Therapeutical effect of astragalus on hypoxic preeclampsia in pregnant mice and screening of its active ingredients and core target genes
Objective To investigate the therapeutic effect of astragalus on hypoxic preeclampsia(PE)in pregnant mice,to explore potential targets and mechanisms combined with network pharmacology methods,and to provide new ideas for the prevention and treatment of PE.Methods PE models of pregnant mice were established,and they were di-cided into the blank control group,model group(0.01 mL/g distilled water),positive control group[0.013 mg/(g·d)as-pirin],low-dose astragalus group(3.9 mg/g astragalus),and high-dose astragalus group(15.6 mg/g astragalus).The mice were given medication and their blood pressures were measured on the 7th day of gestation.The mice were euthanized on the 17th day of gestation.The fetal mice and placentas were collected,the birth mass of fetal mice was recorded,and the intrauterine growth restriction(IUGR)rate was calculated.We observed the morphology of embryonic trophoblast cells and blood vessels by HE staining.The mRNA expression levels of hypoxia-inducible factor-1α(HIF-1α),soluble vascu-lar endothelial growth factor receptor-1(sFLT-1)and placental growth factor(PLGF)in placental tissues were detected by fluorescent quantitative PCR method.TCMSP platform and Gene cards database were used to obtain the intersection target genes of main active ingredients of astragalus and PE disease,and the"Astragalus ingredient-PE disease target"network and protein-protein interaction(PPI)network were constructed to obtain the core target genes,and enrichment analysis of GO and KEGG metabolic pathways were performed.Results Compared with the blank control group,the body mass of the other four groups decreased(P<0.05).Compared with the model group,the blood pressure of pregnant mice in the high-dose Astragalus group and blank control group decreased,and the body mass of fetal mice in the other four groups in-creased(all P<0.05).Compared with the positive control group,the fetal body mass of the high-dose astragalus group and model group decreased,while the fetal body mass of the low-dose astragalus group and blank control group increased(all P<0.05).Compared with the low-dose astragalus group,the body mass of fetal rats in the high-dose astragalus group and model group decreased,while that in the blank control group increased(all P<0.05).Compared with the high-dose astrag-alus group,the body mass of the fetal rats in the model group decreased,and the body mass of the fetal rats in the low-dose astragalus group,positive control group and blank control group increased(all P<0.05).Compared with the model group,IUGR rates in the low-dose astragalus group and positive control group decreased(both P<0.05).In the control group,blood vessels were densely distributed and trophoblast cells were abundant.In the model group,trophoblast cells and blood vessels were significantly reduced,microthrombus formation,local infarction and extensive cellulose exudation in the placental villus space were observed.In the placental tissues of pregnant rats in the positive control group and low-dose astragalus group,blood vessels were densely distributed and the blood supply was abundant.Local cellulose exudation was observed and vascular perfusion was poor in the high-dose astragalus group.Compared with the blank control group,the mRNA relative expression levels of HIF-1α and sFLT-1 increased,while the mRNA relative expression level of PLGF de-creased in the model group(all P<0.05).Compared with the model group,the relative expression of sFLT-1 mRNA de-creased and PLGF mRNA increased in the high-dose astragalus group;the relative expression of HIF-1α and sFLT-1 mRNA decreased in the low-dose astragalus group and positive control group;and the mRNA relative expression levels of HIF-1α and sFLT-1 decreased and PLGF mRNA relative expression level increased in the blank control group(all P<0.05).Compared with the positive control group,the mRNA relative expression levels of HIF-1α and PLGF in the high-dose astragalus group,and the mRNA relative expression levels of HIF-1α and sFLT-1 in the model group increased(all P<0.05).Compared with the low-dose astragalus group,the mRNA relative expression levels of HIF-1α and sFLT-1 in the model group increased(all P<0.05).Compared with the high-dose astragalus group,the relative expression of HIF-1α mRNA in the low-dose astragalus group decreased,and sFLT-1 mRNA relative expression in the model group increased(both P<0.05).A total of 45 potential targets of Astragalus for the treatment of PE were obtained by network pharmacology,involving 14 key compounds.IL-6,TNF,IL-1β,EGFR,and EGF may be the core targets of Astragalus in the treatment of PE.They involved AGE-RAGE,PI3K-Akt,HIF-1,MAPK,IL-17 and other signaling pathways.Conclusions As-tragalus has a therapeutic effect on PE in pregnant rats,with lower dose being more effective.The therapeutic mechanism may involve HIF-1α-mediated regulation of downstream targets like PLGF and sFLT-1.Network pharmacological studies suggest that multiple ingredients of astragalus may play a role in treating PE through multiple core targets and signaling pathways.
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