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Effect of RIG-I activation and thymidine phosphorylase inhibition using Tipiracil on gene expression of human endothelial cells.

ABSTRACT: To investigate the role of RIG-I activation and thymidine phosphorylase inhibition human endothelial cells, we used a dsRNA agonist on HUVECs and HMVECs to activate RIG-I signaling, and further treated with tymp inhibitor TPI. We then performed differential gene expression analysis using data obtained from RNA-seq from each treatment group.

ORGANISM(S): Homo sapiens

PROVIDER: GSE204809 | GEO | 2023/05/01

REPOSITORIES: GEO

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Project description:Purpose: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), a rare mitochondrial encephalomyopathy subtype, is caused by mutations of thymidine phosphorylase (TYMP). As a metabolic enzyme localized in the cytoplasm, the biological processes disturbed by TYMP functional defect are supposed to be not limited in the abnormal replication of mitochondrial DNA. This study aimed to elucidate the characteristic biological alterations and associated homeostatic regulation caused by TYMP deficiency. Methods: Clinical evaluation and genetic analysis were performed on three patients from two independent families carrying heterozygous TYMP variants. Molecular dynamic (MD) simulation and nucleosides detection were used to investigate the pathogenicity of the variants. Plasma from patients with MNGIE and m.A3243G MELAS and healthy volunteers were analyzed by targeted and untargeted metabolomics to characterize the metabolic profiles of MNGIE. Transcriptomics analysis and bioenergetic studies were performed on skin fibroblasts from these three groups of subjects. Results: Three novel TYMP pathogenic variants were identified in our MNGIE patients. Total 72 plasma metabolites were identified as specific alterations of MNGIE patients through comparing the differentially changed metabolites in MNGIE patients and m.A3243G MELAS patients. Beside pyrimidine metabolism, MNGIE patients showed significant changes in multiple metabolisms, such as bile acids metabolism, caffeine metabolism and steroid hormone metabolism. Despite comparable mitochondrial dysfunction existing in fibroblasts from patients with TYMP deficiency and ones with m.A3243G mutation, a distinct downregulated cholesterol metabolism and fatty acids (FAs) metabolism were revealed in the fibroblasts from MNGIE patients via multiple analysis of metabolites levels, metabolic enzymes expression, mitochondrial substrates dependency and transcription factors expression. Conclusions: Our findings revealed a more expansive metabolic disturbance may be caused by TYMP deficiency beyond mitochondrial disfunction, extending a comprehensive understanding of the biochemical outcome of TYMP deficiency.

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Effect of RIG-I activation and thymidine phosphorylase inhibition using Tipiracil on gene expression of human endothelial cells.

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