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An Integrated Proteomics and Bioinformatics Approach Reveals the Anti-inflammatory Mechanism of Carnosic Acid.

ABSTRACT: Drastic macrophages activation triggered by exogenous infection or endogenous stresses is thought to be implicated in the pathogenesis of various inflammatory diseases. Carnosic acid (CA), a natural phenolic diterpene extracted from Salvia officinalis plant, has been reported to possess anti-inflammatory activity. However, its role in macrophages activation as well as potential molecular mechanism is largely unexplored. In the current study, we sought to elucidate the anti-inflammatory property of CA using an integrated approach based on unbiased proteomics and bioinformatics analysis. CA significantly inhibited the robust increase of nitric oxide and TNF-?, downregulated COX2 protein expression, and lowered the transcriptional level of inflammatory genes including Nos2, Tnf?, Cox2, and Mcp1 in LPS-stimulated RAW264.7 cells, a murine model of peritoneal macrophage cell line. The LC-MS/MS-based shotgun proteomics analysis showed CA negatively regulated 217 LPS-elicited proteins which were involved in multiple inflammatory processes including MAPK, nuclear factor (NF)-?B, and FoxO signaling pathways. A further molecular biology analysis revealed that CA effectually inactivated IKK?/I?B-?/NF-?B, ERK/JNK/p38 MAPKs, and FoxO1/3 signaling pathways. Collectively, our findings demonstrated the role of CA in regulating inflammation response and provide some insights into the proteomics-guided pharmacological mechanism study of natural products.

SUBMITTER: Wang LC

PROVIDER: S-EPMC5911474 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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An Integrated Proteomics and Bioinformatics Approach Reveals the Anti-inflammatory Mechanism of Carnosic Acid.

Wang Li-Chao LC Wei Wen-Hui WH Zhang Xiao-Wen XW Liu Dan D Zeng Ke-Wu KW Tu Peng-Fei PF

Frontiers in pharmacology 20180416

Drastic macrophages activation triggered by exogenous infection or endogenous stresses is thought to be implicated in the pathogenesis of various inflammatory diseases. Carnosic acid (CA), a natural phenolic diterpene extracted from <i>Salvia officinalis</i> plant, has been reported to possess anti-inflammatory activity. However, its role in macrophages activation as well as potential molecular mechanism is largely unexplored. In the current study, we sought to elucidate the anti-inflammatory pr ...[more]

PMID: 29713284

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Project description:Long noncoding RNA (lncRNA) refers to the family of RNA transcripts with more than 200 nucleotides in length, but cannot encode proteins. lincRNA (long intergenic noncoding RNA) is a subset of lncRNA that do not overlap with known genes. Increasing evidences have shown that some of these transcripts do in fact contain open reading frames (ORFs) to code short peptides, and do have significant functional roles within the cells. However, many of these peptides remain unannotated and uncharacterized. This study proposes a workflow integrating proteomics, transcriptomics and bioinformatics specifically for lincRNA-encoded peptide discovery. The workflow was tested on the mouse kidney inner medulla (IM), a region that contains the collecting duct system responsible for regulated water transport. In brief, short peptides (from 2 to 20 kDa) were enriched by tricine protein gel and in-gel trypsinized into peptides, then analyzed using high resolution mass spectrometry. However, to match mass fragment ion spectra to peptide sequences requires a reference peptide sequence database which are not available for the noncoding transcripts, and must be generated de novo in the sample of interest. We modified the RNA-Seq mapping workflow by filtering out coding reads first to better quantitate the noncoding transcript expressions. Also, a rule-based ORF prediction was implemented to select one best predicted ORF per noncoding transcript to construct the peptide library. Candidates were further evaluated using several quality control criteria and bioinformatics tools. Three candidates, conserved in rat and human, passed all criteria, maybe truly novel coding genes. In summary, we present a workflow based on the modern transcriptomics and proteomics technologies for lincRNA-encoded peptide discovery. A computational challenge is to generate a hypothetical lincRNA-encoded peptide database for peptide-mass spectra matching. With this workflow, we discovered three previously unannotated peptides in the mouse kidney inner medulla. The same workflow can be applied in any cell or tissue type of interest to quickly advance this research field.

Dataset Information

An Integrated Proteomics and Bioinformatics Approach Reveals the Anti-inflammatory Mechanism of Carnosic Acid.

Publications

An Integrated Proteomics and Bioinformatics Approach Reveals the Anti-inflammatory Mechanism of Carnosic Acid.

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