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Network pharmacology, molecular docking and in vivo experiments were used to explore the pharmacodynamic basis and potential mechanism of Danggui Sini Decoction in the treatment of primary dysmenorrhea(PD). The chemical constituents of Danggui(Angelicae Sinensis Radix), Guizhi(Cinnamomi Ramulus), Tongcao(Tetrapanacis Medulla), Baishao(Paeoniae Radix Alba), Xixin(Asari Radix et Rhizoma), Gancao(Glycyrrhizae Radix et Rhizoma), and Dazao(Jujubae Fructus) from Danggui Sini Decoction were retrieved through TCMSP(Traditional Chinese Medicine Systems Pharmacology Database), and the action targets of Danggui Sini Decoction were collected through DrugBank. "Primary dysmenorrhea" and "dysmenorrhea" were used as the key words to search the corresponding targets in the GeneCards, OMIM and TTD databases, and then the intersection targets of Danggui Sini Decoction and the primary dysmenorrhea targets were taken for reverse screening to obtain the corresponding active ingredients. Cytoscape 3.6.1 software was used to construct a traditional Chinese medicine-compound-target-disease network; STRING database was used to build a protein-protein interaction(PPI) network; Gene ontology(GO) function enrichment analysis and Kyoto encyclopedia of genes and genomes(KEGG) pathway enrichment analysis were conducted by using DAVID database. The action mechanism of the intersection targets were then predicted, and a histogram chart and bubble chart were drawn for visualization. Then the top five targets in the PPI network were used for docking with the most compounds. In animal experiments, Sprague Dawley(SD) female rats were used to establish a primary dysmenorrhea model by intraperitoneal injection of diethylstilbestrol once a day. A total of 60 SD female rats were randomly divided into 6 groups, namely control group, model group, Danggui Sini Decoction low(1.5 g·kg~(-1)), medium(3.0 g·kg~(-1)), high(6.0 g·kg~(-1)) dose groups, and ibuprofen(20 mg·kg~(-1)) positive control group, with 10 rats in each group. From day 4, except for the control group, rats in the other groups were given intragastric administration of corresponding drugs, and the control group received intragastric administration of normal saline for 7 consecutive days. The number of writhing before and after the administration, the ute-rine contraction inhibition rate and the uterine index after administration were observed, and ELISA assay was used to detect the levels of prostaglandin-endoperoxide synthase 2(PTGS2) and vascular endothelial growth factor A(VEGFA) in the tissues of each group as well as the levels of serum inflammatory factors interleukin 1(IL-1), interleukin 6(IL-6), and tumor necrosis factor-alpha(TNF-α). According to network analysis, 7 Chinese medicines contained 114 active ingredients, 149 targets, and 30 common target genes with PD were obtained. The key targets included VEGFA, IL6, PTGS2, TNF, etc.; GO function enrichment analysis showed a total of 399 terms(P<0.05) were obtained, 353 of which were biological process(BP) terms, 21 were cell composition(CC) terms, and 25 were molecular function(MF) terms. In KEGG pathway enrichment analysis, 14 signaling pathways were obtained, 3 of which were related to inflammation, namely arachidonic acid metabolism, MAPK signaling pathway and NOD-like receptor signaling pathway. The compounds in Danggui Sini Decoction can play a therapeutic role in the treatment of PD by acting on VEGFA, IL-6, PTGS2, TNF and other targets to regulate arachidonic acid and inflammatory signaling pathways.
Subject(s)
Animals , Female , Humans , Rats , Drugs, Chinese Herbal , Dysmenorrhea/drug therapy , Molecular Docking Simulation , Rats, Sprague-Dawley , Vascular Endothelial Growth Factor AABSTRACT
Objective: To analyze and predict the Q-marker of Cinnamomi Ramulus in Danggui Sini Decoction based on fingerprint and network pharmacology. Methods: The fingerprints of Cinnamomi Ramulus Decoction and Danggui Sini Decoction were established, and analyzed by using the similarity evaluation system software for chromatographic fingerprint of traditional Chinese medicine (2012 edition); The network pharmacology was used to screen and analyze the function target and pathway of related components of Cinnamomi Ramulus, and the "component-target-pathway" network was constructed to predict the potential Q-marker of Cinnamomi Ramulus in Danggui Sini Decoction. Results: The fingerprints of 15 batches of Cinnamomi Ramulus Decotion and 15 batches of Danggui Sini Decoction were established. The similarity of fingerprints was more than 0.96, and seven common components were identified, including protocatechuic acid, coumarin, cinnamic acid, cinnamaldehyde, cinnamyl alcohol, 2-methoxy cinnamic acid, and 2-methoxy cinnamaldehyde. A total of five active components, seven core target sites and 15 key pathways of Cinnamomi Ramulus were screened out through network pharmacology system, and based on the "Five Principles" of quality markers, 2-methoxy cinnamaldehyde, cinnamaldehyde, and cinnamic acid were predicted as potential quality markers. Conclusion: In this study, the quality markers of Cinnamomi Ramulus in Danggui Sini Decoction are analyzed by fingerprint and network pharmacology, which provides a basis for comprehensive control of the quality of Danggui Sini Decoction, reference for further study on the mechanism of Danggui Sini Decoction, and demonstration for the correlation study of quality markers of compound and single medicine in the classic prescription.
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Objective: To explore the potential Q-marker of Paeoniae Radix Alba in Danggui Sini Decoction based on fingerprint and network pharmacology. Methods: The fingerprints of Paeoniae Radix Alba decoction and Danggui Sini Decoction were established, and the law of components transfer was also defined. The "compounds-targets-pathways" network was then established to predict the potential Q-marker of Paeoniae Radix Alba through the network pharmacology. Results: The fingerprints of 15 batches of Paeoniae Radix Alba decoction and 15 batches of Danggui Sini Decoction were established, and the five chromatographic peaks were identified, they were gallic acid, albiflorin, paeoniflorin, 1,2,3,4,6-O-pentagalloylglucose, and benzoyl paeoniflorin. Through the network pharmacology analysis, the potential two active components, eight core targets and 13 key pathways were screened out, which indicated that paeoniflorin and albiflorin were preliminarily predicted to the potential Q-marker of Paeoniae Radix Alba. Conclusion: The analysis and prediction of the Q-marker in this study can provide a reference for the whole control of the Paeoniae Radix Alba quality, which can also provide the basis for the further research on the efficacy-related substance and mechanism of Paeoniae Radix Alba.
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Objective To observe the clinical effect of Danggui Sini decoction for treatment of patients with chronic non-atrophic gastritis and spleen-stomach deficiency cold syndrome.Methods A prospective randomized control trial was conducted, including 126 in- and out-patients with chronic non-atrophic gastritis diagnosed by gastroscopy and spleen-stomach deficiency cold syndrome differentiated by traditional Chinese medicine (TCM) method admitted to Chinese Medicine Hospital of Haikou City. They were randomly assigned to an observation group (65 cases) and a control group (61 cases). The patients in observation group were given Danggui Sini decoction with addition or/with subtraction of ingredients according to individual situation (ingredients: angelica 15 g, ramulus cinnamomi 15 g, paeonia 15 g, asari 5 g, glycyrrhizae 10 g, Chinese jujube 12, medulla tetrapanacis 10 g ). The warm 200 mL (one dose) decoction was divided into two parts, one part was taken orally before a meal, twice daily, the therapeutic course was 4 weeks and in one week only 6 doses were applied; while the patients in control group, omeprazole capsules (dissolved in intestine), each time 20 mg, once a day combined with domperidone (bite phenanthroline) 10 mg each time, 3 times a day were given. After 4 weeks of treatment, the clinical efficacy, the total integral of symptoms, the therapeutic effect of TCM symptoms score, the improvement of the therapeutic effect of mucosal histological and changes of the number of patients with the patholoyical changes of mucosa under gastroscopy were observed.Results The total effective rate in the observation group was significantly higher than that in the control group [96.9% (63/65) vs. 86.9% (53/61),P < 0.05]. After treatment, the total integral of symptoms and the integrals of main TCM symptoms after treatment were lower than those before treatment, the degree of decrease in the observation group being more marked (the total integral of symptoms score: 12.36±2.11 vs. 15.94±2.37, epigastric distention integral score: 1.23±0.72 vs. 2.12±0.78, epigastric pain score: 1.18±0.67 vs. 2.25±0.94, thermophilic and like pressure integral score: 1.03±0.46 vs. 1.62±0.79, anorexia: 1.06±0.57 vs. 1.43±0.53, integral of loose stools score: 1.36±0.43 vs. 1.67±0.58, lassitude integral score: 1.24±0.32 vs. 1.65±0.42, allP < 0.05). Under gastroscope, the efficacy of mucosal histological change was significantly higher in observation group than that in control group [90.77% (59/65) vs. 81.97% (50/61),P < 0.05]. After treatment, the numbers of patients with chronic inflammatory cell infiltration (47 cases vs. 54 cases), erythema exudation (28 cases vs. 30 cases), flat erosion (8 cases vs. 15 cases), swelling erosion (5 cases vs. 6 cases), bile reflux (2 cases vs. 3 cases) and positive pylorus spirobacteria (20 cases vs. 29 cases) were significantly lower in the observation group than those in the control group (allP < 0.05).Conclusion The therapeutic effects of Danggui Sini decoction for treatment of patients with chronic non-atrophic gastritis and TCM syndrome of spleen-stomach deficiency-cold are remarkable.