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Metabolomics Coupled with Transcriptomics Approach Deciphering Age Relevance in Sepsis.

ABSTRACT: Sepsis is a severe disease frequently occurred in the Intenisive Care Unit (ICU), which has a very high morbidity and mortality, especially in patients aged over 65 years. Owing to the aging effect and the ensuing deterioration of body function, the elder patients may have atypical responses to sepsis. Diagnosis and pathogenesis of sepsis in this population are thus difficult, which hindered effective treatment and management in clinic. To investigated age effects on sepsis, 158 elderly septic patients and 71 non-septic elderly participants were enrolled, and their plasma samples were collected for transcriptomics (RNA-seq) and metabolomics (NMR and GC-MS) analyses, which are both increasingly being utilized to discover key molecular changes and potential biomarkers for various diseases. Protein-protein interaction (PPI) analysis was subsequently performed to assist cross-platform integration. Real time polymerase chain reaction (RT-PCR) was used for validation of RNA-seq results. For further understanding of the mechanisms, cecal ligation and puncture (CLP) experiment was performed both in young and middle-aged rats, which were subjected to NMR-based metabolomics study and validated for several key inflammation pathways by western blot. Comprehensive analysis of data from the two omics approaches provides a systematic perspective on dysregulated pathways that could facilitate the development of therapy and biomarkers for elderly sepsis. Additionally, the metabolites of lactate, arginine, histamine, tyrosine, glutamate and glucose were shown to be highly specific and sensitive in distinguishing septic patients from healthy controls. Significant increases of arginine, trimethylamine N-oxide and allantoin characterized elderly patient incurred sepsis. Further analytical and biological validations in different subpopulations of septic patients should be carried out, allowing accurate diagnostics and precise treatment of sepsis in clinic.

SUBMITTER: Xu D

PROVIDER: S-EPMC6675524 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Metabolomics Coupled with Transcriptomics Approach Deciphering Age Relevance in Sepsis.

Xu Dingqiao D Liao Shanting S Li Pei P Zhang Qian Q Lv Yan Y Fu Xiaowei X Yang Minghua M Wang Junsong J Kong Lingyi L

Aging and disease 20190801 4

Sepsis is a severe disease frequently occurred in the Intenisive Care Unit (ICU), which has a very high morbidity and mortality, especially in patients aged over 65 years. Owing to the aging effect and the ensuing deterioration of body function, the elder patients may have atypical responses to sepsis. Diagnosis and pathogenesis of sepsis in this population are thus difficult, which hindered effective treatment and management in clinic. To investigated age effects on sepsis, 158 elderly septic p ...[more]

PMID: 31440390

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Project description:Background: Sepsis-induced myocardial dysfunction (SIMD) is the most common and severe sepsis-related organ dysfunction. We aimed to investigate the metabolic changes occurring in the hearts of patients suffering from SIMD. Methods: An animal SIMD model was constructed by injecting lipopolysaccharide (LPS) into mice intraperitoneally. Metabolites and transcripts present in the cardiac tissues of mice in the experimental and control groups were extracted, and the samples were studied following the untargeted metabolomics-transcriptomics high-throughput sequencing method. SIMD-related metabolites were screened following univariate and multi-dimensional analyses methods. Additionally, differential analysis of gene expression was performed using the DESeq package. Finally, metabolites and their associated transcripts were mapped to the relevant metabolic pathways after extracting transcripts corresponding to relevant enzymes. The process was conducted based on the metabolite information present in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Results: One hundred and eighteen significant differentially expressed metabolites (DEMs) (58 under the cationic mode and 60 under the anionic mode) were identified by studying the SIMD and control groups. Additionally, 3,081 significantly differentially expressed genes (DEGs) (1,364 were down-regulated and 1717 were up-regulated DEGs) were identified in the transcriptomes. The comparison was made between the two groups. The metabolomics-transcriptomics combination analysis of metabolites and their associated transcripts helped identify five metabolites (d-mannose, d-glucosamine 6-phosphate, maltose, alpha-linolenic acid, and adenosine 5'-diphosphate). Moreover, irregular and unusual events were observed during the processes of mannose metabolism, amino sugar metabolism, starch metabolism, unsaturated fatty acid biosynthesis, platelet activation, and purine metabolism. The AMP-activated protein kinase (AMPK) signaling pathways were also accompanied by aberrant events. Conclusion: Severe metabolic disturbances occur in the cardiac tissues of model mice with SIMD. This can potentially help in developing the SIMD treatment methods.

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Metabolomics Coupled with Transcriptomics Approach Deciphering Age Relevance in Sepsis.

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Metabolomics Coupled with Transcriptomics Approach Deciphering Age Relevance in Sepsis.

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