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Pathway bridge based multiobjective optimization approach for lurking pathway prediction.

ABSTRACT: Ovarian carcinoma immunoreactive antigen-like protein 2 (OCIAD2) is a protein with unknown function. Frequently methylated or downregulated, OCIAD2 has been observed in kinds of tumors, and TGF? signaling has been proved to induce the expression of OCIAD2. However, current pathway analysis tools do not cover the genes without reported interactions like OCIAD2 and also miss some significant genes with relatively lower expression. To investigate potential biological milieu of OCIAD2, especially in cancer microenvironment, a nova approach pbMOO was created to find the potential pathways from TGF? to OCIAD2 by searching on the pathway bridge, which consisted of cancer enriched looping patterns from the complicated entire protein interactions network. The pbMOO approach was further applied to study the modulator of ligand TGF?1, receptor TGF?R1, intermediate transfer proteins, transcription factor, and signature OCIAD2. Verified by literature and public database, the pathway TGF?1-TGF?R1-SMAD2/3-SMAD4/AR-OCIAD2 was detected, which concealed the androgen receptor (AR) which was the possible transcription factor of OCIAD2 in TGF?signal, and it well explained the mechanism of TGF? induced OCIAD2 expression in cancer microenvironment, therefore providing an important clue for the future functional analysis of OCIAD2 in tumor pathogenesis.

SUBMITTER: Zhang R

PROVIDER: S-EPMC4052696 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Pathway bridge based multiobjective optimization approach for lurking pathway prediction.

Zhang Rengjing R Zhao Chen C Xiong Zixiang Z Zhou Xiaobo X

BioMed research international 20140416

Ovarian carcinoma immunoreactive antigen-like protein 2 (OCIAD2) is a protein with unknown function. Frequently methylated or downregulated, OCIAD2 has been observed in kinds of tumors, and TGFβ signaling has been proved to induce the expression of OCIAD2. However, current pathway analysis tools do not cover the genes without reported interactions like OCIAD2 and also miss some significant genes with relatively lower expression. To investigate potential biological milieu of OCIAD2, especially in ...[more]

PMID: 24949437

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Project description:BackgroundTaohong Siwu Decoction (THSWD) is a widely used traditional Chinese medicine (TCM) prescription in the treatment of ischemic stroke. There are thousands of chemical components in THSWD. However, the key functional components are still poorly understood. This study aimed to construct a mathematical model for screening of active ingredients in TCM prescriptions and apply it to THSWD on ischemic stroke.MethodsBotanical drugs and compounds in THSWD were acquired from multiple public TCM databases. All compounds were initially screened by ADMET properties. SEA, HitPick, and Swiss Target Prediction were used for target prediction of the filtered compounds. Ischemic stroke pathological genes were acquired from the DisGeNet database. The compound-target-pathogenic gene (C-T-P) network of THSWD was constructed and then optimized using the multiobjective optimization (MOO) algorithm. We calculated the cumulative target coverage score of each compound and screened the top compounds with 90% coverage. Finally, verification of the neuroprotective effect of these compounds was performed with the oxygen-glucose deprivation and reoxygenation (OGD/R) model.ResultsThe optimized C-T-P network contains 167 compounds, 1,467 predicted targets, and 1,758 stroke pathological genes. And the MOO model showed better optimization performance than the degree model, closeness model, and betweenness model. Then, we calculated the cumulative target coverage score of the above compounds, and the cumulative effect of 39 compounds on pathogenic genes reached 90% of all compounds. Furthermore, the experimental results showed that decanoic acid, butylphthalide, chrysophanol, and sinapic acid significantly increased cell viability. Finally, the docking results showed the binding modes of these four compounds and their target proteins.ConclusionThis study provides a methodological reference for the screening of potential therapeutic compounds of TCM. In addition, decanoic acid and sinapic acid screened from THSWD were found having potential neuroprotective effects first and verified with cell experiments, however, further in vitro and in vivo studies are needed to explore the precise mechanisms involved.

Dataset Information

Pathway bridge based multiobjective optimization approach for lurking pathway prediction.

Publications

Pathway bridge based multiobjective optimization approach for lurking pathway prediction.

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