PCOS is one of the most common gynecological endocrine disorders. In western medicine, insulin sensitizers, compound cyproterone acetate, laparoscopic ovarian drilling or follicular puncture are often used to treat PCOS. However, due to the side effects of hormone drugs, patients are prone to have adverse symptoms. In recent years, TCM has been widely used in the treatment of PCOS, with significant therapeutic effect and high patient satisfaction. TCM can effectively regulate the menstrual cycle of women, improve the related symptoms of patients with PCOS, and restore normal ovulation [33].
As one of the famous prescriptions of TCM, XYS has the remarkable effect of soothing the liver and relieving the depression, nourishing the blood and strengthening the spleen. It is widely used in the treatment of PCOS with liver depression as the main treatment, and has a significant effect [39]. In the treatment of polycystic ovary model rats with modified or Modified XYS, it was found that Modified XYS could up regulate the expression of FSHR and LHR protein in granulosa cells of polycystic ovary rats, and reduce the levels of serum testosterone (T), anti Mullerian hormone (AMH) and egg yolk The expression intensity of AMH protein in the nest. Therefore, AMH can be regulated to reduce the androgen level in rats and improve PCOS [40].
TCM plays an important role in disease prevention and treatment through multi-component and multi-target, which makes the research on the material basis of the efficacy of TCM complex extremely difficult. Network pharmacology can systematically predict and reveal the action and mechanism of different drug molecules. In this study, the mechanism of action of TCM compound was comprehensively analyzed and explained from the molecular network level, and then integrated with disease analysis to achieve the overall analysis of medical theory [45].
In this study, TCM holistic view, principle of syndrome differentiation and treatment, new mode of network target network pharmacology were effectively combined. Using TCMSP, GeneCards, R Project and Cytoscape, the active ingredients and targets were screened and collected, and "XYS-Active ingredients-Target-PCOS" Physical network was constructed. In order to fully elucidate the potential mechanism of XYS in the treatment of PCOS, the key nodes in the network were analyzed and the related biological functions and pathways were studied.
The main chemical components of XYS in the treatment of PCOS are quercetin, kaempferol, isorhamnetin, beta sitosterol, stigmasterol, sitosterol, 3,5,6,7-tetramethoxy-2 - (3,4,5-trimethoxyphyhenyl) chromone, hederagenin, petunidin, areapillin, 8 β - ethoxy atractylolide Ⅲ, 3 β - acetoxyatractylone, α - spinosterol, (+) - catch. Many studies have shown that the active components of XYS have certain pharmacological activities. Quercetin, as a phytoestrogen and antidiabetic, can improve follicular formation in diabetic mice. Quercetin administration in diabetic mice increased the volume of ovaries and growing follicles, the number of growing follicles and corpus luteum, and significantly reduced the number of atretic follicles. Quercetin may be used to treat PCOS and IR by inhibiting TLR / NF - κ B signaling pathway and improving microenvironment inflammation of IR in PCOS [47]. Isorhamnetin can inactivate NF - κ B signaling pathway and inhibit apoptosis and inflammation [49]. Phytosterol (stigmasterol, sitosterol, beta sitosterol) has the effects of regulating lipid metabolism, antioxidation and preventing atherosclerosis [51], and it is possible to treat the disorder of glycolipid metabolism in patients with PCOS. Hederagenin has antitumor, antidepressant, antibacterial, anti-inflammatory, anti diabetes and other pharmacological effects [52]. Catechin can not only enhance the oxidation and energy consumption of fat, but also play an obvious role in the metabolism and distribution of fat, especially in reducing visceral fat. It can also achieve anti-inflammatory effect by regulating NF - κ B factor to alleviate glycolipid metabolic disorder syndrome [54]. Therefore, the efficacy of XYS in the treatment of PCOS is achieved through the joint action of a variety of active compounds in various TCM.
According to the results of go analysis, XYS can treat PCOS by regulating the expression of multiple genes. The collected key targets such as IL6, CASP3, EGFR, ESR1, MYC, VEGFA, AR, PGR and so on are all involved in the disease regulation of PCOS, and play an important role in inflammatory response, cell proliferation and apoptosis, human reproductive and sexual development.
The results of KEGG analysis showed that many biological pathways were involved in many targets regulated by XYS. After analyzing the existing research work, it is found that the collected biological pathways are closely related to the potential therapeutic mechanism and pathogenesis of PCOS. The main biological pathways regulated by the collected cross-linked targets (the cross-linked targets are filled with red in the pathway map, logFC = 1) are: AGE-RAGE signaling pathway in diabetic complications (Fig. 7), Fluid shear stress and atherosclerosis (Fig. 8), Colorectal cancer, Proteoglycans in cancer, Bladder cancer, Breast cancer, Hepatitis B, Endocrine resistance, Hepatocellular carcinoma, Estrogen signaling pathway (Fig. 9), EGFR tyrosine kinase inhibitor resistance, Thyroid hormone signaling pathway, Prolactin signaling pathway, p53 signaling pathway, Platinum drug resistance, Apoptosis, MicroRNAs in cancer, PI3-Akt signaling pathway, NF-kappa B signaling pathway, MAPK signaling pathway, Wnt signaling pathway, etc. Among them, the biological pathways that have been confirmed include: ages receptor (RAGE) is a member of immunoglobulin superfamily, rage on cell membrane can activate several signal pathways after binding with corresponding ligands, and it is expressed in many kinds of cells, which is an indispensable ligand receptor with important functions in human body [56]. Rage can also activate multiple signaling pathways such as PI3K-Akt and NF - κ B through linkers. PI3K-Akt signaling pathway is the main pathway regulating serum insulin, and activation of PI3K-Akt pathway can improve IR [57]. Down regulation of TLR4 / NF - κ B inflammatory signaling pathway and down-regulation of inflammatory cytokines such as IL-6 and TNF - α can effectively inhibit oxidative stress effect [58]. Inhibition of Wnt pathway can inhibit the expression of calcitonin in the endometrium of polycystic ovary rats, promote the normal secretion of sex hormones, reduce the activity of creatine kinase isoenzyme (CK-MB) and lactate dehydrogenase (LDH), and improve the symptoms of PCOS[63,64]. PCOS(PCOS) is a female endocrine disease involving multiple biological pathways. The regulation of key biological pathways is very important for the treatment of PCOS.
Many studies have shown that patients with PCOS have the following complications: type II diabetes, coronary heart disease, atherosclerosis, endometrial cancer and other diseases [66]. Low shear force is closely related to the occurrence of atherosclerotic plaques and is a local risk factor for atherosclerotic formation. Shear force may become one of the indicators to predict atherosclerosis [68]. The most common metabolic disorder caused by PCOS is abnormal lipid metabolism, which is mainly manifested in the increase of apoB, apoB / ApoA1 ratio [69]. In clinic, apoB / ApoA1 ratio and non-high-density lipoprotein cholesterol are often used to predict coronary heart disease before blood lipid measurement [70]. Phosphatidylinositol 3-kinase / protein kinase B (PI3K / Akt) signaling pathway is an important pathway of cell proliferation in the body, which plays an important role in IR of pregnant women and endometrial proliferation [71]. The target gene of MDM2 is p53. Activation of PI3K / Akt pathway will lead to the increase of MDM2 expression, the rapid degradation of p53 and the abnormal proliferation of cells [72]. Pi3k-akt-mdm2 pathway plays an active role in endometrial proliferation and the development of endometrial cancer [73]. Therefore, PCOS is closely related to endometrium related diseases. The pathogenesis of PCOS has been proved to be closely related to IR (IR), hyperandrogenemia, hyperinsulinemia and obesity. It is generally believed that IR is the core of PCOS, and the existing work shows that the main cause of PCOS after IR is secondary hyperinsulinemia, through direct stimulation of ovarian androgen secretion increase, synergistic enhancement of luteinizing hormone induced steroidal hormone synthetase, interference of hypothalamus pituitary gonadal axis, enhancement of the amplitude and frequency of gonadotropin pulse release, leading to To induce ovarian dysfunction, to inhibit the synthesis and secretion of SHBG, to induce hyperandrogenemia, to inhibit the synthesis and secretion of IGFBP-1 α, to increase the level of IGF-1, and to stimulate the synthesis of androgen and hyperinsulinemia, we can promote the anti Mullerian hormone (AMH) Generation inhibition and ovulation of [74,75]. Therefore, PCOS is a complex metabolic disorder syndrome which is closely related to many diseases. Its complex pathogenesis makes it difficult to determine the treatment method, the clinical cure rate is low and the recurrence rate is high.
It is found that the potential mechanism of XYS in the treatment of PCOS lies in the target and biological pathway. The potential mechanism of XYS in the treatment of PCOS is as follows: XYS can reduce the expression of IL-6 inflammatory cytokines, inhibit the effect of oxidative stress and alleviate the long-term inflammatory state of cell tissues, so as to reduce the production of ROS, avoid the production of IR or reduce the symptoms of IR. Jiawei XYS can reduce the positive expression of EGFR protein, improve the ovarian function of PCO rats, promote the normal growth and development of follicles, and improve the ovarian polycystic change and ovulation disorder as a whole, suggesting that the treatment of PCOS with XYS may be related to the reduction of androgen level and the regulation of EGFR protein expression in ovarian granulosa cells [76]. XYS may reduce the expression of androgen receptor (AR) and the secretion of insulin in β cell of islet of Langerhans, so as to avoid the disorder of β cell function and the increase of testosterone concentration in the body, so as to reduce the prevalence of IR [77,78]. XYS may activate estrogen signal and steroid hormone biosynthesis by regulating the protein expression of PGR, ESR1 and ESR2 genes, stimulate ovulation and mediate follicle rupture [79], and alleviate the symptoms of PCOS. XYS may regulate the vegf-vegfr2 signal pathway, up regulate the content of VEGF and its related proteins, promote angiogenesis, so as to treat premature ovarian failure [80,81], improve the ability of ovarian hormone secretion, and alleviate the clinical symptoms of PCOS. In addition, XYS has some therapeutic effects on PCOS, type II diabetes, premature ovarian failure and endometrial cancer.
In this study, the mechanism of XYS in the treatment of PCOS was preliminarily elucidated, but it is difficult to determine whether the data is comprehensive because the components and target information of XYS are all from the existing database. In this study, we did not take into account the deeper chemical reactions of various chemical components of the drug, and ignored the influence of XYS type, dose, and the complexity and difference of human body on drug metabolism and response.