Zi-Tong Fu, Zhi-Peng Zhang, Yue-Yu Zhang, Li-Na Zhang, Guo-Wei Zhang

Discussion on the mechanism of TCM treatment of climacteric syndrome based on TCM inheritance assistance system and network pharmacology

Zi-Tong Fu1, Zhi-Peng Zhang1, Yue-Yu Zhang1, Li-Na Zhang1, Guo-Wei Zhang2*

1College of Chinese Medicine, Hebei University, Baoding 071000, China.

To explore the law of traditional Chinese medicine in the treatment of climacteric syndrome, and to study the potential mechanism of traditional Chinese medicine therapy.For the relevant prescriptions collected from Chinese Journal Full-text Database, Wanfang medical network, PubMed and EMBASE were transferred to the traditional Chinese medicine inheritance assistant system (TCMISSV2.5) to conduct the nucleocentric drug group analysis. In this study, we used BATMAN-TCM (http://bionet.ncpsb.org/batman-tcm/) online analysis tool to analyze Therapeutic Target Database disease enrichment and Kyoto Gene and Genome Encyclopedia (KEGG) pathway enrichment, and Cytoscape (3.7.1) software was used to construct disease-target and KEGG pathway-target networks for visualization.Among the 103 prescriptions, 3 pairs of core drug combinations and 9 new prescriptions were selected by data mining. In the KEGG pathway of Zhimu () and Huangbo (), the most potential targets were found in the neural active ligand receptor interaction pathway.The compatibility ofandmay play a role in the treatment of nervous system symptoms in patients with climacteric syndrome by interfering the neuroactive ligand receptor interaction signaling pathway.

Menopause syndrome, Traditional Chinese Medicine Inheritance Assistance System, Network pharmacology, Traditional Chinese medicine

Through data mining and network pharmacology analysis, this study explored the drug law and mechanism of traditional Chinese medicine treatment of climacteric syndrome. The results showed that the combination of Zhimu () and Huangbo () might improve the nervous system symptoms of climacteric syndrome by interfering the neuroactive ligand receptor interaction pathway.

Background

Climacteric syndrome (CMS), is also known as perimenopausal syndrome, which is summarized by traditional Chinese medicine as “pre-and postmenopausal syndromes”. It refers to a group of syndromes caused by the fluctuation or reduction of sex hormones before and after menopause, which are a series of autonomic nervous system dysfunction and accompanied with neuropsychological symptoms. Common clinical symptoms include menstrual disorders, irritability, hot flashes, night sweats, etc., and it can even cause cardiovascular and cerebrovascular diseases, osteoporosis, etc.[1–2]. In clinical treatment, Western medicine treatment mainly focuses on hormone replacement therapy. Under the guidance of traditional Chinese medicine theory, traditional Chinese medicine adopts the method of treatment based on syndrome differentiation and on classification. The method of treatment chooses targeted prescription treatment, studies its original and considers its target,by which the clinical effect is good and the side effects are small [3]. Experimental studies have shown that traditional Chinese medicine has a sifnificant regulatory effect on neuro-endocrine-immune network, autonomic nerve function and free radical content of patients with CMS [4]. However, in the clinical practice of traditional Chinese medicine treatment for CMS, there is a lack of in-depth exploration on the rules of medication and the mechanism of drug action, which makes the medication specifications and treatment methods unreasonable.

Traditional Chinese medicine inheritance assistance system is an organic combination of computer science and traditional Chinese medicine. It adopts methods and technologies of artificial intelligence, data mining, network science and other disciplines to realize functions such as disease information, syndrome information, traditional Chinese medicine information, prescription information, medical cases and related information sorting and analysis [5].Network pharmacology can construct and integrate a multi-level network system of “disease-phenotype-gene-drug", which is an effective tool for studying the multi-target and drug action mechanism of traditional Chinese medicine compound [6].

This paper collected and sorted out the clinical practice and research literature of traditional Chinese medicine prescription treatment CMS in the past 20 years, and used the traditional Chinese medicine inheritance assistance system combined with BATMAN-TCM online analysis system to help explore the law of traditional Chinese medicine prescription medication and analyze drug targets and disease action pathways, in order to provide reference for the basic and clinical research of traditional Chinese medicine treatment CMS.

Materials and methods

Prescription sources

The literature comes from Chinese Journal Full-text Database, Wanfang medical network, PubMed and EMBASE. In PubMed and EMBASE databases, the subject words “climacteric syndrome” and “traditional Chinese medicine” were input. The retrieval time was 2000–2020, and the retrieval results were 279, 211, 18 and 357 related literatures respectively. Select “advanced search”, the search words are “climacteric syndrome” or “perimenopausal syndrome” and “traditional Chinese medicine” or “traditional Chinese medicine treatment”, the search time is from January 1, 2000 to January 1, 2020, the rest conditions are default. The process of literature extraction is shown in Figure 1.

Data screening

Inclusioncriteria.The clinical prescriptions involved in the treatment of CMS with traditional Chinese medicine; the literature has a clear composition and detailed dosage; the prescriptions involved have a clear effect; the prescription method is oral decoction or pills.

Exclusioncriteria.Treated with non-oral decoctions or pills; only the medication is used and the dose is unknown; the prescriptions repeated in different literatures; the composition of the listed prescriptions is unknown or missing; the follow-up is invalid or aggravated; combined with other serious diseases except CMS.

Screening prescriptions and standardized drug names.According to the above screening criteria, 103 prescriptions with 228 flavors of traditional Chinese medicine were selected. According to the tenth undergraduate textbook of the 13th Five-Year Plan,[8], the names of the traditional Chinese medicines entered are regulated one by one. For example, the Shengdi is recorded as, and the Shudihuang is recorded as, etc.

Recipe check and entry

Enter the checked and corrected 103 prescriptions one by one to traditional Chinese medicine inheritance assistance system (TCMMISS, V2.5). Take 2 people to cooperate to input, 1 person to input and 1 to review, to ensure the accuracy of the entered data.

Prescription analysis

Prescription analysis: use the “data analysis” of traditional Chinese medicine inheritance assistance system (TCMMISS, V2.5) to analyze the drug frequency, the rule of composition and the new formula of 101 prescriptions. Target analysis: input the main drug pairs in the analysis results of prescriptions into the online analysis system of BATMAN-TCM (http://bionet.ncpsb.org/batman-tcm/) to analyze the signal pathways of major drug pairs. Then Cytoscape (3.7.1) software was used to construct disease-target and Kyoto Gene and Genome Encyclopedia (KEGG) pathway-target networks for visualization.

Figure1 The process of literature extraction

Results

Drug frequency analysis

“Frequency statistics” was performed on the 228 Chinese medicines from the 103 prescriptions screened out. There are 14 kinds of Chinese medicines which are used more than 20 times, and the top 5 most frequently used Chinese medicines are Danggui (), Baishao (), Huangbo (), Zhimu (), Shudihuang () (Table 1).

Property, taste and meridial distribution

Among the 103 prescriptions, 228 traditional Chinese medicines with flavor and meridian tropism were selected and counted, cold and cold drugs are the most frequent in the 4 “Qi”, with a frequency of 431, followed by warm drugs, 308; sweet drugs are the most frequent in the 5 flavors, 720, followed by bitter drugs and “Xin” drugs; liver channel is the most frequent, 680, followed by “Kidney Channel” and “Heart Channel”.

Rule analysis of prescription formula based on association rules

Set the number of support levels to 18 and the confidence level to 0.6, and analyze the rule of square. The results show that there are 3 groups of commonly used drugs, involving 6 flavors of traditional Chinese medicine, namely:,Shanyao (),,,, Chaihu ()(Table 2). After that, the related drug pairs with confidence ≥ 0.6 wereà,à,à(Table 3). See attached Figure 2 for the combined network diagram of common drug pairs.

New party analysis

In the “data analysis” module, “new square analysis”, according to the result prediction and debugging, set the “correlation” to 8, and the “penalty” to 2. Based on entropy clustering algorithm, core drug combinations are extracted and new prescriptions are mined. According to the above rules, 12 groups (Table 4) were obtained by taking the drug pairs with correlation coefficient above 0.03. A total of 18 core drug combinations were extracted as the basis of the new prescription combination (Table 5). Obtain 9 pieces of new party (Table 6).

Based on BATMAN-TCM analysis of the potential mechanism of action of the main Chinese medicine compatibility of Anemarrhenae rhizoma and Phellodendri Chinensis cortexin the treatment of CMS

Analysis of the enrichment of single drugs of,and compatible diseases.Set “score cutoff” to 80 and “adjusted-value” to 0.01. A total of 166 Therapeutic Target Database (TTD) diseases and 65 Online Mendelian Inheritance in Man diseases were involved in the combination of single drug and enrichment ofand. TTD diseases with potential target ≥ 5 are shown in Table 7, among which TTD diseases related to CMS include schizophrenia, anxiety, neurodegenerative diseases and depression.

Analysis of the signal pathways of the effects of the single medicine and compatibility ofand.Among the results obtained from the analysis of the BATMAN-TCM software, there are 115 biological signaling pathways of single drug and compatibility enrichment ofand. Among them, there are 12 potential targets whose number is ≥ 6 (Table 8).

Construct disease, target and KEGG pathway visualization network diagram.The diseases, pathways and targets screened by 3.5.1 and 3.5.2 were imported into Cytoscape (3.7.1) software to construct disease-target and KEGG pathway-target networks for visualization. The network consists of 107 nodes and 276 lines. The pink circle represents TTD disease, and the purple hexagon represents KEGG pathway. The size and color of nodes of the disease and pathway reflect the size of degree, the larger the degree, the darker the color. The blue rectangle represents the target, and the color of the node reflects the size of the degree. The larger the degree, the darker the color, as shown in Figure 3.

Discussion

Climacteric syndrome belongs to the category of “pre-and postmenopausal syndromes” in traditional Chinese medicine. According to traditional Chinese medicine, the basic pathogenesis of CMS is “Kidney Qi” decline and “Kidney Yin” deficiency. With the further development of the disease, the dysfunction of the heart, liver, spleen and kidney, blood stasis and phlegm turbidity, and the deficiency of the 2 channels of “Chong” and “Ren” are also important pathological mechanisms [8–10]. The traditional Chinese medicine treatment of CMS mainly focuses on “Tonifying the Kidney”, accompanied with regulating the function of heart, liver, spleen and viscera, treating phlegm, blood stasis and other pathological products. With treatment based on syndrome differentiation, viscera syndrome differentiation, identification of deficiency and excess, grasp the main pathological viscera and pathological factors, and take into account the secondary pathogenesis [11–12].

Table1 Chinese medicine used for treating CMS ≥ 20 times

CMS, climacteric syndrome.

Table2 Combinations of commonly used drugs for the treatment of CMS

CMS, climacteric syndrome.

Table3 Association rule analysis of common drugs in the treatment of CMS

CMS, climacteric syndrome.

Figure 2 Combination network of common drug pairs for CMS treatment. CMS, climacteric syndrome.

The results of data mining analysis of drug use patterns show that there are 14 kinds of traditional Chinese medicines used more than 20 times in the treatment of CMS, and the first 5 kinds of traditional Chinese medicines are,,,and. The four natures of drug attribute are mainly cold and warm, and the 5 flavors are sweet and bitter the most. Among the drugs, the “Liver and Kidney Meridians” are the most. From high to low, the order of the occurrence frequency of the drug pairs was-,-,-. The top three confidence levels wereà,àandà.is bitter in taste and cold. It can be used in the clinical treatment of bone steaming, heat drying and dampness, purging fire and detoxification, protecting liver and cholestasis. It can be used in the clinical treatment of bone steaming and heat exhaustion. The 2 drugs are matched, with the effect of nourishing “Yin” and reducing “Fire”. They are accompanied with the Chinese patent medicine Liuwei Dihuang pills to compose the Chinese patent medicine Zhibai Dihuang pills, with the effect of nourishing “Liver” and “Kidney”, benefiting “Yin” and clearing heat.is bitter, pungent, slightly cold, and belongs to channels of liver and gallbladder. It can be used to soothe the liver and relieve depression.isbitter,sour,slightlycoldandbelongsto channels of liver and spleen. It can be used to “Nourish the Blood” and “Regulate The Meridians”, “Collect Yin” and “Stop Perspiration”, soften the liver and relieve pain, and suppress the liver “Yang”. The 2 drugs can be used together to soothe the liver, soften the liver, and regulate qi and blood. It is an important combination in the classic ancient prescriptionXiaoyao powder.is sweet in flavour and smooth in nature. It belongs to channels of spleen, lung and kidney. It has the functions of nourishing “Qi” and “Yin”, spleen and lung, kidney and essence.has the functions of nourishing “Yin” and blood, nourishing essence and filling marrow. The 2 drugs can be matched, with the effect of nourishing “Kidney” and “Essence”, nourishing spleen and kidney, which conforms to the pathogenesis characteristics of CMS. Modern medical research has shown that MPS is caused by the decline or loss of its function due to the decrease in the number of ovarian follicles, which leads to endocrine disorders, low immunity and neurotic disorders. MPS can lead to pathological changes in multiple systems of the body, resulting in sleep rhythm disorders, emotional excitement, depression, hot flushs and palpitations [13]. Causes of hot flashes for vasomotor dysfunction, and the pathogenesis of menopause vasomotor dysfunction related to the hypothalamus to the regulation of body temperature, the regulating function of disorders involving norepinephrine and serotonin (5-HT) and gonadotropin-releasing hormone such as a variety of neurotransmitters and mutual influence of estrogen to thermoregulation neurons [14]. Through research, Liu Yanfeng et al. [15] found that the occurrence of emotional symptoms of climacausal syndrome was correlated with serum 5-HT and estradiol levels. According to modern pharmacological research, the main chemical components ofasphodeloides are saponins, biphenylpyrones, alkaloids, amino acids, volatile oils, polysaccharide of, etc., which have many functions such as antidepressant, anticoagulant, antioxidant, cholesterol lowering, antitumor, antiviral, anti-inflammatory and anti atherosclerotic [16–18]; the main chemical components ofamurensis are alkaloids flavonoids, sterols, etc. With hypoglycemic, antipyretic and anti-inflammatory, antihypertensive, antioxidant, antigout, immunosuppressive effects [19–20]. Lu Mingzhu et al. [21] through animal experiments, such as the study found thatsaponin B-Ⅱ with antidepressant activity and its mechanism may be related to enhance the brain 5-HT on nervous system functions and low light and,rectification and protection status of adrenocortical function effect better [22]. Qiu Kuncheng et al. [23] established LC-MS-MS to determine the amount of decocting the effective content in the different compatibility ratio ofand. The results showed that when the compatibility ratio ofandwas 1:1, the content of the effective component was the highest, which could play a good role in clearing away heat without dryness, nourishing “Yin” without helping dampness, which indicated that the medicine could obviously improve the “Yin” deficiency and “Fire” in CMS, resulting in the excessive “Fire”. The clinical symptoms of bone steaming, hot flashes, night sweats and so on. It can be seen that the law of drug use through data mining also conforms to the research of modern pharmacology on traditional Chinese medicine.

Table 4 Correlation between drugs in treatment CMS prescription Table 6 core drug combination in treatment CMS prescription

CMS, climacteric syndrome.

Table5 Core drug combinations in CMS prescription for treatment

CMS, climacteric syndrome.

Table6 New prescriptions for CMS

CMS, climacteric syndrome.

Table 7 Analysis results of TTD disease enrichment of Zhimu (Anemarrhenae rhizome)and Huangbo (Phellodendri Chinensis cortex)

Table 7 Analysis results of TTD disease enrichment of Zhimu (Anemarrhenae rhizome)and Huangbo (Phellodendri Chinensis cortex) (continued)

TTD, Therapeutic Target Database.

Table8 Analysis results of KEGG pathway

KEGG, Kyoto Gene and Genome Encyclopedia.

Figure 3 Disease, target, KEGG pathway network diagram. KEGG, Kyoto Gene and Genome Encyclopedia.

In the new prescription analysis, 9 new prescriptions were obtained. Prescription 1, Gancao ()__Baizhu ()_Guijia ()_Sangshen ()_Mudanpi (), nourishing “Kidney” and “Yang”, softening “Liver” and “Yin”, strengthening “Spleen” and “Qi”. Prescription 2, Muli ()_Longgu ()__llex latifolia Thunb, Calming and calming, nourishing yin and moistening dryness; Prescription 3, Poria cum Radix Pini_Jiegeng ()_Danshen ()_Baiziren ()_Cishi (), Calming and tranquilizing, regulating qi and promoting blood circulation; Prescription 4,_Chuanxiong Rhizoma_Shanzha ()_Chenpi ()_Xiangfu (), Regulating qi, activating blood circulation and removing blood stasis; Prescription 5, Heshouwu ()__Danggui ()_Roucongrong ()_Qingdai (), Tonifying the liver and kidney, clearing away the deficiency heat; Prescription 6,__Yinyanghuo ()_Shigao (), Nourishing kidney yin and warming kidney yang; Prescription 7,_Shanzhuyu ()__Zexie (), Warming and nourishing kidney yang, promoting blood circulation and removing blood stasis; Prescription 8,__Bajitian ()__, Nourishing Yin, reducing fire, soothing liver and regulating qi, and nourishing kidney; Prescription 9,_Xianmao ()_Fupenzi ()_, Tonifying kidney and essence.

For the treatment of CMS, with kidney deficiency as the basic pathological mechanism, prescription 2 may be added for patients with non-heart-kidney interaction, prescription 4 may be added for patients with liver qi stagnation and blood stasis, prescription 5 may be added for patients with liver and kidney yin deficiency, prescription 8 may be added for patients with yin deficiency and fire flourishing, and prescription 9 may be added for patients with kidney-yang deficiency and apparent failure.

From the perspective of network pharmacology, based on the results of high-frequency drug use and composition rules, we selected the firstandtraditional Chinese medicine in high-frequency drug combination, and analyzed the 2 drugs through the BATMAN-TCM online analysis system to explore the pharmacological mechanism of the drug for the treatment of CMS. The results showed that there were many targets of schizophrenia, anxiety, neurodegenerative disease and depression in TTD and Online Mendelian Inheritance in Man, which were most closely related to CMS. Wang Xiaoli [24] and other surveys found that the incidence rate of anxiety and depression in menopausal syndrome was higher than that in the general population, and the co morbidity rate of 2 diseases was higher than that of the general population. Large epidemiological survey shows that the incidence rate of neurodegenerative diseases in postmenopausal women is significantly higher than that in [25]. In the analysis of biological signal pathway enrichment of 2-drug compatibility, it was found that the number of potential targets of the interaction pathway of neuroactive ligand receptor was the most. The signal pathway of neuroactive ligand receptor interaction is a collection of all ligands related to intracellular and extracellular signal pathways on plasma membrane, which is most closely related to nerve function, and may be closely related to nerve disease and cognitive function [26–27]. It can be inferred that the combination of the 2 drugs in the treatment of CMS neurological symptoms such as depression and anxiety may be achieved through this pathway. It can be seen from relevant research literature that saponins ofcan increase the biological effect of estrogen, and the possible mechanism is to regulate the level of serum hormone and the expression of hormone receptor mRNA in vivo [28]. Nianhua et al. [29] believed that high dose berberine ofcan increase the content of estradiol in the serum of ovariectomized rats. Zhao Yiming [30] et al. analyzed the dose-response of the Chinese patent medicine Zhibai Dihuang decoction with 3 herbs, namely,and, and found that the Chinese patent medicine Zhibai Dihuang decoction had the effect of reducing serum testosterone in patients with polycystic ovarian syndrome and regulating the level of sexual hormones in vivo, and with the increase of dose, it had a dose-efffect relationship. In conclusion, the combination ofandcan adjust the sex hormone level of CMS patients and improve their clinical symptoms.

Conclusion

To sum up, in this study, from the perspective of the clinical medicine of traditional Chinese medicine literature, summarized the traditional Chinese medicine drugs for the treatment of CMS and new prescription mining, and the core drugandof traditional Chinese medicine compatibility mechanism of target detection and prediction,andmedicine for the compatibility may through the neural activity of ligand receptor interaction signaling pathways nervous system symptoms for the treatment of patients with CMS. This study can provide certain theoretical data reference and experimental research direction for the clinical application of traditional Chinese medicine treatment of CMS. However, there are certain limitations, which still need further experimental and clinical efficacy observation for verification.

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10.12032/MDM2020123005

Guo-Wei Zhang. College of Chinese Medicine, Hebei University, Baoding 071000, China. Email: xxzgw@126.com.

This study was supported by Chinese Medicine Research Program of Hebei Provincial Administration of Traditional Chinese Medicine (2020235); Hebei University College Students Innovation and Entrepreneurship Training Program (2020385); Hebei Province College Students Innovation and Entrepreneurship Training Program (s201910075036); Baoding Social Science Planning Project (2018121).

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CMS, climacteric syndrome; KEGG, Kyoto Gene and Genome Encyclopedia; TTD, Therapeutic Target Database.

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The authors declare that they have no conflict of interest.

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Zi-Tong Fu, Zhi-Peng Zhang, Yue-Yu Zhang, et al. Discussion on the mechanism of TCM treatment of climacteric syndrome based on TCM inheritance assistance system and network pharmacology. Medical Data Mining 2020, 3 (4): 185–196.

:Yu-Ping Shi.

26 September 2020,

10 December 2020,

:30 December 2020