renal-artery-function-histopathology-linked-to-plasma-fecal

Renal Artery Function and Histopathology Linked to Plasma and Fecal Metabolites in Heart Failure Patients

The gut microbiota and its associated host-microbe co-metabolites are increasingly recognized as key regulators of systemic metabolic balance and the ...

Chinese Academy of Medical Sciences & Peking Union Medical College

Cancer stem-like cells (CSCs) is a cell population in glioma with capacity of self-renewal and is critical in glioma tumorigenesis. Parallels between CSCs and normal stem cells suggest that CSCs give rise to tumors. Oncogenic roles of maternal embryonic leucine-zipper kinase (MELK) and enhancer of zeste homolog 2 (EZH2) have been reported to play a crucial role in glioma tumorigenesis. Herein, we focus on mechanistic contributions of downstream molecules to maintaining stemness of glioma stem-like cells (GSCs). Transcriptional factor, NF-κB, co-locates with MELK/EZH2 complex. Clinically, we observe that the proportion of MELK/EZH2/NF-κB complex is elevated in high-grade gliomas, which is associated with poor prognosis in patients and correlates negatively with survival. We describe the interaction between these three proteins. Specifically, MELK induces EZH2 phosphorylation, which subsequently binds to and methylates NF-κB, leading to tumor proliferation and persistence of stemness. Furthermore, the interaction between MELK/EZH2 complex and NF-κB preferentially occurs in GSCs compared with non-stem-like tumor cells. Conversely, loss of this signaling dramatically suppresses the self-renewal capability of GSCs. In conclusion, our findings suggest that the GSCs depend on EZH2 phosphorylation to maintain the immature status and promote self-proliferation through NF-κB methylation, and represent a novel therapeutic target in this difficult to treat malignancy.

EZH2 Phosphorylation Promotes Self-Renewal of Glioma Stem-Like Cells Through NF-κB Methylation.

A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.

A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids.

Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.

Behcet disease (BD) is a multisystemic disorder characterized by variable clinical manifestations that affect nearly all systems and organs. Colchicine, an alkaloid plant extract, is considered as the first-line therapy for gout, pericarditis, and familial Mediterranean fever. However, the role of colchicine in the treatment of different clinical phenotypes of BD has not been clearly described. This narrative review summarizes the clinical use of colchicine in BD.

The Role of Colchicine in Different Clinical Phenotypes of Behcet Disease.

Editorial: What do we know about COVID-19 implications for cardiovascular disease?

The chemokine CCL17 is a novel therapeutic target for cardiovascular aging.

Corrigendum to: "The Role of Colchicine in Different Clinical Phenotypes of Behcet's Disease" [Clin Therapeut 45(2) (2023) 162-176].

Left ventricular noncompaction (LVNC) is a heterogeneous cardiomyopathy that can be classified into different subtypes based on morphologic and functional features. However, the prognosis of the dilated and isolated subtypes of non-pediatric LVNC remains unknown. We retrospectively studied 101 patients with LVNC diagnosed at Peking Union Medical College Hospital from 2006 to 2022 using the Jenni criteria of transthoracic echocardiography. The patients were grouped into those with dilated LVNC ( = 64) or isolated LVNC ( = 37), and 88 patients (54 with dilated LVNC and 34 with isolated LVNC) were followed up successfully. The primary outcome was major adverse cardiovascular events (a composite of cardiovascular mortality, heart failure, severe ventricular arrhythmia, and systolic embolism). The median follow-up time was 5.24 years. The incidence of major adverse cardiovascular events was 43.2%; patients with dilated LVNC had a higher risk (adjusted hazard ratio, 4.43; 95% confidence interval, 1.24-15.81;  = 0.02) than those with isolated LVNC. None of the isolated LVNC patients had cardiovascular deaths or severe ventricular arrhythmias. The risk of systemic embolism was similar between patients with dilated and isolated LVNC. Our findings indicate that transthoracic echocardiography is a useful tool for classifying LVNC into subtypes with distinct clinical outcomes. Dilated LVNC is associated with a poor prognosis, while the isolated subtype is probably a physiological condition.

Long-Term Prognosis of Different Subtypes of Left Ventricular Noncompaction Cardiomyopathy Patients: A Retrospective Study in China.

Cardiac ischemia/reperfusion (I/R) injury has emerged as an important therapeutic target for ischemic heart disease. Currently, there is no effective therapy for reducing cardiac I/R injury. Damage-associated molecular patterns are endogenous molecules released after cellular damage to exaggerate tissue inflammation and injury. RIPK3 (receptor-interacting protein kinase 3), a well-established intracellular mediator of cell necroptosis and inflammation, serves as a circulating biomarker of multiple diseases. However, whether extracellular RIPK3 also exerts biological functions in cardiac I/R injury remains totally unknown.

Extracellular RIPK3 Acts as a Damage-Associated Molecular Pattern to Exaggerate Cardiac Ischemia/Reperfusion Injury.

Medulloblastoma (MB), a heterogeneous pediatric brain tumor, poses challenges in the treatment of tumor recurrence and dissemination. To characterize cellular diversity and genetic features, we comprehensively analyzed single-cell/nucleus RNA sequencing (sc/snRNA-seq), single-nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq), and spatial transcriptomics profiles and identified distinct cellular populations in SHH (sonic hedgehog) and Group_3 subgroups, with varying proportions in local recurrence or dissemination. Local recurrence showed higher cycling tumor cell enrichment, whereas disseminated lesions had a relatively notable presence of differentiated subsets. Chromosomal alteration evaluation revealed distinct genetic subclones during MB progression, such as chr7q gain and chr11 loss in Group_3 disseminations. A subpopulation termed "high cellular plasticity (HCP)" emerged during MB progression and was associated with increased dividing potential and chromatin accessibility, contributing to recurrence. Inhibiting HCP-associated markers, like protein tyrosine phosphatase receptor type Z1 (PTPRZ1), efficiently suppressed MB progression in preclinical models. These findings address critical gaps in understanding the cellular diversity, chromosomal alterations, and biological dynamics of recurrent MB, offering potential therapeutic insights.

High cellular plasticity state of medulloblastoma local recurrence and distant dissemination.

Myocardial ischemia/reperfusion (I/R) injury is a substantial challenge to the management of ischemic heart disease, the leading cause of mortality worldwide. Arachidonic acid (AA) is a prominent polyunsaturated fatty acid in the human body and plays an important role in various physiological and pathological conditions. AA metabolic enzymes determine AA levels; however, currently there is no comprehensive analysis of AA enzymes in cardiac I/R injury.

Intracellular L-PGDS-Derived 15d-PGJ2 Inhibits CaMKII Through Lipoxidation to Alleviate Cardiac Ischemia/Reperfusion Injury.

Hereditary transthyretin amyloidosis (hATTR) is a rare, often fatal disease characterized by the abnormal aggregation of atypical transthyretin fibrils. Given the variability in the penetrance and clinical manifestations of hATTR, the role of nongenetic factors, particularly those related to the gut microbiota, warrants investigation. We conducted a cross-sectional study, examining the untargeted serum metabolome and gut metagenome in 13 patients with hATTR and 22 healthy controls. Significant disparities were observed in both the serum metabolome and gut microbiome of individuals with hATTR when compared to healthy controls. Notably, the serum levels of gamma-aminobutyric acid (GABA) and taurine were markedly decreased in the hATTR group, with the most pronounced reduction in those exhibiting hATTR-related cardiac amyloidosis. Additionally, commensals such as , , and  were significantly diminished in hATTR patients and were positively correlated with the metabolite module containing GABA and taurine. Metagenomic and metabolomic pathway enrichment analyses collectively revealed disruptions in glutamate and taurine metabolism in hATTR. Our findings imply that patients with hATTR may exhibit metabolic irregularities in glutamate and taurine, potentially associated with an imbalance in the gut microbiota.

Unraveling gut microbiome alterations and metabolic signatures in hereditary transthyretin amyloidosis.

Hereditary cardiomyopathies and arrhythmias are major contributors to cardiovascular morbidity and mortality. The advent of next-generation sequencing (NGS) has made genetic testing more accessible, which is crucial for precise diagnosis and targeted therapeutic strategies. The aim of this study is to explore the landscape of genetic variants, the relationship between specific variants and clinical phenotypes, and the impact on clinical decision-making in China. A total of 1,536 probands (median age, 37 years; 1,025 males [66.7%]) with suspected hereditary cardiomyopathy or arrhythmia (covering 15 clinical phenotypes) are recruited from 146 hospitals across 30 provinces and cities in China. Positive results are confirmed in 390 of 1536 probands, leading to a diagnostic yield of 25.4%. Forty-two and three tenths percent (n = 169) of family members carry the same variants as positive probands. Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are the predominant phenotypes, with MYBPC3 variants having the highest frequency in HCM and TTN variants in DCM. In 76.9% of the positive probands, the identified variants are helpful in clinical management, family screening and fertility. This large-scale study provides significant insights into the genetic landscape of hereditary cardiomyopathies and arrhythmias in China.

Article	Year
EZH2 Phosphorylation Promotes Self-Renewal of Glioma Stem-Like Cells Through NF-κB Methylation. Frontiers in oncology\| PubMed ID: 31380279	2019
A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids. American journal of human genetics\| PubMed ID: 35931049	2022
Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis. Genome biology\| PubMed ID: 36575460	2022
The Role of Colchicine in Different Clinical Phenotypes of Behcet Disease. Clinical therapeutics\| PubMed ID: 36732153	2023
Editorial: What do we know about COVID-19 implications for cardiovascular disease? Frontiers in cardiovascular medicine\| PubMed ID: 36733303	2023
The chemokine CCL17 is a novel therapeutic target for cardiovascular aging. Signal transduction and targeted therapy\| PubMed ID: 37072419	2023
Corrigendum to: "The Role of Colchicine in Different Clinical Phenotypes of Behcet's Disease" [Clin Therapeut 45(2) (2023) 162-176]. Clinical therapeutics\| PubMed ID: 37673719	2023
Long-Term Prognosis of Different Subtypes of Left Ventricular Noncompaction Cardiomyopathy Patients: A Retrospective Study in China. Journal of cardiovascular development and disease\| PubMed ID: 37754798	2023
Extracellular RIPK3 Acts as a Damage-Associated Molecular Pattern to Exaggerate Cardiac Ischemia/Reperfusion Injury. Circulation\| PubMed ID: 39411860	2024
High cellular plasticity state of medulloblastoma local recurrence and distant dissemination. Cell reports. Medicine\| PubMed ID: 39809264	2025
Intracellular L-PGDS-Derived 15d-PGJ2 Inhibits CaMKII Through Lipoxidation to Alleviate Cardiac Ischemia/Reperfusion Injury. Circulation\| PubMed ID: 40396239	2025
Unraveling gut microbiome alterations and metabolic signatures in hereditary transthyretin amyloidosis. Microbiology spectrum\| PubMed ID: 40407311	2025
Genetic landscape of hereditary cardiomyopathies and arrhythmias in China. Journal of genetics and genomics = Yi chuan xue bao\| PubMed ID: 40653104	2025

Zeyuan Wang

Biography

JoVE Journal Publications

Other Publications