Abstract
Background Hedysarum multijugum Maxim.-Chuanxiong rhizoma compound (HCC) is a common herbal formula modified from Buyang Huanwu decoction. Clinical trials have demonstrated its therapeutic potential for ischemic stroke (IS). However, the mechanism of HCC remains unclear. Methods The HCC's components were collected from the TCMSP database and TCM@Taiwan database. After that, the HCC's compound targets were predicted by PharmMapper. The IS-related genes were obtained from GeneCards, and OMIM and the protein-protein interaction (PPI) data of HCC's targets and IS genes were obtained from the String database. After that, the DAVID platform was applied for Gene Ontology (GO) enrichment analysis and pathway enrichment analysis and the Cytoscape 3.7.2 was utilized to construct and analyze the networks. Finally, a series of animal experiments were carried out to validate the prediction results of network pharmacology. The expressions of GRP78, p-PERK, and CHOP proteins and mRNAs in different time periods after HCC intervention were detected by Western blot, immunohistochemistry, and RT-qPCR. Results A total of 440 potential targets and 388 IS genes were obtained. The results of HCC-IS PPI network analysis showed that HCC may regulate IS-related targets (such as ALB, AKT1, MMP9, IGF1, and CASP3), biological processes (such as endoplasmic reticulum stress, inflammation modules, hypoxia modules, regulation of neuronal apoptosis and proliferation, and angiogenesis), and signaling pathways (such as PI3K-Akt, FoxO, TNF, HIF-1, and Rap1 signaling). The animal experiments showed that HCC can improve the neurobehavioral scores and protect the neurons of IS rats (P < 0.05). HCC inhibited the expression of p-PERK in the PERK pathway from 12 h after surgery, significantly promoted the expression of GRP78 protein, and inhibited the expression of CHOP protein after surgery, especially at 24 h after surgery (P < 0.05). The results of RT-qPCR showed that HCC can significantly reduce the expression of CHOP mRNA in the neurons in the CA1 region of the hippocampus 72 h after MCAO (P < 0.05). Conclusion HCC may achieve a role in the treatment of IS by intervening in a series of targets, signaling pathways, and biological processes such as inflammation, oxidative stress, endoplasmic reticulum stress, and angiogenesis.
Highlights
Stroke is the leading cause of death and disability, and the cost of medical resources after stroke is high [1, 2]
Hedysarum multijugum Maxim.-Chuanxiong rhizoma compound (HCC) was first used by the First Affiliated Hospital of Hunan University of Chinese Medicine. It was modified from the classic prescription Buyang Huanwu decoction and has applied for a patented product, which is mainly composed of Hedysarum multijugum Maxim., Chuanxiong rhizoma, Pheretima, and Bombyx batryticatus [10]
Through the analysis of the HCC-ischemic stroke (IS) protein-protein interaction (PPI) network, we reveal the potential mechanism of HCC treatment of IS, which is mainly related to inflammation, hypoxia, endoplasmic reticulum stress, oxidative stress, angiogenesis, coagulation and platelet activation, angiogenesis, endothelial damage, the negative regulation of endothelial cell apoptosis, and the regulation of angiogenesis and inflammatory response after IS
Summary
Stroke is the leading cause of death and disability, and the cost of medical resources after stroke is high [1, 2]. Hedysarum multijugum Maxim.-Chuanxiong rhizoma compound (HCC) was first used by the First Affiliated Hospital of Hunan University of Chinese Medicine. It was modified from the classic prescription Buyang Huanwu decoction and has applied for a patented product, which is mainly composed of Hedysarum multijugum Maxim., Chuanxiong rhizoma, Pheretima, and Bombyx batryticatus [10]. The results of HCC-IS PPI network analysis showed that HCC may regulate IS-related targets (such as ALB, AKT1, MMP9, IGF1, and CASP3), biological processes (such as endoplasmic reticulum stress, inflammation modules, hypoxia modules, regulation of neuronal apoptosis and proliferation, and angiogenesis), and signaling pathways (such as PI3K-Akt, FoxO, TNF, HIF-1, and Rap signaling). HCC may achieve a role in the treatment of IS by intervening in a series of targets, signaling pathways, and biological processes such as inflammation, oxidative stress, endoplasmic reticulum stress, and angiogenesis
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