Limits...
System-wide assembly of pathways and modules hierarchically reveal metabolic mechanism of cerebral ischemia.

Zhu Y, Guo Z, Zhang L, Zhang Y, Chen Y, Nan J, Zhao B, Xiao H, Wang Z, Wang Y - Sci Rep (2015)

Bottom Line: The relationship between cerebral ischemia and metabolic disorders is poorly understood, which is partly due to the lack of comparative fusing data for larger complete systems and to the complexity of metabolic cascade reactions.Our analyses revealed 8 significantly altered pathways by MetPA (Metabolomics Pathway Analysis, impact score >0.10) and 15 significantly rewired modules in a complex ischemic network using the Markov clustering (MCL) method; all of these pathways became more homologous as the number of overlapping nodes was increased.We then detected 24 extensive pathways based on the total modular nodes from the network analysis, 12 of which were new discovery pathways.

View Article: PubMed Central - PubMed

Affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China.

ABSTRACT
The relationship between cerebral ischemia and metabolic disorders is poorly understood, which is partly due to the lack of comparative fusing data for larger complete systems and to the complexity of metabolic cascade reactions. Based on the fusing maps of comprehensive serum metabolome, fatty acid and amino acid profiling, we identified 35 potential metabolic biomarkers for ischemic stroke. Our analyses revealed 8 significantly altered pathways by MetPA (Metabolomics Pathway Analysis, impact score >0.10) and 15 significantly rewired modules in a complex ischemic network using the Markov clustering (MCL) method; all of these pathways became more homologous as the number of overlapping nodes was increased. We then detected 24 extensive pathways based on the total modular nodes from the network analysis, 12 of which were new discovery pathways. We provided a new perspective from the viewpoint of abnormal metabolites for the overall study of ischemic stroke as well as a new method to simplify the network analysis by selecting the more closely connected edges and nodes to build a module map of stroke.

No MeSH data available.


Related in: MedlinePlus

Phenotypes alteration of ischemic rats compared with sham-operated rats.(A) The average brain infarction volume and neurological deficits scores of the sham and ischemia groups. Data are presented as mean ± SEM. ***P < 0.001 as determined by Bonferroni corrected t tests. (B,C) The HE stains of cortical neurons of the sham and ischemia groups, respectively. (D,E) The electron microscope of cortical neurons of the sham and ischemia groups, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4664864&req=5

f1: Phenotypes alteration of ischemic rats compared with sham-operated rats.(A) The average brain infarction volume and neurological deficits scores of the sham and ischemia groups. Data are presented as mean ± SEM. ***P < 0.001 as determined by Bonferroni corrected t tests. (B,C) The HE stains of cortical neurons of the sham and ischemia groups, respectively. (D,E) The electron microscope of cortical neurons of the sham and ischemia groups, respectively.

Mentions: Ten rats in the ischemia group were successfully modeled. After 3 days, 5 rats in the ischemia group survived, and their blood samples were therefore collected for the subsequent metabolic network analysis. Meanwhile, 10 rats in the sham group were taken as control samples. The infarct volume (p < 0.001) (see Fig. S2 for TTC result) and neurological deficit score over three days (p < 0.001 on each day) after the induction of ischemia were significantly increased (Fig. 1A). Compared with the cortical tissue of sham-operated animals (Fig. 1B), significant necrosis of the cortical neuronal cells in the core of the infarct was observed in the ischemia group by hematoxylin-eosin (HE) staining, with gap-like structured neurons and enhanced basophilic staining in the cytoplasm; the neuronal cell body was deformed, and the nucleus was condensed, dissolved or disappeared (Fig. 1C). Nerve cell swelling and degeneration, cytoplasmic edema, intracellular component degradation, nuclear condensation, nuclear membrane thickening, and nuclear chromatin aggregation into blocks were observed under ischemic conditions by electron microscopy (Fig. 1E), whereas normal nerve cell structure, abundant cytoplasm, normal mitochondria and endoplasmic reticulum, abundant glycogen granules, normal cell nuclei, double-layered nuclear membranes, and evenly distributed, nuclear staining quality were observed under normal conditions (Fig. 1D). Under ischemic conditions, marked edema was noted in the cytoplasm, the amount of organelles significantly decreased, the envelope and cristae of most mitochondria became fused and obscure, and the rough endoplasmic reticulum mildly expanded, with evident fusion and degranulation.


System-wide assembly of pathways and modules hierarchically reveal metabolic mechanism of cerebral ischemia.

Zhu Y, Guo Z, Zhang L, Zhang Y, Chen Y, Nan J, Zhao B, Xiao H, Wang Z, Wang Y - Sci Rep (2015)

Phenotypes alteration of ischemic rats compared with sham-operated rats.(A) The average brain infarction volume and neurological deficits scores of the sham and ischemia groups. Data are presented as mean ± SEM. ***P < 0.001 as determined by Bonferroni corrected t tests. (B,C) The HE stains of cortical neurons of the sham and ischemia groups, respectively. (D,E) The electron microscope of cortical neurons of the sham and ischemia groups, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664864&req=5

f1: Phenotypes alteration of ischemic rats compared with sham-operated rats.(A) The average brain infarction volume and neurological deficits scores of the sham and ischemia groups. Data are presented as mean ± SEM. ***P < 0.001 as determined by Bonferroni corrected t tests. (B,C) The HE stains of cortical neurons of the sham and ischemia groups, respectively. (D,E) The electron microscope of cortical neurons of the sham and ischemia groups, respectively.
Mentions: Ten rats in the ischemia group were successfully modeled. After 3 days, 5 rats in the ischemia group survived, and their blood samples were therefore collected for the subsequent metabolic network analysis. Meanwhile, 10 rats in the sham group were taken as control samples. The infarct volume (p < 0.001) (see Fig. S2 for TTC result) and neurological deficit score over three days (p < 0.001 on each day) after the induction of ischemia were significantly increased (Fig. 1A). Compared with the cortical tissue of sham-operated animals (Fig. 1B), significant necrosis of the cortical neuronal cells in the core of the infarct was observed in the ischemia group by hematoxylin-eosin (HE) staining, with gap-like structured neurons and enhanced basophilic staining in the cytoplasm; the neuronal cell body was deformed, and the nucleus was condensed, dissolved or disappeared (Fig. 1C). Nerve cell swelling and degeneration, cytoplasmic edema, intracellular component degradation, nuclear condensation, nuclear membrane thickening, and nuclear chromatin aggregation into blocks were observed under ischemic conditions by electron microscopy (Fig. 1E), whereas normal nerve cell structure, abundant cytoplasm, normal mitochondria and endoplasmic reticulum, abundant glycogen granules, normal cell nuclei, double-layered nuclear membranes, and evenly distributed, nuclear staining quality were observed under normal conditions (Fig. 1D). Under ischemic conditions, marked edema was noted in the cytoplasm, the amount of organelles significantly decreased, the envelope and cristae of most mitochondria became fused and obscure, and the rough endoplasmic reticulum mildly expanded, with evident fusion and degranulation.

Bottom Line: The relationship between cerebral ischemia and metabolic disorders is poorly understood, which is partly due to the lack of comparative fusing data for larger complete systems and to the complexity of metabolic cascade reactions.Our analyses revealed 8 significantly altered pathways by MetPA (Metabolomics Pathway Analysis, impact score >0.10) and 15 significantly rewired modules in a complex ischemic network using the Markov clustering (MCL) method; all of these pathways became more homologous as the number of overlapping nodes was increased.We then detected 24 extensive pathways based on the total modular nodes from the network analysis, 12 of which were new discovery pathways.

View Article: PubMed Central - PubMed

Affiliation: Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing, 100700, China.

ABSTRACT
The relationship between cerebral ischemia and metabolic disorders is poorly understood, which is partly due to the lack of comparative fusing data for larger complete systems and to the complexity of metabolic cascade reactions. Based on the fusing maps of comprehensive serum metabolome, fatty acid and amino acid profiling, we identified 35 potential metabolic biomarkers for ischemic stroke. Our analyses revealed 8 significantly altered pathways by MetPA (Metabolomics Pathway Analysis, impact score >0.10) and 15 significantly rewired modules in a complex ischemic network using the Markov clustering (MCL) method; all of these pathways became more homologous as the number of overlapping nodes was increased. We then detected 24 extensive pathways based on the total modular nodes from the network analysis, 12 of which were new discovery pathways. We provided a new perspective from the viewpoint of abnormal metabolites for the overall study of ischemic stroke as well as a new method to simplify the network analysis by selecting the more closely connected edges and nodes to build a module map of stroke.

No MeSH data available.


Related in: MedlinePlus