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. 2020 Oct 6:2020:6072380.
doi: 10.1155/2020/6072380. eCollection 2020.

The Effect of Hedysarum multijugum Maxim.- Chuanxiong rhizoma Compound on Ischemic Stroke: A Research Based on Network and Experimental Pharmacology

Kailin Yang  1   2   3 , Liuting Zeng  4 , Anqi Ge  1 , Yongmei Shi  2 , Xiaofei Zhu  2 , Wenlong Liu  2 , Jinwen Ge  2
Affiliations

The Effect of Hedysarum multijugum Maxim.- Chuanxiong rhizoma Compound on Ischemic Stroke: A Research Based on Network and Experimental Pharmacology

Kailin Yang et al. Oxid Med Cell Longev. .

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.

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Conflict of interest statement

We declare no competing interests.

Figures

Figure 1
Figure 1
The research processes.
Figure 2
Figure 2
HCC's fingerprint ((a) mixed standard and (b) HCC).
Figure 3
Figure 3
(a) Venn diagram of potential targets and IS genes. (b) Herb-potential target network (HQ: Hedysarum multijugum Maxim.; CX: Chuanxiong rhizoma; DL: Pheretima; JC: Bombyx batryticatus).
Figure 4
Figure 4
HCC-IS PPI network (green circle stands for HCC-IS; blue circle stands for IS genes; orange circle stands for HCC targets).
Figure 5
Figure 5
Cluster of HCC-IS PPI network (purple circle stands for HCC-IS; blue circle stands for IS genes; pink circle stands for HCC targets).
Figure 6
Figure 6
Bubble chart of biological processes of Cluster 4 (x-axis stands for fold enrichment).
Figure 7
Figure 7
Herb-biological processes-target network (red diamond stands for biological processes; purple circle stands for HCC-IS; blue circle stands for IS genes; pink circle stands for HCC targets. The gray lines stand for the relationship among herbs and targets; the black lines stand for the relationships among biological processes and targets).
Figure 8
Figure 8
Signaling pathway of HCC-IS PPI network (red diamond stands for signaling pathway; purple circle stands for HCC-IS; blue circle stands for IS genes; pink circle stands for HCC targets. The gray lines stand for the relationship among herbs and targets; the black lines stand for the relationships among pathways and targets).
Figure 9
Figure 9
Bubble chart of the signaling pathway (x-axis stands for fold enrichment).
Figure 10
Figure 10
The main core targets related to the endoplasmic reticulum stress.
Figure 11
Figure 11
Neurobehavioral score (6 h after MCAO. ∗Compared with the model group, P < 0.05. #Compared with the HCC high-dose group, P < 0.05).
Figure 12
Figure 12
Number of the neurons in unit area of hippocampal CA1 area (72 h after MCAO. ∗Compared with the model group, P < 0.05. #Compared with the HCC high-dose group, P < 0.05).
Figure 13
Figure 13
Nissl staining in the hippocampal CA1 area (X400) (72 h after MCAO. (a) The sham operation group. (b) The model group. (c) The HCC low-dose group. (d) The HCC medium-dose group. (e) The HCC high-dose group. (f) The nimodipine group).
Figure 14
Figure 14
Expression of GRP78 protein in each group (24 hours after intervention. (a) The sham operation group. (b) The model group. (c) The HCC low-dose group. (d) The HCC medium-dose group. (e) The HCC high-dose group. (f) The nimodipine group).
Figure 15
Figure 15
Expression of GRP78 protein in each group (72 hours after intervention. (a) The model group. (b) The HCC low-dose group. (c) The HCC medium-dose group. (d) The HCC high-dose group. (e) The nimodipine group).
Figure 16
Figure 16
Average gray value of GRP78 after MCAO (∗compared with the model group, P < 0.05).
Figure 17
Figure 17
Expression of p-PERK protein in each group (24 hours after intervention. (a) The model group. (b) The HCC low-dose group. (c) The HCC medium-dose group. (d) The HCC high-dose group. (e) The nimodipine group).
Figure 18
Figure 18
Expression of p-PERK protein in each group (72 hours after intervention. (a) The model group. (b) The HCC low-dose group. (c) The HCC medium-dose group. (d) The HCC high-dose group. (e) The nimodipine group).
Figure 19
Figure 19
Average gray value of p-PERK after MCAO (∗compared with the model group, P < 0.05).
Figure 20
Figure 20
Expression of CHOP protein in each group (24 hours after intervention. (a) The model group. (b) The HCC low-dose group. (c) The HCC medium-dose group. (d) The HCC high-dose group. (e) The nimodipine group).
Figure 21
Figure 21
Expression of CHOP protein in each group (72 hours after intervention. (a) The model group. (b) The HCC low-dose group. (c) The HCC medium-dose group. (d) The HCC high-dose group. (e) The nimodipine group).
Figure 22
Figure 22
Average gray value of CHOP after MCAO (∗compared with the model group, P < 0.05).
Figure 23
Figure 23
The expressions of GRP78, p-PERK, and CHOP protein detected by Western blot (1: 6 h after operation in the model group; 2: 12 h after operation in the model group; 3: 24 h after operation in the model group; 4: 48 h after operation in the model group; 5: 6 h after operation in the HCC group; 6: 12 h after operation in the HCC group; 7: 24 h after operation in the HCC group; 8: 48 h after operation in the HCC group; 9: the sham operation group).
Figure 24
Figure 24
The relative expressions of GRP78, p-PERK, and CHOP protein detected by Western blot ((a) the expression of GRP78; (b) the expression of p-PERK; (c) the expression of CHOP. ∗Compared with the model group, P < 0.05).
Figure 25
Figure 25
The expressions of GRP78 and CHOP mRNA detected by RT-qPCR ((a) the expression of GRP78; (b) the expression of CHOP. ∗Compared with the model group, P < 0.05).
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