| Purpose: This study intends to summarize the characteristics of ’ categorized formula-main syndrome-prescription ’ by sorting out the literature of traditional Chinese medicine treatment of cancer-related insomnia(CRI),and analyze the medication rules,and summarize the core prescriptions.On this basis,the pharmacodynamic mechanism of traditional Chinese medicine in the treatment of CRI was discussed with Sinisan combined with Suanzaoren Decoction as the breakthrough point.Comprehensive analysis of traditional Chinese medicine treatment of CRI from the perspective of theory,method and prescription,laying a foundation for further clinical application.Through the network pharmacology method,the biological basis of Sinisan combined with Suanzaoren Decoction in the treatment of CRI was interpreted from multiple perspectives and levels,and the drug efficacy was evaluated macroscopically from the perspectives of sleep,mood and fatigue through rat experiments.The results of network pharmacology were verified from the perspective of immune inflammatory response mediated by TNF signaling pathway,and the target of Sinisan combined with Suanzaoren Decoction in intervening CRI was clarified.Material and method:1.Literature retrieval was carried out based on CNKI,VIP and Wanfang databases.’Insomnia,sleep disorder,insomnia,not lying down ’ and ’ tumor,malignant tumor,cancer ’ were used as keywords to search for the literature on the treatment of CRI by traditional Chinese medicine published from the establishment of the database to July2022.The ’ cancer-related insomnia literature database ’ was established,and the ’classical prescriptions ’ and ’ current prescriptions ’ for the treatment of CRI were summarized,and the characteristics and pathogenesis of prescriptions and syndromes were summarized from the perspective of ’ categorized formula-main syndrome-prescription ’.2.Using the ’ cancer-related insomnia literature database ’,Microsoft Excel 2019 software,SPSS Modeler 18.0 and SPSS Statistics 25.0 software were combined to count the characteristics of four diagnostic information and medication rules with the help of multi-platform software,analyze the association rules and clustering relationships between drugs,and find the core prescriptions for the treatment of CRI.3.The active components of Sinisan combined with Suanzaoren Decoction were screened by TCMSP database and the targets were predicted.The therapeutic targets of CRI were obtained by Genecards and OMIM database,and the potential targets of Sinisan combined with Suanzaoren Decoction in the treatment of CRI were obtained by mapping with the predicted targets of drugs.The drug target protein and disease target protein(PPI)were analyzed,and GO analysis and KEGG pathway enrichment analysis were carried out to obtain the key effect components and core therapeutic targets of Sinisan combined with Suanzaoren Decoction in the treatment of CRI.4.On the basis of literature research and network pharmacology research,rat experimental research was carried out.48 rats were randomly divided into normal group(12 rats)and model group(36 rats).Except for the normal group,the insomnia rat model of breast cancer was replicated by subcutaneous transplantation of SHZ-88 rat breast cancer cells combined with intraperitoneal injection of PCPA.After successful modeling,36 rats in the model group were randomly divided into model group,Chinese medicine group and western medicine group,with 12 rats in each group.Continuous drug intervention for 7 days,the Chinese medicine group was given Sinisan combined with Suanzaoren Decoction,and the western medicine group was given diazepam tablets;the model group and the blank group were given an equal volume of normal saline daily according to the conversion method.After the drug intervention,the drug efficacy was evaluated macroscopically by behavioral methods such as pentobarbital sodium righting experiment,open field experiment,sugar water preference experiment,rat tail suspension experiment and exhaustive swimming experiment.On this basis,the contents of inflammatory indexes and neurotransmitters in serum and hypothalamus were detected by enzyme-linked immunosorbent assay(ELISA).The expression levels of key target proteins of TNF signal pathway in hypothalamus of rats were detected by Western-blot and immunohistochemistry(IHC),which provided experimental verification for network pharmacology results.Results:1.In addition to the main complaint of insomnia,patients with Chaihu analogous prescriptions were more likely to have dry mouth,bitter mouth,irritability,anorexia,fatigue,upset,anxiety and other symptoms.The tongue is more common with red tongue and thin yellow fur,and the pulse is mostly string and thready pulse.Patients with Huangqi analogous prescriptions are more likely to have symptoms such as fatigue,anorexia,mental fatigue,dizziness,loose stool,and sallow complexion.The tongue are more common in pale tongue,thin white fur,tooth marks,and fat.The patients with Dihuang analogous prescriptions were mostly complicated with symptoms such as dry mouth,fatigue,tinnitus,upset,soreness and weakness of waist and knees,hot flashes and night sweats,dry stool,bitter mouth,dizziness,dysphoria in chestpalms-soles,etc.The tongue image was more common with red tongue and thin white moss,and the pulse was mostly stringy and thready;patients with Banxia analogous prescriptions are more likely to have symptoms such as dry mouth,bitter mouth,anorexia,palpitations,sweating,upset,and chest tightness.The tongue is more common with pale red tongue,white greasy fur,and yellow greasy fur.The patients with Huanglian analogous prescriptions are often accompanied by symptoms such as dry mouth,irritability,fatigue,and fatigue.The tongue image is more common with red tongue and thin yellow moss,and the pulse condition is mostly stringy veins.The drug treatment of the five core prescriptions,respectively,from the perspective of ’stagnated fire,deficient fire and ministerial fire’,tonifying deficiency and reducing excess,adjust yin and yang.In terms of quantity alone,Chaihu analogous prescriptions accounted for 40.91 %,ranking first in the literature of medical records.It can be seen that stagnation of liver qi transforming into fire and stagnation of fire disturbing mind are the most important pathogenesis of CRI.2.The results of the study on the compatibility rules of CRI : This study screened and sorted out the prescription drugs of traditional Chinese medicine in the treatment of CRI literature in the past three decades.The results showed that the medicinal properties were mostly cold,flat and warm,mainly entering the liver,heart and spleen,and the efficacy was mainly tonic,sedative and heat-clearing drugs.Among them,licorice,semen ziziphi spinosae,radix bupleuri and radix paeoniae alba are the core drugs.The core pairs and core angular drugs obtained by correlation analysis include ’ radix bupleuri-radix paeoniae alba ’,’ radix bupleuri-radix paeoniae albasemen ziziphi spinosae ’,’ radix bupleuri-rhizoma ligustici wallichii ’,’ semen ziziphi spinosae-rhizoma ligustici wallichii ’,etc,which are mostly combinations of soothing liver and qi,nourishing blood and tranquilizing mind,and are highly consistent with the prescription ideas of Sinisan combined with Suanzaoren Decoction.3.Based on network pharmacology,the therapeutic mechanism of Sinisan combined with Suanzaoren Decoction in the treatment of CRI was discussed.Results : Sinisan combined with Suanzaoren Decoction,including Radix Bupleuri,Radix Paeoniae Alba,Fructus Aurantii Immaturus,Radix Glycyrrhizae Preparata,Semen Ziziphi Spinosae,Rhizoma Anemarrhenae,Rhizoma Ligustici Chuanxiong,Poria,8 kinds of traditional Chinese medicines,a total of 179 active ingredients were screened,mainly flavonoids,alcohols and saponins.A total of 49 target proteins were predicted by CRI,mainly including the following categories : neurotransmitters and hormone receptors,immune inflammatory factors,lipid metabolism-related enzymes,tumor cell growth,metastasis,apoptosis-related cytokines,etc.The enrichment results showed that the combined prescription could regulate AGE-RAGE signaling pathway,TNF signaling pathway,p53 signaling pathway,IL-17 signaling pathway,HIF-1 signaling pathway,PI3K-Akt signaling pathway,MAPK signaling pathway,VEGF signaling pathway,etc.The treatment of CRI with Sinisan combined with Suanzaoren Decoction plays a therapeutic role through multiple components,multiple targets,multiple biological processes and signaling pathways.The immune inflammatory response mediated by TNF signaling pathway can affect the sleep of cancer patients,and plays an important role in the pathological process of tumor growth,metastasis and apoptosis,which points out the direction for further experiments.4.The results of the study on the therapeutic mechanism of Sini Powder combined with Suanzaoren Decoction in the treatment of CRI :Experiment 1:(1)The insomnia rat model of breast cancer was successfully replicated by subcutaneous transplantation of SHZ-88 rat breast cancer cells combined with intraperitoneal injection of PCPA.The circadian rhythm of the rats in the model group disappeared,the sleep time decreased,and the subcutaneous tumors increased more than 0.2 cm × 0.2 cm.(2)Compared with the normal group,the sleep latency of the model group was significantly prolonged and the sleep duration was significantly reduced(P<0.01).(3)After drug intervention,the mental state and sleep circadian rhythm and time length of rats in the Chinese medicine group and the western medicine group tended to be normal.Compared with the model group,the sleep latency time of the western medicine group and the Chinese medicine group was significantly shortened(P<0.01);and the sleep duration of the Chinese medicine group was also significantly prolonged(P<0.05).There was no significant difference between the two treatment groups(P>0.05).In the open field experiment,compared with the normal group,the total movement distance and residence time in the central region of the model group were significantly increased(P<0.01).Compared with the model group,the total movement distance of the rats in the Chinese medicine group and the western medicine group was significantly reduced(P<0.05);compared with the model group,the residence time in the central area of the western medicine group was significantly reduced(P<0.05),and the residence time in the central area of the Chinese medicine group was also reduced,but there was no significant difference compared with the model group(P>0.05).In the sucrose preference percentage experiment,compared with the normal group,the sucrose preference percentage of the model group was significantly reduced(P<0.01).Compared with the model group,the sucrose preference percentage of the two treatment groups was increased(P<0.05).In the tail suspension immobility time experiment,compared with the normal group,the tail suspension immobility time of the model group was significantly prolonged(P<0.01);compared with the model group,the immobility time of tail suspension in the two treatment groups was significantly shortened(P<0.01).In the exhaustive swimming time experiment,compared with the normal group,the exhaustive swimming time of the model group was significantly shortened(P<0.01);compared with the model group,the exhaustive swimming time of the two treatment groups was significantly prolonged(P<0.01).Compared with the western medicine group,the exhaustive swimming time of the Chinese medicine group was significantly longer(P<0.05).(4)Compared with the blank group,the contents of5-HT and GABA in the hypothalamus of the model group,the western medicine group and the Chinese medicine group were significantly decreased(P<0.01).Compared with the model group,the contents of 5-HT and GABA in the western medicine group and the Chinese medicine group were significantly increased(P<0.01).There was no significant difference between the Chinese medicine group and the western medicine group(P>0.05).Experiment 2:(1)HE staining of rat hypothalamus showed that in the normal group,various nerve cells in the hypothalamus were abundant,pyramidal cells and glial cells were clearly visible and evenly distributed,and the nucleus of nerve cells in the hypothalamus was dense and structurally complete.In the model group,most of the nerve cells were vacuolar degeneration,pyramidal cells were atrophic,some neurons were atrophic,reduced,loosely arranged,most of the cytoplasmic granules were vacuolar degeneration,the cell boundaries were unclear,and even the cells disappeared,and glial cell proliferation was seen.After drug intervention,most of the nerve cells in the hypothalamus of the Chinese medicine group and the western medicine group were restored.Occasionally,small focal cell atrophy was observed and cell vacuoles were significantly reduced.(2)Enzyme-linked immunosorbent assay(ELISA)results showed that compared with the blank group,the levels of TNF-α,IL-1β and IL-6 in serum and hypothalamus of the model group,western medicine group and Chinese medicine group were significantly increased(P<0.01);compared with the model group,the levels of TNF-α,IL-1β and IL-6 in the western medicine group and the Chinese medicine group were significantly decreased(P<0.01).Compared with the western medicine group,there was no significant difference in the contents of TNF-α,IL-1β and IL-6 in the Chinese medicine group(P >0.05).(3)Western blot(WB)results showed that compared with the blank group,the expression levels of TNFR1,TRADD,JNK,c-Jun and c-Fos proteins in the hypothalamus of rats in the model group,western medicine group and Chinese medicine group were significantly increased(P<0.01).Compared with the model group,the expression levels of TNFR1,TRADD,JNK,c-Jun and c-Fos protein in the western medicine group and the Chinese medicine group were significantly decreased(P<0.01).Compared with the western medicine group,there was no significant difference in the expression level of the above proteins in the Chinese medicine group(P>0.05).(4)Immunohistochemistry(IHC)results showed that compared with the blank group,the expression levels of TNFR1 and TRADD proteins in the hypothalamus of the model group,the western medicine group,the Chinese medicine group,and the rat hypothalamus were significantly increased(P<0.01);compared with the model group,the expression levels of TNFR1 and TRADD protein in the western medicine group and the Chinese medicine group were significantly decreased(P<0.01).Compared with the western medicine group,the expression level of TNFR1 protein in the Chinese medicine group was not statistically significant(P>0.05).Conclusion:1.Through literature research,ten types of prescriptions for CRI treatment were summarized.Based on the theory of analogous prescriptions,the ’ analogous prescriptions-main syndromes-prescriptions ’ of Chaihu analogous prescriptions,Huangqi analogous prescriptions,Dihuang analogous prescriptions,Banxia analogous prescriptions and Huanglian analogous prescriptions were summarized,and the pathogenesis of CRI was discussed from the perspective of ’ stagnated fire,deficient fire and ministerial fire ’.2.This study screened and sorted out the prescription drugs in the literature of traditional Chinese medicine in the treatment of CRI in the past three decades,and counted the medication rules with the help of multi-platform software.It was found that Sinisan combined with Suanzaoren Decoction were the core prescriptions for CRI treatment,highlighting the compatibility ideas of soothing liver and qi,nourishing blood and tranquilizing mind.3.Through network pharmacology,this study found that Sini Powder combined with Suanzaoren Decoction in the treatment of CRI plays a role in improving insomnia through multiple components,multiple targets,multiple biological processes and signaling pathways.The pharmacodynamic mechanism may be related to the immune inflammatory response mediated by TNF signaling pathway,which points out the direction for further experiments.4.On the basis of literature research and network pharmacology,the insomnia rat model of breast cancer was replicated by subcutaneous transplantation of SHZ-88 rat breast cancer cells combined with intraperitoneal injection of PCPA.After the intervention of Sinisan combined with Suanzaoren Decoction,the sleep latency time of the model rats was significantly shortened,the sleep maintenance time was significantly prolonged,and the depression and fatigue symptoms of the model rats were improved.Through molecular biology experiments,it was further verified that Sinisan combined with Suanzaoren Decoction can restore the levels of hypothalamic neurotransmitters 5-HT and GABA,and reduce the secretion of pro-inflammatory cytokines TNF-α,IL-1 β and IL-6.The deep mechanism may be achieved by down-regulating the immune inflammatory response mediated by the over-activated TNF signaling pathway,which provides scientific evidence at the molecular level for the treatment of CRI with Sinisan combined with Suanzaoren Decoction. |
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