title: Phenotype-dependent alteration of pathways and networks reveals a pure synergistic mechanism for compounds treating mouse cerebral ischemia.
abstract: OBJECTIVE
  Our previous studies have showed that ursodeoxycholic acid (UA) and jasminoidin (JA) effectively reduce cerebral infarct volume in mice. In this study we explored the pure synergistic mechanism of these compounds in treatment of mouse cerebral ischemia, which was defined as synergistic actions specific for phenotype variations after excluding interference from ineffective compounds.
  
  
  METHODS
  Mice with focal cerebral ischemia were treated with UA, JA or a combination JA and UA (JU). Concha margaritifera (CM) was taken as ineffective compound. Cerebral infarct volume of the mice was determined, and the hippocampi were taken for microarray analysis. Particular signaling pathways and biological functions were enriched based on differentially expressed genes, and corresponding networks were constructed through Ingenuity Pathway Analysis.
  
  
  RESULTS
  In phenotype analysis, UA, JA, and JU significantly reduced the ischemic infarct volume with JU being superior to UA or JA alone, while CM was ineffective. As a result, 4 pathways enriched in CM were excluded. Core pathways in the phenotype-positive groups (UA or JA) were involved in neuronal homeostasis and neuropathology. JU-contributing pathways included all UA-contributing and the majority (71.7%) of JA-contributing pathways, and 10 new core pathways whose effects included inflammatory immunity, apoptosis and nervous system development. The functions of JU group included all functions of JA group, the majority (93.1%) of UA-contributing functions, and 3 new core functions, which focused on physiological system development and function.
  
  
  CONCLUSIONS
  The pure synergism between UA and JA underlies 10 new core pathways and 3 new core functions, which are involved in inflammation, immune responses, apoptosis and nervous system development.
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China.
authors.forename: Peng-qian
authors.initials: PQ
authors.lastname: Wang
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China.
authors.forename: Ying-ying
authors.initials: YY
authors.lastname: Zhang
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China.
authors.forename: Ya-nan
authors.initials: YN
authors.lastname: Yu
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China.
authors.forename: Xiao-xu
authors.initials: XX
authors.lastname: Zhang
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China.
authors.forename: Zhi-li
authors.initials: ZL
authors.lastname: Guo
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China.
authors.forename: Hong-li
authors.initials: HL
authors.lastname: Wu
authors.affiliation: Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China.
authors.forename: Hai-xia
authors.initials: HX
authors.lastname: Li
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China.
authors.forename: Hai-xia
authors.initials: HX
authors.lastname: Dang
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China.
authors.forename: Shan-shan
authors.initials: SS
authors.lastname: Guo
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D057225:Data Mining; D030541:Databases, Genetic; D004195:Disease Models, Animal; D004338:Drug Combinations; D004357:Drug Synergism; D004365:Drugs, Chinese Herbal / Q000494:pharmacology* / Q000627:therapeutic use*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D023281:Genomics; D008297:Male; D008516:Medicine, Chinese Traditional / Q000379:methods*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D060066:Protein Interaction Maps; D015398:Signal Transduction / Q000187:drug effects; D049490:Systems Biology / Q000379:methods*; D018511:Systems Integration
chemical_list: D004338:Drug Combinations; D004365:Drugs, Chinese Herbal