The Pharmacological Mechanism of the Effect of Plant Extract Compound Drugs on Cancer Pain Based on Network Pharmacology

Objective We systematically analyzed the mechanism of plant-derived drugs alleviating cancer pain in our hospital through network pharmacology, so as to provide the possibility of further application of traditional Chinese medicine in the treatment of cancer pain. Methods We used TCMSP, ETCM, and TCMID databases to mine the active ingredients of plant-derived drugs. We combined OMIM, GeneCards, and DrugBank databases to mine and match the common targets of plant-derived drugs for cancer pain. We used the STRING platform and Cytoscape software to analyze and screen out the core targets. We used GO and KEGG methods to analyze the biological processes, molecular functions, cellular composition, and signaling pathways involved in the reduction of cancer pain by plant-derived drugs. Results We found 153 active ingredients from botanical drugs by TCMSP (Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, TCMSP), ETCM (The Encyclopedia of Traditional Chinese Medicine), and TCMID (Traditional Chinese Medicine Integrated Database) databases, covering 341 protein targets in human body. Combined with OMIM (Online Mendelian Inheritance in Man), GeneCards, and DrugBank databases, we excavated and matched 141 targets of plant-derived drugs and cancerous pain diseases. Through the analysis of the STRING platform and Cytoscape software, 19 core targets including TNF, MAPK1, JUN, and IL-6 were screened out. Go and KEGG enrichment showed that plant-derived drugs alleviated cancer pain processes involving 193 biological processes, 47 molecular functions, 22 cell components, and 118 signaling pathways. By screening genes involved in KEGG signaling pathway, it was found that plant-derived drugs were mainly associated with PI3K-Akt signaling pathway, tumor necrosis factor signaling pathway, MAPK signaling pathway, Toll-like receptor signaling pathway, and HIF-1 signaling pathway in alleviating cancer pain. Conclusion These results indicate that botanical drugs can positively affect the expression of inflammatory factors and apoptotic factors in the process of treatment and relief of cancer pain, which is expected to have a potential therapeutic effect on the relief of cancer pain.


Introduction
Cancer pain is a chronic pain with a unique and complex mechanism. At the early stage, cancer pain is mainly sensitized by primary afferent nerves caused by a series of paincausing substances released by tumor cells and inflammatory cells and continuously activated osteoclasts, while at the later stage, cancer pain is mainly caused by nerve compression and injury caused by tumor growth [1]. In recent years, with the aging of the society and the increasing incidence of cancer, about half of the patients with malignant tumors have different degrees of cancer pain, especially the incidence of cancer pain in advanced patients is as high as 60-80%, which seriously affects the patients' disease recovery and quality of life [2]. Cancerous pain is a kind of pain with areas in need of repair or adjustment after the information transmission to the nerve center of feeling, although the clinical use of "three steps" analgesia method can partly control or relieve patients' pain, but as the disease progresses, the tumor load increases, and the increase of the

Identification and ADME Screening of Candidate Compounds of Traditional Chinese Medicine.
In this study, all the active ingredients of 11 herbal medicines of botanical origin were searched by TCMSP, ETCM, and TCMID [19,20]. e names of 11 traditional Chinese medicines, Astragalus membranaceus, Poria cocos, Honeysuicerae lonicerae, Radix Paeoniae lactiflora, Radix Bupleurum, Hedyotis diffusa, Scutellaria scleroides, Fructus Trichosanthis, Araceae aratidae, Radix Scutellariae, were input, and the main active components were further screened according to the oral availability (OB) ≥30% and drug-like properties (DL) ≥0. 18. OB and DL are the key indicators to evaluate the effective availability of drugs. Generally speaking, active ingredients with OB ≥ 30% and DL ≥ 0.18 can be regarded as the main active ingredients of drugs [21].

Prediction of Related Targets of Active Compounds in
Traditional Chinese Medicine. TCMSP, PharmMapper, SwissTarget, and other databases were used to screen the protein targets corresponding to the main active components of the abovementioned traditional Chinese medicine [22]. By using the retrieval function of UniproKBT in the UniProt database [23], all target gene names were corrected into official gene symbol names by inputting protein names, and active ingredients without targets were removed to obtain the information of active ingredients and related targets.

Cancer Pain Disease Targets and Protein Collection.
According to DrugBank, GeneCards, and OMIM databases, the English "cancer pain" corresponding to pain was used as the key word to search and screen the related targets, and the targets of three disease databases were combined to remove the repetitive base, so as to obtain the potential targets of pain, and by using the retrieval function of UniProKBT in the UniProt database and by inputting the name of protein and limiting the species to human, all the potential targets of pain were identified. e name of target gene was corrected to official gene symbol, and the active components without target were eliminated to obtain the final disease target [24,25].

Construction of "Compound-Target-Cancerous Pain" Signaling Pathway.
e protein-protein interaction (PPI) network of potential targets and disease targets was constructed by using Cytoscape 3.7.2, and the two network graphs were fused and the intersection network was extracted by using the correlation function in the software. e direct and indirect target regulatory networks of 14 herbal medicines for cancer pain relief were obtained.

GO and KEGG Analysis.
In order to clarify the potential action targets of active ingredients in 14 herbal medicines of plant origin, as well as the role of cancer-related pain targets in gene function and signaling pathway, GO and KEGG enrichment analysis was conducted in the DAVID database and Metascape platform based on annotation and visualization modules [26]. In this study, R language programming was used for GO and KEGG pathway analysis, and set thresholds P < 0.05. e possible mechanism of analgesic effects of 14 herbal herbs derived from plants was predicted through gene enrichment analysis, and the results were imported into the mapping software for visual mapping [27] ( Table 1).

Analysis of Components and ADME of Botanical Drugs.
By searching TCMSP, ETCM, and TCMID databases and analyzing ADME, based on OB ≥ 30% and DL ≥ 0. 18 e compound information of 11 Traditional Chinese medicines is shown in Figure 1 and Table 2-12 [28].

Screening of Pain-Related Targets.
Based on OMIM, GeneCards, and DrugBank databases, pain disease-related targets were screened with "cancer pain" as the key word. e results showed that there were 670 pain disease-related targets in the OMIM database, 1086 GeneCards database, and 215 DrugBank database. A total of 1695 targets were obtained from the three databases. Compared with the UniProt database, 1110 verified human pain disease-related targets were obtained. By matching 341 protein targets of active components of plant-derived drugs, 141 common targets of plant-derived drugs and cancer pain diseases were obtained. e Venn diagram and detailed target information are shown in Figure 3 and Table 13, respectively.

PPI Network Construction.
e interaction network of 141 potential targets was constructed by using the STRING database platform. e minimum interaction threshold was set to "0.9," and the results are shown in Figure 4. e nodes in the figure are intersection genes, and the edges represent the association degree of the intersection genes, and the thickness represents the binding degree. As shown in the figure, there are 140 nodes and 538 edges. e PPI network diagram is imported into the software Cytoscape 3.7.2, and the network pictures are analyzed by tools. We selected those targets with greater than average degree and betweenness centrality, a total of 19 targets, as potential key targets for plant-derived drugs to exert analgesic effects e main proteins closely related to analgesic effect of botanical drugs are TNF, mapk1, Jun, and IL-6, as shown in Figure 5 and Table 14.

Construction of "Compound Traditional Chinese Medicine Compound Target Disease" Network Diagram of Analgesic
Effect of Botanical Drugs. Nineteen core targets of botanical drug analgesia were obtained from 2.4, and the corresponding compounds and traditional Chinese medicine were screened and matched. e network diagram of "compound traditional Chinese medicine compound target disease" of botanical drug analgesia was predicted by using

GO and KEGG Enrichment Analysis.
rough DAVID and STRING databases, 141 targets of botanical drug pain disease were enriched and analyzed, including biological process (BP), molecular function (MF), and cell composition (CC).
ere are 193 biological processes, 47 molecular functions, and 22 cell components; 20 enriched genes are selected and mapped through the mapping software, as shown in Figure 8; 118 signaling pathways are involved in KEGG pathway abdominal muscle analysis, and 20 enriched genes are screened according to the number of enriched genes, as shown in Figure 9.

Discussion
Modern medicine believes that cancer pain is mainly caused by the disease itself or the pain caused in the treatment process. Tumors infiltrate bone tissue, and bone tissue destruction results in the release of prostaglandins. It invades the viscera, causing vasospasm, occlusion, and eventually necrosis of the viscera. Or it may compress peripheral nerves, nerve roots, spinal cord, etc. e patient's own mental tension and psychological pressure can cause pain disorders.
ere is no name for cancer pain in Chinese medicine, but according to the pain of different parts of cancer, it can be assigned to the pain syndrome of the corresponding parts. For example, pain caused by brain tumor, nasopharyngeal cancer, and cancer brain metastasis is classified as "headache." Cancer of the esophagus and lung can be classified as "chest pain." Pain caused by gastric cancer is classified as "stomachache." Pain caused by liver cancer is classified as "flank pain." Pain caused by pancreatic and colorectal cancer is classified as "abdominal pain." e pain caused by bone cancer and cancer bone metastasis is classified as "Bi syndrome" or "Gubi syndrome." Pain is a kind of feeling of human disease caused by tissue injury, which stimulates the sensory system [29]. It is of great significance and research value in clinical diagnosis and treatment. Usually, the clinical pain mainly comes from the noxious stimulation of internal and external conditions caused by disease or surgery, which not only includes the defense response of the human body to noxious stimulation, but also a clinical manifestation of a variety of diseases and postoperative reactions [30]. Most of the patients have severe pain or chronic long-term pain and need to be treated with analgesic drugs. Cancer pain usually accompanies the whole course of cancer patients, so that patients are in pain, anxiety and even depression, and other negative emotions for a long time, causing some patients to lose confidence in life, which seriously affects the quality of life of patients. erefore, how to effectively control the degree of cancer pain of cancer patients has great significance for the treatment of cancer and the improvement of life quality of cancer patients [31,32]. We need to understand the meaning of this. erefore, the research of analgesic drugs has become one of the hot directions of modern drug research, but the clinical use of chemical drugs for acute or chronic pain, such as opioids and nonopioids: morphine, codeine, pethidine, aspirin, indomethacin, ibuprofen, and so on [33]. Although        [34,35]. e clinical analgesic effect of chemical drugs has been fully recognized, but for patients with chronic pain, long-term use will produce dependence, peptic ulcer, and other adverse reactions. Accordingly, with the development of traditional Chinese medicine industry, the research of natural plant extracts for pain treatment is gradually deepening [36,37]. Botanical medicine is an important method for the treatment of cancer pain.
is method should be highly valued by medical staff. External application of traditional Chinese medicine is directly administered to patients on the body surface of medical staff. Under the condition of absorption on the skin or mucous membrane surface of the patient, it can reach the pain site of the patient, produce good analgesic effect, and gradually reduce the side effects caused by oral drugs [38]. In this study, 11 plant-derived drugs widely used in clinical pain treatment were selected as follows: Astragalus membranaceus, Poria cocos, Honeysuckle, Cyperus, Paeonia lactiflora, Bupleurum, Hedyotis diffusa, Scutellaria barbata, Trichosanthes kirilowii, Arisaema, and Scutellaria baicalensis. Among them, Astragalus is sweet in taste and mild in nature. It is mainly used for blood numbness of limbs and hemiplegia. Poria cocos is sweet and light, and has a mild nature. Honeysuckle has the characteristics of sweet-cold clearing, light aroma, and drooping, is good for clearing away heat and detoxification, and treats carbuncle sores and boils. Cyperus is pungent, relieves bitterness, and tastes sweet, and it is harmonious, smooth, and unbiased, and works well for soothing the liver, regulating qi, and relieving pain. Paeonia lactiflora has sour, sweet, and bitter taste, it is mild cold in nature, and it has the effect of softening the liver and relieving pain. Bupleurum is bitter and mildly cold, and aromatic, relieves diarrhea, and mainly treats flank pain, irregular menstruation, and dysmenorrhea. Hedyotis diffusa is bitter and cold to clear diarrhea, and sweet and cold to  rough TCMSP, PharmMapper, SwissTarget database retrieval, and comparison with the UniProt database, 341 protein targets of plant-derived drugs were obtained. rough 1110 targets related to human pain diseases, 141 common targets of plant-derived drugs pain diseases were obtained. e interaction network of 141 potential targets was constructed by using the STRING database platform, and the PPI network diagram was imported into Cytoscape 3.7.2 in the software, the network images were analyzed by tools, and the 19 targets with degree and betweenness centrality >15 were the potential key targets for the analgesic effect of botanical drugs. e main proteins closely related to the analgesic effect of botanical drugs were TNF, MAPK1, JUN, IL-6, and so on. GO enrichment analysis by the DAVID platform showed that the mechanism of pain relief by botanical drugs mainly involved 193 biological processes, 47 molecular functions, and 22 cell components; 118 signaling pathways were obtained by the abdominal muscle analysis of the KEGG pathway. e main biological processes are as follows: RNA polymerase II promoter, transcriptional DNA template, inflammatory reaction, transcriptional positive regulatory DNA template, apoptosis process, immune reaction, active regulation of angiogenesis, regulation of cell proliferation, activation of cysteine-type endopeptidase activity, regulation of apoptosis process, steroid hormone-mediated signaling pathway, lipopolysaccharide-mediated signaling pathway, and sequence-specific DNA binding transcription, positive regulation of NF-kappa B transcription factor activity, negative regulation of cell proliferation, negative regulation of transcription, and so on. Cell components include nucleus, cytoplasm, extracellular space, extracellular exosomes, cytosol, organic components of plasma membrane, intracellular mitochondria, external plasma membrane, endoplasmic reticulum, cell surface, extracellular matrix, postsynaptic membrane, complex receptors, membrane rafts, neuronal projection, cell junction, nuclear chromatin,    Journal of Healthcare Engineering spindle, RNA polymerase II transcription factor complexings. Molecular functions include zinc ion binding, ATP binding transcription factor activity, DNA binding, heme node, cytokine activity, protein dimer activity, RNA polymerase II core promoter proximal region-specific sequence DNA binding, chromatin binding, steroid hormone receptor activity, growth factor activity, iron ion binding, transcriptional activator activity, steroid binding, transcriptional regulatory region DNA binding, amino acid endopeptidase activity, adrenaline binding, monooxygenase activity metalloendopeptidase activity, norepinephrine binding, aromatase activity, tumor necrosis factor receptor binding, MAPK activity, peroxidase activity, transmembrane receptor protein tyrosine kinase activity, core promoter sequence-specific DNA binding, drug binding, and        microRNAs in tumors. It can be seen from the above signaling pathways that plant-derived drugs not only regulate the expression of inflammatory factors through inflammatory signaling pathways to relieve pain, but also actively participate in prostate cancer, pancreatic cancer, small cell lung cancer, and other cancer pathways, in order to achieve the effect of relieving cancer pain.

Conclusion
In conclusion, the material basis and the possible mechanism of action of the active components of plantderived drugs were preliminarily discussed through network pharmacology. In this article, the effective chemical components and corresponding targets of plantderived drugs were obtained by TCMSP, ETCM, TCMID, and other databases. GeneCards, OMIM, DrugBank, and other databases were used to screen out pain-related targets. Cytoscape software and STRING database were used to construct the "compound target" interaction network and protein interaction (PPI) network to screen the key components and key targets for therapeutic effects. GO and KEGG pathway enrichment analysis was performed on key targets through the DAVID platform, and the potential action mechanism of 11 herbal extracts of plant origin drugs was learned. We found 153 active ingredients from botanical drugs by TCMSP, ETCM, and TCMID databases, covering 341 protein targets in the human body. Combined with OMIM, GeneCards, and DrugBank databases, we excavated and matched 141 targets of plant-derived drugs and cancerous pain diseases. rough the analysis of the STRING platform and Cytoscape software, 19 core targets including TNF, MAPK1, JUN, and IL-6 were screened out. Go and KEGG enrichment showed that plant-derived drugs alleviated cancer pain processes involving 193 biological processes, 47 molecular functions, 22 cell components, and 118 signaling pathways. By screening genes involved in the KEGG signaling pathway, it was found that plant-derived drugs were mainly associated with PI3K-Akt signaling pathway, tumor necrosis factor signaling pathway, MAPK signaling pathway, Toll-like receptor signaling pathway, and HIF-1 signaling pathway in alleviating cancer pain. ese results indicate that botanical drugs can positively affect the expression of inflammatory factors and apoptotic factors in the process of treatment and relief of cancer pain, which is expected to have a potential therapeutic effect on the relief of cancer pain. Although Table 13: Common targets of botanical drugs and cancer pain diseases.   141 common target proteins  ACHE  CD40LG  EGFR  HRH1  MAPK14  NR1I2  RAF1  ACTB  CES1  ERBB2  HSD3B2  MAPK8  NR3C1  RASA1  ADRA1A  CHEK2  ESR1  HSP90AA1  MDM2  NR3C2  RB1  ADRA2A  CHRM2  ESR2  HSPB1  MET  ODC1  RELA  ADRA2C  CHRM3  F3  HTR3A  MMP1  OPRD1  SCN5A  ADRB1  COMT  F7  ICAM1  MMP2  OPRM1  SELE  ADRB2  COX5A  FASLG  IFNG  MMP3  PCNA  SERPINE1  AKR1C1  COX6B1  FECH  IGF2  MMP9  PGR  SLC6A2  AKT1  CRP  FN1  IGFBP3  MPO  PIK3CG  SLC6A3  ALOX5  CXCL10  FOS  IKBKB  MT-CO1  PLAT  SLC6A4  AR  CXCL8  GABRA2  IL10  MTHFR  PLAU  SPP1  BAX  CYCS  GABRA3  IL1A  MTR  PON1  STAT1  BCL2  CYP19A1  GRIN1  IL1B  MYC  PPARA  THBD  BIRC5  CYP1A1  GRIN2A  IL2  NFE2L2  PPARG  TNF  CACNA2D1  CYP1A2  GRIN2B  IL4  NFKB1  PRKCA  TOP2A  CASP8  CYP27B1  GRIN2D  IL6  NFKBIA  PRSS1  TP53  CASP9  CYP2C9  GSTM1  IRF1  NOS2  PTGES  TYR  CAT  CYP3A4  GSTP1  JUN  NOS3  PTGS1  VCAM1  CAV1  DNMT1  HIF1A  KDR  NPPB  PTGS2  VDR  CCL2  EGF  HMOX1  MAPK1  NR0B1 PYGM VEGFA CCND1  TNF  TNF  TNF  CXCL8  NR3C1  MAPK1  MAPK14  MAPK1  IL6  AKT1  MAPK1  IL1B  NFKB1  IL4  JUN  MAPK1  RELA  EGFR  TNF  RELA  ESR1  AKT1  JUN  MAPK14  IL6  EGFR  HSP90AA1  RELA  VEGFA  ESR1  MAPK8  JUN  TP53  JUN  TP53  HSP90AA1  CXCL8  VEGFA  HSP90AA1  IL6  AKT1  FOS  TP53 TCMSP and other databases were used to obtain the chemical components of plant-derived drugs, these data are not complete. In the later stage, UPLC, UPLC-Q-TOF-MS, and other methods should be used to detect the chemical components of plant-derived drugs, in order to obtain more comprehensive chemical information to study the mechanism of action of traditional Chinese medicine monomer.
Data Availability e datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Conflicts of Interest
e authors declare no conflicts of interest.