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Met-Controlled Allosteric Module of Neural Generation as A New Therapeutic Target in Rodent Brain Ischemia

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Abstract

Objective

To investigate a Met-controlled allosteric module (AM) of neural generation as a potential therapeutic target for brain ischemia.

Methods

We selected Markov clustering algorithm (MCL) to mine functional modules in the related target networks. According to the topological similarity, one functional module was predicted in the modules of baicalin (BA), jasminoidin (JA), cholic acid (CA), compared with I/R model modules. This functional module included three genes: Inppl1, Met and Dapk3 (IMD). By gene ontology enrichment analysis, biological process related to this functional module was obtained. This functional module participated in generation of neurons. Western blotting was applied to present the compound-dependent regulation of IMD. Co-immunoprecipitation was used to reveal the relationship among the three members. We used IF to determine the number of newborn neurons between compound treatment group and ischemia/reperfusion group. The expressions of vascular endothelial growth factor (VEGF) and matrix metalloproteinase 9 (MMP-9) were supposed to show the changing circumstances for neural generation under cerebral ischemia.

Results

Significant reduction in infarction volume and pathological changes were shown in the compound treatment groups compared with the I/R model group (P<0.05). Three nodes in one novel module of IMD were found to exert diverse compound-dependent ischemic-specific excitatory regulatory activities. An anti-ischemic excitatory allosteric module (AME) of generation of neurons (AME-GN) was validated successfully in vivo. Newborn neurons increased in BJC treatment group (P<0.05). The expression of VEGF and MMP-9 decreased in the compound treatment groups compared with the I/R model group (P<0.05).

Conclusions

AME demonstrates effectiveness of our pioneering approach to the discovery of therapeutic target. The novel approach for AM discovery in an effort to identify therapeutic targets holds the promise of accelerating elucidation of underlying pharmacological mechanisms in cerebral ischemia.

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Acknowledgement

Special thanks to Hang XY and Fang WB for their technical assistances in this study.

Author information

Authors and Affiliations

  1. Department of Traditional Chinese Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China

    Kang-ning Li

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

    Ying-ying Zhang, Ya-nan Yu, Hong-li Wu & Zhong Wang

Authors
  1. Kang-ning Li
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  2. Ying-ying Zhang
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  3. Ya-nan Yu
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  4. Hong-li Wu
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  5. Zhong Wang
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Contributions

Li KN and Wang Z designed the research. Li KN, Zhang YY, and Yu YN performed the research and analyzed data. Wu HL performed the text mining. Li KN drafted the manuscript. All authors gave final approval of the version to be published, and agree to be accountable for all aspects of the work.

Corresponding author

Correspondence to Zhong Wang.

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Conflict of Interest

All authors have no conflict of interest regarding this paper.

Supported by Beijing Natural Science Foundation (No. 7174298), Miaopu Project of Beijing Tiantan Hospital affiliated to Capital Medical University (No. 2014MP04) and the 51th lot General Financial Grant from the China Postdoctoral Science Foundation (No. 2012M510723)

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Li, Kn., Zhang, Yy., Yu, Yn. et al. Met-Controlled Allosteric Module of Neural Generation as A New Therapeutic Target in Rodent Brain Ischemia. Chin. J. Integr. Med. 27, 896–904 (2021). https://doi.org/10.1007/s11655-019-3182-8

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  • DOI: https://doi.org/10.1007/s11655-019-3182-8

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