Systems Pharmacology-based Approach For Dissecting The Mechanisms Of Herb Combination Theories: “Addition And Subtraction” And “Jun-chen-zuo-shi”

Traditional Chinese medicine(TCM), one of the treasures of the splendid culture of the Chinese nation, has been the essence of practice experience in clinical by numerous TCM specialists since thousands years ago. Formula(Fufang in Chinese), which is the combination of different herbs, is the most popular way to maximize efficacy and minimize adverse effects or toxicity clinically according to certain TCM basis theories. However, to understand the mechanisms of combination theories of TCM from molecular level is still challenged by the defects of traditional methods. In this thesis, we established a systems method, which integrates ADME screening, target prediction, disease pattern analysis and network pharmacology, to identify potential active ingredients in Traditional Chinese herbs and to study the mechanisms of action. Then we applied this systems method on(1) two classical prescriptions, Xiao Chaihu decoction(XCHD) and Da Chaihu decoction(DCHD), to dissect the addition and subtraction theory(AST); and on(2) a popular anti-cardiovascular diseases formula, Radix Curcumae formula, to elucidate the mechanism of efficiency of this formula for the prevention of CCVD and the mechanisms of compatible mechanism of the complex prescription, i.e., “jun–chen–zuo–shi”. The main results are as follows:(1) A total of 63 bioactive ingredients with 65 potential targets in the XCHD and DXHD were obtained, which explains why they have anti-inflammatory, antioxidant and anti-cytotoxicity activities.(2) Several targets have been identified for the additive herbs of each formula. We summarized as follows: HTR3 A, IDO, IL1 B, OPRD1, OPRM1, PDE3 A, PDE4 and SLC5A2(Figure 3, red) are for Panax ginseng and Licorice; While, there are 14 proteins including ADRA1 A, ADRA2 A, ADRA2 B, ADRA2 C, ADRB1, LOX15, ALOX5, CCR4, eNOS, HMOX1, LGALS3, MGAM, PYGM and TNF(Figure 3, yellow) are for Paeonia lactiflora and Fructus aurantii immaturus.(3) As for XCHD and DCHD, that “fundamental formula” is responsible for the major therapeutic effects, whereas the “additive herbs” synergistically enhance the treatment outcomes by targeting the same or complementary proteins between the foundational and additive herbs;(4) With regard to Radix Curcumae formula, the jun herb Radix Curcumae has the most active ingredients and represents the principal targets for the prevention of CCVD targets; chen herb Fructus Gardeniae has less active ingredients than the jun herb, but share the most targets with the jun herb, which can assist the theraputic effects of the jun herb; zuo herb and shi herb can improve the bioavailability or decrease the toxicity of Jun herb or Chen herb, which together probably display synergistic actions. Our work successfully provides a new strategy to understand the compatibility mechanism and other basis theories of traditional Chinese medicine, and meanwhile, is beneficial for the TCM recipe optimization as well as the production of new herbal formula with desirable therapeutic effects.