Convergent and Divergent Pathways Decoding Hierarchical Additive Mechanisms in Treating Cerebral Ischemia–Reperfusion Injury

Zhang, Yingying; Li, Haixia; Chen, Yinying; Fang, Hong; Yu, Yanan; Li, Jun; Jing, Zhiwei; Zhong, Wang; Wang, Yongyan

doi:10.1111/cns.12205

Cited by 18 publications

(36 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The differentially expressed genes identified by microarray analysis consisted of 11,644 cDNAs. One‐way analysis of variance models and significance analyses of microarrays were used to compare the means of the altered genes between groups 11, 12. A total of 414, 470, and 401 significantly differentially expressed genes were found among JA vs. vehicle, UA vs. vehicle, and JU (jasminoidin and ursodeoxycholic acid) vs. vehicle, respectively.…”

Section: Methodsmentioning

confidence: 99%

Mining the Synergistic Core Allosteric Modules Variation and Sequencing Pharmacological Module Drivers in a Preclinical Model of Ischemia

Zhang

Zhao

et al. 2018

CPT Pharmacom & Syst Pharma

Self Cite

View full text Add to dashboard Cite

Identifying the variation of core modules and hubs seems to be critical for characterizing variable pharmacological mechanisms based on topological alteration of disease networks. We first identified a total of eight core modules by using an approach of multiple modular characteristic fusing (MMCF) from different targeted networks in ischemic mice. Interestingly, the value of module disturbance intensity (MDI) increased in drug combination group. Second, we redefined a weak allosteric module and a strong allosteric module. Then, we identified 15 pharmacological module drivers (PMDs) by leave‐one‐out screening with a cutoff of two folds, which were at least, in part, validated by expression and variation of topological contribution. Finally, we revealed the fusional and emergent variation of PMD in core modules contributing to multidimensional synergistic mechanism in ischemic mice and rats. Our findings provide a new set of drivers that might promote the pharmacological modular flexibility and offer a potential avenue for disease treatment.

show abstract

Section: Methodsmentioning

confidence: 99%

Mining the Synergistic Core Allosteric Modules Variation and Sequencing Pharmacological Module Drivers in a Preclinical Model of Ischemia

Zhang

Zhao

et al. 2018

CPT Pharmacom & Syst Pharma

Self Cite

View full text Add to dashboard Cite

show abstract

“…Images of these slices were captured by a digital camera (Color CCD camera TP-6001A, Topica Inc, Tokyo, Japan). The area of the infarction region was calculated using a Pathology Image Analysis System (Topica Inc), and the ratio of the infarction volume to the total slice volume was calculated as described in our previous study [21][22][23][24][25][26] .…”

Section: Drug Administrationmentioning

confidence: 99%

“…The cDNA microarray, including 374 cDNA ischemia-related genes, was selected from the Science STKE database. The details of this process are described in our previous studies [21][22][23][24][25][26] .…”

Section: Rna Extraction and Microarraymentioning

confidence: 99%

“…The results were submitted to the Array Express database. All data were normalized by locally weighted scatter plot smoothing (Lowness) to reduce experimental variability [21][22][23][24][25][26] . One-way analysis of variance and significant analysis of micro-arrays were employed to compare the mean numbers of the altered genes between the vehicle and sham, CM and vehicle, UA and CM, JA and CM, and JU and CM groups.…”

Section: Rna Extraction and Microarraymentioning

confidence: 99%

“…Our previous studies have shown that ursodeoxycholic acid (UA) and jasminoidin (JA) can significantly reduce ischemic infarct volume [21][22][23][24][25] . In the current study, we further explored the pure synergistic mechanism of these drugs, excluding interference from any negative phenotype compounds.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Phenotype-dependent alteration of pathways and networks reveals a pure synergistic mechanism for compounds treating mouse cerebral ischemia

Wang

et al. 2015

Acta Pharmacol Sin

Self Cite

View full text Add to dashboard Cite

Aim: 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. Conclusion: 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.

show abstract

Development of Fangjiomics for Systems Elucidation of Synergistic Mechanism Underlying Combination Therapy

Wei

et al. 2018

Computational and Structural Biotechnology Journal

Self Cite

View full text Add to dashboard Cite

The rapid development of omics technology provides an opportunity for fulfilling the understanding of the synergistic mechanism of combination therapy. However, a systems theory to analyze synergy remains an ongoing challenge. Fangjiomics is a novel systems science based on a holistic theory integrated with reductionism which has been utilized to systematically elucidate the synergistic mechanisms underlying combination therapy using multi-target-, pathway- or network-based quantitative methods. Besides, our ability to understand the polyhierarchical structure in synergy is driven based on multi-level omics data fusion in Fangjiomics. According to the basic principle of “Jun-Chen-Zuo-Shi”, further global integration across various omics platforms and phenotype-driven quantitative multi-scale modeling would accelerate development in Fangjiomics-based dissection of synergy in multi-drug combination therapies.

show abstract

Convergent and Divergent Pathways Decoding Hierarchical Additive Mechanisms in Treating Cerebral Ischemia–Reperfusion Injury

Abstract: 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.

Cited by 18 publications

References 48 publications

Mining the Synergistic Core Allosteric Modules Variation and Sequencing Pharmacological Module Drivers in a Preclinical Model of Ischemia

Mining the Synergistic Core Allosteric Modules Variation and Sequencing Pharmacological Module Drivers in a Preclinical Model of Ischemia

Phenotype-dependent alteration of pathways and networks reveals a pure synergistic mechanism for compounds treating mouse cerebral ischemia

Development of Fangjiomics for Systems Elucidation of Synergistic Mechanism Underlying Combination Therapy

Contact Info

Product

Resources

About