Preliminary Study On The Data Mining of Prescriptions Containing Schisandra And The Mechanism of Diabetes

Background Data mining builds a bridge between ancient books of traditional Chinese medicine and modern medicine. It provides a new perspective for the precise compatibility of prescriptions and the scheme of diagnosis and treatment. Meanwhile, the mechanism of schisandrae chinensis and its compound in treating diabetes and diabetic complications is not clear. This limits the clinical application of Schisandra chinensis. Methods Apply TCMISS to mine the core drugs with the highest frequency of combined use with Schisandra chinensis to form a new prescription. And analyze the compatibility law. Use databases such as TCMSP, TCMID, PubChem, Swiss arget prediction, disgenet and Cytoscape software. The interaction between drugs and diseases and related pathways were analyzed. In addition, autodock Vina and other software are used to calculate the molecular docking and binding energy between compounds and key targets. Finally, the therapeutic effect of the new prescription of Fructus schisandrae chinensis S·(Core) on diabetic mice was evaluated by biological experiments. membranaceus Poria Pueraria Coptis chinensi Yam Chinses stomach meridian( Ophiopogon japonicus , Snakegourd root , Licorice , Pueraria lobata , Anemarrhena asphodeloides, Coptis chinensi ). Lung governing management and regulation.Lung also plays an indispensable role in body fluid metabolism the main source of water. The traditional Chinese medicine for returning the spleen, stomach and heart meridian has the functions of nourishing kidney yin, warming and recuperating kidney yang, tonifying the heart yin. It shows that the Chinese herb of Schisandra chinensis has compatibility and general tendency in treating diabetes mellitus. GO: Gene KEGG: of Genes and Genomes; S·core: core group; FBG: Fasting blood glucose; OB: Oral bioavailability; DL: Drug-likeness; IR: insulin resistance;


Results
The study employed a data mining S·(Core) was obtained. Using network pharmacology method, mainly containing target prediction, network construction, functional enrichment analysis, and molecular docking to systematically research the mechanisms of S·(Core) in treating diabetes. The putative targets of S·(Core) that treat diabetes mainly involved AKT1, GAPDH, IL-6, MAPK3, VEGFA and other targets. The functional enrichment analysis suggested that the produced therapeutic effect of S·(Core) against diabetes is mediated by synergistical regulation of several biological pathways, AGE-RAGE signaling pathway in diabetic complications , Insulin resistance, HIF-1 and Insulin signaling pathway. The results of molecular docking showed that the core chemical components of S·core had good affinity with the key targets of diabetes. In addition,We confirmed that S·Core can improve glucose and lipid metabolism in diabetic mice. Enhanced islet β Quantity and quality of cells. Reduce the inflammatory response in the body. Liver protection.

Conclusion
This study explored the mechanism of action of S·(Core) in diabetes by multi-component and multi-target multi pathways, which could provide a theoretical basis for the development and clinical application of S·(Core).

Background
Diabetes is a serious global public health problem. About 5.6% of the world population. The prevalence of diabetes in adults in China is 10.9%, and the number of patients in the world is the highest [1] . Persistent hyperglycemia and long-term metabolic disturbances can lead to diabetic nephropathy, diabetic ophthalmopathy and nervous system damage. It has a serious impact on the quality of life and overall life span [2] . The main drugs for treating diabetes include guanidine, sulfonylurea, benzoic acid derivatives, and so on. α-Glycosidase inhibitors, etc. The main purpose of these drugs is to control blood sugar. It needs to be taken for a long time. With the development of the disease, the dose increases gradually, which will lead to liver and kidney function injury and a variety of complications [3] . Traditional Chinese medicine regards diabetes as a "Xiaoke" , so the idea of treatment is similar to that of diabetes therapy. Traditional Chinese medicine takes "both symptoms and treatment" as the principle. Through syndrome differentiation and treatment, it can not only effectively reduce blood glucose, but also effectively control complications [4] . It has certain advantages in the understanding and treatment of diabetes.
Many herbs have been used in the treatment of diabetes and the development of new drugs.
Schisandra chinensis is one of them. Modern pharmacological studies show that the chemical components of Schisandra chinensis mainly include lignans, triterpenes, polysaccharides, volatile oils, flavonoids, organic acids and so on. Schisandra chinensis has many activities, such as protecting liver, anti-oxidation, anti-tumor, anti-aging, enhancing immune function and so on [5] .
The extract of Schisandra chinensis has hypoglycemic effect on STZ induced diabetic rats, with little toxic side effects. [6] 。 Fructus Schisandra chinensis polysaccharide can significantly reduce fasting blood glucose level, increase fasting serum insulin level and insulin sensitivity index in diabetic rats [7] . Schisandra chinensis was not a key herbal medicine for the treatment of "Xiaoke" in ancient times. Schisandra chinensis in treating diabetes mellitus. The Evidence can be found in ancient books and modern basic clinical research. For example, sour Yuxiao Decoction (Schisandra chinensis as the king drug) with good clinical efficacy, Shenggan Jiangtang formula (Schisandra chinensis as the king drug) [8] [9] , etc. Prescription is the essence of Chinese medicine, which embodies the theoretical characteristics of Chinese medicine "differentiation of symptoms and signs, monarch and discipline", "Jun-Chen-Zuo-Shi", "strengthening the body and eliminating evil". Prescription has the characteristics of multi-component, multi-channel and multi-target synergy, and has unique advantages in the prevention and treatment of complex diseases.
However, the mechanism of Schisandrae chinensis and its compound in the treatment of diabetes and diabetic complications is not clear. This limits the clinical application of Schisandra chinensis. This study is based on the Chinese Pharmacopoeia, the online database of yaozhi.com and the tested prescriptions in ancient medical books. TCMISS was used to make frequency statistics and composition law analysis of target prescriptions. Based on the biomolecular network, the correlation mechanism between prescription and disease syndrome was established by using the method of network pharmacology. Analyzing the hidden patterns or laws between traditional Chinese medicine and body. To explore the potential mechanism of Schisandra chinensis seed core drug in treating diabetes mellitus. Using molecular docking and animal in vivo experiments are the key ways to verify the results of network pharmacology. To provide theoretical basis for the compatibility of Fructus schisandrae chinensis prescription and the clinical practice of diabetes prescription. Figure 1 shows the flow chart of this whole analysis.

Prescription data mining analysis and standardization
Collection of traditional Chinese medicine prescriptions for the the treatment of "Xiaoke" or "Diabetes" with Schisandra chinensis in the Chinese Pharmacopoeia of (2020 Edition) [10] . Subject to the explicit inclusion of Schisandra chinensis in the prescription ; Collect the prescription   database  of  proprietary  Chinese  medicine  provided  by  Yaozhi  online database(https://www.yaozh.com/), which is clearly marked as treatment of thirst or diabetes mellitus. Chinese patent medicine varieties clearly marked for the treatment of "Xiaoke" or "Diabetes" and containing Schisandra chinensis and its processed products (Schisandra by vinegar, Schisandra by wine or Schisandra by honey); Collect 25 ancient medical books such as "Zhouhoubeijifang", "Waitai", "Yitong", "Shengji master record", "Qianjin" and "Danxi master record", Screening "main treatment" or "function" column in the above source prescription; It contains It clearly contains the syndrome names of "Xiaoke", "Shanxiao", "Shangxiao", "Zhongxiao", "Xiaxiao", "Pidan", "Liangxiao", "Xiaodan"; and The prescription composition is clear, and the Schisandra chinensis and its processed products shall prevail (The above names are the names of classical b diseases and syndromes of traditional Chinese medicine). Finally, 67 prescriptions containing Schisandra chinensis and its processed products were included.
To ensure the correctness of data mining results,The drug names of the collected prescriptions shall be standardized according to the Chinese Pharmacopoeia of (2020 Edition). After standardizing the prescription name, input the data information into TCMISS software.
TCMISS can carry out data mining on the medication law of clinical prescriptions. The high-frequency drugs, the nature and taste of the drugs in the formula, the frequency of meridian attribution and the drug combination obtained by association rules were analyzed.

PPI network construction and core target analysis
The above 145 common targets were input into the String database (https://string-db.org/) for retrieva. Set the protein type as "Homo sapiens". The minimum interaction threshold is 0.4.Obtain the network relationship data of target interaction. It was imported into Cytoscape software to draw the network diagram of protein-protein interaction. The size, color, and depth of the node represent the size of the degree value.

Construction of potential target tissue distribution map
The target tissue distribution map was constructed through GeneCards database. Inductive target distribution of tissues and organs. In other words, the core drug group treats the tissues and organs with high distribution of diabetes. Reveal potential target sites.

Molecular docking
Autodock Vina software was used to rank the top five target proteins in the degree of core target.
Molecular docking verification with potential active components in the core drug group.
Metformin, a traditional therapeutic drug, was compared with glibenclamide, which is widely used in clinic. The 2D structures of traditional Chinese medicine components, metformin and glibenclamide were downloaded from PubMed(https://www.ncbi.nlm.nih.gov/pubmed) database.
3D structures of small molecules were generated using Chem3D software. Download the 3D structure of the core target protein through the PDB(https://www.rcsb.org/) database. The pretreatment of ligand and protein receptor molecules was completed by PyMOL and autodocktools-1.5.6 software. Set the pocket parameters and parameter text file of protein receptor.
Batch docking under Linux virtual environment using autodockvina software. The docking results of the five target proteins with the strongest binding activity were displayed by PyMOL software.
Preparation of decoction of Schisandra chinensis core herbal medicine group (S·Core) Continuous injection for three days. The mice in the control group were given the same amount of citric acid buffer. During injection, STZ solution was kept in ice bath and dark environment. 7 days after STZ injection, all mice showed high fasting blood glucose level (≥11.1mmol/L) and were considered as successful models. The mice were randomly divided into three groups (8 in each group): diabetes group (Model), Schisandra core compatibility group (S· Core) and metformin hydrochloride group (MET). S·core600mg/kg and MET300mg/kg were administered orally. The control group and the model group were given the same amount of distilled water.In the last 8 weeks of the experiment, normal saline and drugs were given by gavage. FBG and body weight were measured weekly after administration. Measure food and water intake every day.
After 8 weeks of treatment, mice were euthanized and tissues were collected for further analysis.

Tissue sampling and histological staining
Mice were euthanized with pentobarbital sodium injection (100mg/kg). At the same time, inhale ether to maintain anesthesia after fasting for 12 hours. Blood samples were collected from retroorbital hemorrhage after anesthesia. Then centrifuged at 3500g for 15min to obtain serum for serological detection. The liver and pancreas tissues of different groups were fixed in 10% neutral buffered formalin for paraffin section. Cut the tissue into 4 pieces μ M thick. Stained with hematoxylin and eosin (H&E) [11] . The quantitative data of histological staining were analyzed by Image Proplus software.

Western blot analysis
The liver tissue of mice was extracted with Ripa lysate. Liver tissues were harvested and stored at −80℃for western blot analyses. The cells were lysed with biyuntian Western IP lysate to extract total protein. The total protein of each cell lysate was quantified by BCA protein quantitative Kit (all gold). Draw standard curve. Calculate the concentration of protein sample to be determined.

Statistical analyses
The data were represented by means ± standard deviation (SD). And statistical analyses were performed using one-way analysis of variance (GraphPad Software, San Diego, CA, USA).
Results were considered to be statistically significant at p< 0.05 between various groups.

Medication frequency statistics
Screening of 67 prescriptions "Xiaoke" and "diabetes". The frequency of 130 traditional Chinese medicines included was counted. There are 17 kinds of drugs with frequency≥10, in Table 1. 130 traditional Chinese medicines are classified according to traditional Chinese medicine edited by Gao Xuemin, in Table 2. It indicates that compatibility with Fructus schisandrae chinensis in treating diabetes is often combined with "tonifying drugs", "clearing away heat drugs" and "collecting astringent drugs" (frequency>99 times). These three categories salty taste(2.94%), astringent taste(2.85%) is shown in Figure 2B. Most of the traditional chinese medicine combined with Schisandra chinensis in the treatment of diabetes mellitus is cold, warm and flat. Cumulative frequency is 93.7%.The top three medicine flavor frequencies were sweet taste, bitter taste, pungent taste. The cumulative frequency is 85.38%. In traditional Chinese medicine, the pathogenesis of diabetes is Yin and fluid, the exuberance of dryness-heat. It is worth noting that Yin defi-ciency is the initiating factor, the root cause. Dryness-heat in superficiality.
The two are cause and effect other. According to the theory of traditional Chinese Medicine "The more yin deficiency and dryness, the more dryness and heat, and the more yin deficiency". Take cold medicine as the main medication principle. Traditional Chinese medicine believes that "water-wetne" hinders the transportation of "Qi""water-wetne" generates "phlegm turbidity".So diabetes is induced. "water-wetne" should be resisted with warm medicine. Strengthening clinical curative effect with flat medicine. From the perspective of traditional Chinese medicine to see the pathogenesis of diabetes: "lung and stomach heat, kidney yin deficiency". The clinical treatment is mainly traditional Chinese medicine with sweet-nourishing, bitter-discharge,pungent-warm. In the meantime, The application of bitter cold traditional Chinese medicine should pay attention to whether the spleen and stomach are damaged. Prevent injury to human immunity. Therefore, the Chinese herbal medicine with many characteristics of compatibility is good.
Meridian tropisof. The theory of channel tropism is an important part of the theory of TCM, which can reflect the attribution of TCM and prefers certain viscera, meridians, or specific parts.
Schisandra chinensis is often used in combination with Ginseng, Ophiopogon japonicus, Rehmannia glutinosa, Astragalus mongholicus and Snakegourd root in the treatment of diabetes.
Network display under different "support" is shown in Figure 2D. In the famous medical books of ancient books, all these traditional Chinese medicines have prominent therapeutic effects on diabetes. Therefore, the above 6 closely related traditional Chinese medicines are recombined. As a drug combination with schisandra chinensis as the core S·(Core). In order to explore the mechanism of their treatment of "diabetes" and carry out follow-up studies.  [12], [13], [14], [15], [16], [17], [18], [19], [20], [21] . Additional file 1: Table S1 displayed the elaborated data of active components of S·(Core). A total of 139 potential active components were obtained.

Screening of core drug components and obtaining results of action targets
975 drug targets were screened using Swiss Target Prediction database.
The keywords "diabetes" were searched in OMIM, Disgenet and Genecards databases. A total of 1136 disease targets were obtained after removing the rrepeat. 975 drug targets and 1136 disease targets were input into Venny2.1 online software mapping tool platform. A Venn diagram was drawn, and 145 drug-disease common targets were obtained after the intersection of the two ( Figure 3A). Details about S·(Core)-genes, diabetes-genes, and S·(Core)-disease overlapping target genes were presented in Additional file 2: Table S2.

Construction of component target network
The 139 potential active components of the core drug group and 145 drug-disease common targets were input into Cytoscape software. Delete the isolated components that have no intersection with the target. The network of drug-component-target-disease interactions was plotted ( Figure 3B).
Network graph topology analysis is performed using Network Analyzer.Degree value indicates the number of correlation between the component and the target. The higher the Degree value is, the more critical the component is in the network [22] . Additional file 3:

PPI network analysis and core target screening
To further explore the relationship between potential targets at protein level. The 145 common targets above are entered into the String database for retrieval. The conditional protein species was Homo sapiens and the minimum interaction threshold was 0.4.Obtain network relationship data of target interaction. The above results were imported into Cytoscape software to draw the protein interaction network diagram ( Figure 3C). The size, color, and shade of the node represent the size of the Degree value. These targets may be highly regulatory in the treatment of diabetes.

Target tissue distribution
Cytoscape 3.7.1 software was used to construct the potential target-tissue distribution network map of the core drug group containing Schisandra chinensis. Reflect the degree of interaction between target and organization ( Figure 3D). 168 nodes and 2173 edges are obtained. The circular node represents the potential target. Arrow nodes represent tissues and organs with target distribution. The darker the color of the arrow, the higher the distribution proportion of the target in the tissue and organ. The results showed that 145 potential targets were highly expressed in nervous system (140), blood (136), liver(133), muscle (133) respectively. Additional file 4: Table   S4 Targets and Tissues Organs.

The core compounds in S·(Core) are docked with key proteins
The top five key targets of degree in PPI network were used to conduct preliminary verification of molecular docking. Target protein receptors for VEGFA (PDF ID 6V7K), AKT1 (PDF ID 3096), GAPDH (PDF ID 3GPD), IL6 (PDF ID 409H), TNF(PDF ID 2ZPX) were downloaded from RCSB PDB database. Verification with TCM ingredients with degree ≥ 14 (Table 3). Listed metformin and glyburide were selected as positive drugs for docking with the target (Table 4). It is generally believed,Binding energy < 0 has binding activity, <-5 has better binding activity, <-7 has strong binding activity [23] . The results show that the minimum binding energy of all molecules to the target protein is less than 0. Suggesting that ligand and receptor can spontaneously bind.
Moreover, The docking results with the strongest binding activity of the five target proteins are that the same component oleanolic acid comes from Ophiopogon japonicus. The docking model is shown ( Figure 5).

In vivo experimental validation
Effects of S·(Core) on blood glucose, insulin resistance and pancreas function in diabetic mice.
Network pharmacology results indicate that diabetes is associated with increased IR and impaired glucose tolerance. Therefore, we studied the effects of S·(Core) on blood glucose control, insulin sensitivity and pancreas protection in diabetic mice. A sixteenth week OGTT analysis ( Figure 6E) and fasting blood glucose ( Figure 6A) showed that high fat diet successfully induced diabetes. As Administration of S·(Core) and metformin could effectively reduce the level of HbA1c (P<0.05) ( Figure 6D). It shows that S·(Core) group has a long-term effect on alleviating hyperglycemia.
OGTT and ipitt analysis at the end of the test showed that, S·(Core) treatment increased glucose tolerance in diabetic mice effectively ( Figure 6E)(P<0.05). And increased insulin sensitivity ( Figure 6F) (P<0.05). Compared with the blank control group, the islets in the model group shrank and the morphology was destroyed. Compared with the model group, the islet morphology in the S·(Core) group was significantly restored and the degree of atrophy was better reversed ( Figure   6G)(P<0.05). It indicated that S·(Core) components could significantly improve pancreatic injury and protect pancreatic tissue in diabetic mice. In addition, immunofluorescence experiments showed that, Pancreatic islets in diabetic mice β the number of cells decreased significantly. but α the number of cells increased significantly and the distribution was more uniform( Figure   6H)(P<0.05). Metformin or S·(Core) treatment not only increased β the number of cells decreased α number of cells. This shows a good protective effect on pancreatic islets in diabetic mice. All these analyses confirmed the anti diabetic effect of S·(Core). It is characterized by regulating blood glucose, insulin homeostasis and insulin sensitivity.
Effects of S·(Core) on blood lipids, liver and inflammation in diabetic mice. H&E dyeing and visual shooting display. Compared with the control group, the liver of the model group showed inflammation and abnormal lipid accumulation. However, S·(Core) improved significantly after treatment ( Figure 7A) (P<0.05). We also detected two important transaminases ALT and AST. The results also support the above conclusions ( Figure 7F,G) (P<0.05). Hyperlipidemia is a major risk factor for diabetes mellitus. It is characterized by increased lipid accumulation in serum [24] .
Compared with the blank group, the model group significantly increased the levels of TC and TG in serum . After 16 weeks of treatment, it was found that the levels of serum TG and TC in the S·(Core) group were significantly lower than those in the model group. The curative effect was similar to that of metformin group ( Figure

Discussion
Diabetes is a metabolic disease caused by various causes. This disease is easy to cause macrovascular, microvascular and nervous system diseases. The incidence rate and disability rate of diabetes and its complications increase year by year. It has become the third major killer that seriously affects human health after tumor and cardiovascular disease. Hypoglycemic drugs are the main treatment for diabetes. On the basis of oral hypoglycemic drugs single treatment, combined treatment or insulin combined with oral hypoglycemic drugs. To control the change of blood glucose level throughout the day and delay the progress of the disease, it is necessary to take medicine for life. However, if the medication period is prolonged, the body's drug resistance can gradually increase, resulting in limited drug effect. Chinese medicine is a popular treatment for diabetes in recent years. In a large number of reports, practical therapeutic effects and complication prevention effects were obtained. It is found that Schisandra chinensis has therapeutic effect on diabetes mellitus. However, the lack of clinically effective prescriptions containing Schisandra chinensis in the market limits its clinical application. In order to better summarize and inherit the academic thought and medication experience of doctors. Data mining and network pharmacological analysis were used in this study. We screened and collected anti diabetic Chinese herbal compound containing Fructus schisandrae chinensis. To clarify its molecular mechanism and provide basis for new drug research and development and clinical application. 67 prescriptions met the standard. The "frequency", "efficacy", "meridian tropism", "four Qi" and "five flavors" were analyzed and counted by tcmiss. The compatibility frequency of "Schisandra chinensis -ginseng" is the highest. This combination is a classic clinical compatible drug pair, which originates from Shengmai Powder in Qianjin prescription. The combination of the two drugs can enter the lung and kidney meridians, and has the effects of generating fluid and restoring Qi, nourishing yin and generating fluid, tonifying deficiency and strengthening [25] . The drugs used to treat diabetes with Fructus Schisandrae are mainly supplementation and clearing away heat, while astringent drugs are auxiliary. Traditional Chinese medicine believes that the treatment of diabetes should take "deficiency of Qi and Yin" as the root cause, "dryness and heat", "blood stasis" as the standard, "body fluid consumption injury" as the symptom. Therefore, in addition to taking dialectics as the basis, the formulation focuses on strengthening the body's schisandrin B [26] , ginsenoside [27] , astragaloside IV [28] , Rehmannia glutinosa [29] , Ophiopogon japonicus polysaccharides [30] and total saponins [31] , Snakegourd root [32] can resist diabetes. It can effectively improve the symptoms of diabetes, and meet the needs of modern clinical hypoglycemic treatment.
The development of network pharmacology provides a new idea for the exploration of pharmacodynamic components of traditional Chinese medicine. The five traditional Chinese medicines mined in this paper have the strongest correlation with Schisandra chinensis, and are set as new prescriptions. Using network pharmacology research methods. Explore the mechanism of new prescription in treating diabetes mellitus from microcosmic perspective. The PPI network analysis showed that the core targets of the new prescription containing Schisandrae chinensis against diabetes were AKT1, VEGFA, GAPDH, IL6 and TNF. AKT1, also known as protein kinase B, is mainly involved in the regulation and release of cytokines, apoptosis and glucose metabolism. The expression of AKT1 protein was down regulated and PI3K/Akt signaling pathway was activated, so as to improve the glucose decomposition ability of cells [33] . The expression of vascular endothelial growth factor (VEGFA) is correlated with diabetes mellitus.
VEGFA can lead to inflammatory factor secretion, donation and moistening [34] . Hyperglycemia inhibits the key glycolytic enzyme glycerol 3-phosphate dehydrogenase (GAPDH) by over activating poly ADP ribose polymerase (PARP), which causes the accumulation of glycolytic intermediates and finally increases the glucose level [35] . The activation of inflammatory response by innate immune system can lead to cell apoptosis, tissue fibrosis and organ dysfunction, resulting in insulin resistance, impaired insulin secretion and renal failure. IL-6 plays a certain role in the inflammatory cascade [36] . In 1993, an article in science first introduced the relationship between tumor necrosis factor (TNF) and obesity, and the relationship between inflammation and insulin resistance [37] . TNF can affect insulin sensitivity and islets β Cell function through the action of blood and/or paracrine, which in turn causes IR. We selected the common drugs on the market (metformin and glibenclamide) as the positive control of molecular docking. The results of molecular docking showed that the binding energies of important active compounds and main targets were less than -2 kJ/mol, indicating that they had good affinity and binding activity. In conclusion, the target may protect islets by down regulating the activity of inflammatory factors and inhibiting insulin resistance β Cells maintain blood glucose homeostasis, thereby improving the symptoms of diabetes.
BP analysis showed that the core drug group was involved in monosaccharide metabolism, glucose metabolism and blood glucose homeostasis. The regulation of blood glucose homeostasis depends on the synergy of multiple tissues and organs. Each tissue senses or regulates blood glucose by absorbing, consuming and storing glucose or releasing hormones and metabolites. For diabetic patients, severe fluctuations in blood sugar can cause damage to human organs. And accelerate the occurrence and development of Diabetic Acute and chronic complications.
Therefore, maintaining blood glucose homeostasis is very important. KEGG enrichment analysis showed that the core drug group involved AGE-RAGE signaling pathway, insulin resistance pathway and HIF-1 signaling pathway in diabetic complications. AGEs can act directly on islets β Cells, induced islets β Cells respond to oxidative stress,Cause insulin synthesis and secretion dysfunction, promote islets β cells Apoptosis [38] . ZHU [39] et al found that AGEs interacts with RAGE, triggering a series of inflammatory reactions, leading to diabetes and its complications. IR is an important part of diabetes. It has been reported that over 70% of diabetic patients have IR, and IR is also the common pathological basis of hypertension, coronary heart disease, metabolic syndrome, polycystic ovary syndrome and other diseases. HIF-α It is closely related to the occurrence and development of diabetes and its complications [40] . Under the condition of high glucose and hypoxia, a large amount of HIF-α will accumulate in cells. Exacerbate the ischemic hypoxia state of diabetic patients and promote the occurrence of diabetic complications [41] . These indicate that the development of diabetes and complications is related to insulin resistance, blood glucose homeostasis and immune disorders.
The results of tissue distribution of potential targets in Schisandra chinensis core drug group showed that 145 potential targets were highly expressed in nervous system, blood and liver respectively. Recent studies have shown that the liver is not only an important place for glucose and lipid metabolism, but also one of the main target organs of insulin. Hepatic insulin resistance is the key cause of impaired fasting glucose, and is also an important factor in the occurrence and development of diabetes [42] . Traditional Chinese medicine believes that, liver governing free coursing. The liver plays a role in regulating and controlling the dynamic process of blood glucose production, distribution, application, storage and metabolism. Liver failing to govern free coursing.
The food could not be distributed in time. It turns into sugar turbidity and soaks the blood vessels.
The external manifestation is that the postprandial blood glucose is high and fluctuates greatly [43] .
Compared with continuous hyperglycemia, blood glucose fluctuation can aggravate oxidative stress, inflammatory reaction and accelerate the occurrence of complications [44,45,46] . The function of "liver" has a good effect on improving lipid metabolism disorder and protecting liver in diabetic mice. In addition, we selected blood and liver for verification according to the distribution of potential target tissues. AGEs-RAGE can activate NF-kB. NF-kB activated by AGEs-RAGE signaling pathway enters the nucleus, which can cause a large number of adhesion molecules, growth factors and pro-inflammatory cytokines (such as TNF-α, IL-6, IL-2). Therefore, it causes tissue injury and inflammatory reaction, which is an important mechanism of T2DM and its complications [47] . INSR on hepatocyte surface would activate insulin receptor substrate (IRS) after binding with insulin, and then functionally mediate downstream like glucose/lipid metabolism, hepatocyte proliferation, DNA synthesis, and cell cycle regulation [48] . GSK-3 is a post insulin receptor signal protein with two isomers GSK-3α And GSK-3β. It belongs to constitutive activated kinase, that is the phosphate state of GSK-3 is inactivated and the dephosphorylation state is activated. Normally, insulin phosphorylates GSK-3β Inactivate it, inactivated GSK-3β It loses the inhibitory effect on hepatic glycogen synthesis and can promote hepatic glycogen synthesis. In type 2 diabetes, insulin resistance occurs in the body. Absolute or relative deficiency of insulin efficacy. Dephosphorylated GSK-3 β increase. the synthesis of liver glycogen decreases and the content of liver glycogen decreases, resulting in the increase of blood glucose level [49] . The regulation of S·(Core) on the key targets of these two pathways was confirmed by serum biochemistry and Western blotting.

Conclusion
To sum up, this study summarized the law of compatibility and common drug combinations

Declaration Ethics approval and consent to participate
The animal experiment complies with the publication of guidelines for the care and use of laboratory animals of the National Institutes of Health (NIH Publication No. 80231, revised in 978). It was approved by the experimental animal Committee of Heilongjiang University of traditional Chinese medicine.

Consent for publication
Not applicable.

Availability of data and materials
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.