Network Pharmacology-Based Dissection of the Active Ingredients and Protective Mechanism of the Salvia Miltiorrhiza and Panax Notoginseng Herb Pair against Insulin Resistance

Abstract

The Salvia miltiorrhiza and Panax notoginseng herb pair (DQ) has been widely utilized in traditional Chinese medicine for the longevity and for preventing and treating cardio-cerebrovascular diseases. Often associated with cardio-cerebrovascular diseases are comorbidities such as insulin resistance. However, the protective mechanisms of DQ against insulin resistance remain not well understood. Through network pharmacology analysis, a total of 94 candidate active compounds selected from DQ (61 from S. miltiorrhiza Bunge and 33 from P. notoginseng (Burk.) F. H. Chen) interacted with 52 corresponding insulin resistance-related targets, which mainly involved insulin resistance and the AMPK signaling pathway. Furthermore, the contribution index calculation results indicated 25 compounds as the principal components of this herb pair against insulin resistance. Among them, ginsenoside F2, protocatechuic acid, and salvianolic acid B were selected and validated to promote glucose consumption through activating AMPK phosphorylation and upregulating GLUT4 in insulin-resistant cell model (HepG2/IR) cells. These findings indicated that DQ has the potential for repositioning in the treatment of insulin resistance mainly through the AMPK signaling pathway.

Figure 1

Venn diagram showing the numbers of the overlapped and specific targets among the Salvia miltiorrhiza and Panax notoginseng herb pair (pink circle) and insulin resistance (green circle).

Figure 2

GO enrichment (A) and KEGG pathway (B) analysis of the insulin-resistant targets of the Salvia miltiorrhiza and Panax notoginseng herb pair.

Figure 3

Compound-target-pathway network of the Salvia miltiorrhiza and Panax notoginseng herb pair against insulin resistance. The light blue and yellow nodes are active ingredients of S. miltiorrhiza and P. notoginseng, respectively. The light green nodes are the potential targets, while the red nodes represent the pathways.

Figure 4

Contribution index of active ingredients (top 25) in the Salvia miltiorrhiza and Panax notoginseng herb pair against insulin resistance.

Figure 5

Glucose consumption in HepG2/IR cells by active ingredients of the Salvia miltiorrhiza and Panax notoginseng herb pair. Data were expressed as mean ± SD (n = 3). **P < 0.01 versus the control (Con) group; ^#P < 0.05, ^##P < 0.01 versus the insulin resistance (IR) group.

Figure 6

Effects of active ingredients of the Salvia miltiorrhiza and Panax notoginseng herb pair on AMPK, p-AMPK, PGC-1α, and GLUT4 protein expression in HepG2/IR cells. (A) Bands of AMPK, p-AMPK, PGC-1α, and GLUT4. β-Actin was used as the loading control. Protein expression levels of AMPK (B), p-AMPK (C), PGC-1α (D), and GLUT4 (E). Data were expressed as mean ± SD (n = 3). *P < 0.05 versus the control (Con) group; ^#P < 0.05 versus the insulin resistance (IR) group.