| BackgroundCancer-related fatigue is a disturbing,persistent,and unmitigated subjective feeling of fatigue or fatigue caused by the tumor itself or by tumor-related treatment.The incidence of cancer-induced fatigue is 60%-90%,which seriously affects patients' quality of life and ability to live,may also increase the fear of tumor metastasis and recurrence,and may even affect the survival of patients.At present,the pathogenesis of cancer-related fatigue is still unclear,leading to a serious lag in the development of drugs for cancer-related fatigue,and there is no FDA-approved drug for the treatment of cancer fatigue.Traditional Chinese medicine has obvious advantages in the treatment of cancer-induced fatigue.Qijiafuzheng prescription is a hospital preparation used in the adjuvant treatment of non-small cell lung cancer,especially lung adenocarcinoma.It has the functions of strengthening spleen and kidney,strengthening and strengthening the body.It is composed of Astragalus membranaceus,Trionyx sinensis,black plum,Herb sinensis,corundum,Gentiana macrophylla,Brachiophora sinensis,Zedoaiy turmeric,Rhizoma sinensis and other drugs,and has been used in clinical practice for many years.Previous clinical studies have shown that it can improve the symptoms of fatigue and shortness of breath in patients with non-small cell lung cancer,especially lung adenocarcinoma.However,the efficacy of Qijia fuzheng prescription in the treatment of cancer-induced fatigue is not clear yet,and its specific molecular mechanism of action remains to be further explored.Objectives1 To confirm the effectiveness of Qijiafuzheng prescription in the treatment of spleen and kidney deficiency lung cancer fatigue through clinical trials.2 To explore the mechanism of Qijiafuzheng prescription against cancer-induced fatigue of lung cancer from the perspective of immune inflammation by in vivo experiments.Methods1 A self-controlled observational clinical trial was designed and the scores of patients with cancer-related lung cancer fatigue before and after one cycle(28 days)of taking Qijia Fuzheng prescription Recipe were recorded by the Piper fatigue revised scale and the Kali rating scale.Paired t test was used to analyze and compare the two scores to determine the effectiveness of Qijia Fuzheng prescription in the treatment of cancer-induced fatigue of lung cancer.2 Based on TCMSP,TCMID,PubChem and Swiss Target Prediction database,the effective components and action targets of the 9 traditional Chinese medicines contained in Qijia Fuzheng prescription were collected.Target genes related to "lung adenocarcinoma associated fatigue" were obtained through GeneCards,OMIM and other databases.The set of drug action targets was mapped to the set of disease-related targets to obtain the intersection genes.String was used to construct protein-protein interaction(PPI)network and screen important targets;The drug-component-target regulatory network was constructed by Cytoscape.GO and KEGG enrichment analysis of the intersection genes were performed by David database.Genebank database was used to analyze tissue and organ localization of intersection genes.Finally,Autodock Vina1.1.2 was used to analyze the binding ability of the main active ingredients and key targets,and the docking results were visualized by PyMol software.3 To observe the effect of Qijia Fuzheng prescription on the prevention and treatment of cancer-induced fatigue of lung cancer and the mechanism of immune inflammation.?The fatigue model of mice induced by tumor transplantation was established.The control group(normal control group),the tumor-bearing group(tumor-bearing model group)and the traditional Chinese medicine group were established.Distilled water was given to the control group and the tumor-bearing group,and Qijiafuzhengfang decoction was given to the traditional Chinese medicine group,with a concentration of 3.905 g/mL and a dosage standard of 0.1mL/10g per day from the 7th day of tumor transplantation.Each group was intervened once daily for 14 consecutive days.By comparing the general condition,body weight,frequency of electric shock in treadmill test,immobile time of tail suspension test,ATP content in skeletal muscle and blood routine indexes of mice in the control group and the tumor-bearing group at 5 time points on the 0,7,14,17 and 21 days after tumor implantation.To determine whether there is fatigue behavior in transplanted tumor mice and the change rule of fatigue behavior with time;In order to clarify the preventive effect of Qijiafuzheng formula on fatigue behavior induced by tumor transplantation,the electroshock frequency of the treadmill test,the immobile time of the tail suspension test and the blood routine indexes were compared between the traditional Chinese medicine group and the tumor-bearing group on the 7th,14th,17th and 21st day of the tumor implantation test.?After administration,the percentage of T cell subsets in peripheral blood of each group was analyzed by flow cytometry.The expression levels of IL-1?,IL-6,IL-17 and CD25 in peripheral blood of each group were detected by flow microsphere capture chip technology.?At the 7th,14th,17th and 21st day of administration,the long and short longitude of the tumor in the tumor-bearing group and the traditional Chinese medicine group were measured with a vernier caliper,and the volume of the tumor was calculated to draw the growth curve of the tumor.After administration,the tumor body was stripped and weighed,and the tumor morphology of mice in the tumor-bearing group and the TCM group was observed by hematoxylin-eosin staining.The expression level of Ki67 protein in the tumor tissues of mice in the tumor-bearing group and the TCM group was compared by immunohistochemistry.?The protein expression levels of key targets of Akt/c-Myc signaling axis,such as Akt,p-Akt and c-Myc,were detected by Western Blot,and the protein expression levels of c-Myc in tumor tissues of the tumor-bearing group and the control group were detected by immunohistochemical method.Results1 A total of 29 spleen and kidney deficiency patients with cancer-related lung cancer fatigue were included in this study.PFS-R score showed that the total score of fatigue before treatment was(7.07±1.36),and the total score of fatigue after treatment was(6.78± 1.32).Compared with that before treatment,the total score of fatigue after treatment was lower than that before treatment(P<0.05).The scores of behavioral dimension were(7.05 ± 1.58)points before treatment and(6.77±1.50)points after treatment,which were lower than those before treatment(P<0.05).The score of affective dimension was(6.92± 1.29)points before treatment and(6.66± 1.21)points after treatment,which was lower than that before treatment(P<0.05).The score of sensory dimension was(7.18± 1.47)points before treatment and(6.83 ±1.49)points after treatment,and the score after treatment was lower than that before treatment(P<0.05),The cognitive dimension score was(7.10± 1.54)points before treatment and(6.85± 1.55)points after treatment,which was lower than that before treatment(P<0.05).The KPS score was(80.24 ± 10.14)before treatment and(87.83±8.73)after treatment(P<0.05),which was lower than that before treatment(P<0.05).2 The regulation network of Qijia fuzheng prescription against lung cancer-related fatigue contains 9 Chinese herbs,108 active ingredients and 87 target genes.The top 5 components and genes with high degree were quercetin,kaempferol,baicalin,ellagic acid,isorhamnetin and CASP3,VEGFA,EGFR,MYC and IL-6.respectively.KEGG enrichment analysis involved PI3K-Akt,P53,TNF,MAPK,ErbB,RAS and FoxO Pathways.The key genes were mainly distributed in lung,red blood cell,T cell and B cell.Molecular docking results showed that EGFR had strong binding ability to luteolin,IL-6,MAKP3 to ?-sitosterol,and MAKP8 to ellagic acid.3 To observe the effect of Qijia fuzheng formula on the prevention and treatment of cancer-induced fatigue of lung cancer and the mechanism of immune inflammation?Compared with the control group,the mice in the tumor-bearing group gradually showed dry hair,fatigue,weakened grasping resistance,decreased activity and other conditions during the experiment,and the first mouse died before sampling.Compared with the control group,the frequency of electric shock increased in the tumor-bearing group on the 14th,17th and 21st days(P<0.05).Compared with the control group,the immobilization time of tail suspension in the tumor-bearing group was longer on day 7,14,17 and 21(P<0.05).Compared with the control group,the ATP content in skeletal muscle of mice in tumor-bearing group was decreased(P<0.05).Compared with the control group,the white blood cell count was increased,the red blood cell count was decreased and the hemoglobin content was decreased in the tumor-bearing group(P<0.05).?Compared with the tumor-bearing group,with the extension of the experiment time,the traditional Chinese medicine group was better than the tumor-bearing group in terms of hair dryness,fatigue,grasping resistance and activity.Compared with the tumor-bearing group,the frequency of electric shock in the TCM group on the 21st day was lower than that in the tumor-bearing group(P<0.05).Compared with the tumor-bearing group,the immobility time of tail suspension in TCM group was lower than that in tumor-bearing group on days 14,17 and 21(P<0.05).Compared with the tumor-bearing group,the content of ATP in skeletal muscle of mice in TCM group was higher than that in tumor-bearing group(P<0.05).Compared with the tumor-bearing group,the WBC count decreased,the RBC count increased and the hemoglobin content in the TCM group was higher than that in the tumor-bearing group(P<0.05).?Compared with the control group,the percentages of CD3+and CD4+and the ratio of CD4+to CD8+in the peripheral blood of mice in the tumor-bearing group were decreased,with statistical significance(P<0.05).Compared with the tumor-bearing group,the percentages of CD3+and CD4+in the peripheral blood of mice in the TCM group were higher than those in the tumor-bearing group,and the ratios of CD4+and CD8+were higher than those in the tumor-bearing group,with statistical significance(P<0.05).Compared with the control group,the expressions of IL-1?,IL-6,IL-17 and CD25 in the peripheral blood of mice in the tumor-bearing group were increased,with statistical significance(P<0.05).Compared with the tumor-bearing group,the expressions of IL-1?,IL-6,IL-17 and CD25 in the peripheral blood of mice in the TCM group were decreased,with statistical significance(P<0.05).?Compared with the tumor-bearing group,the volume of mice in the TCM group was less than that in the tumor-bearing group on the 7th,10th and 14th days after intervention(P<0.05).Compared with the tumor-bearing group,the tumor weight in the TCM group was lower than that in the tumor-bearing group(P<0.05).Compared with the tumor-bearing group,the division of tumor cells in the TCM group was less than that in the tumor-bearing group,and the number of Ki67 positive cells in the TCM group was lower than that in the tumor-bearing group.?Compared with the tumor-bearing group,the tumor body p-Akt and AKT/p-Akt in TCM group were lower than those in tumor-bearing group(P<0.05).Compared with the tumor-bearing group,the number of c-Myc positive cells in the TCM group was lower than that in the tumor-bearing group.Conclusion1 Qijia Fuzheng prescription is an effective drug to treat spleen and kidney deficiency lung cancer fatigue and improve the living ability of patients.2 The mouse model of cancer-induced fatigue of lung cancer can be successfully established by tumor transplantation induction.Qi Jia Fuzheng Decoction alleviates the fatigue degree of the mouse model of cancer-induced fatigue induced by transplanted tumor.Qijiafuzheng formula can improve the immune function related to T lymphocytes in mouse model of cancer induced fatigue,reduce the expression of IL-?,IL-,IL-and CD released by each subtype of CD4+T lymphocytes,inhibit the proliferation mediated by Akt activation,and thus play an anti-cancer effect on cancer induced fatigue. |
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