title: Time-dependent variation of pathways and networks in a 24-hour window after cerebral ischemia-reperfusion injury.
abstract: BACKGROUND
  Cerebral ischemia-reperfusion injury may simultaneously result in functional variation of multiple genes/pathways. However, most prior time-sequence studies on its pathomechanism only focused on a single gene or pathway. Our study aimed to systematically analyze the time-dependent variation in the expression of multiple pathways and networks within 24 h after cerebral ischemia-reperfusion injury.
  
  
  RESULTS
  By uploading 374 ischemia-related genes into the MetaCore software, the variation in the expression of multiple pathways and networks in 3 h, 12 h, and 24 h after cerebral ischemia-reperfusion injury had been analyzed. The conserved TNFR1-signaling pathway, among the top 10 pathways, was consistently enriched in 3 h, 12 h, and 24 h groups. Three overlapping pathways were found between 3 h and 12 h groups; 2 between 12 h and 24 h groups; and 1 between 3 h and 24 h groups. Five, 4, and 6 non-overlapping pathways were observed in 3 h, 12 h, and 24 h groups, respectively. Apart from pathways reported by earlier studies, we identified a novel pathway related to the time-dependent development of cerebral ischemia pathogenesis. The process of apoptosis stimulation by external signals, among the top 10 processes, was consistently enriched in 3 h, 12 h, and 24 h groups; 2, 1, and 2 processes overlapped between 3 h and 12 h groups, 12 h and 24 h groups, and 3 h and 24 h groups, respectively. Four, 5, and 5 non-overlapping processes were found in 3 h, 12 h and 24 h groups, respectively. The presence of apoptotic processes was observed in all the 3 groups; while anti-apoptotic processes only existed in 3 h and 12 h groups. Additionally, according to node degree, network comparison identified 1, 8,and 5 important genes or proteins (e.g. Pyk2, PKC, E2F1, and VEGF-A) in 3 h, 12 h, and 24 h groups, respectively. The Jaccard similarity index revealed a higher level of similarity between 12 h and 24 h groups than that between 3 h and 12 h groups.
  
  
  CONCLUSIONS
  Time-dependent treatment can be utilized to reduce apoptosis, which may activate anti-apoptotic pathways within 12 h after cerebral ischemia-reperfusion injury. Pathway and network analyses may help identify novel pathways and genes implicated in disease pathogenesis.
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Dongzhimennei Nanxiaojie 16#, Beijing, 100700, China. liying_w@126.com.
authors.forename: Li-Ying
authors.initials: LY
authors.lastname: Wang
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Dongzhimennei Nanxiaojie 16#, Beijing, 100700, China. franlj1104@aliyun.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Beijing University of Chinese Medicine, No. 11 East Road, North of 3rd Ring Road, Beijing, 100029, China. coldmoon_ly@163.com.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Information on Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, Dongzhimennei Nanxiaojie 16#, Beijing, 100700, China. libingtcm@163.com.
authors.forename: Bing
authors.initials: B
authors.lastname: Li
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Dongzhimennei Nanxiaojie 16#, Beijing, 100700, China. ljszyy@126.com.
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Zhang
authors.affiliation: China Academy of Chinese Medical Sciences, Dongzhimennei Nanxiaojie 16#, Beijing, 100700, China. drjzw@163.com.
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Jing
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Dongzhimennei Nanxiaojie 16#, Beijing, 100700, China. pumpkinnaicha@163.com.
authors.forename: Ya-Nan
authors.initials: YN
authors.lastname: Yu
authors.affiliation: Guang'anmen Hospital, China Academy of China Medical Sciences, No.5 Beixiange, Beijing, 100053, China. 2272236055@qq.com.
authors.forename: Hai-Xia
authors.initials: HX
authors.lastname: Li
authors.affiliation: Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Dongzhimennei Nanxiaojie 16#, Beijing, 100700, China. ruochushan@163.com.
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Guo
authors.affiliation: China Academy of Chinese Medical Sciences, Dongzhimennei Nanxiaojie 16#, Beijing, 100700, China. zhaoyijun4421@163.com.
authors.forename: Yi-Jun
authors.initials: YJ
authors.lastname: Zhao
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Dongzhimennei Nanxiaojie 16#, Beijing, 100700, China. zhonw@vip.sina.com.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Dongzhimennei Nanxiaojie 16#, Beijing, 100700, China. wangyongyan2010@sina.cn.
authors.forename: Yong-Yan
authors.initials: YY
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis; D002545:Brain Ischemia / Q000150:complications* / Q000378:metabolism; D020869:Gene Expression Profiling; D008297:Male; D051379:Mice; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D015427:Reperfusion Injury / Q000150:complications* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D012984:Software; D049490:Systems Biology; D013997:Time Factors
chemical_list: D047888:Receptors, Tumor Necrosis Factor, Type I