The transcription factor carbohydrate response element binding protein (ChREBP) activates genes of glucose, fructose, and lipid metabolism in response to carbohydrate feeding. Integrated transcriptomi Show more
The transcription factor carbohydrate response element binding protein (ChREBP) activates genes of glucose, fructose, and lipid metabolism in response to carbohydrate feeding. Integrated transcriptomic and metabolomic analyses in rats with GalNac-siRNA-mediated suppression of ChREBP expression in liver reveal other ChREBP functions. GalNac-siChREBP treatment reduces expression of genes involved in coenzyme A (CoA) biosynthesis, with lowering of CoA and short-chain acyl-CoA levels. Despite suppression of pyruvate kinase, pyruvate levels are maintained, possibly via increased expression of pyruvate and amino acid transporters. In addition, expression of multiple anaplerotic enzymes is decreased by GalNac-siChREBP treatment, affecting TCA cycle intermediates. Finally, GalNAc-siChREBP treatment suppresses late steps in purine and NAD synthesis, with increases in precursors and lowering of end products in both pathways. In sum, our study reveals functions of ChREBP beyond its canonical roles in carbohydrate and lipid metabolism to include regulation of substrate transport, mitochondrial function, and energy balance. Show less
Fel d1, the major cat allergen responsible for over 90% of human IgE-mediated allergies, has an incompletely defined physiological role. To explore its function and assess the feasibility of producing Show more
Fel d1, the major cat allergen responsible for over 90% of human IgE-mediated allergies, has an incompletely defined physiological role. To explore its function and assess the feasibility of producing hypoallergenic cats, we knocked out the CH2 domain of Fel d1 using CRISPR/Cas9 in feline skin cells. An optimized sgRNA introduced a frameshift mutation, with knockout efficiency validated by sequencing, qRT-PCR, and Western blot. Transcriptomic alterations were profiled by RNA-seq, and functional consequences were investigated via GO, KEGG, and GSEA analyses. Key findings were confirmed by qPCR, and phenotypes were assessed using CCK-8, EdU, and flow cytometry. The approach successfully generated a three-base insertion, resulting in near-complete loss of CH2 mRNA and Fel d1 protein. RNA-seq identified 3,469 differentially expressed genes (DEGs), with significant enrichment in pathways for hypertrophic cardiomyopathy (HCM) and rheumatoid arthritis (RA). Key genes in these pathways (e.g., Show less
Pediatric primary cardiomyopathies (PCMs) are rare diseases with complex causes and nonspecific treatment. The influence of electrolytes and amino acids (AAs) on cardiomyopathies has not been extensiv Show more
Pediatric primary cardiomyopathies (PCMs) are rare diseases with complex causes and nonspecific treatment. The influence of electrolytes and amino acids (AAs) on cardiomyopathies has not been extensively studied. This study aimed to explore clinical characteristics and the usage of electrolytes and AAs in children with PCMs. Children diagnosed with PCMs who had genetic test reports were included. Relevant information was collected and processed, and clinical characteristics and mutated genes were clarified. Gene databases were searched to explore related electrolytes and AAs in the treatment of PCMs. The effect of calcium was explored in children with DCM. Paired samples T tests and nonparametric Wilcoxon signed-rank tests were performed for comparison between before and after using calcium. In this study, 27 children with gene test results were enrolled to perform gene-related analysis. The median age was 2.5 years old. Mutated genes were collected, including pathogenic, likely pathogenic, uncertain significance, and other mutations. The most frequently mutated genes related to dilated cardiomyopathy (DCM) were For children with DCM, calcium supplements may be beneficial. AAs, including serine, cysteine, and arginine, could be used for supplementary treatment in children with DCM and HCM. Show less
Heart failure (HF) is a serious cardiovascular condition resulting from abnormalities in multiple biological processes, affecting over 64 million people worldwide. We sought to expand our understandin Show more
Heart failure (HF) is a serious cardiovascular condition resulting from abnormalities in multiple biological processes, affecting over 64 million people worldwide. We sought to expand our understanding of the genetic basis of HF and more specific NICM subtype in the East Asian populations and evaluate the biological pathways underlying subclinical left ventricular dysfunction. We conducted a meta-analysis of genome-wide association studies (GWAS) for all-cause HF in the East Asian populations (N cases ~ 13,385) and a more precise definition of nonischemic cardiomyopathy (NICM) subtype in multi-ancestry populations (N cases~3,603). We identified a low-frequency East-Asian enriched coding variant near MYBPC3 and a NICM specific locus. Follow up analyses demonstrated male-specific HF association at the MYBPC3 locus, and highlighted SVIL as a candidate causal gene for NICM. Moreover, we demonstrated that SVIL deficiency aggravated cardiomyocyte hypertrophy, apoptosis and impaired cell viability in phenylephrine (PE)-treated H9C2 cells. In addition, the gene expression level of B-type natriuretic peptide (BNP) which was deemed as a hallmark for HF was further elevated by SVIL silencing in PE-stimulated H9C2 cells. RNA-sequencing analysis of H9C2 cells revealed that the function of SVIL might be mediated through pathways relevant to regulation and differentiation of heart muscle. These results enhance our understanding of the genetic architecture of HF in the East Asian populations, and provide important insight into the biological pathways underlying NICM and sex-specific relevance of the MYBPC3 locus that warrants further replication in another datasets. Show less
Familial hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease (CVD). Related mutations contributing to hypercontractility and poor relaxation in HCM are not completely u Show more
Familial hypertrophic cardiomyopathy (HCM) is the most common genetic cardiovascular disease (CVD). Related mutations contributing to hypercontractility and poor relaxation in HCM are not completely understood. This study aimed to explore and verify a novel variant of cardiac myosin-binding protein C (cMyBP-C, encoded by MYBPC3) in an HCM family. Clinical information and cardiac parameters were collected in the pedigree. Genomic DNA was extracted from peripheral blood and second-generation sequencing technology was used to investigate the proband and his family members. Subsequent sequence analysis was performed with DNAMAN software. The cardiac expression levels of MYBPC3 mRNA and cMyBP-C protein were assessed using RT-qPCR and Western blot analysis, respectively. Typical interventricular septal thickening was detected in all four HCM patients without left ventricular outflow tract obstruction. The c.1042₁₀₄₃insCGGCA mutation in MYBPC3 was verified in the proband and family members. In silico analysis of the mutation revealed that c.1042₁₀₄₃insCGGCA led to a shift in the sequence of nucleotides, creating a premature stop codon at the new reading frame. RT-qPCR analysis of MYBPC3 mRNA revealed a marked reduction in HCM heart compared to the normal controls (P < 0.05). Consistently, Western blot analysis showed significantly reduced expression of cMyBP-C in the pedigree in comparison with the controls (P < 0.05). The novel c.1042₁₀₄₃insCGGCA MYBPC3 mutation is a genetic basis for HCM due to c-MyBP-C haploinsufficiency. Show less
Hypertrophic cardiomyopathy (HCM) is an inherited cardiovascular disorder characterized by left ventricular hypertrophy and an elevated risk of sudden cardiac death. Cardiac myosin binding protein C ( Show more
Hypertrophic cardiomyopathy (HCM) is an inherited cardiovascular disorder characterized by left ventricular hypertrophy and an elevated risk of sudden cardiac death. Cardiac myosin binding protein C (MYBPC3) is the most frequently mutated gene leading to HCM. In this study, peripheral blood mononuclear cells isolated from an HCM patient harboring a heterozygous MYBPC3 missense mutation (c.3072C > A; p.S1024R) were reprogrammed via Sendai virus vectors to generate a patient-specific induced pluripotent stem cell (iPSC) line. The iPSC line exhibits normal morphology and karyotype, alongside definitive hallmarks of pluripotency, including trilineage differentiation potential. Show less
Hypertrophic cardiomyopathy (HCM) is a common inherited heart condition. Traditional genetic testing is typically conducted on the proband only, with family members undergoing Sanger sequencing, which Show more
Hypertrophic cardiomyopathy (HCM) is a common inherited heart condition. Traditional genetic testing is typically conducted on the proband only, with family members undergoing Sanger sequencing, which may overlook other pathogenic variants. This study explores the gene sequencing strategy in a three-generation family based on genetic carrier status and examines the relationship between phenotypic characteristics and genotype. High-throughput second-generation sequencing was performed on the proband to analyze HCM-related pathogenic genes. Subsequently, the identified pathogenic variants were validated by Sanger sequencing in the proband and family members. Clinical, electrocardiographic, and echocardiographic assessments were conducted for family members. Second-generation sequencing of the proband (III7) revealed a pathogenic variant MYBPC3-P453Lfs. Initially, no HCM-related pathogenic variants were detected in another patient (III11), prompting additional sequencing of III11, which identified the MYH7-G823E pathogenic variant. Both patients had severe left ventricular outflow tract obstruction. Sanger sequencing showed that five family members carried both mutations. Among them, three died suddenly before age 40, one required an implantable cardioverter defibrillator for arrhythmias, and one developed HCM before adulthood. Cardiac magnetic resonance imaging (MRI) of patients carrying both mutations showed myocardial fibrosis of 32.75%, significantly higher than the 6.98% observed in patients carrying only one mutation. In families with varying HCM phenotypes, second-generation sequencing should be considered for all members. In this family, carrying one variant led to outflow tract obstruction, while carrying both variants resulted in severe disease, including sudden death and early onset. Cardiac MRI is crucial for assessing the severity of the disease within the family. Show less
No studies have explored the genetic differences between the Chinese and other ethnic hypertrophic cardiomyopathy (HCM) populations. This cross-sectional study included Chinese patients ( Chinese HCM Show more
No studies have explored the genetic differences between the Chinese and other ethnic hypertrophic cardiomyopathy (HCM) populations. This cross-sectional study included Chinese patients ( Chinese HCM patients have a higher proportion of rare variants (52.8% vs 13.6%, Our findings suggested that patients of Chinese ancestry with HCM have a higher proportion of rare variants but are less likely to be classified as P/LP variants in HCM genes than those of European origin. The variants of c.3624del in Show less
Xuesen Liu, Yaoyu Song, Jing Zhang+3 more · 2025 · Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics · added 2026-04-24
To investigate the genetic etiology of six adult patients with Dilated cardiomyopathy (DCM), and analyze the structure of the identified variants, for providing reference for the diagnosis of DCM. Six Show more
To investigate the genetic etiology of six adult patients with Dilated cardiomyopathy (DCM), and analyze the structure of the identified variants, for providing reference for the diagnosis of DCM. Six adult patients with DCM (patients 1-6) admitted to the Department of Cardiology of Zhumadian Central Hospital from January 2023 to December 2023 were recruited. Clinical data of the patients were retrospectively collected. And 5 mL of peripheral blood was collected from each patient. Pathogenic variants of the patients were detected by whole exome sequencing (WES), and candidate variants were verified by Sanger sequencing. The possible functional significance of the identified missense variants was evaluated using software including SIFT, PolyPhen-2 and Mutation Taster. Specific regions of the MYBPC protein encoded by the MYBPC3 gene from different species were aligned using Mutation Taster. The wild-type and mutant MYBPC proteins were constructed using homologous modeling software MODELLER v10.4 and three-dimensional structures were visualized using PyMOL software. The molecular interaction between MYBPC-C5 domain and myosin with or without the mutation was further analyzed using ZDOCK module in Discovery Studio 2019 software. Pathogenicity ratings for the detected variant sites were performed in accordance with the Standards and Guidelines for the Interpretation of Sequence variants by the American College of Medical Genetics and Genomics (ACMG) (hereafter referred to as the ACMG Guidelines). This study was reviewed and approved by the Ethics Committee of Zhumadian Central Hospital (Approval No. 2022092007). The six DCM patients had typical symptoms of heart failure, and echocardiography showed whole-heart dilation and decreased ventricular wall motion, left ventricular end-diastolic dimension (LVEDD) was 59-74 mm, left ventricular ejection fraction (LVEF) was 35%-43%, and left ventricular fractional shortening (LVFS) was 17%-28%. Variations of the DCM related genes, including a c.98473A>T (p.Lys32825*) variation of the TTN gene and a c.1976T>C (p.Ile659Thr) variation of the MYBPC3 gene, were identified in two patients. Multiple software predicted that both mutations were deleterious. MYBPC3-Ile659Thr mutation affected the highly conserved residue within the C5 domain of MYBPC. Three-dimensional structural analysis of homologous modeling revealed the alterations in amino acid properties and interactions with surrounding amino acids caused by the MYBPC3-Ile659Thr mutation. Further molecular docking analysis showed that the Ile659Thr mutation altered both the hydrogen bond and salt-bridge interactions between the MYBPC-C5 domain and the ligand myosin. Two mutations associated with DCM were identified in this study. The abnormal conformation of the mutant protein further affected its interaction with the ligand myosin, resulting in the phenotype of DCM. Show less
Asian populations are underrepresented in the hypertrophic cardiomyopathy (HCM) genomic databases, which are currently largely dominated by Caucasian population. We aim to characterize the genetic lan Show more
Asian populations are underrepresented in the hypertrophic cardiomyopathy (HCM) genomic databases, which are currently largely dominated by Caucasian population. We aim to characterize the genetic landscape of HCM in patients from Hong Kong Chinese population. From March 2023 to March 2024, fifty-three unrelated patients with an unequivocal clinical diagnosis of HCM were enrolled at a single tertiary center in Hong Kong and underwent genetic testing using a standardized 19-gene panel. In this cohort study, we identified 13 patients (24.5%) with a predominant pathogenic or likely pathogenic (P/LP) variant and 12 patients (22.6%) with a predominant variant of unknown significance (VUS). Most of the P/LP variants identified were in Our study provided insight into the genetic landscape of HCM in Hong Kong Chinese population. We identified several recurrent variants and novel variants in our HCM cohort. Patients with P/LP variants were associated with an increased risk of developing left ventricular dysfunction. Future studies on the potential founder effects of these recurrent variants, cumulative effects of multiple variants, and longitudinal follow up of HCM patients would be useful. Show less
Heart failure is a complex trait, influenced by environmental and genetic factors, affecting over 30 million individuals worldwide. Here we report common-variant and rare-variant association studies o Show more
Heart failure is a complex trait, influenced by environmental and genetic factors, affecting over 30 million individuals worldwide. Here we report common-variant and rare-variant association studies of all-cause heart failure and examine how different classes of genetic variation impact its heritability. We identify 176 common-variant risk loci at genome-wide significance in 2,358,556 individuals and cluster these signals into five broad modules based on pleiotropic associations with anthropomorphic traits/obesity, blood pressure/renal function, atherosclerosis/lipids, immune activity and arrhythmias. In parallel, we uncover exome-wide significant associations for heart failure and rare predicted loss-of-function variants in TTN, MYBPC3, FLNC and BAG3 using exome sequencing of 376,334 individuals. We find that total burden heritability of rare coding variants is highly concentrated in a small set of Mendelian cardiomyopathy genes, while common-variant heritability is diffusely spread throughout the genome. Finally, we show that common-variant background modifies heart failure risk among carriers of rare pathogenic truncating variants in TTN. Together, these findings discern genetic links between dysregulated metabolism and heart failure and highlight a polygenic component to heart failure not captured by current clinical genetic testing. Show less
Mutations in the sarcomere protein, particularly in cardiac myosin binding protein C gene ( We used multi-omics approaches and super-resolution imaging to explore the effects of MyBPC3 P459fs mutation Show more
Mutations in the sarcomere protein, particularly in cardiac myosin binding protein C gene ( We used multi-omics approaches and super-resolution imaging to explore the effects of MyBPC3 P459fs mutation on humans and cells. HCM patients carrying MyBPC3 P459fs mutation (MyBPC3-P459fs HCMs) and healthy controls (HCs) were evaluated for myocardial function using both conventional and advanced echocardiography. In parallel, H9C2 myocardial cells infected with either MyBPC3 P459fs mutation (P459fs cells) or its wild type (WT cells) were investigated for myocardial fiber formation and the potential pathways behind this using super-resolution imaging and metabolomics and proteomics. First, conventional and advanced echocardiography showed that MyBPC3-P459fs HCMs exhibited left ventricular diastolic and systolic dysfunction. Subsequently, super-resolution imaging indicated that P459fs cells formed fewer and shorter myocardial fibers in the cytoplasm compared to WT cells. Moreover, our metabolomic and proteomic data suggested several key components of mitochondrial membrane integrity, myocardial remodeling, myocardial energy metabolism, oxidative stress, inflammation, and actin binding capacity were significantly altered in response to P459fs mutation. This investigation indicated myocardial dysfunction and myocardial fiber disarray in clinical HCMs with MyBPC3 P459fs mutation and added potential pathways underlying this. These findings provided a link between the observed structural and functional disorders in MyBPC3 P459fs mutation and its onset of HCM pathogenesis and might have a significant translational contribution to effective treatment in HCM patients with MyBPC3 P459fs mutation. Show less
Weilai Dong, Sheng Chih Jin, Michael C Sierant+36 more · 2025 · Proceedings of the National Academy of Sciences of the United States of America · National Academy of Sciences · added 2026-04-24
Variants with large effect contribute to congenital heart disease (CHD). To date, recessive genotypes (RGs) have commonly been implicated through anecdotal ascertainment of consanguineous families and Show more
Variants with large effect contribute to congenital heart disease (CHD). To date, recessive genotypes (RGs) have commonly been implicated through anecdotal ascertainment of consanguineous families and candidate gene-based analysis; the recessive contribution to the broad range of CHD phenotypes has been limited. We analyzed whole exome sequences of 5,424 CHD probands. Rare damaging RGs were estimated to contribute to at least 2.2% of CHD, with greater enrichment among laterality phenotypes (5.4%) versus other subsets (1.4%). Among 108 curated human recessive CHD genes, there were 66 RGs, with 54 in 11 genes with >1 RG, 12 genes with 1 RG, and 85 genes with zero. RGs were more prevalent among offspring of consanguineous union (4.7%, 32/675) than among nonconsanguineous probands (0.7%, 34/4749). Founder variants in Show less
Hypertrophic cardiomyopathy (HCM) is a hereditary disease of the myocardium characterized by asymmetric hypertrophy (mainly the left ventricle) not caused by pressure or volume load. Most cases of HCM Show more
Hypertrophic cardiomyopathy (HCM) is a hereditary disease of the myocardium characterized by asymmetric hypertrophy (mainly the left ventricle) not caused by pressure or volume load. Most cases of HCM are caused by genetic mutations, particularly in the gene encoding cardiac myosin, such as Show less
Lung squamous cell carcinoma (LUSC) is a highly aggressive malignancy with limited targeted therapies and poor clinical outcomes. Ferroptosis, an iron-dependent form of regulated cell death, plays a c Show more
Lung squamous cell carcinoma (LUSC) is a highly aggressive malignancy with limited targeted therapies and poor clinical outcomes. Ferroptosis, an iron-dependent form of regulated cell death, plays a crucial role in tumor progression, metabolic reprogramming, and immune modulation. Increasing evidence suggests that dysregulation of ferroptosis contributes to therapeutic resistance and immune escape in various cancers. MYO19, a mitochondrial trafficking protein, has recently been implicated in oxidative stress and metabolic control, but its role in ferroptosis and tumor immunity remains unclear. Meanwhile, microRNAs (miRNAs) are recognized as key post-transcriptional regulators in cancer biology. Among them, hsa-miR-520a-3p has been reported to exhibit tumor-suppressive functions in several malignancies. However, the interplay between hsa-miR-520a-3p and MYO19, and their potential involvement in ferroptosis regulation and immune modulation in LUSC, has not been systematically investigated. Data were collected from TCGA, UCSC XENA, ENCORI, HPA, and UALCAN public database. Differential expression, prognostic, correlation analyses and miRNA analyses were performed using bioinformatics tools including TIMER, TISIDB, Kaplan-Meier Plotter, and ENCORI. Ferroptosis-related analysis utilized Ze-Xian Liu's dataset. Functional assays, including CCK-8 viability, Transwell migration, and MDA/GSH measurements, were performed in NCI-H226 and NCI-H2170 cells after transfection with miR-520a-3p mimics/inhibitors or MYO19 knockdown/overexpression constructs. Ferroptosis sensitivity was further tested under RSL3 treatment, and ferroptosis protein markers as well as rescue experiments were analyzed by Western blotting. The result revealed that MYO19 was significantly upregulated in multiple tumor types and correlated with unfavorable prognosis. Especially in LUSC, elevated MYO19 expression was associated with advanced stage, reduced immune infiltration, and enrichment of ferroptosis-resistant transcriptional programs, whereas hsa-miR-520a-3p showed opposite patterns. Overexpression of hsa-miR-520a-3p in NCI-H226 and NCI-H2170 cells increased lipid peroxidation (MDA increased), reduced intracellular GSH, and enhanced RSL3-induced cytotoxicity, indicative of ferroptosis activation. Conversely, MYO19 knockdown elevated ACSL4 and reduced SLC7A11, changes that were partially reversed by MYO19 re-expression. These findings suggest that the hsa-miR-520a-3p/MYO19 axis is associated with ferroptosis susceptibility and may influence the immunosuppressive tumor microenvironment. Show less
Individual differences in immune responses to African swine fever virus (ASFV), whether induced by vaccination or natural infection, may be linked to genetic variation in the genes involved in antigen Show more
Individual differences in immune responses to African swine fever virus (ASFV), whether induced by vaccination or natural infection, may be linked to genetic variation in the genes involved in antigen presentation. A total of nine pigs from the 112-population were selected for RNA-seq analysis. To pinpoint key transcription factors (TFs) regulating gene expression in the lymph nodes, weighted Kendall's Tau rank correlation analysis was performed to link the TF binding potential with the extent of differential expression of target genes. CD8 These mutations may disrupt TFs binding to the ELK4 promoter, potentially reducing ELK4 expression and impairing antigen processing and presentation. Show less
Breast cancer (BRCA) is a prevalent malignant tumor among women, and the use of anesthetic drugs during surgical resection may influence tumor biology and patient prognosis. This study aimed to identi Show more
Breast cancer (BRCA) is a prevalent malignant tumor among women, and the use of anesthetic drugs during surgical resection may influence tumor biology and patient prognosis. This study aimed to identify prognostic biomarkers associated with dexmedetomidine and dezocine (DD) in BRCA patients. Through Mendelian Randomization analysis, we screened four DD targets that had a causal relationship with BRCA. Subsequently, utilizing TCGA-BRCA data, univariate and Lasso Cox analyses revealed two significant prognostic biomarkers (NR1H3 and ADRB1) associated with BRCA patient prognosis, leading to the successful construction and validation of a prognostic risk model. Kaplan-Meier survival curves indicated that patients with higher NR1H3 and ADRB1 expression had longer overall survival (OS). Immunoinfiltration analysis showed that high-risk group patients exhibited increased infiltration levels of CD56 bright natural killer cells, CD56 dim natural killer cells, eosinophils, and plasmacytoid dendritic cells. Conversely, activated B cells and immature B cells demonstrated greater infiltration in the low-risk group. Correlation analysis revealed significant associations between prognostic biomarkers and various immune cells, including CD56 bright natural killer cells, CD56 dim natural killer cells, and activated CD8 T cells. NR1H3 was highly positively correlated with immune checkpoints such as TIGIT, PDCD1, CD274, CTLA4, LAG3, and HAVCR2 (|cor|≥0.3, The online version contains supplementary material available at 10.1007/s12672-025-03694-7. Show less
Male infertility, often linked to impaired spermatogenesis, is increasingly associated with environmental pollutants such as bisphenol S (BPS), a common bisphenol A substitute, yet its molecular mecha Show more
Male infertility, often linked to impaired spermatogenesis, is increasingly associated with environmental pollutants such as bisphenol S (BPS), a common bisphenol A substitute, yet its molecular mechanisms in human Sertoli cells remain unclear. In this study, immortalized human Sertoli cells were exposed to BPS, and cell viability, proliferation, and transcriptomic changes were assessed, with bulk RNA sequencing integrated with single-cell transcriptomic profiles from non-obstructive azoospermia (NOA) testes to identify key regulatory factors. Potential BPS targets were predicted via pharmacophore mapping and confirmed through molecular docking, molecular dynamics simulations, and MM/GBSA binding free energy calculations, while functional validation was performed using NR1H3 knockdown and overexpression assays with luciferase reporter and Western blot analyses. BPS significantly inhibited cell viability and proliferation at concentrations ≥ 20 μM, inducing transcriptomic dysregulation involving cell cycle suppression, metabolic pathway alterations, and steroid biosynthesis disruption. Integration of computational and transcriptomic analyses identified NR1H3 as a direct BPS target, with docking and dynamics simulations demonstrating stable binding (-20.64 ± 2.26 kcal/mol), and experimental data showing that BPS reduced NR1H3 protein levels and transcriptional activity, while NR1H3 knockdown impaired cell survival and overexpression partially rescued BPS-induced cytotoxicity. These findings provide the first evidence that BPS impairs human Sertoli cell function by targeting NR1H3, revealing a critical role of NR1H3 in Sertoli cell survival and suggesting that BPS exposure may contribute to male infertility through NR1H3-mediated pathways. Show less
Impaired excretion of lipid deposits within vascular smooth muscle cell-derived foam cells (VSMC-FCs) contributes to the ongoing expansion of the plaque necrotic core. This study aims to explore the e Show more
Impaired excretion of lipid deposits within vascular smooth muscle cell-derived foam cells (VSMC-FCs) contributes to the ongoing expansion of the plaque necrotic core. This study aims to explore the effects and underlying mechanisms of exosomes secreted by M2 macrophage (M2-exos) on lipid metabolism of VSMC-FCs and plaque stability. First, immunofluorescence was used to detect the expression levels of CD45 (a recognized differentially-expressed molecule of myeloid and VSMC-FCs) and the key proteins of cholesterol efflux pathway, ABCA1 and ABCG1, in human early and late plaques. Next, an in vitro foam cell model was used to assess the effect and mechanism of M2-exos on lipid metabolism in vascular smooth muscle cells by western blot, Oil red O staining and cell total cholesterol assays. RNA-seq and quantitative real-time PCR were employed to characterize the miRNA profiles within M2-exos. The dual-luciferase reporting system and gene silencing approaches were utilized to assess the regulatory effect of candidate miRNA on target genes and signaling pathways. Subsequently, the effect of M2-exos on plaque progression and stability in ApoE Immunofluorescence revealed that compared to early plaques, VSMC-FCs (CD45 M2-exos exerted an obvious atherosclerotic protective effect, and the underlying mechanism was closely related to MiR-7683-3p, which targeted the 3'UTR of HOXA1 mRNA and activated the PPARγ-LXRα-ABCG1 mediated cholesterol efflux in VSMC-FCs. Show less
By 2020, breast cancer (BRCA) surpassed lung cancer as the most prevalent cancer globally, exhibiting high morbidity and mortality. Given the emerging role of circadian rhythm in cancer progression, t Show more
By 2020, breast cancer (BRCA) surpassed lung cancer as the most prevalent cancer globally, exhibiting high morbidity and mortality. Given the emerging role of circadian rhythm in cancer progression, this study aimed to develop a prognostic signature based on circadian rhythm-related genes (CRRGs) to predict BRCA patient survival. Gene expression profiles and clinical data were sourced from the Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), and the Molecular Signatures Database (MSigDB). A multigene signature was constructed using LASSO-penalized Cox regression. Patients were stratified into high- and low-risk groups based on median risk scores. Pathway activity was assessed via gene set variation analysis (GSVA). Prognostic performance was evaluated using ROC curves, Kaplan-Meier (K-M) analysis, and multivariate Cox regression. A 20-CRRG prognostic signature was identified, effectively stratifying patients into distinct risk groups (K-M *P* < .05). ROC analysis demonstrated high predictive accuracy (AUC > 0.7). Functional enrichment linked these CRRGs to circadian regulation, nuclear components, and DNA binding. Further refinement revealed a 9-gene subset (ADRB1, BHLHE41, BTG1, EGR3, NONO, NR1H3, NTRK3, OPN4, PIGF) with superior 5-year survival prediction (AUC 0.82) compared to 1- and 3-year outcomes. The CRRG-based signature, particularly the 9-gene subset, robustly predicts BRCA patient survival, offering potential clinical utility for long-term prognosis. These findings underscore the role of circadian rhythms in BRCA progression and highlight novel biomarkers for risk stratification. Show less
Atherosclerosis is the leading cause of cardiovascular disease-related morbidity and mortality. The traditional Chinese medicine Qingre Sanjie Formula (QRSJF), composed of Prunellae Spica, Sargassum, Show more
Atherosclerosis is the leading cause of cardiovascular disease-related morbidity and mortality. The traditional Chinese medicine Qingre Sanjie Formula (QRSJF), composed of Prunellae Spica, Sargassum, Fritillariae Thunbergii Bulbus, Leonuri Herba, and Forsythiae Fructus, has shown efficacy in treating cardiovascular diseases, although its mechanisms are unclear. This study aimed to explore the protective effects of QRSJF against atherosclerosis and the mechanisms involved. The composition of QRSJF was analyzed using Ultra Performance Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometry. An 8-week high-fat diet (HFD)-induced atherosclerosis model was established in ApoE Both low- and high-dose QRSJF effectively attenuated dyslipidemia and decreased serum inflammatory cytokine levels in HFD-fed ApoE QRSJF improves dyslipidemia and reduces atherosclerotic plaque in ApoE Show less
Foamy macrophages are pivotal contributors to the development and progression of atherosclerotic plaques, posing a substantial threat to human health. Presently, there is no pharmaceutical interventio Show more
Foamy macrophages are pivotal contributors to the development and progression of atherosclerotic plaques, posing a substantial threat to human health. Presently, there is no pharmaceutical intervention available to effectively eliminate foamy macrophages. In this study, we demonstrate that probiotic membrane vesicles (MVs) can induce atherosclerotic plaque regression by modulating foamy macrophages. MVs isolated from Lactobacillus rhamnosus exhibited a specific uptake by foamy macrophages. Near-infrared fluorescence (NIRF) imaging, aortic oil red O staining, and hematoxylin and eosin staining showed reductions in the plaque area following MVs treatment. Mechanistically, bioinformatics analysis provided insights into how MVs exert their effects, revealing that they promote lipid efflux and macrophage polarization. Notably, MVs treatment upregulated NR1H3, which in turn increased ABCA1 expression, facilitating lipid efflux from foamy macrophages. Moreover, MVs shifted macrophage polarization from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype, highlighting their potential to create a more protective environment against plaque progression. This study is significant as it introduces MVs as a novel therapeutic platform for the targeted delivery of anti-inflammatory agents to atherosclerotic sites. By specifically modulating macrophage function, MVs hold considerable potential for the treatment of atherosclerosis and related cardiovascular diseases, addressing an unmet need in current therapeutic strategies. Show less
Liver X receptor α (LXRα) plays an important role in inflammatory immune response induced by hepatic ischemia-reperfusion injury (IRI) and acute rejection (AR). Macrophage M1-polarization play an impo Show more
Liver X receptor α (LXRα) plays an important role in inflammatory immune response induced by hepatic ischemia-reperfusion injury (IRI) and acute rejection (AR). Macrophage M1-polarization play an important role in the occurrence and development of AR. Although the activation of LXR has anti-inflammatory effects, the role of LXRα in AR after liver transplantation (LT) has not been elucidated. We aimed to investigate LXRα anti-inflammatory and macrophage polarization regulation effects and mechanisms in acute rejection rat models. LXRα anti-inflammatory and liver function protective effects was initially measured in primary Kupffer cells and LT rat models. Subsequently, a flow cytometry assay was used to detect the regulation effect of LXRα in macrophage polarization. HE staining, TUNEL and ELISA were used to evaluate the co-treatment effects of TO901317 and tacrolimus on hepatic apoptosis and liver acute rejection after LT. In this study, we found that LPS can inhibit the expression of LXRα and activate MAPK pathway and PI3K/AKT/mTOR. We also found that LXRα agonist (TO901317) could improve liver function and rat survival after LT by activating the level of ABCA1 and inhibiting MAPK. TO901317 could inhibit macrophage M1-polarization by activating PI3K/AKT/mTOR signal pathway to improve the liver lesion of AR rats after liver transplantation. Additionally, co-treatment with TO901317 and tacrolimus more effectively alleviated the damaging effects of AR following LT than either drug alone. Our results suggest that the activation of LXRα can improve liver function and rat survival after LT by regulate ABCA1/MAPK and PI3K/AKT/mTOR signaling axis in macrophages. Show less
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by progressive cognitive decline and behavioral impairments in the elderly. Microglia, the resident immune cells of the Show more
Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by progressive cognitive decline and behavioral impairments in the elderly. Microglia, the resident immune cells of the central nervous system, play a crucial role in modulating the pathological processes associated with AD. Jiajian Shuyu Pills (JJSYP) are frequently employed in the treatment of AD, purportedly by enhancing the physiological functions of human tissues and organs to modulate the immune response. Nevertheless, the underlying mechanisms by which JJSYP exert their therapeutic effects in the context of AD remain inadequately elucidated. This study aimed to assess the effects of JJSYP on cognitive enhancement and the alleviation of neuroinflammation in the treatment of AD, as well as to explore the underlying mechanisms using mouse models. The components of JJSYP in serum were analyzed using HPLC-Q/TOF-MS. APP/PS1 transgenic mice served as AD models in this investigation. Cognitive function in the AD mice was assessed through the Mirror Water Maze Test and the Novel Object Recognition Test. The quantification of apoptotic hippocampal cells was conducted using Nissl staining and TUNEL staining. Immunofluorescence (IF) and Western blot (WB) analyses were employed to examine microglial activation and the expression of relevant proteins. Transcriptomic sequencing analysis and network pharmacology were administrated to explore the potential mechanisms of JJSYP in AD treatment. Inflammatory cytokine levels in the brain were measured using RT-PCR. A total of 74 absorbed prototype components from JJSYP were identified. JJSYP effectively improved cognitive function and neuroapoptosis in AD model mice by modulating the activation of microglia. The JJSYP intervention alleviated neuroinflammation by suppressing microglial activation and reducing the accumulation of amyloid β-protein. Through transcriptome sequencing and WB verification, 34 differentially expressed genes (DEGs) were identified, including ACKR3, NR1H3 and Adra1a. Following treatment with a high dose of JJSYP, both ACKR3 and NR1H3 showed a significant decrease compared to the model group. Conversely, ADRA1A expression was reduced in model group compared to the control group, but increased following high dose JJSYP treatment. Research involving RNA sequencing and network pharmacology indicated that JJSYP altered the activation of CXCL12/ACKR3 signaling pathways in the hippocampus. JJSYP exhibits potential anti-Alzheimer's Disease effects and warrants further investigation and development as a prosper treatment for AD. Show less
Diabetic kidney disease (DKD), a common diabetes complication, often progresses to end-stage renal disease (ESRD) Lipid accumulation is crucial in DKD progression, and its dysregulation causes ectopic Show more
Diabetic kidney disease (DKD), a common diabetes complication, often progresses to end-stage renal disease (ESRD) Lipid accumulation is crucial in DKD progression, and its dysregulation causes ectopic fat distribution, inflammation, and renal damage. Soyasapogenol C (SSC) has various therapeutic potentials. However, its effect on DKD and the underlying mechanisms are unknown. This study explores SSC's role in improving DKD, especially in db/db mice, an ideal DKD research model. We hypothesize that by modulating lipid metabolism, especially cholesterol metabolism, SSC could treat DKD. Results show SSC inhibits cholesterol accumulation, interstitial fibrosis, and renal inflammation in db/db mice. In vitro, it suppresses cholesterol accumulation in HK2 cells and increases ABCA1 and ABCG1 levels. Mechanistically, SSC upregulates ABCA1 and ABCG1 via liver X receptor α (LXRα), and this is inhibited by LXRα inhibitor or siRNA knockdown. Our findings offer new insights into SSC's role in cholesterol metabolism and lipid deposition, and new DKD treatment targets. Show less
Endometritis in dairy cows involves complex molecular regulatory mechanisms. Therefore, uncovering the molecular regulatory mechanisms of endometritis in dairy cows is crucial to understand its develo Show more
Endometritis in dairy cows involves complex molecular regulatory mechanisms. Therefore, uncovering the molecular regulatory mechanisms of endometritis in dairy cows is crucial to understand its development, prevention, and treatment. This study aimed to screen and validate key genes associated with endometritis using transcriptome sequencing of blood samples and previously obtained metabolomic sequencing data. Based on gain-of-function and loss-of-function experiments on the gene, multiple techniques, including qRT-PCR, western blotting, detection of reactive oxygen species (ROS), measurement of mitochondrial membrane potential, EdU assay, flow cytometry, and CCK-8 assay were used to explore the function of the key gene in lipopolysaccharide (LPS)-stimulated bovine endometrial epithelial cells (BEECs). The results identified 536 differentially expressed genes (DEGs) between healthy cows and those with endometritis. These DEGs were significantly enriched in apoptosis and HIF-1 signaling pathways. Weighted gene co-expression network analysis of transcriptomic and metabolomic data identified CD83, CTNNAL1, LRRC25, and NR1H3 as potential key genes for endometritis in dairy cows, with CD83 being more significantly expressed in LPS-induced BEECs. Consequently, in vitro functional studies were performed on CD83. In overexpression experiments, downregulation of the expression of inflammatory markers interleukin (IL)-1β, IL-6, and IL-8 and reduced ROS release primarily indicated the role of CD83 in attenuating the inflammatory response of BEECs. Furthermore, overexpression of CD83 regulated the S/G2 phase transition of BEECs by affecting the mRNA and protein expression of proliferation marker genes, thereby promoting proliferation of BEECs. The increased EdU positivity and the cell proliferation rate further provided evidence for the promotion of cell proliferation after overexpression of CD83. Additionally, overexpression of CD83 attenuated LPS-stimulated mitochondrial damage in BEECs, as well as the downregulation of apoptosis marker gene expression. In contrast, knockdown of CD83 expression showed the opposite trend. In summary, CD83 attenuated the inflammatory response of BEECs, promoted their proliferation, and inhibited apoptosis. This study provided basic data for understanding the mechanisms of endometritis regulation at the gene level in dairy cows. Show less
Colorectal cancer (CRC) is a prevalent digestive system malignancy accompanied by peritoneal metastasis occurring in 7% of cases. Methyltransferase-like 3 (METTL3) promoted the progression of CRC wher Show more
Colorectal cancer (CRC) is a prevalent digestive system malignancy accompanied by peritoneal metastasis occurring in 7% of cases. Methyltransferase-like 3 (METTL3) promoted the progression of CRC whereas its function in peritoneal metastasis was incompletely understood. Here, we found that METTL3 was upregulated in peritoneal metastasis tissues of CRC patients compared with CRC tissues. By sequencing the mRNA of above tissues, we discovered that METTL3-mediated N6-methyladenosine (m6A) modification regulated the downstream target Show less
Meningioma is a common primary central nervous system tumor that can cause a heavy burden on patients. Despite its well-established treatment modalities, pharmacological treatments are not sufficientl Show more
Meningioma is a common primary central nervous system tumor that can cause a heavy burden on patients. Despite its well-established treatment modalities, pharmacological treatments are not sufficiently abundant. Therefore, we explored potential therapeutic targets for meningiomas by integrating genomic and proteomic data. We integrated meningioma data from the UK Biobank and Finnish databases and subsequently explored potential therapeutic targets for meningiomas through multi-omics data using bioinformatics techniques and Mendelian randomization. These targets were finally evaluated using phenotype-wide association group analysis. We found that BET1L, COL17A1, CFAP43, SH3PXD2A, TTC28, ZNRF3, SLK, AKR1C3, NRXN3, and RSPO3 can be potential therapeutic targets for meningiomas. This study provides evidence and explores the biological significance of BET1L, COL17A1, CFAP43, SH3PXD2A, TTC28, ZNRF3, SLK, AKR1C3, NRXN3, and RSPO3 as potential therapeutic targets for meningiomas, providing new insights into the development of targeted therapy for meningiomas. Show less
This study aims to identify genetically influenced metabolites (GIMs) associated with SSBP and elucidate their regulatory pathways through metabolome genome-wide association studies (mGWASs). Untarget Show more
This study aims to identify genetically influenced metabolites (GIMs) associated with SSBP and elucidate their regulatory pathways through metabolome genome-wide association studies (mGWASs). Untargeted metabolomics and genome-wide genotyping were performed on 54 participants from the Systematic Epidemiological Study of Salt Sensitivity (EpiSS). The mGWAS was conducted on 970 plasma metabolites, and their potential biological mechanisms were explored. The multivariable logistic regression model and mendelian randomization (MR) were employed to investigate the association and causal relationship between GIMs and SSBP. Metabolomic analysis was performed on 100 subjects in the replication analysis to validate the GIMs identified in the discovery set and their causal association with SSBP. The mGWAS revealed associations between 1485 loci and 18 metabolites. After performing linkage disequilibrium analysis, 368 independent mQTLs were identified and annotated to 141 genes. These functional genes were primarily implicated in the signal transduction of sinoatrial node and atrial cardiac muscle cells. Five key genes were identified using CytoHubba, including Show less