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Metabolomics and proteomics annotate therapeutic properties of geniposide: targeting and regulating multiple perturbed pathways.

ABSTRACT: Geniposide is an important constituent of Gardenia jasminoides Ellis, a famous Chinese medicinal plant, and has displayed bright prospects in prevention and therapy of hepatic injury (HI). Unfortunately, the working mechanisms of this compound are difficult to determine and thus remain unknown. To determine the mechanisms that underlie this compound, we conducted a systematic analysis of the therapeutic effects of geniposide using biochemistry, metabolomics and proteomics. Geniposide significantly intensified the therapeutic efficacy as indicated by our modern biochemical analysis. Metabolomics results indicate 9 ions in the positive mode as differentiating metabolites which were associated with perturbations in primary bile acid biosynthesis, butanoate metabolism, citrate cycle (TCA cycle), alanine, aspartate and glutamate metabolism. Of note, geniposide has potential pharmacological effect through regulating multiple perturbed pathways to normal state. In an attempt to address the benefits of geniposide based on the proteomics approaches, the protein-interacting networks were constructed to aid identifying the drug targets of geniposide. Six identified differential proteins appear to be involved in antioxidation and signal transduction, energy production, immunity, metabolism, chaperoning. These proteins were closely related in the protein-protein interaction network and the modulation of multiple vital physiological pathways. These data will help to understand the molecular therapeutic mechanisms of geniposide on hepatic damage rats. We also conclude that metabolomics and proteomics are powerful and versatile tools for both biomarker discovery and exploring the complex relationships between biological pathways and drug response, highlighting insights into drug discovery.

SUBMITTER: Wang X

PROVIDER: S-EPMC3744542 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Metabolomics and proteomics annotate therapeutic properties of geniposide: targeting and regulating multiple perturbed pathways.

Wang Xijun X Zhang Aihua A Yan Guangli G Sun Wenjun W Han Ying Y Sun Hui H

PloS one 20130815 8

Geniposide is an important constituent of Gardenia jasminoides Ellis, a famous Chinese medicinal plant, and has displayed bright prospects in prevention and therapy of hepatic injury (HI). Unfortunately, the working mechanisms of this compound are difficult to determine and thus remain unknown. To determine the mechanisms that underlie this compound, we conducted a systematic analysis of the therapeutic effects of geniposide using biochemistry, metabolomics and proteomics. Geniposide significant ...[more]

PMID: 23967205

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Project description:BackgroundSubstantial research has investigated the adverse effects of traffic-related air pollutants (TRAP) on human health. Convincing associations between TRAP and respiratory and cardiovascular diseases are known, but the underlying biological mechanisms are not well established. High-resolution metabolomics (HRM) is a promising platform for untargeted characterization of molecular mechanisms between TRAP and health indexes.ObjectivesWe examined metabolic perturbations associated with short-term exposures to TRAP, including carbon monoxide (CO), nitrogen dioxide (NO2), ozone (O3), fine particulate matter (PM2.5), organic carbon (OC), and elemental carbon (EC) among 180 participants of the Center for Health Discovery and Well-Being (CHDWB), a cohort of Emory University-affiliated employees.MethodsA cross-sectional study was conducted on baseline visits of 180 CHDWB participants enrolled during 2008-2012, in whom HRM profiling was determined in plasma samples using liquid chromatography-high-resolution mass spectrometry with positive and negative electrospray ionization (ESI) modes. Ambient pollution concentrations were measured at an ambient monitor near downtown Atlanta. Metabolic perturbations associated with TRAP exposures were assessed following an untargeted metabolome-wide association study (MWAS) framework using feature-specific Tobit regression models, followed by enriched pathway analysis and chemical annotation.ResultsSubjects were predominantly white (76.1%) and non-smokers (95.6%), and all had at least a high school education. In total, 7821 and 4123 metabolic features were extracted from the plasma samples by the negative and positive ESI runs, respectively. There are 3421 features significantly associated with at least one air pollutant by negative ion mode, and 1691 features by positive ion mode. Biological pathways enriched by features associated with the pollutants are primarily involved in nucleic acids damage/repair (e.g., pyrimidine metabolism), nutrient metabolism (e.g., fatty acid metabolism), and acute inflammation (e.g., histidine metabolism and tyrosine metabolism). NO2 and EC were associated most consistently with these pathways. We confirmed the chemical identity of 8 metabolic features in negative ESI and 2 features in positive ESI, including metabolites closely linked to oxidative stress and inflammation, such as histamine, tyrosine, tryptophan, and proline.ConclusionsWe identified a range of ambient pollutants, including components of TRAP, associated with differences in the metabolic phenotype among the cohort of 180 subjects. We found Tobit models to be a robust approach to handle missing data among the metabolic features. The results were encouraging of further use of HRM and MWAS approaches for characterizing molecular mechanisms underlying exposure to TRAP.

Project description:Anaplasma phagocytophilum is an emerging zoonotic pathogen that causes human granulocytic anaplasmosis. These intracellular bacteria establish infection by affecting cell function in both the vertebrate host and the tick vector, Ixodes scapularis. Previous studies have characterized the tick transcriptome and proteome in response to A. phagocytophilum infection. However, in the post-genomic era, the integration of omics datasets through a systems biology approach allows network-based analyses to describe the complexity and functionality of biological systems such as host-pathogen interactions and the discovery of new targets for prevention and control of infectious diseases. This study reports for the first time a systems biology integration of metabolomics, transcriptomics and proteomics data to characterize essential metabolic pathways involved in the response of tick cells to A. phagocytophilum infection. The results showed that infection affected protein processing in endoplasmic reticulum and glucose metabolic pathways in tick cells. These results supported tick-Anaplasma co-evolution by providing new evidence of how tick cells limit pathogen infection, while the pathogen benefits from the tick cell response to establish infection. The results suggested that A. phagocytophilum induces protein misfolding to limit the tick cell response and facilitate infection, but requires protein degradation to prevent ER stress and cell apoptosis to survive in infected cells. Additionally, A. phagocytophilum may benefit from the tick cellâs ability to limit bacterial infection through PEPCK inhibition leading to decreased glucose metabolism, which also results in the inhibition of cell apoptosis that increases infection of tick cells. These results support the use of this experimental approach to systematically identify tick cell pathways and molecular mechanisms involved in tick-pathogen interactions Two samples with two replicates each were analyzed. Samples included Ixodes scapularis ISE6 cells uninfected (control) and infected with Anaplasma phagocytophilum human NY18 isolate.

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Metabolomics and proteomics annotate therapeutic properties of geniposide: targeting and regulating multiple perturbed pathways.

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Metabolomics and proteomics annotate therapeutic properties of geniposide: targeting and regulating multiple perturbed pathways.

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