| ObjectiveThis study sorts out the source of the method of soothing the liver and harmonizing stomach,and discusses the clinical application of Shuganhewei Decoction in treating depression with liver-stomach discord(incoordination between liver and stomach).Preliminary research of active ingredients of Shuganhewei Decoction,combined with network pharmacology to predict the antidepressant targets and signal pathways of Shuganhewei Decoction,and study the antidepressant mechanism of Shuganhewei Decoction via the PI3K/Akt pathway.In-depth study of the antidepressant-related signal pathways of traditional Chinese medicine compounds provides experimental evidence.Methods1.Theoretical study:Using the literature analysis method to sort out the academic sources of the method of soothing the liver and harmonizing stomach.Summarizing the understanding and application of ancient and modern physicians on the soothing of the liver and the stomach.Discuss the clinical application of self-desighed Shuganhewei Decoction.Collect and sort out the literature on depression,discuss the relationship between PI3K/Akt signaling pathway and the pathogenesis of depression.2.Experimental study:(1)Modeling and evaluation: using chronic unpredictable stress combined with orphaning for 5 weeks,giving Shuganhewei Decoction low,medium and high doses and fluoxetine intervention for 14 days,using sugar water consumption experiment,open field experiment for behavior evaluation.(2)Determination of the chemical components of Shuganhewei Decoction in vivo and in vitro: HPLC-TOF-MS/MS was used to detect the ingredients of Shuganhewei Decoction and the blood serum of the medicated depression model rats.(3)Prediction of antidepressant targets and related signal pathways of of Shuganhewei Decoction components in blood: using network pharmacology technology to obtain the key antidepressant effect of Shuganhewei Decoction targets and signal pathways.(4)Detection of related indicators: ELISA was used to detect the content of serum brain-derived neurotrophic factor(BDNF)in depression model rats.Western blot(WB)was used to detect the expression of PI3 K,p-PI3 K,Akt,p-Akt,PTEN,BDNF and NR1 in the hippocampus(HIP)and prefrontal cortex(PFC).Results1.Theoretical study:(1)From the "The Medical Classics of the Yellow Emperor",it was put forward that "earth being dredged by wood".After the long-term clinical practice and experience of doctors of the past dynasties,the theory was gradually improved until the Ming and Qing Dynasties formally formed the liver and stomach method and a large number of related representatives emerged Prescription drugs.(2)Shuganhewei Decoction is used to treat depression with liver-stomach discord.The treatment method is mainly to soothe the liver and relieve depression,regulate qi and stomach,and then add or subtract drugs and dosages according to the heaviness of qi,blood,body fluid,yin and yang disorders,which can often be obtained clinically Better curative effect.(3)The PI3K/Akt signaling pathway can inhibit neuronal cell apoptosis and enhance synaptic plasticity in multiple ways.The treatment of depression with traditional Chinese medicine may be through the PI3K/Akt signaling pathway.2.Experimental study:Experiment 1: Behavioral changes of depression model rats and the effect of Shuganhewei Decoction(1)After chronic unpredictable stress combined with orphan breeding methods and gavage treatment,compared with the blank group,the rats in the model group are lighter and have a significant increase in body weight Decrease(P<0.01);Compared with the model group,the weight of rats in each treatment group increased,and the weight growth rate increased significantly(P<0.01 or P<0.05).(2)Compared with the blank group,the sugar water preference rate of the model group decreased significantly(P<0.01).Compared with the model group,the sugar water preference rate of each treatment group was significantly increased(P<0.05 or P<0.01).(3)Compared with the blank group,the total movement distance of the model group was significantly shortened(P<0.01);compared with the blank group,the static time of the model group was significantly longer(P<0.01);compared with the blank group,the number of times the model group traversed the central area was significantly reduced(P<0.01).Compared with the model group,the total distance of exercise in each drug group was significantly shortened,the resting time was significantly extended,and the number of crossing the central area was significantly reduced(P<0.05 or P<0.01).Experiment 2: Study on the in vivo and in vitro chemical components of Shuganhewei Decoction for antidepressant.Using HPLC-TOF-MS/MS technology,39 in vitro chemical components of Shuganhewei Decoction were detected,and 8 prototype components were detected in the medicated serum.4 metabolic components.Experiment 3: Using network pharmacology technology to explore the antidepressant mechanism of Shuganhewei Decoction.The blood components of Shuganhewei Decoction were analyzed by network pharmacology,and 45 potential targets were obtained,and 1578 targets related to depression diseases were obtained,of which Shuganhewei Decoction has 25 antidepressant targets.The GO biological process and the enrichment analysis of KEGG signal pathway are carried out.It is speculated that Shuganhewei Decoction may be involved in 31 biological processes including DNA template transcription regulation and negative regulation of cell apoptosis by regulating targets such as RAF1,TP53,BCL2,CASP3,JUN,and regulating such as TNF,MAPK,PI3K/Akt and NF-κB Signal pathways play an antidepressant effect.Experiment 4: Effect of Shuganhewei Decoction on the expression of PI3K/Akt pathway related proteins in hippocampus and prefrontal cortex of depression model rats(1)The relative expressions of PI3 K and Akt total protein in hippocampus and prefrontal cortex of rats in each group were not significantly different(P>0.05).(2)Compared with the blank group,the expression of p-PI3 K in the hippocampus of the model group was significantly reduced(P<0.01);compared with the model group,the expression of p-PI3 K in the hippocampus of each administration group was significantly increased(P<0.05 or P<0.01).Compared with the Sini Powder group,the expression of p-PI3 K in the hippocampus was significantly increased in the low and high dose groups of Shuganhewei Decoction(P<0.05 or P<0.01).Compared with the blank group,the expression of p-PI3 K in the prefrontal cortex of the model group was significantly reduced(P<0.01);compared with the model group,the expression of p-PI3 K in the prefrontal cortex of the Shuganhewei Decoction low and high dose groups and the fluoxetine group were obvious increased(P<0.05 or P<0.01);compared with the Sini powder group,the expression of p-PI3 K in the prefrontal cortex of the Shuganhewei Decoction high-dose group was significantly increased(P<0.05).Compared with the blank group,the expression of p-Akt in the hippocampus of the model group was significantly reduced(P<0.01);compared with the model group,the expression of p-Akt in the hippocampus of each administration group increased(P < 0.05 or P <0.01).Compared with the Sini Powder group,the expression of p-Akt in the hippocampus was significantly increased in the low-dose and high-dose groups of Shuganhewei Decoction and the fluoxetine group(P<0.05 or P<0.01).Compared with the blank group,the expression of p-Akt in the prefrontal cortex of the model group was significantly reduced(P<0.01);compared with the model group,the expression of p-Akt in the prefrontal cortex of the Shuganhewei Decoction low and high dose groups and the fluoxetine group were significantly reduced increase(P<0.05 or P<0.01).Compared with the Sini Powder group,the expression of p-Akt in the prefrontal cortex was significantly increased in the low and high dose groups of Shuganhewei Decoction and the fluoxetine group(P<0.05 or P<0.01).(3)Compared with the blank group,the expression of PTEN in the hippocampus and prefrontal cortex of the model group was significantly increased(P<0.01);compared with the model group,the expression of PTEN in the hippocampus and prefrontal cortex of rats in each administration group was significantly reduced(P < 0.05 or P < 0.01)Compared with the Sini Powder group,the hippocampal PTEN expression was more in the Shuganhewei Decoction low and high groups and the fluoxetine group,and the PTEN expression in the prefrontal cortex was less(P<0.05 or P<0.01).Experiment 5: The effect of Shuganhewei Decoction on the changes of serum,hippocampus and prefrontal cortex BDNF and NR1 protein in depression model rats(1)Compared with the blank group,the serum BDNF content of the model group was significantly decreased(P<0.01);compared with the model group,Shuganhewei Decoction low and high dose group and fluoxetine group serum BDNF content significantly increased(P <0.01 or P <0.05).(2)Compared with the blank group,BDNF in the hippocampus and prefrontal cortex of the model group was significantly reduced(P<0.01);compared with the model group,the expression of BDNF in the hippocampus and prefrontal cortex of each administration group was significantly increased(P < 0.01 or P < 0.05);Compared with Sini Powder group,the expression of BDNF in hippocampus and prefrontal cortex of Shuganhewei Decoction low and high dose groups and fluoxetine group increased(P<0.01 or P<0.05).(3)Compared with the blank group,the expression of NMDR1 in the hippocampus and prefrontal cortex of the model group was significantly reduced(P<0.01);compared with the model group,the expression of NMDR1 in the hippocampus and prefrontal cortex of each administration group was significantly increased(P<0.05 or P<0.01);Compared with the Sini Powder group,the expression of NMDR1 in the prefrontal cortex of the Shuganhewei Decoction low and high dose groups and the fluoxetine group was significantly increased(P<0.01 or P<0.05).Conclusion(1)Based on the physiological and pathological connection of liver,spleen,and stomach,physicians of the previous dynasties gradually developed,perfected,and expanded the cause,mechanism,and treatment of the same diseases of liver and stomach,and proposed the method of soothing the liver and harmonizing stomach and related representative prescription drugs.The national master of traditional Chinese medicine Mei Guoqiang expanded the clinical application of classical prescription Based on Sini Powder,he formulated Soothing Liver and Harmonizing Stomach Decoction as the basic prescription to treat disharmony between liver and stomach The main symptoms of clinical patients are depression and gastric discomfort.The pathogenesis is examined together with tongue and pulse.If liver-qi stagnation is the main symptom,the yin and yang imbalance of Qi,blood and body fluid should be distinguished.The treatment method is to soothe the liver and relieve depression,regulate qi and harmony.Stomach is the mainstay,and treatment with Shugan Hewei Decoction can often achieve better results.(2)The traditional Chinese medicine compound may activate the PI3K/Akt signaling pathway,inhibit neuronal cell apoptosis,enhance synaptic plasticity,and thus exert the antidepressant effect.(3)The blood components of Soothing Liver and Harmonizing Stomach Decoction include Naringin,Neohesperidin,Berberine,Costunolide,Nobiletin Dehydroevodiamine,Palmatine hydrochloride and Glycyrrhizic acid,etc.ingredient.Shuganhewei Decoction may have antioxidant effects,regulate depression-related enzymes,or regulate inflammatory factors and related pathways,enhance neurotrophic factor expression,improve neurotransmitter levels,and inhibit neuronal cell apoptosis to exert antidepressant effects.(4)Shuganhewei Decoction may also be involved in biological processes such as DNA template transcription regulation and negative regulation of cell apoptosis by regulating gene targets such as RAF1,TP53,BCL2,CASP3,JUN,and regulating such as TNF,MAPK,PI3K/Akt and NF-κB Signal pathways,and promote cell proliferation,reduce cell apoptosis,reduce inflammation,protect neurons,and exert antidepressant effects to treat depression.(5)Shuganhewei Decoction can increase the expression of NR1 receptors in the hippocampus and prefrontal cortex;increase the content of serum,hippocampus and prefrontal cortex BDNF;up-regulate the levels of phosphorylated PI3 K and Akt in the hippocampus and prefrontal cortex,and down-regulate PTEN Improve the activity of the PI3K/Akt signaling pathway,thereby cooperating with multiple downstream apoptotic pathways to promote neuronal development,survival,repair and reduce neuronal apoptosis,improve synaptic plasticity and play an antidepressant effect. |
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