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Transcriptomics and Metabolomics Unveil the Neuroprotection Mechanism of AnGong NiuHuang (AGNH) Pill Against Ischaemic Stroke Injury

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Abstract

As a famous prescription in China, AnGong NiuHuang (AGNH) pill exerts good neuroprotection for ischaemic stroke (IS), but its mechanism is still unclear. In this study, the neuroprotection of AGNH was evaluated in the rat IS model which were established with the surgery of middle cerebral artery occlusion (MCAO), and the potential mechanism was elucidated by transcriptomic analysis and metabolomic analysis. AGNH treatment obviously decreased the infarct volume and Zea-Longa 5-point neurological deficit scores, improved the survival percentage of rats, regional cerebral blood flow (rCBF), and rat activity distance and activity time. Transcriptomics showed that AGNH exerted its anti-inflammatory effects by affecting the regulatory network including Tyrobp, Syk, Tlr2, Myd88 and Ccl2 as the core. Integrating transcriptomics and metabolomics identified 8 key metabolites regulated by AGNH, including L-histidine, L-serine, L-alanine, fumaric acid, malic acid, and N-(L-arginino) succinate, 1-pyrroline-4-hydroxy-2-carboxylate and 1-methylhistamine in the rats with IS. Additionally, AGNH obviously reduced Tyrobp, Syk, Tlr2, Myd88 and Ccl2 at both the mRNA and protein levels, decreased IL-1β, KC-GRO, IL-13, TNF-α, cleaved caspase 3 and p65 nucleus translocation, but increased IκBα expression. Network pharmacology analysis showed that quercetin, beta-sitosterol, baicalein, naringenin, acacetin, berberine and palmatine may play an important role in protecting against IS. Taken together, this study reveals that AGNH reduced neuroinflammation and protected against IS by inhibiting Tyrobp/Syk and Tlr2/Myd88, as well as NF-κB signalling pathway and regulating multiple metabolites.

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Data Availability

All data supporting described findings can be obtained from the corresponding authors upon reasonable request.

Abbreviations

IS:

Ischaemic stroke

AD:

Alzheimer disease

AGNH:

AnGong NiuHuang

BBB:

Blood-brain barrier

DEGs:

Differentially expressed genes

DMs:

Differentially expressed metabolites

ELISA:

Enzyme-linked immunosorbent assay

GO:

Gene Ontology

rCBF:

Regional cerebral blood flow

I/R:

Ischaemia/reperfusion

IF:

Immunofluorescence staining

KEGG:

Kyoto Encyclopedia of Genes and Genomes

MCAO:

Middle cerebral artery occlusion

SD:

Sprague-Dawley

TCM:

Traditional Chinese medicine

TTC:

2,3,5-Triphenyltetrazolium chloride

Ccl2:

C-C motif chemokine ligand 2

Tlr2:

Toll-like receptor 2

Tlr7:

Toll-like receptor 7

Myd88:

Myeloid differentiation factor 88

Tyrobp:

TYRO protein tyrosine kinase-binding protein

Syk:

Spleen tyrosine kinase

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Acknowledgements

We are grateful for the professor for Yanan Sun for her technical support.

Funding

The authors would like to acknowledge the financial support from the National Natural Science Foundation of China (81974550), Scientific and Technological Innovation Project of China Academy of Chinese Medical Science (CI2021A04612, CI2021B017-03) and Fundamental Research Funds for the Central Public Welfare Research Institutes (ZZ13-YQ-046, ZXKT21007 and ZXKT23019).

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  1. Liangliang Tian and Guangzhao Cao contributed equally to this work.

Authors and Affiliations

  1. Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China

    Liangliang Tian, Guangzhao Cao, Xiaotong Zhu, Yi Zhang, He Xu, Lixia Wang, Hongjun Yang & Jingjing Zhang

  2. Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, 100700, China

    Guangzhao Cao, Lihan Wang, Jingyi Hou & Hongjun Yang

  3. Fujian Pien Tze Huang Enterprise Key Laboratory of Natural Medicine Research and Development, Zhangzhou, 363000, Fujian, China

    Shicong Wang & Chen Zhao

  4. Chinese Institute for Brain Research, Beijing, 102206, China

    Jingjing Zhang

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Contributions

Jingjing Zhang: data curation, analysis, conceptualization, funding acquisition, investigation, writing—original draft; Liangliang Tian, Guangzhao Cao: data curation, investigation, visualization, software, validation; Xiaotong Zhu, Lihan Wang, Jingyi Hou, Yi Zhang, He Xu, Lixia Wang, Shicong Wang, Chen Zhao: data curation, investigation; Hongjun Yang: conceptualization, supervision, writing—review and editing. All data were generated in-house, and no paper mill was used. All authors agree to be accountable for all aspects of work ensuring integrity and accuracy.

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Correspondence to Hongjun Yang or Jingjing Zhang.

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Tian, L., Cao, G., Zhu, X. et al. Transcriptomics and Metabolomics Unveil the Neuroprotection Mechanism of AnGong NiuHuang (AGNH) Pill Against Ischaemic Stroke Injury. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04016-8

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