| Objective: 1)To understand the distribution of direct symptoms and their clinical significance in patients with insomnia through a multi-center cross-sectional study.2)To evaluate the clinical efficacy of Yanggan Anhun Decoction in the treatment of insomnia of liver not storing sou type through a single-center prospective study.3)Based on the TCM inheritance computing platform,the prescription analysis of Zhang Xingping for the treatment of insomnia of liver not storing sou type was conducted.4)To explore the impact of Yanggan Anhun Decoction in the treatment of insomnia of liver not storing sou type based on p38MAPK signaling pathway.Methods: 1)A multi-center cross-sectional study was conducted to select the case data in accordance with the standards of emissions and discharges from 9 hospitals for analysis.2)186 insomnia of liver not storing sou type patients were randomly divided into a western medicine group,a traditional Chinese medicine group,and a combined group according to the ratio of 1:1:1,with each group stopping medication after 30 days of treatment;the case collection and shedding reasons were analyzed.The PSQI,TCMP,therapeutic effect of sleep quality and syndromes in TCM of the three groups were compared,and adverse reactions were recorded;the recurrence indexes of the three groups were compared within 30 days after medication withdrawal.3)The medical records of insomnia of liver not storing sou type were collected,and the frequency of drug use,sex,taste,and meridians,and efficacy of the prescription drugs were statistically analyzed by association rules,clustering,and factor analysis methods;the highfrequency drug combinations,high-frequency drug factors,and core combinations of traditional Chinese medicine based on association rules and cluster analysis were obtained.4)The drug components,action targets,and insomnia of liver not storing sou type disease targets of Yanggan Anhun Decoction were retrieved,and the signaling pathway and targets of Yanggan Anhun Decoction in the treatment of insomnia of liver not storing sou type were determined by topology analysis,GO analysis,KEGG analysis,and molecular docking.5)SPF male SD rats were randomly divided into normal group,model group,western medicine group,agonist group,inhibitor group and Yanggan Anhun Decoction low,medium and high dose groups,a total of 8 groups,6 rats in each group;insomnia of liver not storing sou type model rats were established by compound multi-factor stimulation method,and each group was given drug intervention for 14 days;ECG/EMG and pentobarbital sodium sleep experiment were used to monitor the sleep of rats;Morris water maze and open field experiment were used to detect behavioral changes;HE,Nissl staining and modified Bielschowsky nerve staining were used to observe the pathological morphological changes of hypothalamus;TUNEL staining was used to detect the apoptosis of hypothalamus cells;IHC,WB and RT-q PCR were used to detect the protein expression levels and mRNA relative expression levels of IL-6,TNF-α,p38MAPK,Bcl-2,Bax and Caspase-3 in hypothalamus;biochemical instrument was used to detect eight items of liver function and three items of renal function in each group.Results: 1)The direct symptoms of insomnia were multiple dreams in night sleep,difficult to fall asleep,various thoughts before asleep,light and easy to awakening in night sleep,and early awakening in night sleep,and no other direct symptoms were found except the above five categories or different permutations of the above five categoriest;the direct symptoms of insomnia with a single type accounted for about 37.92% of all patients,and the composite type accounted for about 62.08%;there were differences in gender distribution,average age,occupational nature,marriage and education status among patients with different primary diseases(P<0.05);the ratio of male to female patients was 1:1.52;the population aged 41 years and over was the main body of insomnia patients,accounting for 79.51%;among the five different primary diseases,the average age of patients with various thoughts before asleep was younger,and the average age of patients with early awakening in night sleep was older;the main direct symptoms of insomnia were difficult to fall asleep,light and easy to awakening in night sleep,multiple dreams in night sleep,early wake up in night sleep,and various thoughts before asleep,respectively.2)There were no differences in the shedding of cases,the distribution of causes,and the baseline data of patients among the three groups(P>0.05);the PSQI and TCMP in the TCM group and the combined group were lower than those before treatment(P<0.05),and only the PSQI in the western medicine group was lower than that before treatment(P<0.05);there were significant differences among the three groups in sleep disorders,daytime dysfunction,nighttime dreaminess,dizziness,tinnitus,chest pain,dry mouth and forgetfulness(P<0.05);there were statistically significant differences in the therapeutic effect of syndromes in TCM in the three groups after treatment(P<0.05);the recurrence rate after drug withdrawal was 44.64% in the western medicine group,31.48% in the TCM group,and 21.02% in the combined group,with the PSQI score of the relapse patients in the western medicine group > the TCM group > the combined group(P<0.05);the adverse reaction rate in the TCM group and the combined group was lower than that in the western medicine group(P<0.05).3)A total of 305 prescriptions were included,involving 136 flavors of TCM,and the top 10 frequency of TCM use was more than 220 times;the main medicinal properties were cold,warm,and flat,the most bitter flavor,and the spleen meridian,liver meridian,and heart meridian were common;the main effects were regulating qi,tonifying deficiency,clearing heat and calming the mind.Based on association rules,178 groups of high-frequency drug combinations were obtained;based on cluster analysis,4core drug combinations were obtained;the cumulative contribution rate of 10 common factors of high-frequency drugs in 305 prescriptions was 66.49%.4)A total of 301 active ingredients,321 potential targets and 20 key targets were screened out.Kaempferol,quercetin,and rehmannia glutinosa flavonoids had good binding activity and stability with MAPK,TNF,and IL-6;the overall binding ability of MAPK14 target protein with each compound was the best.5)Yanggan Anhun Decoction could increase SWS and TST of model rats(P<0.05),reduce REMS(P<0.05),shorten sleep latency(P<0.05),and prolong sleep time(P<0.05).Yanggan Anhun Decoction could shorten the total distance of water maze and escape latency of model rats(P<0.05),increase the number of standing times,central duration,central activity distance,total activity time and total distance of open field experiment(P<0.05),and reduce defecation times(P<0.05);Yanggan Anhun Decoction could increase the number of Nissl bodies in hypothalamus of model rats(P<0.05),improve the morphological structure of hypothalamic neuronal cell body,Nissl body disintegration,glial cell/interstitial lymphocyte infiltration and nerve fiber arrangement in hypothalamus of model rats;Yanggan Anhun Decoction could improve apoptosis of hypothalamus cells in model rats(P<0.05),reduce the protein and mRNA relative expression of IL-6,TNF-α,p38MAPK,Caspase-3,and Bax(P<0.05),and increase the protein and mRNA relative expression of Bcl-2 and Bcl-2/Bax ratio(P<0.05);there were no differences in eight items of liver function and three items of kidney function among the groups(P>0.05).Conclusion:1)The direct symptoms of insomnia patients can be divided into five types: multiple dreams in night sleep,difficult to fall asleep,various thoughts before asleep,light and easy to awakening in night sleep,and early awakening in night sleep;most patients showed different permutations of the above five types,and multi-center cross-sectional studies did not find the existence of other direct symptoms of insomnia except for the above five types or different permutations of the above five types.2)Yanggan Anhun Decoction can improve the sleep quality of patients with ILNSS,improve the discomfort symptoms;combined with Western medicine can increase the effect and reduce the side effects,reduce the recurrence rate of the disease,prolong the recurrence time and reduce the severity of the recurrence.3)Professor Zhang Xingping treated insomnia of liver not storing sou type from the liver,spleen,lung and heart,treats both tonic and drainage,both deficiency and excess,and focuses on soothing liver,relieving depression and soothing soul.4)Yanggan Anhun Decoction can improve insomnia of liver not storing sou type by inhibiting p38MAPK signaling pathway,reducing neuroinflammatory response,inhibiting apoptosis. |
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