Traditional Chinese medicine composition for treating alimentary canal polyp and alimentary canal tumor as well as preparation and application of traditional Chinese medicine composition

Abstract

The invention discloses a traditional Chinese medicine composition for treating alimentary canal polyp and alimentary canal tumor and a preparation and application thereof, and belongs to the technical field of traditional Chinese medicine and network pharmacology, the traditional Chinese medicine composition comprises the following raw material medicines: frankincense, myrrh, leech, radix aconiti carmichaeli, codonopsis pilosula, pepper, dark plum, dried ginger, mustard, bighead atractylodes rhizome, liquorice, stiff silkworm, edible tulip, aspongopus, angelica sinensis and prepared rehmannia root. The traditional Chinese medicine composition disclosed by the invention is cheap in raw materials, simple and convenient to prepare and convenient to use, and has remarkable curative effects in the aspects of invigorating spleen, replenishing qi, reducing swelling, removing stasis and the like through clinical application and pharmacological research for many years. The related action mechanism of the traditional Chinese medicine composition is clear, and more choices and discussion bases are provided for clinical prescription application through network pharmacological research.

Description

Technical Field

[0001] The present invention relates to the technical field of traditional Chinese medicine and network pharmacology, and in particular to a traditional Chinese medicine composition for treating digestive tract polyps and digestive tract tumors, and a preparation and application thereof. Background Art

[0002] With the changes in people's lifestyles and eating habits at this stage, the number of cases of gastrointestinal polyps and tumors is increasing, which has also attracted widespread attention in the field of gastroenterology.

[0003] The word "polyp" was first recorded in Huangdi Neijing. Lingshu Shuizhang Pian said: "Cold Qi invades the outside of the intestines, and the defensive Qi fights each other. Qi cannot be nourished, and because of something, it becomes attached to the inside, and then evil arises, and polyps are born." Due to improper diet and emotional injury, the spleen and stomach lose their power to transport and transform, dampness, heat, phlegm and turbidity are generated internally, and Qi and blood stagnate, so that Qi, dampness, phlegm and stasis gather together, and eventually become polyps over time. Digestive tract polyps refer to localized lesions that are raised on the surface of the mucosa and protrude into the digestive cavity. They are common digestive system diseases in clinical practice. They are benign lesions with hidden onset. Patients generally have no discomfort in the early stage of the disease. They are often found accidentally during routine endoscopic examinations (gastroscopy / colonoscopy). As the disease progresses, they may be accompanied by discomfort such as abdominal distension and diarrhea. They are often ignored due to lack of specificity and have the risk of canceration. Currently, surgical operations are the main treatment. Among them, endoscopic resection has gradually replaced traditional surgical operations due to its advantages such as minimal invasiveness and short recovery time. However, gastrointestinal bleeding is prone to occur after the operation. Massive bleeding can cause hypovolemic shock and even death in severe cases.

[0004] Digestive tract tumors generally refer to tumorous lesions that occur in the digestive tract. Digestive tract tumors are mostly malignant. Once a malignant tumor occurs in the digestive tract, it will cause serious harm to the patient, affect the quality of life in the future, and even threaten life. According to statistics from the International Agency for Cancer, about 3 million people die from cancer in my country each year, of which four of the top five cancers with the highest mortality rate are digestive tract tumors, and the incidence of digestive tract tumors is expected to increase significantly in the future. Modern medicine believes that the occurrence and development of digestive tract tumors are the result of long-term interaction of multiple factors, and its mechanism is relatively complex. At present, the intrinsic factors that induce digestive tract tumors have not yet been clearly identified. However, with the in-depth development of medical research, at the molecular level, it is believed that the onset of digestive tract tumors involves abnormal expression of genes, transcription, protein, metabolism, and other aspects such as single nucleotide polymorphism sites (SNP), RNA sequences, and protein characteristics. Traditional Chinese medicine believes that the pathogenesis of tumors is mainly due to deficiency of vital energy and stagnation of qi and blood, so in treatment, the spleen should be strengthened and the body should be strengthened, and qi should be replenished and collaterals should be unblocked. At present, the treatment of gastrointestinal tumors is mainly surgical resection in the early stage, and chemotherapy in the middle and late stages. However, surgical treatment requires high technical skills from doctors, and there is also a certain risk of recurrence after surgery. Patients often experience various adverse reactions after chemotherapy, such as fatigue, nausea, vomiting, etc.

[0005] Traditional Chinese medicine has great potential in the treatment of gastrointestinal polyps due to its clear clinical efficacy and few side effects. In addition, many studies have shown that traditional Chinese medicine is effective in the auxiliary treatment of gastrointestinal tumors and is safe and reliable. It can not only improve the efficacy and treat clinical symptoms, but also reduce or eliminate postoperative and chemotherapy adverse reactions, reduce patient pain, improve patient quality of life, and reduce mortality. Although traditional Chinese medicine has been studied to a certain extent in the treatment of gastrointestinal polyps and gastrointestinal tumors, the mechanism of action of existing related Chinese patent medicines is still unclear, and there is a lack of effective demonstration of the effect, which has affected the further development of traditional Chinese medicine in the research and application of the treatment of gastrointestinal polyps and gastrointestinal tumors. Summary of the invention

[0006] Based on this, it is necessary to provide a Chinese medicine composition with a clear mechanism of action for the treatment of gastrointestinal polyps and gastrointestinal tumors, as well as its preparation and application, in order to address the problems of unclear clinical action mechanism of traditional Chinese medicine currently used for the treatment of gastrointestinal polyps and gastrointestinal tumors and lack of effective demonstration of the effect of the medicine.

[0007] The invention provides a traditional Chinese medicine composition for treating digestive tract polyps and digestive tract tumors. The traditional Chinese medicine composition comprises the following raw materials: frankincense, myrrh, leech, aconite root, codonopsis pilosula, prickly ash, black plum, dried ginger, mustard, atractylodes macrocephala, licorice, bombyx batryticatus, trillium, nine-scented worm, angelica, and rehmannia root.

[0008] Preferably, the traditional Chinese medicine composition comprises the following raw materials in parts by weight: 8-12 parts of frankincense, 8-12 parts of myrrh, 4-8 parts of leech, 4-8 parts of aconite, 12-18 parts of codonopsis, 18-22 parts of zanthoxylum bungeanum, 18-22 parts of ebony, 6-12 parts of dried ginger, 12-18 parts of mustard, 8-12 parts of atractylodes, 4-8 parts of licorice, 6-12 parts of bombyx batryticatus, 8-12 parts of trifoliate orange, 8-12 parts of schizonepeta tenuifolia, 12-18 parts of angelica, and 18-22 parts of rehmannia root.

[0009] The present invention also provides a traditional Chinese medicine preparation for treating digestive tract polyps and digestive tract tumors, wherein the traditional Chinese medicine preparation is prepared from the traditional Chinese medicine composition for treating digestive tract polyps and digestive tract tumors described in any of the aforementioned technical solutions.

[0010] Preferably, the Chinese medicine preparation is a decoction, and the decoction is prepared according to the following steps:

[0011] (1) Weigh the raw material according to weight, add 5-10 times the weight of water and soak for 30-120 minutes;

[0012] (2) heating and boiling the soaked API together with water, filtering, and collecting the filtrate;

[0013] (3) adding 5-10 times the weight of water to the residue, boiling, filtering, and collecting the filtrate;

[0014] (4) The filtrates obtained after the two decoctions are combined, heated and concentrated to obtain a decoction.

[0015] Preferably, the two decoctions are each 30-60 minutes in duration.

[0016] Preferably, the filtrates are combined and concentrated by heating to 10%-20% of the original volume.

[0017] In addition, the present invention also provides the use of the traditional Chinese medicine composition for treating digestive tract polyps and digestive tract tumors as described in any of the aforementioned technical solutions in the preparation of drugs for treating digestive tract polyps and digestive tract tumors.

[0018] The Chinese medicine composition for treating digestive tract polyps and digestive tract tumors of the present invention is explained as follows:

[0019] Dried ginger, Atractylodes macrocephala, and Trillium gracile all belong to the spleen meridian and are the main medicines. Dried ginger is good at warming the middle and dispersing cold, restoring yang and unblocking meridians, Atractylodes macrocephala replenishes qi and strengthens the spleen, and Trillium gracile clears heat and detoxifies, resolves phlegm and disperses nodules; it is combined with Zanthoxylum bungeanum, mustard, and Ampelopsis pilosula to warm the middle and relieve pain, and is the assistant medicine. Among them, mustard is beneficial to qi and disperses nodules, and helps Trillium gracile to strengthen the effect of resolving phlegm and dispersing nodules; Aconite and dried ginger are both pungent and hot, and they must be used together to enhance the effects of warming yang and guarding the middle, restoring yang and rescuing adverse conditions; Rehmannia glutinosa and Angelica sinensis replenish blood and nourish blood, Codonopsis pilosula replenishes qi and strengthens the spleen, and together with Atractylodes macrocephala, they replenish both qi and blood; frankincense and myrrh promote blood circulation and relieve pain, while Prunus mume is sour and astringent, and the three medicines enter the liver meridian together to reduce swelling, relieve pain, soften the liver and soothe the liver; Bombyx batryticatus and leech have a salty and flat taste, "can go down and soften", and together they play the role of dispersing nodules and eliminating symptoms, and strengthen the effect of dispersing nodules; Licorice harmonizes the middle and relieves urgency, and harmonizes the properties of the medicine, and is the adjuvant medicine. The Chinese medicine composition is used together to regulate qi and blood, attack and supplement at the same time, treat both the symptoms and the root cause, and play the effects of strengthening the spleen and replenishing qi, eliminating symptoms and dispersing knots. It has the characteristics of attacking evil without hurting the body, considerable curative effect, and safe application.

[0020] Specifically, each Chinese medicine raw material has the following pharmacological properties:

[0021] Frankincense: It is a resin exuded from the bark of Boswellia carterii Birdw. and Boswelliabhawdajian Birdw., a plant of the same genus. It tastes pungent, bitter and warm. It enters the heart, liver and spleen meridians and has the effects of promoting blood circulation, relieving pain, reducing swelling and promoting tissue regeneration.

[0022] Myrrh: It is the dried resin of the plant Commiphora myrrha Engl. or Comniphoramolmol Engl. of the olive family. It is pungent, bitter and neutral in nature. It enters the heart, liver and spleen meridians and has the effects of dispersing blood stasis, relieving pain, reducing swelling and promoting tissue regeneration.

[0023] Leech: The dried whole body of the leech Whitemania pigra Whitman, Hirudonipponia Whitman or Whitemania acranulata Whitman, which are animals of the Hirudinidae family. It tastes salty, bitter, and flat; it is slightly toxic. It enters the liver meridian and has the effects of breaking blood, promoting menstruation, removing blood stasis and eliminating symptoms.

[0024] Aconite: It is a processed product of the root of Aconitum carmichaeli Debx., a plant of the Ranunculaceae family. It tastes spicy and sweet, very hot, and is poisonous. It enters the heart, kidney, and spleen meridians, and has the effects of restoring yang, replenishing fire and yang, and dispelling cold and relieving pain.

[0025] Codonopsis: It is the dried root of Codonopsis pilosula (Franch.) Nannf., Codonopsis pilosula Nannf. var. modesta (Nannf.) LTShen or Codonopsis tangshen Oliv. of Campanulaceae. It is sweet, flat, and enters the spleen and lung meridians. It has the effects of tonifying the spleen and lungs, nourishing blood and promoting body fluid.

[0026] Zanthoxylum schinifolium Sieb.et Zucc. or Zanthoxylum bungeanum Maxim., a plant of the Rutaceae family, is a dry, mature peel. It is spicy and warm. It enters the spleen, stomach, and kidney meridians, and has the effects of warming the middle and relieving pain, killing insects, and relieving itching.

[0027] Wumei: It is the dried nearly mature fruit of Prunus mume (Sieb.) Sieb. et Zucc. of the Rosaceae family. It tastes sour, astringent, and flat. It has the effects of astringing the lungs, astringing the intestines, promoting the production of body fluids, and calming ascaris.

[0028] Dried ginger: It is the dried rhizome of Zingiber officinale Rosc., a plant of the ginger family. It is pungent and hot. It enters the spleen, stomach, kidney, heart, and lung meridians, and has the effects of warming the middle and dispelling cold, restoring yang and unblocking meridians, and warming the lungs and eliminating phlegm.

[0029] Mustard: It is the dried mature seeds of the cruciferous plant white mustard Sinapis alba L. or Brassicajuncea (L.) Czern.et Coss., which is pungent and warm. It enters the lung meridian and has the effects of warming the lungs and resolving phlegm, promoting qi and dispersing stagnation, and dredge meridians to relieve pain.

[0030] Atractylodes: It is the dried rhizome of Atractylodes macrocephala Koidz., a plant of the Asteraceae family. It tastes sweet, bitter, and warm. It enters the spleen and stomach meridians and has the effects of replenishing qi and strengthening the spleen, drying dampness and promoting diuresis, and stopping sweating.

[0031] Licorice: It is the dried root and rhizome of Glycyrrhiza uralensis Fisch., Glycyrrhiza inflate Bat. or Glycyrrhiza glabra L. of the Leguminosae family. It is sweet and flat in taste. It enters the heart, lung, spleen and stomach meridians and has the effects of tonifying the spleen and replenishing qi, clearing away heat and detoxifying, removing phlegm and relieving cough, relieving acute pain and harmonizing various medicines.

[0032] Bombyx mori: The dried body of the 4th to 5th instar larvae of the silkworm Bombyx mori Linnaeus, an insect of the Bombyceae family, infected (or artificially inoculated) with Beauveria bassiana (Bals.) Vuillant, which killed the insect. It tastes salty, pungent, and neutral. It enters the liver, lung, and stomach meridians, and has the effects of calming wind and stopping spasms, dispelling wind and relieving pain, and resolving phlegm and dispersing nodules.

[0033] Trillium: It is the dried pseudobulb of Cremastra appendiculata (D.Don) Makino, Pleione bulbocodioides (Franch.) Rolfe or Pleione yunnanensis Rolfe of the orchid family. It tastes sweet, slightly spicy and cool. It enters the liver and spleen meridians and has the effects of clearing away heat, detoxifying, resolving phlegm and dispersing stagnation.

[0034] Nine-scented insect: It is the dried body of the insect Aspongopus chinensis Dallas of the family Pentatomidae. It tastes salty and warm. It enters the liver, spleen, and kidney meridians, and has the effects of regulating qi and relieving pain, warming the kidney and supporting yang.

[0035] Angelica sinensis: It is the dried root of Angelica sinensis (Oliv.) Diels, a plant of the Umbelliferae family. It is sweet, spicy and warm in taste. It enters the liver, heart and spleen meridians and has the effects of nourishing blood, regulating menstruation and relieving pain, and moistening the intestines and facilitating bowel movements.

[0036] Rehmannia glutinosa: It is the dried root of Rehmannia glutinosa Libosch., a plant of the Scrophulariaceae family. It is processed and made into a sweet, slightly warm product. It enters the liver and kidney meridians and has the effects of nourishing blood, nourishing yin, and replenishing essence and filling marrow.

[0037] The Chinese medicine composition for treating digestive tract polyps and digestive tract tumors of the present invention has been studied through network pharmacology, and the specific details of the mechanism of action, target and pathway are as follows:

[0038] Compared with the prior art, the present invention has the following advantages:

[0039] (1) The Chinese medicine composition of the present invention has low-cost raw materials, is simple to prepare, and is convenient to use. After many years of clinical application and pharmacological research, it has significant therapeutic effects in strengthening the spleen and replenishing qi, reducing swelling and dispersing nodules.

[0040] (2) The main compounds of the Chinese medicine composition of the present invention for treating gastrointestinal polyps are quercetin, kaempferol, β-sitosterol, etc. These compounds can participate in the regulation of signal pathways such as PI3K-Akt, MAPK, Ras, etc. through targets such as STAT3, HIF1A, IL6, TNF, etc., thereby exerting a therapeutic effect.

[0041] (3) The effective compounds of the Chinese medicine composition of the present invention for treating digestive tract tumors are kaempferol, quercetin, glycyrrhizin, licorice B, etc. These compounds can regulate key targets such as ESR1, ESR2, AR, etc. through signal pathways such as oxytocin and apelin, thereby playing an anti-cancer role, inhibiting cancer cell proliferation, regulating the immune system, etc.

[0042] (4) Through network pharmacology research and analysis, the research results obtained have certain reference value for guiding the clinical use of drugs to treat gastrointestinal polyps and gastrointestinal tumors, and provide more choices and discussion basis for clinical prescription and medication. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 A Venn diagram of potential therapeutic targets and disease targets of digestive tract polyps for the Chinese medicine composition in Example 1 of the present invention;

[0044] Figure 2 This is a protein-protein interaction network diagram of potential therapeutic targets of the Chinese medicine composition for treating digestive tract polyps in Example 1 of the present invention;

[0045] Figure 3 This is a target-pathway diagram of the Chinese medicine composition for treating digestive tract polyps in Example 1 of the present invention;

[0046] Figure 4 This is a potential core gene target map of the Chinese medicine composition for treating digestive tract polyps in Example 1 of the present invention;

[0047] Figure 5 This is a key target map of the Chinese medicine composition for treating digestive tract polyps in Example 1 of the present invention;

[0048] Figure 6 This is a gene map of important functional modules of the Chinese medicine composition for treating digestive tract polyps in Example 1 of the present invention;

[0049] Figure 7 This is a drug-active ingredient-potential target interaction network diagram of the Chinese medicine composition for treating digestive tract polyps in Example 1 of the present invention;

[0050] Figure 8 This is a GO function enrichment analysis diagram of potential therapeutic targets for the Chinese medicine composition for treating digestive tract polyps in Example 1 of the present invention;

[0051] Fig. 9 This is a KEGG pathway enrichment analysis diagram of potential therapeutic targets for the Chinese medicine composition for treating digestive tract polyps in Example 1 of the present invention;

[0052] Fig.10 This is a disease-pathway-drug-active ingredient-potential target interaction network diagram of the Chinese medicine composition for treating digestive tract polyps in Example 1 of the present invention;

[0053] Fig.11 This is a target map of the main compounds and important modules of the Chinese medicine composition for treating digestive tract tumors in Example 2 of the present invention (A represents subcluster A, and B represents subcluster B);

[0054] Fig.12 This is the gene map of the important disease modules of the Chinese medicine composition for treating digestive tract tumors in Example 2 of the present invention;

[0055] Fig.13 A Venn diagram of potential therapeutic targets and disease targets of digestive tract tumors for the Chinese medicine composition of Example 2 of the present invention;

[0056] Fig.14 This is a protein-protein interaction network diagram of potential therapeutic targets of the Chinese medicine composition for treating digestive tract tumors in Example 2 of the present invention;

[0057] Fig.15 This is a map of 149 target genes for the Chinese medicine composition for treating digestive tract tumors in Example 2 of the present invention;

[0058] Fig.16 This is a core gene target map of the Chinese medicine composition for treating digestive tract tumors in Example 2 of the present invention;

[0059] Fig.17 This is a GO function enrichment analysis diagram of potential therapeutic targets of the Chinese medicine composition for treating digestive tract tumors in Example 2 of the present invention;

[0060] Fig.18 This is a KEGG pathway enrichment analysis diagram of potential therapeutic targets for the Chinese medicine composition for treating digestive tract tumors in Example 2 of the present invention;

[0061] Fig.19 This is a schematic diagram of the “traditional Chinese medicine-compound-target-pathway” network of the traditional Chinese medicine composition for treating digestive tract tumors in Example 2 of the present invention;

[0062] Fig. 20 This is a schematic diagram of the docking of the core compound and key target molecule of the Chinese medicine composition for treating digestive tract tumors in Example 2 of the present invention (wherein Fig. 20 A is the binding mode of ESR1-glyasperin-B, Fig. 20 B is the binding mode of ESR2-(R)-naringenin, Fig. 20 C is the binding mode of NOS2-Quercetin, Fig. 20 D is the binding mode of AR-(R)-naringenin, Fig. 20 E is the binding mode of PTGS2-(R)-naringenin);

[0063] Fig.21This is a diagram showing the interaction between the small molecule glyasperin-B and the ESR1 protein in the treatment of digestive tract tumors by the Chinese medicine composition of Example 2 of the present invention;

[0064] Fig. 22 This is the RMSD graph of the small molecule glyasperin-B and the ESR1 protein for treating digestive tract tumors with the Chinese medicine composition of Example 2 of the present invention;

[0065] Fig.23 This is the RMSF graph of the small molecule glyasperin-B and ESR1 protein of the Chinese medicine composition in Example 2 of the present invention for treating digestive tract tumors. DETAILED DESCRIPTION

[0066] In order to make the above-mentioned objects, features and advantages of the present invention more obvious and easy to understand, the specific embodiments of the present invention are described in detail below in conjunction with the accompanying drawings. In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention can be implemented in many other ways different from those described herein, and those skilled in the art can make similar improvements without violating the connotation of the present invention, so the present invention is not limited by the specific embodiments disclosed below.

[0067] Example 1 Network pharmacology experiment related to the treatment of digestive tract polyps with Chinese medicine composition

[0068] 1.1 Screening of effective ingredients for Chinese medicine composition in treating digestive tract polyps

[0069] The active ingredients of the drugs were retrieved using the TCMSP, a database and analysis platform for Chinese medicine system pharmacology. Oral bioavailability (OB) reflects the absorption, distribution, metabolism, and excretion of drugs, and drug-likeness (DL) reflects the similarity of compounds to known drug molecules. With OB ≥ 30% and DL ≥ 0.18 as screening conditions, the active ingredients of 16 Chinese medicines in the Chinese medicine composition of the present invention were obtained; in addition, TCMID, SymMap, and BATMAN-TCM were used as supplementary databases.

[0070] A total of 203 active ingredients of the Chinese medicine composition of the present invention were retrieved from databases such as TCMSP, TCMID, SymMap and BATMAN-TCM (2 Radix Rehmanniae, 2 Semen Mustardae, 10 Radix Aconiti Lateralis, 5 Dried Ginger, 8 Plums Mume, 5 Zanthoxylum Bunge, 17 Codonopsis Pilosula, 2 Angelicae Sinensis, 2 Bombyx Batryticatus, 13 Leech, 2 Rhizoma Cibotii, 2 Tripterygium wilfordii, 8 Olibanum, 36 Myrrha, 4 Atractylodes macrocephala, and 85 Licorice). According to the OB value, the top 5 active ingredients of each medicine are listed (the active ingredients with score cutoff=20 and Adjusted P-value<0.05 are collected for leech and Rhizoma Cibotii), as shown in Table 1.

[0071] Table 1 Active ingredients of the Chinese medicine composition for digestive tract polyps

[0072]

[0073]

[0074]

[0075] 1.2 Chinese medicine composition and prediction of digestive tract polyp disease targets

[0076] The SMILES structure of the active ingredient of the Chinese medicine composition of the present invention was searched in PubChem, and the corresponding targets were searched in Swiss TargetPrediction, and the targets with "Probability>0.1" were retained; Leeches and schizonts were not included in the TCMSP database, and the corresponding targets were obtained through the BATMAN-TCM database. The targets of digestive tract polyps were searched in the GengCards database, and the targets with "score≥6.5" were retained.

[0077] A total of 1,161 targets were retrieved from PubChem, Swiss Target Prediction and BATMAN-TCM databases; 578 gastrointestinal polyp targets were retrieved from GengCard database.

[0078] 1.3 Potential targets of Chinese herbal medicine compositions for the treatment of digestive tract polyps

[0079] The drugs and disease targets were mapped in Venny2.1.0, the potential targets of the Chinese medicine composition of the present invention for treating gastrointestinal polyps were screened out, and a Venn diagram was drawn; using the STRING platform, "multiple proteins" were selected, potential targets were imported, the potential target interaction network diagram was obtained, TSV data was obtained, and visualization analysis was performed using Cytoscape software.

[0080] 1161 drug targets and 578 disease genes were mapped in Venny2.1.0, and 144 potential targets for the Chinese medicine composition of the present invention to treat digestive tract polyps were screened out. Figure 1 The PPI interaction network of potential therapeutic targets was obtained in the STRING platform. Figure 2 Visualized in Cytoscape 3.10.2, containing 144 nodes and 3485 edges, see Figure 3 The larger the node area in the figure, the greater the node connectivity. The top 10 targets are screened out, see Figure 4The top 10 core targets (STAT3, HIF1A, IL6, TNF, MMP9, ALB, BCL2, AKT1, PTGS2, and INS) were determined using the MCC algorithm in the CytoHubba plugin. Figure 5 The MCODE plug-in was used to screen important modules for 144 potential targets: 3 different subclusters were obtained, mainly in subcluster A (score 51.094, including 65 nodes and 1635 edges), see Figure 6 .

[0081] 1.4 Construction of drug-active ingredient-potential target interaction network diagram

[0082] The Cytoscape platform was used to construct a drug-active ingredient-potential target interaction network diagram, which includes 327 nodes and 2021 edges. The larger the area of ​​the node, the stronger the correlation and the more important the node is. Figure 7 (The squares in the figure represent each Chinese medicine, the V-shapes represent the active ingredients of each Chinese medicine, and the circles represent potential targets.) The top five active ingredients in terms of target number are quercetin, kaempferol, beta-sitosterol, (2R)-5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one, and glyasperin B, as shown in Table 2.

[0083] Table 2 Information on the top 5 active ingredients in the degree ranking of traditional Chinese medicine compositions

[0084]

[0085] 1.5 Functional analysis of potential targets

[0086] GO biological function enrichment analysis and KEGG pathway enrichment analysis were performed on potential targets in the DAVID database to obtain GO biological process (BP), cellular component (CC) and molecular function (MF) data. "FDR < 0.05" was used as the screening condition, and the top 10 GO biological functions and the top 25 KEGG signaling pathways enrichment results arranged from small to large by FDR were presented in the form of bubble charts.

[0087] GO functional enrichment analysis was performed on 144 potential therapeutic targets in DAVID, and a total of 220 entries were obtained, of which BP, CC and MF were involved in 161, 12 and 47 entries respectively. According to the FDR value, the top 10 BP, MF and CC were drawn into bubble charts for analysis, see Figure 8 In terms of BP, it includes phosphorylation, positive regulation of phosphatidylinositol 3-kinase / protein kinase B signal transduction, protein autophosphorylation, development of multicellular organisms, positive regulation of kinase activity, etc. In CC, it involves receptor complexes, transcriptional regulatory complexes, extracellular matrix, late endosomes, pseudoplatforms, phosphatidylinositol 3-kinase complexes, etc. In terms of MF, it involves ATP binding, protein tyrosine kinase activity, protein serine kinase activity, protein serine / threonine kinase activity, transmembrane receptor protein tyrosine kinase activity, heme binding, etc.

[0088] Through KEGG pathway analysis of 144 potential targets, it was found that there were 156 related pathways. According to the FDR value, the top 25 pathways were selected for analysis in the bubble chart. Fig. 9 The size of the node indicates the number of targets enriched. The larger the node, the more targets are significantly enriched in the pathway. The horizontal axis indicates the enrichment factor. A high enrichment factor means that among all potential targets, more targets are enriched in the pathway. The FDR values ​​of PI3K-Akt signaling pathway, MAPK signaling pathway, Ras signaling pathway, and EGFR tyrosine kinase inhibitor resistance are low and statistically significant.

[0089] 1.6 Construction of disease-pathway-drug-active ingredient-potential target interaction network diagram

[0090] The Cytoscape platform was used to construct a disease-pathway-drug-active ingredient-potential target interaction network diagram. The 203 main active ingredients, 144 potential therapeutic targets and the top 25 pathways closely related to the mechanism of action of the Chinese medicine composition of the present invention were integrated and analyzed in Cytoscape to construct a disease-pathway-drug-active ingredient-potential target interaction network diagram, such as Fig.10 (In the figure, the diamond represents the disease, the V shape represents the pathway, the square represents each Chinese medicine, the triangle represents the active ingredient of each Chinese medicine, and the circle represents the potential target). It can be seen that the active ingredients of the drug can exert their effects through multiple targets and multiple pathways, and the targets and pathways coordinate and influence each other.

[0091] 1.7 Network pharmacology analysis of Chinese medicine combination in the treatment of digestive tract polyps

[0092] A total of 203 effective active ingredients of the Chinese medicine composition of the present invention were screened out by network pharmacology methods, and quercetin, kaempferol, β-sitosterol, etc. were found to be the main ingredients. Studies have shown that quercetin has a significant down-regulating effect on TNF-α, IFN-γ, IL-6, IL-17 levels and STAT3 phosphorylation in the serum of mice with colitis-related colon cancer, suggesting that quercetin may reduce inflammation and play an anti-inflammatory role by down-regulating the activity of the IL-6 / STAT3 signaling pathway. Further studies have found that β-sitosterol can inhibit the activation of inflammasome nucleotide binding oligomerization domain-like receptor protein 3 (NLRP3) in epidermal cells and macrophages, thereby inhibiting the production of cysteine ​​protease-1 (CAS1) and the activation of the MAPK signaling pathway, reducing the expression of inflammatory factors in cells, and achieving the purpose of anti-inflammatory. Kaempferol can inhibit vascular endothelial cells induced by VEGF by regulating vascular endothelial growth factor (VEGF) / vascular endothelial growth factor receptor 2 (VEGFR-2) and its downstream PI3K / AKT, mitogen-activated extracellular signal-regulated kinase (MEK) / extracellular regulated protein kinase (ERK) signaling pathways, inhibit angiogenesis, and prevent the development of gastrointestinal polyps. For the phenomenon of weight loss, diarrhea with mucus and blood, histological abnormalities, and shortened colon in ulcerative colitis model mice induced by dextran sulfate sodium (DSS), kaempferol can improve the intestinal barrier function by increasing ZO-1 expression, thereby playing a mitigating role and reducing the incidence of gastrointestinal polyps.

[0093] Through the visualization analysis of Cytoscape software, it was found that STAT3, HIF1A, IL6, TNF, etc. were its core genes. Wang et al. found that in colon cancer Caco-2 cells, the expression intensity of STAT3 was significantly correlated with the differentiation degree and prognosis of colon cancer tumors. Further studies also found that after blocking the activity of STAT3, the proliferation of colorectal cancer cells can be significantly inhibited, indicating that it is closely related to tumorigenesis. HIF1 mainly maintains its active state through HIFIA to regulate the oxygen balance and normal metabolism between tumors, and promote tumor proliferation and invasion and metastasis. Jiang Congqing et al. found that in the expression of HIFIA mRNA in two tissues, colorectal adenocarcinoma and colorectal adenoma, the former had a positive rate of 67.7%, which was much higher than the latter's expression rate of 38.9%, and the difference was statistically significant (p < 0.05), indicating that the large-scale expression of HIFIA plays a huge role in the sequence changes of adenoma eventually developing into adenocarcinoma. TNF is divided into TNF-α and TNF-β, which are mainly secreted by macrophages and can induce cell death in some tumor cell lines. TNF-α plays an important role in tissue damage and repair. When blood vessels are damaged, it can induce the expression of a variety of vascular growth factors. However, when high levels of TNF-α act on tumors, they can selectively destroy the vascular structure of tumor tissues and play an anti-tumor role. IL6 is a potent inducer of acute phase reactions, which can induce the proliferation and differentiation of B cells, as well as the proliferation and differentiation of cytotoxic T lymphocytes. It is closely related to tumors and thus inhibits the development of digestive tract polyps.

[0094] Enrichment analysis found that the Chinese medicine composition of the present invention is related to the PI3K-Akt, MAPK, Ras and other signaling pathways in the treatment of gastrointestinal polyps. The PI3K-AKT pathway is an intracellular signal transduction pathway that responds to extracellular signals and is an important pathway for regulating cell proliferation, apoptosis and migration. It is abnormally activated in colorectal cancer, and inhibiting its activation has been shown to inhibit growth signals and accelerate apoptosis and metabolism of tumor cells. Therefore, effective targeting of the PI3K-Akt signaling pathway is expected to become an important strategy for the prevention and treatment of gastrointestinal polyps. Studies have shown that the MAPK signaling pathway is involved in the entire process of UC pathogenesis, and inhibiting the MAPK pathway can significantly reduce the inflammatory response and cell apoptosis caused by UC. ERK1 / 2 and Mek1 / 2 are important subtypes in the MAPK and MAPK kinase systems, respectively, which can promote the proliferation and migration of intestinal mucosal epithelial cells and have the effect of repairing the intestinal mucosa. Abdel-Wahab et al. found that Ras protein inhibited the downstream signaling pathway PI3K / AKT / m TOR, promoted cell apoptosis, increased the expression of apoptotic factors Caspase-3 and Bax genes, and reduced the expression of anti-apoptotic factor Bcl-2. This shows the influence of Ras signaling pathway on the occurrence and progression of polyps.

[0095] Example 2 Network pharmacology experiment on Chinese medicine composition and treatment of digestive tract tumors

[0096] 2.1 Screening of effective ingredients in traditional Chinese medicine compositions for the treatment of digestive tract tumors

[0097] In the traditional Chinese medicine database TCMSP, the main compounds of the traditional Chinese medicine composition of the present invention were searched, and the compounds satisfying both OB≥30% and DL≥0.18 were retained; in addition, TCMID and BATMAN-TCM were used as supplementary databases.

[0098] A total of 219 main compounds of the Chinese medicine composition of the present invention were retrieved from the traditional Chinese medicine databases TCMSP, TCMID, and BATMAN-TCM (8 frankincense, 45 myrrh, 3 leeches, 21 aconites, 21 codonopsis, 5 zanthoxylum, 8 ebony, 5 dried ginger, 3 mustard seeds, 7 atractylodes, 92 liquorice, 2 bombyx batryticatus, 3 trillium, 2 schizonepeta, 2 angelica, 2 rehmannia glutinosa, a total of 219 after deduplication). According to the OB value of each medicine, the top 5 compounds are listed, as shown in Table 3.

[0099] Table 3 Active ingredients of Chinese medicine composition for digestive tract polyps

[0100]

[0101]

[0102] 2.2 Screening of targets for Chinese medicine compositions in the treatment of digestive tract tumors

[0103] The SMILES structures of the main compounds of the Chinese medicine composition of the present invention were searched in the PubChem database, and then imported into the Swiss Target Prediction database to search for the corresponding targets, and the targets with "Probability greater than or equal to 0.1" were retained; in addition, the TCMSP and BATMAN-TCM databases were used as supplements. Afterwards, the MCODE plug-in was used in the Cytoscape3.7.2 software to screen out important modules and visualize them.

[0104] The related targets of 219 main compounds of the Chinese medicine composition of the present invention were searched in PubChem, TCMSP and BATMAN-TCM databases, and 1161 related targets with high matching degree were retained after deduplication. Visualization was performed in Cytoscape 3.7.2 software, which contained 1106 nodes and 25222 edges. The important modules were screened using the MCODE plug-in: mainly located in subcluster A (score 46.364, containing 67 nodes, 1530 edges) and subcluster B (score 30.171, containing 83 nodes, 1237 edges), see Fig.11 .

[0105] 2.3 Collection of digestive tract tumor disease genes

[0106] In the GeneCards database, disease genes of gastrointestinal tumors were retrieved using "Homo sapiens" as the condition, and disease genes with "score greater than or equal to 15" were retained; and the MCODE plug-in was used in the Cytoscape 3.7.2 software to screen out important modules and visualize them.

[0107] 702 major disease genes of digestive tract tumors were retrieved from the GeneCards database and visualized in Cytoscape3.7.2 software, which contained 526 nodes and 24141 edges. The MCODE plug-in was used to screen important modules: they were mainly located in subcluster A (score 98.788, containing 133 nodes and 6520 edges), subcluster B (score 21.921, containing 77 nodes and 833 edges) and subcluster C (score 13.413, containing 76 nodes and 503 edges), see Fig.12 .

[0108] 2.4 Prediction of potential targets for Chinese herbal medicine combinations in the treatment of digestive tract tumors

[0109] The drug targets and disease genes were introduced into Venny2.1 for Wayne analysis to screen out potential therapeutic targets of the Chinese medicine composition of the present invention for treating digestive tract tumors; the PPI interaction network diagram of potential therapeutic targets was obtained in STRING; and it was visualized in Cytoscape3.7.2 software.

[0110] 1161 drug targets and 702 disease genes were introduced into Venny2.1 for Wayne analysis, and 149 potential therapeutic targets for the Chinese medicine composition of the present invention in treating digestive tract tumors were screened out. Fig.13 The PPI interaction network diagram of potential therapeutic targets was obtained in STRING, see Fig.14 Visualized in Cytoscape 3.7.2 software, containing 149 nodes and 4272 edges, see Fig.15 According to the node connectivity, the top 20 key targets are taken and plotted in a bar chart, as shown in Fig.16 .

[0111] 2.5 Functional analysis of potential therapeutic targets

[0112] GO and KEGG enrichment analysis were performed on the potential therapeutic targets of the Chinese medicine composition of the present invention for treating digestive tract tumors in the DAVID database, wherein the GO enrichment analysis included biological process BP, cellular component CC and molecular function MF, and the KEGG pathway enrichment analysis retained the entries with "FDR < 0.05".

[0113] The 149 potential therapeutic targets were imported into the DAVID database for GO functional analysis, and a total of 146 entries were obtained (BP 108, CC 12, MF 26). According to the FDR value, the top 10 BP, CC and MF were plotted into bubble charts for analysis, see Fig.17 In terms of BP, it involves the ErbB / HER signaling pathway, positive regulation of I-kB kinase / NF-kB signaling, positive regulation of interleukin-6 production, regulation of insulin secretion, cell response to ultraviolet A, positive regulation of endothelial cell proliferation, and extracellular matrix decomposition; in terms of CC, it involves transcription factor complexes, chromatin, chromosome telomeric regions, cyclin-dependent protein kinase holoenzyme complexes, extracellular matrix, Bcl-2 family protein complexes, and early endoplasmic bodies; in terms of MF, it involves insulin receptor binding, estrogen response element binding, steroid binding, fibroblast growth factor-activated receptor activity, chromatin binding, sequence-specific DNA binding, and SH2 domain binding.

[0114] 149 potential therapeutic targets were imported into the DAVID database for KEGG pathway enrichment analysis, and a total of 22 qualified pathways were obtained. These 22 pathways were drawn into bubble charts for visual analysis. Fig.18 These mainly include signaling pathways such as RIG-I-like receptor, B cell receptor, Insulin and AMPK.

[0115] 2.6 Construction of “TCM-compound-target-pathway” network

[0116] The 16 medicinal herbs, 219 main compounds, 149 relevant therapeutic targets for treating digestive tract tumors and 22 signal pathways closely related to the mechanism of action of the Chinese medicine composition of the present invention were integrated in Cytoscape 3.7.2 software to construct a multi-level interactive "Chinese medicine-compound-target-pathway" network diagram. It was found that the main compounds of the Chinese medicine composition of the present invention were distributed in various signal pathways and acted in coordination with each other. Fig.19 .

[0117] 2.7 Molecular docking

[0118] The key targets and core components were molecularly docked using AutoDockTools software. The protein crystal structure used for docking was downloaded from the PDB database. The 3D structure of the small molecule was constructed using Chem3D20.0 and energy minimized under the MMFF94 force field. The receptor protein was processed using PyMoL 2.5.52, including the removal of water molecules, salt ions and small molecules. The docking box was then set to wrap the entire protein structure. In addition, all processed small molecules and receptor proteins were converted to PDBQT format using ADFRsuite 1.03. Finally, molecular docking was completed using Autodock vina 1.1.2. The docking results were visualized using PyMol 2.5.5 and Discovery Studio Visualizer.

[0119] After topological analysis of the network, the top five core compounds and key targets were screened for molecular docking. The energy involved in the process of two molecules combining to form a stable conformation is low, indicating that the possibility of interaction between them is high. If the binding energy is lower than the threshold of -2.0 kcal / mol, it is considered to prove that the two molecules can bind, and if it is lower than the threshold of -7.0 kcal / mol, it can be considered that the two are tightly bound, and the latter is used as the screening condition. The molecular docking results show that the binding energy of the core compounds of the Chinese medicine composition of the present invention and the key targets is mostly less than -7.0 kcal / mol, indicating that the core compounds have a high binding ability with the key targets, as shown in Table 4.

[0120] Table 4 Molecular docking binding energy

[0121]

[0122] Five docking combinations, ESR1-glyasperin-B (-9.217 kcal / mol), ESR2-(R)-naringenin (-8.883 kcal / mol), NOS2-Quercetin (-9.206 kcal / mol), AR-(R)-naringenin (-8.58 kcal / mol), and PTGS2-(R)-naringenin (-8.377 kcal / mol), were selected to draw docking models, corresponding to Fig. 20 A, B, C, D, E, see Fig. 20 The interaction between the five docking groups is mainly through hydrogen bonds, the length of which is between 1 and Not waiting. Fig. 20A is the binding mode of ESR1-glyasperin-B. Glyasperin-B forms a hydrogen bond with ARG-394 and THR-347 respectively, and its length is and Fig. 20 B is the binding mode of ESR2-(R)-naringenin. (R)-naringenin forms a hydrogen bond with ARG-346 and LEU-339, respectively, with lengths of and Fig. 20 C is the binding mode of NOS2-Quercetin. Quercetin forms a hydrogen bond with ASP-382, TRP-346, GLY-371, and VAL-352, respectively, with lengths of Fig. 20 D is the binding mode of AR-(R)-naringenin. (R)-naringenin forms a hydrogen bond with ARG-752 and ASN-705, respectively, with lengths of Fig. 20 E is the binding mode of PTGS2-(R)-naringenin. (R)-naringenin forms a hydrogen bond with SER-530 and MET-522, respectively, with lengths of

[0123] 2.8 Molecular dynamics simulation

[0124] The small molecule and protein complex obtained by docking were used as the initial structure for all-atom molecular dynamics simulations, and the simulations were performed using AMBER 22 software. Before the simulation, the charge of the small molecule was calculated using the antechamber module and the Hartree-Fock (HF) SCF / 6-31G* of the gaussian 09 software. Afterwards, the small molecule and protein were described using the GAFF2 small molecule force field and the ff14SB protein force field, respectively. Each system used the LEaP module to add hydrogen atoms to the system. Add a truncated octahedral TIP3P solvent box at a distance of 1.5 m and add Na + / Cl - Used to balance the system charge and finally output the topology and parameter files for simulation.

[0125] The molecular dynamics simulation was performed using AMBER 22 software. Before the simulation, the system was energy optimized, including 2500 steps of the steepest descent method and 2500 steps of the conjugate gradient method. After the system energy optimization was completed, the system was heated for 200ps at a fixed volume and constant heating rate to slowly increase the system temperature from 0K to 298.15K. While maintaining the system temperature at 298.15K, a 500ps NVT (isothermal isobaric) system simulation was performed to make the solvent molecules more evenly distributed in the solvent box. Finally, under the NPT (isothermal and isobaric) condition, the entire system was subjected to a 500ps equilibrium simulation. Finally, the two composite systems were subjected to 100ns NPT (isothermal and isobaric) system simulations under periodic boundary conditions. During the simulation, the non-bonded cutoff distance was set to The particle mesh Ewald (PME) method was used to calculate the long-range electrostatic interaction, the SHAKE method was used to limit the hydrogen atom bond length, and the Langevin algorithm was used for temperature control, where the collision frequency γ was set to 2ps. -1 The system pressure was 1 atm, the integration step was 2 fs, and the trajectory was saved every 10 ps for subsequent analysis.

[0126] like Fig.21 As shown, glyasperin-B forms a hydrogen bond with LEU-387 on the ESR1 protein, and the formation of hydrogen bonds makes the protein and small molecules bind more tightly. In addition, glyasperin-B also forms hydrophobic interactions with LEU-391, VAL-533, PHE-404, LEU-349, LEU-384, LEU-525, TRP-383, and ALA-350, providing strong van der Waals energy for the molecule.

[0127] The root mean square deviation of molecular dynamics simulation can reflect the movement process of the complex. The larger the RMSD and the more violent the fluctuation, the more violent the movement. On the contrary, the movement is stable. Fig. 22 As shown in the figure, there is no large RMSD fluctuation during the protein simulation, which means that the protein structure has not collapsed, providing a basis for the binding of small molecules; the RMSD of small molecules reaches stable fluctuations in the early stage of the simulation, and fluctuates stably in the range of 0-1 angstroms (very small). This shows that the small molecule binds very closely to the protein and the binding stability of the small molecule is very good.

[0128] RMSF can reflect the flexibility of proteins during molecular dynamics simulation. Usually, after drugs bind to proteins, the flexibility of proteins decreases, thereby stabilizing the proteins and exerting the enzyme activity. Fig.23 As shown, except for the local region of the protein, the RMSF of the protein is within 2 angstroms, indicating that the main structure of the protein is very rigid, which may be achieved by combining with the small molecule glyasperin-B.

[0129] 2.9MMGBSA binding free energy calculation

[0130] Directly calculate the binding free energy, that is, calculate the energy of the receptor, ligand and their complex in the solution separately and take the difference. However, in actual calculations, the energy contribution mainly comes from the interaction between solutions, and the fluctuation amplitude of the total energy is much larger than the binding energy, and it takes a very long time to converge. The MM / GBSA method has the advantages of both accuracy and speed, and is widely used in the calculation of receptor-ligand binding free energy. Therefore, the MM / GBSA method is used here to calculate the binding free energy, that is, to split the binding free energy into molecular mechanics terms and solvation free energy and calculate them separately. In this study, 90-100ns MD trajectories were used for calculation, and the specific formula is as follows:

[0131] ΔG bind =ΔG complex -(ΔG receptor +ΔG ligand )

[0132] =ΔE internal +△E VDW +△E elec +△G GB +ΔG SA

[0133] In the above formula, ΔE internal represents internal energy, ΔE VDW represents the van der Waals interaction, ΔE elec represents electrostatic interaction, and these three constitute the molecular mechanics term. The internal energy includes bond energy (Ebond), angular energy (Eangle), and torsion energy (Etorsion); ΔG GB and ΔG GA Collectively referred to as solvation free energy. Among them, GGB is polar solvation free energy and GSA is non-polar solvation free energy. GB In this paper, the GB model developed by Nguyen et al. is used for calculation (igb = 2). The nonpolar solvation free energy (ΔGSA) is calculated based on the product of surface tension (γ) and solvent accessible surface area (surface area, SA), ΔGSA = 0.0072 × ΔSASA. Entropy change is ignored in this study due to its high computational resource consumption and low precision.

[0134] Based on the trajectory of molecular dynamics simulation, we used the MM-GBSA method to calculate the binding energy, which can more accurately reflect the binding effect of small molecules and target proteins. As shown in Table 5, the binding energy of ESR1_glyasperin-B is -47.47±3.50kcal / mol. A negative value indicates that the two molecules have binding affinity with the target protein, and the lower the value, the stronger the binding. Obviously, our calculations show that the binding affinity of ESR1_glyasperin-B is very strong. Through residue decomposition, we can see that the main contribution to the binding of ESR1_glyasperin-B is van der Waals energy, followed by electrostatic energy, and then non-polar solvation free energy.

[0135] Table 5 Binding free energy and energy components predicted by MM / GBSA

[0136]

[0137] Note: ΔE vdW :Van der Waals energy

[0138] ΔE elec :Electrostatic energy.

[0139] ΔG GB : Polar solvation free energy.

[0140] ΔG SA : Nonpolar solvation free energy

[0141] ΔG bind : Binding free energy

[0142] 2.10 Network pharmacology analysis of Chinese medicine combination in the treatment of digestive tract tumors

[0143] A total of 219 main compounds of the Chinese medicine composition of the present invention were screened by network pharmacology, among which kaempferol, quercetin, glabridin, pubescent licorice B, (R)-naringenin, galangin, isorhamnetin-3-O-neohesperidoside, etc. are its core compounds. Kaempferol has a similar chemical structure to quercetin, and can be anti-tumor, anti-oxidant, anti-osteoporotic, anti-fertility, hypoglycemic, etc., and is mostly used in clinical diseases such as digestive tract tumors. Glabridin has anti-tumor, anti-inflammatory, antioxidant and other effects and regulatory activities of multiple signal pathways; it inhibits the migration, invasion and proliferation of colon cancer cells through the PI3K-AKT-m TOR pathway, induces apoptosis, and has significant therapeutic effects without obvious side effects; it can also inhibit the proliferation, invasion and migration of esophageal cancer cells, and promote apoptosis. Pubescent licorice B has a significant improvement effect on liver damage and fibrosis in mice with liver fibrosis induced by dimethylnitrosamine. However, there are few studies on the effects of (R)-naringenin, naringenin, and isorhamnetin-3-O-neohesperidoside on gastrointestinal tumors.

[0144] The protein-protein interaction network diagram of the Chinese medicine composition of the present invention for treating digestive tract tumors was constructed by Cytoscape3.7.2 software, and ESR1, ESR2, AR, PTGS2, NOS2, PTGS1, EGFR, GSK3B, CDK2, PPARG, etc. were found to be its key targets. Related studies have shown that ESR1 can inhibit inflammatory signals by selectively activating pro-apoptotic signals mediated by estrogen receptor β. Most components on the ESR1, ESR2, and AR targets can directly exert anti-tumor effects, and abnormalities in the AR signaling pathway are associated with the development of a variety of tumors. PTGS2 is an effective enzyme responsible for inflammatory response. Inhibition of PTGS2 can reduce the occurrence and expansion of inflammatory response, and PTGS2 can promote tumor formation. PTGS1 is also closely related to tumors. NOS2 has the effect of inhibiting tumor growth, proliferation, metastasis, and angiogenesis.

[0145] According to the analysis of GO and KEGG enrichment results, it can be found that the mechanism of action of the Chinese medicine composition of the present invention in treating digestive tract tumors mainly includes anti-cancer, inhibition of cancer cell proliferation, and regulation of the immune system. ERBB2 and ERBB3 receptors belong to the HER family. Studies have shown that abnormal activation of HER kinase activity will lead to the occurrence and progression of various tumors and is closely related to tumor resistance. Among them, ERBB2 is a high-affinity co-receptor, which can be activated by forming homodimers when the gene mutates or amplifies. The tyrosine kinase abnormality of ERBB3, due to its unique structure and unique ability to activate downstream signaling pathways, has become a key node in the complex signaling network of various tumors; ERBB3 is commonly found in cancers such as gastric cancer, colon cancer, and pancreatic cancer. Although it lacks kinase activity, it can still bind to other receptors in the same family to induce tumor cell proliferation, invasion, and drug resistance. FcγR includes FcγRIIIA (CD16a), FcγRIIIB (CD16b), FcγRIIA (CD32a), FcγRIIB (CD32b), and FcγRI (CD64). FcγR-positive cells include monocytes, NK cells, neutrophils, and macrophages. Antigen-presenting cells phagocytize, recognize, and present tumor-specific antigens to downstream immune cells, which is an important step in activating anti-tumor immunity. The apelin signaling pathway is involved in physiological processes such as cell proliferation and angiogenesis, and plays an important role in the occurrence and development of tumors. When the endogenous neuropeptide apeli is overexpressed in tumor tissues, it can be used as a tumor marker. The oxytocin signaling pathway is related to inflammation and neurotransmission. Oxytocin can not only act as an anti-inflammatory factor, but also act as a neuropeptide to regulate mood disorders.

[0146] The molecular docking results show that the core components (kaempferol, quercetin, glabridin, pubescent licorice B, etc.) of the Chinese medicine composition of the present invention for treating digestive tract tumors have a high degree of binding with key targets such as ESR1, ESR2, AR, PTGS2, and NOS2. Therefore, the Chinese medicine composition of the present invention may mainly treat digestive tract tumors through kaempferol, quercetin, glabridin, and pubescent licorice B.

[0147] In the molecular dynamics simulation, it can be seen that the RMSD of the small molecule reaches stable fluctuations in the early stage of the simulation, and fluctuates stably in the range of 0-1 angstroms (very small). Except for the local area of ​​the protein, the RMSF of the protein is within 2 angstroms. The binding energy of ESR1_glyasperin-B is -47.47±3.50kcal / mol, and the main contribution to the binding is van der Waals energy, followed by electrostatic energy, and then non-polar solvation free energy. After analysis, it is shown that ESR1 is closely bound to glyasperin-B and has good stability. ESR1 is very rigid after binding, which may be the effect achieved by combining with the small molecule glyasperin-B. The affinity between the small molecule and the protein is very strong, which is consistent with the molecular docking results.

[0148] Example 3 Practical clinical application of Chinese medicine composition in treating digestive tract polyps and digestive tract tumors

[0149] Digestive tract polyp case 1:

[0150] Zuo, female, 32 years old, first visit to the outpatient clinic on October 13, 2023. She reported that she had found gastric polyps for more than 2 months. Examination: Gastroscopy (Beijing Hospital on August 17, 2023): A polyp of about 0.4 cm was found on the anterior wall of the upper part of the stomach body, chronic non-atrophic gastritis; Colonoscopy (Beijing Hospital on August 17, 2023): No abnormalities were found. Family history: Grandfather had small cell lung cancer and was undergoing chemotherapy. Current symptoms: impatience and irritability, easy oral ulcers, like to drink water, poor appetite, conscious abdominal distension, aggravated after eating, chills in the lower limbs, especially in winter, poor sleep and easy awakening, yellow urine, one bowel movement per day, loose stools. The Chinese medicine doctor gave this compound preparation for oral administration, including 20g of Rehmannia glutinosa, 15g of mustard seeds, 6g of aconite, 9g of dried ginger, 20g of black plum, 20g of Sichuan pepper, 15g of Codonopsis pilosula, 15g of Angelica sinensis, 9g of Bombyx batryticatus, 6g of Leech, 10g of Nine-scented Wormwood, 10g of Trillium, 10g of Frankincense, 10g of Myrrh, 10g of Atractylodes macrocephala, 6g of Licorice, 15g of Aucklandia lappa, 5g of Amomum villosum, and 15g of Tangerine peel. One dose per day, divided into morning and evening. After taking this medicine for 2 weeks, the patient's symptoms such as abdominal distension, loose stools, poor sleep and easy awakening were significantly improved. After regular follow-up visits, the addition and subtraction of Chinese medicine were adjusted according to the symptoms, and the follow-up was 3 months. Post-examination: Gastroscopy (2024-10-30): No obvious abnormalities were found. The patient's gastrointestinal symptoms were significantly improved, and the symptoms such as bloating, poor appetite, poor sleep, and cold lower limbs disappeared, and the mood was comfortable and the bowel movements were regulated. Gastroscopy showed no abnormalities such as polyps. The subsequent outpatient follow-up was based on the original prescription with additions and subtractions.

[0151] Digestive tract polyp case 2:

[0152] Wang, female, 53 years old, first visited the outpatient clinic on September 27, 2024. She reported that she had left breast cancer surgery (modified radical mastectomy of left breast cancer under laparoscopy at Beijing Anzhen Hospital Affiliated to Capital Medical University on September 8, 2021; postoperative pathology: invasive breast cancer), 8 chemotherapy sessions after surgery, and regular follow-up. Her condition was stable, with no obvious signs of recurrence or metastasis. She is currently undergoing endocrine treatment. The colonoscopy report of the Affiliated Hospital of Chengde Medical College on June 8, 2023 showed: A 0.2×0.3cm polyp was found in the liver area near the ascending colon; pathology showed chronic inflammation of the mucosa, and the glands in the focal area showed adenomatous (grade I) hyperplasia. The colonoscopy review report of the Affiliated Hospital of Chengde Medical College on August 2, 2023 showed: A 0.6×0.6cm Yamada II type polyp was found 18cm away from the anus. Family history: Father died of cirrhosis and mother died of intestinal cancer. The patient's main clinical manifestations are fatigue, tinnitus, poor appetite, acid reflux and heartburn, numbness of hands and feet, slightly poor sleep, normal urination, bowel movements every 2-3 days, and alternating dry and loose stools. The Chinese medicine doctor gave this compound preparation with additions and subtractions for oral administration, including 20g of Rehmannia glutinosa, 15g of mustard seeds, 6g of aconite, 9g of dried ginger, 20g of black plum, 20g of Sichuan pepper, 15g of Codonopsis pilosula, 15g of Angelica sinensis, 9g of Bombyx batryticatus, 6g of leech, 10g of nine-scented insect, 10g of Trillium, 10g of frankincense, 10g of myrrh, 10g of Atractylodes macrocephala, 6g of licorice, 2g of scorpion, 12g of Poria, and 10g of Corydalis yanhusuo, one dose per day, divided into morning and evening. After taking this medicine for 3 weeks, the patient's gastrointestinal symptoms such as hiccups and acid reflux and heartburn were significantly improved. After intermittent follow-up visits, the addition and subtraction of Chinese medicine was adjusted according to the symptoms. After 3 months of follow-up, all symptoms improved. Examination: Colonoscopy (Wangjing Hospital, 2024-11-7) showed no obvious abnormalities in the terminal ileum and the large intestinal mucosa. The patient's anorexia, hiccups, acid reflux and heartburn disappeared, fatigue and tinnitus were alleviated, numbness of hands and feet improved, and bowel movements returned to normal, with one bowel movement every 1-2 days. After the follow-up visit, the prescription was modified based on this prescription.

[0153] Digestive tract tumor case 1:

[0154] Ren, male, 74 years old, first visited the outpatient clinic on January 15, 2024. He reported that he had undergone gastric cancer surgery (laparoscopic-assisted radical gastrectomy in the First Department of General Surgery of China-Japan Friendship Hospital on June 24, 2020; postoperative pathology: poorly differentiated adenocarcinoma; stage: pT2N0M0) for more than 3 years after surgery. He took oral S-1 chemotherapy for 2 cycles after surgery, and then took S-1 (40 mg, po, bid, d1-14) combined with injection of oxaliplatin (100 mg, d8) Q21 chemotherapy for 5 cycles. Regular follow-up afterwards. The main clinical manifestations were intermittent epigastric pain, general fatigue, poor appetite, poor sleep and easy awakening, normal urination, loose stools, about 5-6 times a day, and a weight loss of 10 kg since the onset of the disease. The tongue was dark, thick and greasy with white fur, and the right pulse was thin and the left pulse was deep and stringy. Specialist examination: KPS score 60 points, NRS score 3 points. Examination: Postoperative pathology (China-Japan Friendship Hospital, June 24, 2020): (stomach) poorly differentiated adenocarcinoma (size 2.5*2*0.8), invading the superficial muscle layer; bilateral stumps were clean, without involving the greater omentum, vascular tumor thrombus was visible, no clear nerve invasion was seen, no metastatic cancer was found in the lymph nodes 0 / 12 (0 / 6 lymph nodes on the lesser curvature, 0 / 6 lymph nodes on the greater curvature); moderate chronic inflammation of the surrounding gastric mucosa, mild intestinal metaplasia, lymphoid follicle formation, and high-grade intraepithelial neoplasia were seen. Immunohistochemistry results: CgA (-), CEA (+), CK7 (-), Syn (-), CD56 (-), KI67 (MIB-1) 30%, CD31 (+), CD34 (+), D2-40 (+); special staining results: AB-PAS (focus +), D-PAS (focus +). (2024-1-14, our hospital) Abdominal CT scan: reexamination after radical surgery for gastric cancer, compared with the previous: intrahepatic calcification, left kidney low-density lesions, prostate calcification, roughly the same as the previous film, other changes are not significant. (2024-1-14, our hospital) 8 cytokine tests, five thyroid function tests: no obvious abnormalities. Tumor markers: serum ferritin 15.42ng / ml↓, cytokeratin 19 fragment 6.22ng / ml↑; biochemistry: prealbumin 0.15g / L↓; blood routine: hemoglobin determination 104g / L↓, red blood cell count 3.96*101 / L↓, hematocrit 32.9%↓, mean corpuscular hemoglobin content 26.3pg↓, mean corpuscular hemoglobin concentration 316g / L↓, red blood cell distribution width coefficient of variation 15.9%↑. The Chinese medicine doctor gave the compound preparation with additions and subtractions for oral administration, including 20g of Rehmannia glutinosa, 15g of mustard seeds, 3g of cinnamon bark, 6g of aconite root, 9g of dried ginger, 15g of Codonopsis pilosula, 15g of Angelica sinensis, 9g of Bombyx batryticatus, 10g of Nine-scented Wormwood, 10g of Trillium, 10g of Frankincense, 10g of Myrrh, 10g of Atractylodes macrocephala, 6g of Licorice, 15g of Mother of Pearl, and 3g of Aquilaria sinensis, one dose per day, divided into morning and evening. After taking the medicine for 2 weeks, the patient's symptoms such as fatigue, poor sleep and frequent bowel movements were significantly improved. Afterwards, the Chinese medicine additions and subtractions were adjusted according to the symptoms at regular follow-up visits, and the follow-up was 2 months.Examination: (2024-4-24, our hospital) Tumor markers: serum ferritin 17.5ng / ml↓, cytokeratin 19 fragment 4.06ng / ml↑; biochemistry: prealbumin 0.15g / L↓; blood routine: hemoglobin determination 108g / L↓, red blood cell count 4.16*101 / L↓, hematocrit 34.2%↓, mean corpuscular hemoglobin content 26pg↓, red blood cell distribution width variation coefficient 15.7%↑, no other abnormalities. The patient's fatigue improved significantly, poor sleep, epigastric pain and discomfort and other symptoms basically disappeared, and bowel movements were normal. KPS score 80 points, NRS score 1 point, hemoglobin determination, red blood cell count and other indicators increased, and tumor marker cytokeratin 19 fragment decreased. After regular follow-up visits, the prescription was added and subtracted based on the taste until now. On November 18, 2024, Wangjing Hospital gastroscopy annual review: anastomotic stomatitis, no polyps and other abnormalities.

[0155] Digestive tract tumor case 2:

[0156] Zhang, female, 55 years old, first visited the outpatient clinic on March 26, 2024. She reported rectal cancer (rectal + right appendix + omentectomy at Ditan Hospital on January 12, 2022; postoperative pathology: moderately differentiated adenocarcinoma; stage: ypT3N1M1 IV stage) more than 2 years after surgery. She underwent 2 cycles of XELOX chemotherapy before surgery, 6 cycles of intraperitoneal hyperthermic perfusion chemotherapy after surgery, and 6 cycles of XELOX (Xeloda 1500mg bid d1-14 + OHP 150mg) + Avastin300mg from 2022-2-16 to 2022-5-30. The efficacy evaluation was SD after the 2nd and 4th cycles. After regular follow-up, the condition was stable and no obvious signs of recurrence were found. The main clinical manifestations were fatigue, shortness of breath, general appetite, normal urination, constipation, and general sleep. The tongue was pale, greasy and slightly yellow, and the pulse was stringy and slippery. Specialist examination: KPS score 70 points, NRS score 3 points. Examination: Postoperative pathology (Ditan Hospital, 2022-1-12): moderately differentiated adenocarcinoma of the rectum, right appendages and appendix, cancer tissue penetrated the muscle layer to the subserous fat layer, involved the ovary, did not accumulate the fallopian tube and appendix, intravascular cancer thrombus and nerve invasion were seen; surgical margins on both sides of the intestinal tube, circumferential margins, appendix margins and fallopian tube margins showed no cancer: fallopian tube cysts, periintestinal lymph nodes (1 / 17), and another cancer nodule. No cancer was found in the greater omentum. Pathological stage pT3N1M1IV stage. Immunohistochemistry results: IHC: CDX-2 (+), CEA (+), AE1 / AE3 (+), CK20 (+), Ki-67 (50%), MLH-1 (+), MSH-2 (+), MSH-6 (+), PMS-2 (+), P53 (+), PD-1 (tumor cells -, immune cells 20%), SATB2 (+), PD-L1 (tumor cells 1%, immune cells 20%). (2023-12-12, our hospital) Colonoscopy: After rectal Ca surgery, no obvious abnormalities were found in the terminal ileum and the large intestinal mucosa. (2024-3-15, our hospital) No obvious abnormalities were found in blood routine, biochemistry, and tumor markers. The Chinese medicine doctor gave the compound preparation with additions and subtractions for oral administration, including 20g of Rehmannia glutinosa, 15g of mustard seeds, 20g of black plum, 20g of pepper, 15g of Codonopsis pilosula, 15g of Angelica sinensis, 9g of Bombyx batryticatus, 10g of Nine-scented Wormwood, 10g of Trillium, 10g of Frankincense, 10g of Myrrh, 10g of Atractylodes macrocephala, 6g of Licorice, 15g of Schisandra chinensis, 30g of Cannabis sativa seeds, and 10g of Gypsum gypsum, one dose per day, divided into morning and evening. After taking this medicine for 2 weeks, the patient's symptoms such as fatigue, shortness of breath and constipation were significantly improved. After regular follow-up visits, the addition and subtraction of Chinese medicine were adjusted according to the symptoms, and the follow-up was 2 months. Examination: (2024-7-30, our hospital) Abdominal CT: 1. Left kidney stone, roughly the same as before; 2. The mass shadow in the left adnexal area is slightly smaller than the previous film (2023-01-11 abdominal CT); 3. The soft tissue density nodule on the left upper edge of the uterus, uterine fibroids are roughly the same as before; 4. Postoperative changes in the rectum; 5. Abdominal wall cord shadows, roughly the same as the previous film. No other abnormalities were found. The patient's fatigue was significantly improved, his appetite and sleep improved, and his bowel movements were normal.KPS score is 90 points, NRS score is 0 points, and all indicators are normal. Regular follow-up visits are conducted based on the ingredients of this prescription. Colonoscopy at Wangjing Hospital on 2024-11-28 showed: no obvious abnormalities.

[0157] Although the present invention has been described in detail in the embodiments through general explanations, specific implementation methods and experiments, modifications or improvements can still be made without departing from the core of the present invention, and all belong to the scope of protection required by the present invention.

Claims

1. A Chinese medicine composition for treating digestive tract polyps and digestive tract tumors, characterized in that: The traditional Chinese medicine composition comprises the following raw materials: frankincense, myrrh, leech, aconite root, codonopsis pilosula, prickly ash, black plum, dried ginger, mustard, atractylodes macrocephala, licorice, bombyx batryticatus, trillium, nine-scented worm, angelica, and rehmannia root.

2. The Chinese medicine composition for treating digestive tract polyps and digestive tract tumors according to claim 1, characterized in that: The traditional Chinese medicine composition comprises the following raw materials in parts by weight: 8-12 parts of frankincense, 8-12 parts of myrrh, 4-8 parts of leech, 4-8 parts of aconite, 12-18 parts of codonopsis, 18-22 parts of zanthoxylum bungeanum, 18-22 parts of ebony, 6-12 parts of dried ginger, 12-18 parts of mustard, 8-12 parts of atractylodes, 4-8 parts of liquorice, 6-12 parts of bombyx batryticatus, 8-12 parts of trifoliate ash, 8-12 parts of schizonepeta tenuifolia, 12-18 parts of angelica, and 18-22 parts of rehmannia root.

3. A Chinese medicine preparation for treating digestive tract polyps and digestive tract tumors, characterized in that: The Chinese medicine preparation is prepared from the Chinese medicine composition for treating digestive tract polyps and digestive tract tumors according to any one of claims 1-2.

4. The Chinese medicinal preparation for treating digestive tract polyps and digestive tract tumors according to claim 3, characterized in that: The Chinese medicine preparation is a decoction, and the decoction is prepared according to the following steps: (1) Weigh the raw material according to weight, add 5-10 times the weight of water and soak for 30-120 minutes; (2) heating and boiling the soaked API together with water, filtering, and collecting the filtrate; (3) adding 5-10 times the weight of water to the residue, boiling, filtering, and collecting the filtrate; (4) The filtrates obtained after the two decoctions are combined, heated and concentrated to obtain a decoction.

5. The Chinese medicinal preparation for treating digestive tract polyps and digestive tract tumors according to claim 4, characterized in that: The decoction time for both times is 30-60 minutes.

6. The Chinese medicinal preparation for treating digestive tract polyps and digestive tract tumors according to claim 4, characterized in that: The filtrates were combined and concentrated by heating to 10%-20% of the original volume.

7. Use of the traditional Chinese medicine composition for treating digestive tract polyps and digestive tract tumors according to any one of claims 1-2 in the preparation of medicines for treating digestive tract polyps and digestive tract tumors.

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