enhanced standard error estimation. Of the 686 patients, 263 experienced cardiovascular events during follow-up (incidence rate: 38.3%). A logistic regression model was constructed based on eight variables selected using the Boruta feature selection algorithm: sex, age, PLT, EOS, LYM, CO2, GLU and APO-B. Among the five models evaluated, the CatBoost classifier achieved the best performance, with the highest area under the ROC curve (AUC) of 0.976 and the recall of 0.971. Furthermore, SHAP (SHapley Additive exPlanations) values were employed to provide both global and individual-level interpretability of the CatBoost model. To assess the model's generalization performance, bootstrap resampling was performed 10 times. Based on these results, the standard error was improved using machine learning-based enhancement methods, thereby optimizing the model's robustness and predictive stability. The logistic regression analysis revealed that age (OR=1.351, p<0.001), CO2 (OR=0.603, p=0.004), eosinophil count (OR=2.128, p=0.001), and platelet count (OR=0.961, p<0.001) were significantly associated with the outcome, indicating their potential roles as independent predictors. Notably, while APO_B (p=0.138) and sex (p=0.132) showed no significant association, glucose levels (OR=2.1, p=0.066) exhibited a marginal trend toward significance, warranting further investigation. This tool may support clinicians in identifying high-risk individuals, enabling early interventions and optimized management strategies. This study has several limitations. First, the analysis was based on a single-center dataset, which may limit the generalizability of the findings. External validation in multi-center and prospective cohorts, along with an expanded sample size, is warranted to confirm these results. Second, key confounding factors such as medication use, lifestyle habits, and gout flare frequency were not included in the analysis; future studies should incorporate these variables to provide a more comprehensive assessment. Show less

The spleen is essential for immunity, mediating host defense against pathogens and regulating immunological homeostasis. Western-style diets commonly cause the aggregation of body fat and the emergence of obesity. This state might lead to damage to the spleen's functions. However, the effects of Western-style diets on gene expression and metabolic regulation in the spleen have not yet been fully explored. In this study, 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

Several protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to significantly reduce low-density lipoprotein cholesterol (LDL-C) levels in statin-intolerant patients, but none have been verified in Chinese patients. This study aimed to evaluate the efficacy and safety of ongericimab, a novel PCSK9 monoclonal antibody, in Chinese statin-intolerant patients with primary hypercholesterolemia or mixed dyslipidemia. This was a randomized, multicenter, double-blind, placebo-controlled phase 3 study designed to enroll 120 statin-intolerant adult patients. Eligible patients were randomly assigned in a 2:1 ratio to receive ongericimab 150 mg or placebo subcutaneously every 2 weeks for 12 weeks in the double-blind treatment period, followed by 40 weeks of ongericimab treatment during the open-label period. The primary endpoint was a percentage change in LDL-C from baseline to week 12. The key secondary endpoints included percentage change from baseline to week 12 in non-high density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), total cholesterol (TC), and lipoprotein(a) [Lp(a)]. From February 6, 2023, to September 23, 2024, a total of 139 patients were enrolled. The least-squares (LS) mean difference between ongericimab and placebo groups in LDL-C from baseline to week 12 was -66.2 % (95 % CI: 74.2 %, -58.2 %; p < 0.0001), with reductions sustained up to week 52. Ongericimab also significantly reduced levels of non-HDL-C, ApoB, TC, and Lp(a). The overall incidence of treatment-emergent adverse events was comparable between the ongericimab and placebo groups. Ongericimab significantly reduced LDL-C as well as other atherogenic lipid levels and was well tolerated in Chinese statin-intolerant patients with primary hypercholesterolemia or mixed dyslipidemia. http://www. gov; Unique Identifier: NCT05621070. Show less

Crystals or stones within the gallbladder wall in patients with gallbladder stones (GBS) have been occasionally reported, but their clinical features and aetiology remain unclear. This retrospective study analysed 323 consecutive patients with GBS who underwent rigid choledochoscopic gallbladder-preserving cholecystolithotomy to determine the detection rate, clinical features, and potential risk factors of gallbladder intramural stones (IS). IS were found in 24.1% (78/323) of patients, characterised by distinct cholangioscopic findings, including stone shadows, yellow floating bands, or a combination of both within the gallbladder wall. Compared to patients without IS, those with IS had a higher prevalence of Clonorchis sinensis (C. sinensis) eggs (60.3% vs. 40.8%, P < 0.05) and elevated serum cholesterol, LDL cholesterol, and Apo-B levels (P < 0.05). However, stone composition and C. sinensis egg detection rates did not differ between intraluminal stones and IS within the same patient (P > 0.05). Logistic regression analysis revealed that IS were associated with C. sinensis infection and elevated Apo-B levels. In conclusion, IS share homology with intraluminal stones in the same patient with GBS and exhibit unique appearances in rigid choledochoscopy. For patients with GBS and IS, elevated serum Apo-B levels and C. sinensis infection were independent risk factors. Show less

Mixed dyslipidaemia, characterised by elevated concentrations of circulating triglycerides and LDL cholesterol (LDL-C), is associated with an increased risk of atherosclerotic cardiovascular disease. Solbinsiran, a GalNAc-conjugated small interfering RNA targeting hepatic angiopoietin-like protein 3 (ANGPTL3), reduced triglycerides and LDL-C concentrations in a phase 1 study. This study aimed to assess the durability and efficacy of solbinsiran in reducing concentrations of atherogenic lipoproteins in adults with mixed dyslipidaemia. This double-blind, parallel-arm, randomised, placebo-controlled, phase 2 trial enrolled adults (aged ≥18 years) with mixed dyslipidaemia at 41 clinical research units across seven countries. Patients receiving moderate-intensity or high-intensity statins, and with concentrations of fasting triglycerides between 1·69 mmol/L and 5·64 mmol/L, LDL-C of at least 1·81 mmol/L, and non-HDL cholesterol of at least 3·36 mmol/L were included. Using an interactive web-response system, patients were randomly assigned (1:2:2:2) to receive either solbinsiran 100 mg, solbinsiran 400 mg, solbinsiran 800 mg, or placebo, by subcutaneous injection on days 0 and 90. Patients were followed up for at least 270 days. The primary outcome was percent change in apolipoprotein B (apoB) concentration from baseline to day 180 with solbinsiran compared with placebo, analysed under an efficacy estimand (in patients who received at least one dose of the study drug). This trial is completed and registered with ClinicalTrials.gov, NCT05256654. Of 585 patients screened, 205 patients were enrolled in the study between July 20, 2022, and March 4, 2024. Patients (111 [54%] female and 94 [46%] male; median age 57 years [IQR 49-65]) were randomly assigned to receive solbinsiran 100 mg (n=30), solbinsiran 400 mg (n=58), solbinsiran 800 mg (n=59), or placebo (n=58). At baseline, median concentrations were 111 mg/dL (IQR 96-130) for apoB, 2·64 mmol/L (2·06-3·29) for triglycerides, and 3·16 mmol/L (2·57-3·82) for LDL-C. The placebo-adjusted percent change in apoB concentration from baseline at day 180 was -2·8% (95% CI -15·5 to 11·9; p=0·69) for solbinsiran 100 mg; -14·3% (-23·6 to -3·9; p=0·0085) for solbinsiran 400 mg; and -8·3% (-18·3 to 2·9; p=0·14) for solbinsiran 800 mg. Solbinsiran administration was well tolerated, with a low incidence of adverse events. The number of patients with treatment-emergent adverse events was 18 [60%] of 30 patients in the solbinsiran 100 mg group, 30 [52%] of 58 patients in the solbinsiran 400 mg group, 26 [44%] of 59 patients in the solbinsiran 800 mg group, and 37 [65%] of 57 patients in the placebo group. Solbinsiran 400 mg reduced apoB in patients with mixed dyslipidaemia and was generally well tolerated. The impact of solbinsiran on cardiovascular outcomes remains to be investigated. Eli Lilly and Company. Show less

The incidence of Type 2 Diabetes Mellitus (T2DM) continues to rise steadily, significantly impacting human health. Early prediction of pre-diabetic risks has emerged as a crucial public health concern in recent years. Machine learning methods have proven effective in enhancing prediction accuracy. However, existing approaches may lack interpretability regarding underlying mechanisms. Therefore, we aim to employ an interpretable machine learning approach utilizing nationwide cross-sectional data to predict pre-diabetic risk and quantify the impact of potential risks. The LASSO regression algorithm was used to conduct feature selection from 30 factors, ultimately identifying nine non-zero coefficient features associated with pre-diabetes, including age, TG, TC, BMI, Apolipoprotein B, TP, leukocyte count, HDL-C, and hypertension. Various machine learning algorithms, including Extreme Gradient Boosting (XGBoost), Random Forest (RF), Support Vector Machine (SVM), Naive Bayes (NB), Artificial Neural Networks (ANNs), Decision Trees (DT), and Logistic Regression (LR), were employed to compare predictive performance. Employing an interpretable machine learning approach, we aimed to enhance the accuracy of pre-diabetes risk prediction and quantify the impact and significance of potential risks on pre-diabetes. From the China Health and Nutrition Survey (CHNS) data, a cohort of 8,277 individuals was selected, exhibiting a disease prevalence of 7.13%. The XGBoost model demonstrated superior performance with an AUC value of 0.939, surpassing RF, SVM, DT, ANNs, Naive Bayes, and LR models. Additionally, Shapley Additive Explanation (SHAP) analysis indicated that age, BMI, TC, ApoB, TG, hypertension, TP, HDL-C, and WBC may serve as risk factors for pre-diabetes. The constructed model comprises nine easily accessible predictive factors, which prove highly effective in forecasting the risk of pre-diabetes. Concurrently, we have quantified the specific impact of each predictive factor on the risk and ranked them based on their influence. This result may serve as a convenient tool for early identification of individuals at high risk of pre-diabetes, providing effective guidance for preventing the progression of pre-diabetes to T2DM. Show less

Rotator cuff tear is the most common tendon injury. Currently, arthroscopic rotator cuff repair (ARCR) is the primary method for diagnosing and treating rotator cuff tear. One of the major complications following ARCR is retear. This study aims to evaluate the correlation between systemic lipid metabolism and retear occurrence after ARCR through a retrospective analysis of postoperative patients. This retrospective study reviewed consecutive patients of a single surgeon who underwent ARCR from January 2021 to January 2022. Eligibility for inclusion required complete sequential follow-up data, encompassing preoperative laboratory tests and a series of postoperative magnetic resonance imaging (MRI) evaluations at 1, 2, 3, and 6 months. Exclusion criteria included patients with incomplete laboratory tests, a history of tumors, prior shoulder surgeries, isolated subscapularis tendon tears, the rotator cuff related muscles are not clearly or completely displayed in MRI, absence of follow-up MRI, or those under treatment with lipid-lowering medications. Logistic regression analysis was employed to identify preoperative factors associated with retear, with statistical significance adjudged at P < .05. From the initial cohort of 400 patients who underwent ARCR during the study period, 202 met both inclusion and exclusion criteria. These patients were subsequently divided into a training group (n = 122) and a test group (n = 80), maintaining a ratio of 6:4. Statistical analysis revealed significant risk factors for post-ARCR retear including high body mass index (>27.1; odds ratio (OR): 5.994, 95% confidential interval (CI): 1.762-13.980; P = .042), subscapularis muscle fatty infiltration of Grades 3 and 4 (OR: 8.509, 95%CI: 3.811-17.702; P = .009), serum apolipoprotein B (ApoB) levels exceeding 1.4 g/L (OR: 9.658, 95%CI: 3.520-21.753; P = .028), and an ApoB/A1 ratio greater than 1.8 (OR: 5.098, 95%CI: 1.787-10.496; P = .016). Conversely, the serum high-density lipoprotein level above 1.2 mmol/L (OR: -3.342, 95%CI: -7.466 to 0.659; P = .039) served as a protective factor. The model incorporating these 5 factors predicted retear with a sensitivity of 78.3% and specificity of 98.0% (area under the curve = 0.924, accuracy = 90.3%). Moreover, a new model comprising 3 lipid metabolism-related factors including high-density lipoprotein, ApoB and the ApoB/A1 ratio showed a sensitivity of 80.5% and specificity of 83.2% (area under the curve = 0.866, accuracy = 85.8%) for predicting retear after ARCR. A predictive model utilizing key systemic lipid metabolism markers including HDL, ApoB, and the ApoB/A1 ratio, demonstrates effective forecasting of retear incidence following ARCR. Show less

In preliminary research and literature review, we identified a potential link between chronic obstructive pulmonary disease (COPD) and lipid metabolism. Therefore, this study employed Mendelian randomization (MR) analysis to investigate the potential causal connection between blood lipids and COPD. A genome-wide association study (GWAS) on COPD was conducted, encompassing a total of 112,583 European participants from the MRC-IEU. Additionally, extensive UK Biobank data pertaining to blood lipid profiles within European cohorts included measurements for low-density lipoprotein cholesterol (LDL-C) with 440,546 individuals, high-density lipoprotein cholesterol (HDL-C) with 403,943 individuals, triglycerides (TG) with 441,016 individuals, total cholesterol (TC) with 187,365 individuals, apolipoprotein A-I (apoA-I) with 393,193 individuals, and apolipoprotein B (apoB) with 439,214 individuals. Then, MR analyses were performed for lipids and COPD, respectively. The primary analytical technique employed was the inverse-variance weighted (IVW) approach, which included a 95% confidence interval (CI) to calculate the odds ratio (OR). Additionally, a sensitivity analysis was conducted to assess the dependability of the MR analysis outcomes. MR analysis was primarily based on IVW, unveiled a causal link between COPD and LDL-C (OR=0.994, 95% CI (0.989, 0.999), P=0.019), TG (OR=1.005, 95% CI (1.002, 1.009), P=0.006), and apoA-I (OR=0.995, 95% CI (0.992, 0.999), P=0.008), in addition, no causal link was found with HDL-C, TC, apoB. Sensitivity analysis demonstrated the robustness of these causal relationships. However, through multivariate MR(MVMR) and multiple testing correction, LDL-C and TG had no causal effect on the outcome. ApoA-I remained a protective factor for the risk of COPD (OR=0.994, 95% CI (0.990-0.999), P=0.008). Through MR analysis, this study offers evidence of a causal link between apoA-I with COPD. This further substantiates the potential role of lipid metabolism in COPD, and has significant clinical implications for the prevention and management of COPD. Show less

Elevated lipoprotein(a) (Lp[a]) and apolipoprotein B (apoB) are individually associated with the risk of atherosclerotic cardiovascular disease (ASCVD). Moreover, previous basic research has implicated the potential interaction between apoB and Lp(a) in the atherogenic process. We aimed to determine whether apoB levels significantly modulate ASCVD risk associated with Lp(a) in a large community-based population without baseline cardiovascular disease. Plasma Lp(a) and apoB were measured in the Atherosclerosis Risk in Communities (ARIC) study. Elevated Lp(a) was defined as the highest race-specific quintile, and elevated apoB was defined as ≥89 mg/dl (median value). The modifying effect of apoB on the Lp(a)-related risk of ASCVD and coronary heart disease (CHD) was determined using Cox regression models adjusted for cardiovascular risk factors. Among 12,988 ARIC participants, 3,888 ASCVD events and 1754 CHD events were observed. Elevated apoB (≥89 mg/dl) and elevated Lp(a) (race-specific quintile 5) were independently associated with ASCVD (hazard ratio [HR]: 1.19; 95% CI: 1.08-1.30; P <0.001; HR: 1.27; 95% CI: 1.16-1.40; P < .001, respectively). Lp(a)-by-apoB interaction was noted [Lp(a) (quintile 1-4 or quintile 5) * apoB (<89 or ≥89 mg/dl) = 0.002]. Compared to the concordantly low Lp(a) group, the individuals with high Lp(a) had a greater ASCVD risk only when apoB was elevated (HR: 1.48; 95% CI: 1.34-1.63; P < .001). In the context of primary prevention, ASCVD risk associated with Lp(a) was observed only when apoB was elevated. The measurement of apoB can further refine and contextualize the ASCVD risk associated with Lp(a). Show less

The association between apolipoprotein B (apoB) and residual cardiovascular (CV) risk in patients with chronic coronary syndrome (CCS) remains unclear. We aimed to investigate the association between apoB levels and CV outcomes in statin-treated CCS patients. We enrolled 8641 statin-treated CCS patients at Fuwai Hospital. The patients were divided into 5 groups based on to apoB quintiles (Q1 to Q5). The primary endpoint was 3-year CV events, including CV death, nonfatal myocardial infarction, and nonfatal stroke. During a median follow-up of 3.17 years, there were 232 (2.7%) CV events. After multivariable adjustment, a restricted cubic spline illustrated a J-shaped relationship between apoB levels and 3-year CV events, with the risk remaining flat until apoB levels exceeded 0.73g/L, after which the risk increased (nonlinear P <.05). Kaplan-Meier curves showed the lowest CV event rate in the Q3 group (0.68-0.78g/L). Compared with the Q3 group, multivariable Cox regression models revealed that both low (Q1, ≤0.57g/L) and high (Q5, >0.93g/L) apoB levels were associated with an increased risk of major adverse cardiac events (all P <.05). Notably, patients with low apoB levels (Q1) had the highest risk of CV death (HR, 2.44; 95%CI, 1.17-5.08). Our analysis indicates that both low and high levels of apoB are associated with elevated CV risk, with the risk being particularly pronounced at higher levels (> 0.73g/L). Show less

Recurrent implantation failure (RIF) is a complex and poorly understood clinical disorder characterized by failure to conceive after repeated embryo transfers. Endometrial receptivity (ER) is a prerequisite for implantation, and ER disorders are associated with RIF. However, little is known regarding the molecular mechanisms underlying ER in RIF. In the present study, RNA sequencing data from the mid-secretory endometrium of patients with and without RIF were analyzed to explore the potential long non-coding RNAs (lncRNAs) and messenger RNAs (mRNAs) involved in RIF. The analysis revealed 213 and 1485 differentially expressed mRNAs and lncRNAs, respectively (fold change ≥ 2 and p < 0.05). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated that these genes were mostly involved in processes related to immunity or inflammation. 5 key genes (TTR, ALB, TF, AFP, and CFTR) and a key module including 14 hub genes (AFP, ALB, APOA1, APOA2, APOB, APOH, FABP1, FGA, FGG, GC, ITIH2, SERPIND1, TF and TTR) were identified in the protein-protein interaction (PPI) network. The 5 key genes were used to further explore the lncRNA-miRNA-mRNA regulatory network. Finally, the drug ML-193 based on the 14 hub genes was identifed through the CMap. After ML-193 treatment, endometrial cell proliferation was increased, the hub genes were mostly down-regulated, and the ER marker HOXA10 was up-regulated. These results offer insights into the regulatory mechanisms of lncRNAs and mRNAs and suggest ML-193 as a therapeutic agent for RIF by enhancing ER. Show less

Lipid metabolism may be linked to chronic gastritis, but its causal role remains unclear. While current research emphasizes inflammation, mucosal changes, immune regulation, genetics, and the gut microbiota, the contribution of lipid metabolism is understudied. This study aims to evaluate the impact of serum lipids and the mechanistic roles of lipid-lowering drug targets in chronic gastritis. We conducted a cross-sectional study using data from real world. Multivariable logistic regression was performed to assess the association between serum lipid profiles and gastritis. Mendelian randomization (MR) analyses based on genome-wide association study (GWAS) datasets were performed to detect the causal relationship of serum lipids, plasma lipid species, and lipid-lowering drug targets. Experimental validation was conducted using high-fat diet (HFD)-fed mice and chemically induced CAG rat models. Four thousand sixty one person, including 1,023 patients with chronic atrophic gastritis (CAG), 1,742 with non-atrophic gastritis (NAG), and 1,296 as healthy population were included in the analysis. Through covariates adjustment, TC, ApoA1, and HDL-C showed to be associated with an increased risk of chronic gastritis, whereas TG exhibited a protective effect. MR analysis confirmed a significant inverse causal relationship between TG and gastritis (OR = 0.889, 95% CI: 0.825-0.958). Ten plasma lipid species and lipid-lowering gene targets, including LPL and APOC3, were identified as causally associated with disease risk. Mediation analysis revealed six plasma lipid species as potential intermediaries linking genetic variation to gastritis. In vivo experiments demonstrated progressive hepatic steatosis and mild gastric mucosal changes in HFD-fed mice. Immunohistochemical analysis further revealed a significant reduction in LPL and APOC3 expression in gastric tissue (P < 0.05). In the CAG rat model, histological analysis revealed hepatocyte disarray, edema, and gastric mucosal atrophy. Elevated levels of TNF-α, IL-6, IL-1β and decreased levels of GAS-17 and PG I/II were also observed (P < 0.05). Western blot analyses further confirmed the downregulation of LPL and APOC3 expression in gastric tissue (P < 0.05). This study provides genetic and experimental evidence, supporting a causal role of lipid metabolism in chronic gastritis. LPL and APOC3 are implicated in its pathogenesis, highlighting potential lipid-targeted strategies for prevention and treatment. 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

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

Current evidence suggests that apolipoprotein E (APOE) is associated with lipid metabolism, cardiovascular diseases, and neurodegenerative disorders. However, the physiological pathways of APOE-mediated inflammation remain incompletely elucidated, and a specific inflammatory marker that captures the pro-inflammatory activity of the APOE ε4 allele remains elusive. As a composite peripheral blood biomarker, Systemic immune-inflammation index (SII) is a novel marker of inflammation. This study aimed to investigate the association between APOE alleles and Systemic Immune-Inflammation Index. A total of 13,926 participants (9,098 males and 4,828 females) were recruited from The People’s Liberation Army General Hospital (November 2017 to July 2019). APOE alleles (ε2, ε3, and ε4) were determined by genotyping rs429358 and rs7412 SNPs. SII was calculated as (platelet count × neutrophil count)/lymphocyte count. Multivariable linear regression models (adjusted for demographics, lifestyle, and clinical covariates) and subgroup analyses were performed to assess the APOE-SII associations, with ε3 as the reference. The frequencies of APOE alleles ɛ3, ɛ2, and ɛ4 were70.7%, 13.8%, and 15.5% respectively in 13,926 Chinese patients. The mean SII was lower in ɛ2 carriers than in ɛ3 (373.74*10⁹/L vs. 403.53*10⁹/L, APOE contributes to elevated disease risk by inducing a state of chronic low-grade inflammation, resulting from modulation of both adaptive and innate immune responses. Show less

Cholesterol plays a crucial role in regulating synaptic membrane fluidity and ion channels. Due to the blood-brain barrier, cholesterol in the brain is primarily self-synthesized by astrocytes. However, limited research has been conducted on the effects of polystyrene nanoplastic (PS-NPs) on intracranial cholesterol metabolic pathways. In this study, we exposed whole-brain organoids (WBOs) to PS-NPs and identified significant changes in endoplasmic reticulum stress and cholesterol biosynthesis pathways through whole-transcriptome sequencing. To investigate potential mechanisms of altered cholesterol pathways, we constructed a Transwell neuronal-astrocyte co-culture model. Results demonstrated that PS-NPs induced significant endoplasmic reticulum stress in astrocytes, specifically manifested by elevated levels of ATF4 and CHOP, along with increased autophagy indicated by the elevated LC3-II/I ratio. PS-NPs significantly inhibited the AKT/ACLY pathway of cholesterol biosynthesis, leading to marked reductions in acetyl-CoA and cholesterol within astrocytes (P < 0.05). In addition, PS-NPs led to a significant reduction of apolipoprotein APOE, which hindered cholesterol transport and ultimately inhibited synaptin (SYN) formation. In summary, PS-NPs induce endoplasmic reticulum stress and autophagy in astrocytes, impair cholesterol de novo synthesis and apolipoprotein-mediated transport, ultimately inhibiting neuronal synaptogenesis. Furthermore, specific inhibition of ERs restored cholesterol synthesis in astrocytes and neuronal synapses. This study demonstrates that PS-NPs produce neurotoxic effects by affecting cholesterol homeostasis in the brain. Show less

Many patients are suffering from atherosclerosis without typical risk factors, which can cause severe cardiovascular complications. Trimethylamine N-oxide (TMAO), derived from gut microbes, is a key unconventional contributor to the development of atherosclerosis. Here we present a strategy performed by orally administered nano-functionalized probiotics (PDMF@LGG) to inhibit TMAO through the gut microbiota-trimethylamine (TMA)-TMAO axis. PDMF@LGG, composed of polydopamine-coated Lacticaseibacillus rhamnosus GG and nanoparticles based on a reactive oxygen species (ROS)-responsive polymeric prodrug of fluoromethylcholine (FMC), can promote the retention of probiotics and nanoparticles in the intestine to persistently scavenge elevated ROS and release drugs. This process suppresses TMA production and absorption, lowering plasma TMAO levels. The therapeutic effects on male ApoE Show less