👤 Xiaofeng Yuan

This article presents a case of a rare lymphoplasmacytic lymphoma (LPL) complicated by spherocytosis in a 74-year-old male. The patient reported progressive fatigue and anemia and had a medical history of type 2 diabetes, hypertension, and cerebral infarction. Laboratory tests indicated moderate anemia (hemoglobin 80 g/L) and a monoclonal increase in serum IgG. A bone marrow biopsy combined with immunohistochemistry confirmed the diagnosis of lymphoplasmacytic lymphoma (IgG-κ type, MYD88 L265P negative). A peripheral blood smear revealed an increase in spherocytes, a positive acidified glycerolysis test (AGLT50), abnormal erythrocyte osmotic fragility, and a negative direct antiglobulin test. Genetic screening for hereditary erythrocyte diseases showed no pathogenic variations. The patient's condition stabilized following targeted therapy with zanubrutinib and rituximab (ZR regimen). This case underscores the complexity of diagnosing dual hematological anomalies, highlights the importance of multidisciplinary collaboration, and seeks to explore the potential pathophysiological link between LPL and spherocytosis, offering a reference for diagnosis and treatment in similar clinical scenarios. Show less

To investigate the toxic effects of PFNA on aquatic organisms, this study used large yellow croaker (L. crocea) as a model and examined the impacts of 1000 ng/L PFNA exposure for 3, 7, and 14 days on the hepatic and intestinal systems. Histopathological examination, transcriptomic profiling, and 16S rRNA gene sequencing were employed to evaluate tissue damage, gene expression changes, and gut microbial alterations. The results revealed that PFNA exposure induced progressive histopathological changes in the liver, including nuclear enlargement and vacuolization, with increasing severity over time. In the intestine, PFNA caused structural damage to villi, characterized initially by vacuolization and subsequently by erosion, swelling, and dissolution as exposure duration increased. Transcriptomic analysis of liver showed early activation of the peroxisome proliferator-activated receptor (PPAR) signaling pathway, followed by the predominant enrichment of the phosphatidylinositol-3-kinase/protein kinase B (PI3K-Akt) pathway at later stages. These findings suggest a "two-phase" mechanism by which PFNA disrupted lipid and carbohydrate metabolism. Gut microbiota analysis showed that PFNA exposure significantly reduced α-diversity, increased the abundance of Proteobacteria, enriched opportunistic pathogens such as Vibrio spp., and altered functional profiles related to amino acid and carbohydrate metabolism. Correlation analysis identified significant associations between specific gut microbial taxa (e.g., Deferribacterota, Dependentiae) and the expression levels of key hepatic metabolic genes (lpl, foxo3), suggesting a potential mediating role of the gut-liver axis in PFNA-induced hepatotoxicity. From the perspective of aquaculture, this study provided a view of metabolic disruption and host-microbe interaction caused by PFNA. It contributes critical scientific evidence for assessing the ecological risks of per- and polyfluoroalkyl substances (PFAS) in aquatic environments. Show less

Excessive fat deposition compromises the health of companion animals and the carcass quality of food-producing livestock. Follicle-stimulating hormone (FSH) has been demonstrated to play a critical regulatory role in fat deposition, with its function dependent on binding to its cognate receptor (FSHR) in target organs. In this study, female Sprague-Dawley (SD) rats were immunized with subunit vaccines targeting FSHβ and FSHR, respectively, and obesity was induced by a high-fat diet (HFD) to investigate the effects of these vaccines on adipose deposition in female mammals. The results revealed that active immunization against FSHβ and FSHR effectively suppressed HFD-induced obesity and the elevated serum triglyceride levels. Histological observations found that FSHβ and FSHR immunity decreased adipocyte hypertrophy and increased the cross-sectional area of skeletal muscle fibers caused by HFD, partially ameliorated HFD-associated hepatic sinusoidal spaces and vacuolated steatosis in the cytoplasm. RT-qPCR results indicated that FSHβ and FSHR immunization inhibited lipid synthesis by downregulating adipogenic-related genes, including C/ebpα, Creb, Pparγ, Lpl, and Perilipin. These findings suggest that both vaccines can mitigate HFD-induced adipose deposition in rats, with the FSHR vaccine exhibiting more pronounced effects. This study provides a novel strategy to mitigate pet health deterioration caused by excessive obesity and the decline in carcass quality of food-producing livestock. Show less

Sleep is essential for health and regulated by genetic and environmental factors. We perform genome-wide association studies of device-measured sleep duration, efficiency, and accelerometer-derived rapid eye movement (REM) and non-rapid eye movement (NREM) sleep in 80,013 UK Biobank participants. We identify 20 autosomal loci, 12 of which have not been previously reported, including genome-wide significant associations for REM and NREM sleep duration. MEIS1 shows strong opposing effects on REM and NREM durations and is intolerant to loss-of-function mutations, suggesting an essential role in the regulation of REM/NREM sleep balance. Functional enrichment analysis identifies statistically significant pathways related to chromatin remodelling, lipid metabolism, and metal ion homeostasis while tissue enrichment analysis highlights significant signals in the hypothalamus and frontal cortex. Sex-stratified analyses identify distinct loci, including FOXP2 and NRXN3 in females and LRP1B, NPBWR2, and PABPC4 in males. Mendelian randomization supports associations between shorter sleep duration and higher cardiometabolic risk. These findings highlight sex- and phase-specific regulators of human sleep architecture, providing biological insights and potential therapeutic targets. Show less

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a globally prevalent disease, yet its genetic architecture remains incompletely characterized. We integrated genome-wide association study data from multiple cohorts totaling nearly 3 million individuals of European ancestry and applied cross-trait genomic modeling of hepatic fat and seven cardiometabolic traits to construct an MASLD-specific polygenic architecture. We identified 128 risk variants across 100 loci and prioritized 55 effector genes, including established (e.g., Show less

Glaucoma is a leading cause of irreversible blindness, yet the circulating proteins and metabolic pathways that causally contribute to different glaucoma subtypes remain poorly defined. We analyzed baseline plasma proteomics in 1485 glaucoma cases (447 primary open‑angle glaucoma [POAG], 177 primary angle-closure glaucoma [PACG], 120 normal-tension glaucoma [NTG]) in the UK Biobank using Cox models with graded adjustment. We then integrated five independent protein quantitative trait loci resources with FINLAND R12 genome-wide association study data to perform two‑sample Mendelian randomization (MR) and cross‑cohort meta‑analysis for overall glaucoma and each subtype. To prioritize effector genes and pathways, we conducted summary-data-based Mendelian randomization (SMR) using eQTLGen and two‑step mediation MR using metabolite quantitative trait loci data for ∼1400 plasma metabolites from the Canadian Longitudinal Study on Aging cohort. In fully adjusted Cox models, 484 proteins were associated with incident glaucoma, 135 with NTG, 59 with POAG, and 1 with PACG (false discovery rate <0.05). Multicohort MR and meta‑analysis identified eight proteins with robust causal effects: NRP2, TSPAN1, and HAVCR2 for overall glaucoma; NRXN3 for PACG; MANSC4 for NTG; and LTBP2, CD69, and SMAD1 for POAG. SMR supported NRP2 (overall glaucoma) and SMAD1 (POAG) as causal genes. Mediation MR revealed that sphingomyelins, acylcarnitines, and bile acid-related metabolites partially mediated the effects of several proteins, defining shared (e.g., sphingolipid) and subtype‑specific metabolic pathways. By integrating epidemiologic, proteomic, genetic, and metabolomic data, we identify convergent systemic protein and metabolic signatures associated with glaucoma susceptibility and its clinical subtypes. These findings nominate NRP2, SMAD1, and related pathways as promising biomarkers and therapeutic targets and support a systems‑level view of glaucoma pathogenesis beyond intraocular pressure alone. Show less

Male infertility affects approximately one in seven couples worldwide. Prenatal cadmium (Cd) exposure has been shown to affect offspring phenotypes and increase susceptibility to diseases later in life. However, the effects of prenatal Cd exposure on multi-generational offspring fertility and the mechanisms remain unknown. A novel murine multi-generational (F1-F3 offspring) male subfertility model induced by prenatal Cd exposure was developed. The levels of testosterone and steroidogenic enzymes were also lower in these offspring's testes. The ubiquitin-dependent degradation of NR4A1, the upstream transcription factor regulating steroidogenic enzymes, was enhanced across generations upon prenatal Cd exposure. After treatment with MG132, an inhibitor of the ubiquitin-proteasome system, the levels of NR4A1 and steroidogenic enzymes were higher in offspring testes with prenatal Cd exposure. Based on the analysis of the UbiBrowser database and testicular global transcriptome, RAPSN was identified as a novel ubiquitin E3 ligase containing the RING-H2_Rapsyn domain that mediates multi-generational testicular NR4A1 ubiquitination. m Show less

Autophagy regulates intermittent hypoxia (IH)-induced obstructive sleep apnea-hypopnea syndrome (OSAHS). We investigated the effects of IH and its withdrawal on cognitive function, autophagy, and lysophagy in OSAHS. An OSAHS rat model was established, and rats were divided into five groups: normoxia control, IH-4w (4-week IH), IH-6w (6-week IH), IH-8w (8-week IH), and IH-8w + 4w (8-week IH and 4-week normoxia). The cognitive behavior; mitochondrial and lysosomal morphology of the hippocampal tissue; mitochondrial respiratory function, permeability, and membrane potential; lysosomal function; autophagy- and lysophagy-related protein levels; and hypoxia-associated autophagy gene expression in rats were assessed. The cognitive function of rats in the IH-4w, IH-6w, and IH-8w groups was significantly impaired. In IH-8w cells, mitochondrial function was damaged with swollen morphology and decreased quantity, respiration, permeability, and membrane potential, along with significantly increased mitophagy-related protein ATG5 and LC3II/LC3 levels and decreased p62 levels. Expression of hypoxia-associated autophagy genes Becn1, Hif1, Bnip3, Bnip3l, and Fundc1 was significantly higher in the IH-8w group. Significantly increased LAMP2, CTSB, and ACP2 levels in IH-8w cells further indicated impaired lysosomal function. Lysophagy-related protein LAMP1, LC3II/LC3I, and TFEB levels were significantly increased in the IH-8w group, whereas p62 level was significantly decreased. The above listed evidence indicated damage to the mitochondria and lysosomes, as well as stimulation of mitophagy and lysophagy in IH-treatment OSAHS rat model. After withdrawing IH and culturing for 4 weeks in normal conditions, the cognitive function of rats improved, and mitophagy and lysophagy decreased. Our findings indicate that IH impairs cognitive function and promotes mitophagy and lysophagy in an OSAHS rat model, and IH withdrawal recovered the above effects. Show less

Adipose tissue-derived mesenchymal stromal/stem cells (ASCs) possess regenerative potential. Obesity induces a pro-inflammatory environment that compromises their function. Here we investigate how obesity affects ASC biology, focusing on primary cilia. Our data show that obesity alters ASC gene expression, particularly in pathways related to the extracellular matrix, transforming growth factor-β (TGFβ) signaling, cell motility, and differentiation. The gene levels of regulatory factor X2 (RFX2) and adenylate cyclase 3 (ADCY3), important for ciliary biogenesis, are downregulated in obese ASCs. TGFβ treatment significantly decreases the expression of RFX2 and ADCY3 in lean ASCs. Knockdown of ADCY3 reduces primary cilium length, whereas pharmacological activation restores it and improves cell motility. These results suggest that obesity impairs ASC ciliary function, contributing to defective adipogenesis and reduced regenerative capacity. Restoring ADCY3 activity partially rescues ciliary integrity and cellular function, highlighting the role of primary cilia in ASC dysfunction and offering potential therapeutic targets for obesity-related disorders. Show less

Previous experiments have demonstrated that BGM0504, a GLP-1R/GIPR dual agonist drug by molecular dynamics-guided optimization, had enhanced agonistic activity compared to tirzepatide. This study aims to investigate its safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) in Chinese healthy volunteers. A randomized, double-blind, placebo-controlled and dose-escalation Phase I study was conducted as follows: a single dose (2.5 mg) and once-weekly administration for 2 weeks to reach target doses (5, 10 and 15 mg) by titration. A total of 40 volunteers received at least one dose of BGM0504 or placebo. The PK profile of BGM0504 was investigated over a wide dose range and supported once-weekly administration. It was observed that C BGM0504 was generally safe and well tolerated with favourable PK profile and potential role in weight loss was also confirmed. These findings support subsequent development of BGM0504 for type 2 diabetes mellitus (T2DM) and obesity. Show less

Glucagon-like peptide-1 receptor (GLP1R) agonists and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonists may help treat metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). However, their definitive effects are still unclear. Our study aims to clarify this uncertainty. We utilised conventional Mendelian randomisation (MR) analysis to explore potential causal links between plasma GLP-1/GIP concentrations and MASLD and its related traits. Next, we conducted drug-target MR analysis using highly expressed tissue data to assess the effects of corresponding drug perturbation on these traits. Finally, mediation analysis was performed to ascertain whether the potential causal effect is direct or mediated by other MASLD-related traits. Circulating 2-h GLP-1 and GIP concentrations measured during an oral glucose tolerance test showed hepatoprotective effects on MASLD risk (OR GLP-1/GIP receptor agonists offer promise in lowering MASLD/MASH risk. GIP receptor agonists can exert direct and indirect effects on MASLD mediated by weight reduction or glycemic control improvement. Show less

To clarify the possible mechanism of leptin and α-MSH on the onset of puberty in female offspring rats after prenatal androgen exposure. Sixteen 8-week-old specific pathogen free (SPF) healthy Sprague Dawley (SD) pregnant rats were randomly divided into the testosterone-treated group (TG, female offspring termed PNA group) or the olive oil control group (OOG, female offspring termed VEH group). The female offspring rats of two groups were raised to 21 days (PND21) and weaned. Six female offspring rats at PND21 (VEH:PNA = 3:3) were randomly selected for transcriptome sequencing. Twenty-seven offspring female rats were randomly divided into three groups (VEHI:VEHII:PNA = 9:9:9). VEHI group was observed until the onset of puberty, VEHII and PNA groups were observed until the 8th week. Compared with VEH group, onset of puberty was not observed in PNA group, and hypothalamic Pomc gene expression at PND21 was lower. Compared with the VEHI group, the body weight, abdominal fat, serum testosterone (T), dehydroepiandrosterone (DHEA) and leptin (LEP) levels were upregulated in the PNA group, while serum gonadotropin-releasing hormone (GnRH), mRNA of hypothalamic estrogen receptor α (ERα), α-melanocyte stimulating hormone (α-MSH), melanocortin receptor-4 (MC4R), GnRH and adipose AR, and the protein of androgen receptor (AR) and leptin receptor (LEPR) in the hypothalamic arcuate nucleus (ARC) were decreased. In the PNA group, there were positive correlations between serum DHEA and mRNA of hypothalamic ERα, MC4R and AR, negative correlations between mRNA of adipose AR and serum T and free testosterone (FT). Prenatal androgen exposure delayed the onset of puberty in female offspring, the possible mechanism of which is that prenatal androgen exposure may increase the levels of androgen and LEP, decreases their sensitivity and the expression of AR, LEPR, and MC4R, reducing GnRH secretion. Show less

Obesity is a major global public health issue linked to a wide range of chronic diseases. Understanding its complex causal pathways requires robust analytical methods. Mendelian randomization (MR), which employs genetic variants as instrumental variables, effectively addresses confounding and reverse causation and has become a key tool in obesity research. This review summarizes the development of MR methodologies, from single-sample to multivariable, mediation, and time-series models, and highlights key findings from the past decade. MR studies have revealed causal associations between obesity and nine major disease categories, including cardiovascular, metabolic, cancer, psychiatric, respiratory, renal, reproductive, musculoskeletal, and dermatological disorders. Obesity influences disease risk through mechanisms involving energy metabolism, hormonal regulation, and inflammation, with heterogeneity by age, sex, and fat distribution. Key genes such as Show less

Angiopoietin-like proteins (ANGPTLs) represent a family of secreted glycoproteins that are extensively expressed in vivo and are integral to various pathophysiological processes, including glucose and lipid metabolism, stem cell proliferation, local inflammation, vascular permeability, and angiogenesis. Particularly interesting is ANGPTL4, which has been identified as a significant factor in the development and progression of diabetic retinopathy (DR), thus becoming a central focus of DR research. ANGPTLs modulate metabolic pathways, enhance vascular permeability, and facilitate pathological angiogenesis, in addition to causing intraocular inflammation. As promising molecular targets, ANGPTLs not only serve as biomarkers for predicting the onset and progression of DR but also present therapeutic potential through antibody-based interventions. This paper discusses the pathogenesis of DR and the potential applications of ANGPTLs in early diagnosis and targeted therapy. It provides references for advancing precision diagnosis and personalized treatment strategies through more profound ANGPTLs research in the future. Show less

The Huainan pig (HN) is known for its impressive litter size and exquisite meat quality. However, it also exhibits certain drawbacks such as excessive fat deposition, a relatively low percentage of lean meat percentage, and a slower growth rate. Crossbreeding with lean-type breeds, such as Large White, Landrace, and Berkshire can enhance offspring traits, and increase genetic diversity. In this study we employed RNA-seq technology to identify differentially expressed genes (DEGs) in subcutaneous adipose tissue (SAT) samples from HN pigs and their crosses with multiple breeds (with three replicates per group). In the SAT of Huainan × Berkshire pigs (BH), Huainan × Yorkshire pigs (YH), and Huainan × Landrace pigs (LH), numerous key functional genes were identified, including In conclusion, these findings offer valuable insights and provide a foundation for future research on the molecular mechanisms underlying fat deposition in pigs. Show less

Diabetes mellitus-related erectile dysfunction (DMED) is characterized by complicated pathogenesis and unsatisfactory therapeutic remedies. Glycolysis plays an essential role in diabetic complications and whether it is involved in the process of DMED has not been expounded. The aim of this study was to investigate the genetic profiling of glycolysis and explore potential mechanisms for DMED. Glycolysis-related genes (GRGs) and gene expression matrix of DMED were obtained from the molecular signatures database and gene expression omnibus dataset. Differentially expressed analysis and support vector machine-recursive feature elimination (SVM-RFE) method were both used to obtain hub GRGs. Interactive network and functional enrichment analyses were performed to clarify the associated biological roles of these genes. The expression profile of hub GRGs was validated in cavernous endothelial cells, animals, and clinical patients. The subpopulation distribution of hub GRGs was further identified. In addition, a miRNA-GRGs network was constructed and expression patterns as well as molecular functions of relevant miRNAs were explored and validated. In addition, the relationship between hypoxia and DMED was also uncovered. Based on the combined analysis, 48 differentially expressed GRGs were obtained. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that these genes were significantly enriched in carbon metabolism and oxidoreductase activities. Then hub GRGs including down-regulated as well as up-regulated genes in DMED were identified ultimately. Among them, We clarified the expression signature of GRGs in DMED based on multi-omics analysis for the first time. It will be significantly important to reveal pathological mechanisms and promising treatments in DMED. Show less

Therapies targeting the LPL (lipoprotein lipase) pathway are under development for cardiometabolic disease. Insights into their efficacy-both alone and in combination with existing lipid-lowering therapies-modes of action, and safety of these agents are essential to inform clinical development. Using Mendelian randomization, we aimed to (1) evaluate efficacy, (2) explore shared mechanisms, (3) assess additive effects with approved lipid-lowering drugs, and (4) identify secondary indications and potential adverse effects. We selected triglyceride-lowering genetic variants located in the genes encoding ANGPTL3 (angiopoietin-like 3), ANGPTL4 (angiopoietin-like 4), APOC3 (apolipoprotein C3), and LPL and conducted drug target Mendelian randomization on primary outcomes including coronary artery disease and type 2 diabetes, and secondary outcomes, including apolipoprotein B, waist-to-hip ratio, body mass index, and 233 metabolic biomarkers. We conducted interaction Mendelian randomization analyses in 488 139 UK Biobank participants to test the effect of combination therapy targeting the LPL and LDLR (low-density lipoprotein receptor) pathways. Finally, we investigated potential secondary indications and adverse effects by leveraging genetic association data on 1204 disease end points. Genetically predicted triglyceride lowering through the perturbation of LPL pathway activation targets ANGPTL4, APOC3, and LPL was associated with a lower risk of coronary artery disease and type 2 diabetes and lower apolipoprotein B. Genetically predicted triglyceride lowering through ANGPTL4 was associated with a lower waist-to-hip ratio, suggestive of a favorable body fat distribution. There was no evidence of a multiplicative interaction between genetically proxied perturbation of ANGPTL4, APOC3, and LPL and that of HMGCR (HMG-CoA reductase) and PCSK9 (proprotein convertase subtilisin/kexin type 9) on coronary artery disease and type 2 diabetes, consistent with additive effects. Finally, associations of genetically predicted LPL pathway targeting were supportive of the broad safety of these targets. Our findings provide genetic evidence supporting the efficacy and safety of LPL pathway activation therapies for the prevention of coronary artery disease and type 2 diabetes, alone or in combination with statins or PCSK9 inhibitors. Show less

Polyethylene terephthalate microplastics (PET-MPs) have emerged as significant environmental pollutants with potential health risks. This study investigates the cytotoxic effects of PET-MPs on BEAS-2B lung epithelial cells through integrated transcriptomic and metabolomic analyses. The results of the CCK8 assay showed a reduction in the viability of BEAS-2B cells following continuous exposure to PET-MPs. Transcriptomic analysis identified 1412 differentially expressed genes (DEGs) mainly enriched in apoptosis and extracellular matrix organization processes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that these DEGs are predominantly involved in the PI3K-Akt, TNF, and MAPK signaling pathways. Metabolomic analysis identified 2869 differentially expressed metabolites (DEMs), mainly associated with pyrimidine, arginine, proline, and β-alanine metabolism pathways. Multi-omics analysis indicated that PET-MPs primarily disrupt lipid metabolism, which may lead to an increased risk of apoptosis. We hypothesize that PET-MPs affect lipid metabolism by up-regulating the ANGPTL4 gene, thereby promoting cellular apoptosis. This study reveals the mechanisms of PET-MPs toxicity, emphasizing the potential risks they pose to human health. Show less

To investigate the association between polymorphisms of the A case-control study was conducted, enrolling 100 HTG patients and 100 age-matched controls with normal triglyceride levels from the physical examination cohort at Guangzhou 11th People's Hospital (January-December 2023) The observation group showed significant differences in genotype frequencies of Show less

Oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) reflect pro-inflammatory properties of Lp(a) (lipoprotein(a)). The effect of OxPL-apoB on major adverse cardiovascular events (MACE) in patients with acute coronary syndrome in recent the era is not known. OxPL-apoB levels and Lp(a) were measured in 11 630 participants before and 5185 participants 4 months after randomization to alirocumab or placebo in the ODYSSEY OUTCOMES trial. Proportional hazards models adjusted for baseline covariates evaluated associations between log Participants were followed for a median 2.9 years; the median age was 58 years, and 23.9% were female. Alirocumab reduced median placebo-adjusted OxPL-apoB by 13.0% and Lp(a) by 26.2% (both In patients with recent acute coronary syndrome receiving optimized statin treatment, elevated OxPL-apoB levels predicted MACEs, a relationship abrogated by alirocumab. The interaction of OxPL-apoB and Lp(a) in the placebo group indicates that OxPL-apoB independently predicts MACEs when Lp(a) levels are relatively low. URL: https://www.clinicaltrials.gov; Unique identifiers: NCT001747 and NCT01663402. Show less

Women diagnosed with PCOS exhibit a high prevalence of obstructive sleep apnea (OSA). This study aims to assess risk factors of OSA among patients with PCOS. This retrospective study included 126 patients with PCOS who were categorized into an OSA group (n = 30) and a non-OSA group (n = 96) according to the apnea-hypopnea index (AHI). A control group comprised 72 patients without PCOS who presented during the same period for infertility due to fallopian tube, pelvic, or male factors. Patients with PCOS A multivariate logistic regression model was used to analyze independent risk factors for OSA in the PCOS group. Patients with PCOS had significantly higher AHI values and elevated values for various physical indicators, including body mass index (BMI) and neck, waist, and hip circumferences; prolactin (PRL); fasting plasma glucose (FPG); insulin (FINS); triglycerides (TG); homeostasis model assessment of insulin resistance (HOMA-IR); 2-hour postprandial glucose (2-hPG) and insulin (2-hINS); AHI; and oxygen desaturation index (ODI). Conversely, levels of high-density lipoprotein cholesterol (HDL-C) and lowest oxygen saturation (LSaO OSA in PCOS patients is linked to metabolic indicators. High neck circumference and BMI levels were independent risk factors, highlighting the need for OSA in routine PCOS screening, particularly in the context of metabolic dysregulation. Show less

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

Metabolic diseases such as high blood lipids, high blood sugar, and disrupted gut microbiota pose a serious threat to people's physical health. The occurrence of these diseases is closely related to the lack of nutrients in daily rice staple foods, but there is a lack of comprehensive analysis of the underlying mechanisms. This study used fully nutritious brown rice as raw material, and after germination under various stress conditions, it significantly increased the levels of gamma aminobutyric acid (GABA, four carbon non protein amino acid), resistant starch, flavonoids, and other components that regulate metabolic diseases. Using rats as experimental subjects, a model of hyperlipidemia and hyperglycemia was constructed, with rice consumption as the control. The experimental period was 8 weeks. Research has found that feeding sprouted brown rice can significantly improve the accumulation of white fat in the liver caused by a high-fat diet, significantly reduce TC, TG, LDL-C, apoB, HL, LPL, and LCAT, significantly increase HDL-C and apoA1, and significantly reduce the levels of inflammatory factors IL-6 and TNF-α. Therefore, consuming sprouted brown rice can reduce the risk of hyperlipidemia, inflammation, and tumor occurrence by promoting fat breakdown, and can also increase the abundance of metabolic-promoting microorganisms (especially Euryarchaeota and Lactobacillus) in the intestine, improving the entire metabolic ecological network of rats. Show less

In Traditional Chinese Medicine (TCM), dampness is a pathogenic factor arising from impaired production and transportation of bodily fluids. While Fuling Zexie decoction (FLZXD) has demonstrated therapeutic efficacy in dampness constitution (DC) treatment, the material basis underlying its constitutional modulatory effects remains unclear. This study proposes objective indicators for the differentiation and therapeutic evaluation of DC and elucidates the material basis of FLZXD in DC treatment. Serum exosome proteomic profiling was conducted across two independent cohorts to identify DC-related indicators and assess the therapeutic efficacy of FLZXD in DC-associated hyperlipidemia (DC-hyperlipidemia). The bioactive compounds of FLZXD were prioritized through a comprehensive analysis of patent documentation and network pharmacology, with subsequent validation of DC-related targets using enzyme-linked immunosorbent assay (ELISA). Proteomic analysis of serum exosomes revealed signatures that differentiate individuals with a balanced constitution (BC) from those with DC. The differentially expressed proteins (DEPs) were enriched predominantly in pathways related to the complement cascade and cardiovascular diseases. FLZXD demonstrated therapeutic efficacy against DC-hyperlipidemia, as evidenced by the reversal of DEPs expression following treatment, which was supported by the patentable findings and network pharmacology analysis. Through experimental validation and pharmacological evidence, the active herbs of FLZXD (Fuling, Zexie and Baizhu, collectively referred to as FZB) were identified, and a total of 73 putative therapeutic targets involved in the dampness-resolving effects of FZB were revealed. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment further confirmed that FLZXD exerts its anti-dampness effects primarily through regulation of the complement and coagulation cascades. Among eight candidate indicators specifically associated with DC, four proteins were validated via ELISA, indicating potential utility for the differentiation of DC. The sensitivity (%), specificity (%), fold change (FC), p-value, and area under the curve (AUC) for each indicator were as follows: apolipoprotein B-100 (APOB) (100.00, 80.00, 0.63, 0.0051, 0.94), complement factor H-related protein 1 (CFHR1) (90.00, 100.00, 0.55, 0.0001, 0.98), alpha-1-acid glycoprotein 1 (ORM1) (100.00, 80.00, 0.71, 0.0043, 0.92), and pigment epithelium-derived factor (SERPINF1) (90.00, 70.00, 0.66, 0.0002, 0.87). The integrative approach, combining proteomic profiling, network pharmacology analysis, and clinical validation, establishes an integrative approach for research on TCM constitutions. This approach provides (1) molecular insights into the differentiation of DC, (2) a foundation for mechanism-based, targeted therapeutic strategies, and (3) enhanced patient stratification to support personalized treatment approaches. Show less

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

The therapeutic value of lipid-lowering drugs in pulmonary vascular disease remains uncertain due to insufficient studies and evidence. This study aims to investigate the causal effects of lipid-lowering drugs (specifically, inhibitors of APOB, CETP, HMGCR, NPC1L1, and PCSK9) on pulmonary vascular diseases using a Mendelian randomization (MR) approach. We utilized summary-level statistics from genome-wide association studies (GWAS) to simulate the exposure to low-density lipoprotein cholesterol (LDL-C) and its outcomes on pulmonary arterial hypertension (PAH), pulmonary embolism (PE), and pulmonary heart disease (PHD). Single-nucleotide polymorphisms (SNPs) within or near drug target-associated LDL-C loci were selected as proxies for the lipid-lowering drugs. Data from the FinnGen cohort and UK Biobank (UKB) were incorporated to enhance the robustness and generalizability of the findings. The inverse variance weighted (IVW) and MR-Egger methods were employed to estimate MR effects. Our MR analysis indicated that LDL-C mediated by NPC1L1 (odds ratio [OR] = 104.76, 95% confidence interval [CI] = 2.01-5457.01, 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

Patients with dyslipidemia are at higher risk for inflammatory bowel disease (IBD), yet the impact of lipid-lowering medications on IBD remains unclear. This study investigates the causal relationship between lipid-lowering drug target and IBD, with a focus on the roles of gut microbiota and inflammatory cytokines. Genetic variants associated with lipid-lowering drug targets were extracted from the Global Lipids Genetics Consortium, whereas summary statistics for IBD, Crohn's disease (CD), and ulcerative colitis were sourced from the International Inflammatory Bowel Disease Genetics Consortium. Drug-target Mendelian randomization analysis revealed that inhibiting angiopoietin-like protein 3 increased the risk of IBD and CD, whereas inhibition of apolipoprotein C-III (APOC3) heightened the risk of CD. Conversely, enhancement of LPL and LDL receptor reduced the risk of IBD and CD. Mediation analysis demonstrated that gut microbiota and inflammatory cytokines partially mediated these effects, with specific pathways such as Lachnospiraceae FCS020 (17.26%) for APOC3 and Clostridium sensu stricto 1 (20.12%) for LPL accounting for significant portions of the effects. These findings suggest that lipid-lowering drugs targeting angiopoietin-like protein 3 and APOC3 may increase the risk of IBD, whereas those targeting LPL and LDL receptor may reduce the risk. The results highlight potential for repurposing lipid-lowering drugs for IBD prevention and warrant future clinical trials to explore these targets further. Show less