title: Convergent and divergent pathways decoding hierarchical additive mechanisms in treating cerebral ischemia-reperfusion injury.
abstract: BACKGROUND
  Cerebral ischemia is considered to be a highly complex disease resulting from the complicated interplay of multiple pathways. Disappointedly, most of the previous studies were limited to a single gene or a single pathway. The extent to which all involved pathways are translated into fusing mechanisms of a combination therapy is of fundamental importance.
  
  
  OBJECTIVE
  We report an integrative strategy to reveal the additive mechanism that a combination (BJ) of compound baicalin (BA) and jasminoidin (JA) fights against cerebral ischemia based on variation of pathways and functional communities.
  
  
  RESULTS
  We identified six pathways of BJ group that shared diverse additive index from 0.09 to 1, which assembled broad cross talks from seven pathways of BA and 16 pathways of JA both at horizontal and vertical levels. Besides a total of 60 overlapping functions as a robust integration background among the three groups based on significantly differential subnetworks, additive mechanism with strong confidence by networks altered functions.
  
  
  CONCLUSIONS
  These results provide strong evidence that the additive mechanism is more complex than previously appreciated, and an integrative analysis of pathways may suggest an important paradigm for revealing pharmacological mechanisms underlying drug combinations.
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, China.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Zhang
authors.forename: Hai-Xia
authors.initials: HX
authors.lastname: Li
authors.forename: Yin-Ying
authors.initials: YY
authors.lastname: Chen
authors.forename: Hong
authors.initials: H
authors.lastname: Fang
authors.forename: Ya-Nan
authors.initials: YN
authors.lastname: Yu
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Jing
authors.forename: Zhong
authors.initials: Z
authors.lastname: Wang
authors.forename: Yong-Yan
authors.initials: YY
authors.lastname: Wang
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004365:Drugs, Chinese Herbal / Q000627:therapeutic use*; D005419:Flavonoids / Q000627:therapeutic use*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy*; D039823:Iridoids / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D025341:Principal Component Analysis; D015427:Reperfusion Injury / Q000188:drug therapy*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004365:Drugs, Chinese Herbal; D005419:Flavonoids; D039823:Iridoids; C007835:geniposide; C038044:baicalin
keywords: Additive effect; Cerebral ischemia; Drug combination; Ingenuity Pathway Analysis; Pharmacological mechanism