Dataset Information

Metabolomics Based Profiling of Dexamethasone Side Effects in Rats.

ABSTRACT: Dexamethasone (Dex) is a synthetic glucocorticoid that has anti-inflammatory and immunosuppressant effects and is used in several conditions such as asthma and severe allergy. Patients receiving Dex, either at a high dose or for a long time, might develop several side effects such as hyperglycemia, weight change, or osteoporosis due to its in vivo non-selectivity. Herein, we used liquid chromatography-tandem mass spectrometry-based comprehensive targeted metabolomic profiling as well as radiographic imaging techniques to study the side effects of Dex treatment in rats. The Dex-treated rats suffered from a ?20% reduction in weight gain, hyperglycemia (145 mg/dL), changes in serum lipids, and reduction in total serum alkaline phosphatase (ALP) (?600 IU/L). Also, compared to controls, Dex-treated rats showed a distinctive metabolomics profile. In particular, serum amino acids metabolism showed six-fold reduction in phenylalanine, lysine, and arginine levels and upregulation of tyrosine and hydroxyproline reflecting perturbations in gluconeogenesis and protein catabolism which together lead to weight loss and abnormal bone metabolism. Sorbitol level was markedly elevated secondary to hyperglycemia and reflecting activation of the polyol metabolism pathway causing a decrease in the availability of reducing molecules (glutathione, NADPH, NAD+). Overexpression of succinylacetone (4,6-dioxoheptanoic acid) suggests a novel inhibitory effect of Dex on hepatic fumarylacetoacetate hydrolase. The acylcarnitines, mainly the very long chain species (C12, C14:1, C18:1) were significantly increased after Dex treatment which reflects degradation of the adipose tissue. In conclusion, long-term Dex therapy in rats is associated with a distinctive metabolic profile which correlates with its side effects. Therefore, metabolomics based profiling may predict Dex treatment-related side effects and may offer possible novel therapeutic interventions.

SUBMITTER: Malkawi AK

PROVIDER: S-EPMC5820529 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Metabolomics Based Profiling of Dexamethasone Side Effects in Rats.

Malkawi Abeer K AK Alzoubi Karem H KH Jacob Minnie M Matic Goran G Ali Asmaa A Al Faraj Achraf A Almuhanna Falah F Dasouki Majed M Abdel Rahman Anas M AM

Frontiers in pharmacology 20180216

Dexamethasone (Dex) is a synthetic glucocorticoid that has anti-inflammatory and immunosuppressant effects and is used in several conditions such as asthma and severe allergy. Patients receiving Dex, either at a high dose or for a long time, might develop several side effects such as hyperglycemia, weight change, or osteoporosis due to its <i>in vivo</i> non-selectivity. Herein, we used liquid chromatography-tandem mass spectrometry-based comprehensive targeted metabolomic profiling as well as r ...[more]

PMID: 29503615

Similar Datasets

Project description:BACKGROUND:Excessive or prolonged usage of dexamethasone can cause serious side effects, but few studies reveal the related mechanism. Dexamethasone work differently in blood tumors and solid tumors, and the cause is still obscure. The aims of this study was to identify potential biomarkers associated with the side effects of dexamethasone in different tumors. METHODS:Gene Expression Omnibus database (GEO) datasets of blood tumors and solid tumors were retrieval to selected microarray data. The differentially expressed genes (DEGs) were identified. Gene ontology (GO) and pathway enrichment analyses, and protein-protein interaction (PPI) network analysis were performed. RESULTS:One hundred and eighty dexamethasone-specific DEGs (92 up and 88 downregulated) were obtained in lymphoma cell samples (named as DEGs-lymph), including APOD, TP53INP1, CLIC3, SERPINA9, and C3orf52. One hundred and four specific DEGs (100 up and 4 downregulated) were identified in prostate cancer cell samples (named as DEGs-prostate), including COL6A2, OSBPL5, OLAH, OGFRL1, and SLC39A14. The significantly enriched GO terms of DEGs-lymph contained cellular amino acid metabolic process and cell cycle. The most significantly enriched pathway of DEGs-lymph was cytosolic tRNA aminoacylation. The DEGs-prostate was enriched in 39 GO terms and two pathways, and the pathways were PPARA activates gene expression Homo sapiens, and insulin resistance. The PPI network of DEGs-lymph gathered into two major clusters, WARS1 and CDC25A were representatives for them, respectively. One cluster was mainly involved in cytosolic tRNA aminoacylation, aminoacyl-tRNA biosynthesis and the function of amino acid metabolism; another was associated with cell cycle and cell apoptosis. As for the PPI network of DEGs-prostate, HELZ2 was the top nodes involved in the most protein-protein pairs, which was related to the pathway of "PPARA activates gene expression Homo sapiens." CONCLUSIONS:WARS1 and CDC25A might be potential biomarkers for side effects of dexamethasone in lymphoma, and HELZ2 in prostate cancer.

Project description:BACKGROUND: Marrow-derived stromal cells (MSCs) maintain the capability of self-renewal and differentiation into multiple lineages in adult life. Age-related changes are recognized by a decline in the stemness potential that result in reduced regeneration potential of the skeleton. To explore the molecular events that underline skeletal physiology during aging we catalogued the profile of gene expression in ex vivo cultured MSCs derived from 3 and 15 month old rats. The ex vivo cultured cells were analyzed following challenge with or without Dexamethasone (Dex). RNA retrieved from these cells was analyzed using Affymetrix Gene Chips to compare the effect of Dex on gene expression in both age groups. RESULTS: The molecular mechanisms that underline skeletal senescence were studied by gene expression analysis of RNA harvested from MSCs. The analysis resulted in complex profiles of gene expression of various differentiation pathways. We revealed changes of lineage-specific gene expression; in general the pattern of expression included repression of proliferation and induction of differentiation. The functional analysis of genes clustered were related to major pathways; an increase in bone remodeling, osteogenesis and muscle formation, coupled with a decrease in adipogenesis. We demonstrated a Dex-related decrease in immune response and in genes that regulate bone resorption and an increase in osteoblastic differentiation. Myogenic-related genes and genes that regulate cell cycle were induced by Dex. While Dex repressed genes related to adipogenesis and catabolism, this decrease was complementary to an increase in expression of genes related to osteogenesis. CONCLUSION: This study summarizes the genes expressed in the ex vivo cultured mesenchymal cells and their response to Dex. Functional clustering highlights the complexity of gene expression in MSCs and will advance the understanding of major pathways that trigger the natural changes underlining physiological aging. The high throughput analysis shed light on the anabolic effect of Dex and the relationship between osteogenesis, myogenesis and adipogenesis in the bone marrow cells.

Dataset Information

Metabolomics Based Profiling of Dexamethasone Side Effects in Rats.

Publications

Metabolomics Based Profiling of Dexamethasone Side Effects in Rats.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets