| ObjectiveThis study summarizes the understanding of the etiology and pathogenesis of normal and abnormal eating in Treatise on Febrile Diseases and Miscellaneous Diseases by analyzing the articles related to abnormal feeding in Treatise on Febrile Diseases and Miscellaneous Diseases.The main gene targets leading to abnormal feeding in depression and the targets and signaling pathways of antidepressant active ingredients of Shugan Hewei Decoction were predicted by systematic pharmacology,the changes of Ghrelin/GOAT/GHS-R1a system and LEAP2 were studied via animal experiment,through these study,this paper explained the possible causes of abnormal food intake in syndrome of disharmony between liver and stomach and therapeutic mechanism of Shugan Hewei Decoction in regulating abnormal food intake and provide experimental evidence for further study on the mechanism of traditional Chinese medicine compound treatment of abnormal food intake in depression syndrome.Method1 Theoretical research:Using the method of literature analysis,the full text of "Treatise on Febrile Diseases and Miscellaneous Diseases" was searched with keywords such as "hunger","eat","loss of appetide","can’t eat","diarrhea",etc.In Treatise on Febrile Diseases and Miscellaneous Diseases,the articles clearly describe food intake and abnormal food intake.Through the analysis of the articles,the necessary conditions for normal food intake and the etiology and pathogenesis of abnormal food intake are summarized.2 Systematic pharmacology research:the active ingredients and target information of Shugan Hewei Decoction（Bupleurum,Citrus,Baishao,Turmeric,Amomum,Atractylodes,Rhizoma Coptidis,Evodia,Muxiang,Licorice）were searched in the TCMSP database.Oral bioavailability（OB）value ≥ 30%and drug similarity（DL）value ≥0.18 were used as screening conditions,and the target genes were further screened and deduplicated.Search the GeneCards database,OMIM database,Disgenet database and TTD database with the keywords "depression","depressive disorder" and "major depressive disorder" to collect depression-related disease genes,and perform GO and KEGG on key target genes Enrichment analysis,protein interaction network analysis;at the same time,by drawing the drug active ingredient-target regulatory network,the overall relationship between the drug active ingredient and the target was evaluated,and the degree of connectivity between proteins was calculated with the help of Cytoscape software.The core protein is docked with the main active components by the relative size of the connectivity,and a multi-dimensional network of "component-target-pathway-disease" is constructed.At the same time,the citespace software was used to include the 2000-2022 Web of Science core collection database of depression and brain-gut peptide research related literature for visual analysis.Method retrieval,visual analysis of the keywords in the field of depression and brain-gut peptides,and research of the most relevant brain-gut peptides in the two fields.By combining the result above to explore the potential molecules of Shugan Hewei Decoction in the treatment of depression Mechanisms,key target genes and potential signaling pathways to predict its possible antidepressant and improved feeding mechanisms.3 Experimental study:The model was established by chronic unpredictable stress combined with the solitary method,and one stimulus was randomly selected every day:day and night reversed,water cut off for 24 h,fasting for 24 h,swimming in ice water at 4℃ for 5 min,tail cliPPIng for 1 min,shaking（1 time/s,lasted for 5 min）,restrained for 2 h,each stimulus was used an average of 6 times,and the model was established for a total of 6 w.After modeling,ELISA method was used to detect the content of AG,UAG and LEAP2 in peripheral blood of depression model rats,and the ratio of AG to UAG content was calculated.The expression of GOAT in gastric fundus and LEAP2 in liver was detected by RT-PCR.The optical density changes of Arc NPY and c-Fos in the hypothalamus were detected by double fluorescence immunoassay.Result1 Theoretical researchBy studying the symptoms related to food intake in Treatise on Febrile Diseases and Miscellaneous Diseases,the following conclusions are drawn:Normal eating depends on:①Healthy movement of the spleen and stomach:The spleen and stomach are external and internal.Mutual gain,rise and fall,dryness and dampness complement each other,and together complete the digestion of food and water;② Unobstructed qi of the fu-organs:the six fu-organs are used for smooth operation,and the smoothness of the fu-organs can transfer water and food,so that the stomach can accept food and water normally;③ Harmony of the liver and stomach:The normal dredging of the liver is the premise of the passage of the stomach qi,and the stomach qi is harmonious and the person can eat.Dysfunction of the spleen and stomach caused by various reasons can cause abnormal food intake,showing symptoms such as "no appetite" and "can’t eat":①If the stomach qi is healthy and strong,the stomach is decomposed and the spleen’s transportation and transformation functions are normal.It can be seen that the person wants to eat,and there is no special discomfort after eating;②Cold pathogens attack the stomach and injure the yang qi and cannot eat,and heat pathogens attack the stomach and stomach heat,which can be seen to eliminate grain and improve hunger.The change in food intake is used to distinguish the pathogens from cold and heat;③Cold pathogens are abundant in the interior,greatly injure the spleen and yang,and the cold nature is absorbed.Stagnation,the pulse is tight,and the abdominal pain is acute,the patient does not want to eat,accompanied by severe abdominal pain,cannot be approached,the spleen and stomach are deficient and cannot be given water and fluids,and the stool is loose or loose after drying.④Stomach-heat syndrome is too hot for stomach-fire to be excessively rotten,which can eliminate grain and help hunger;⑤if the pathogen is in the stomach,it is more common to vomit in the morning and evening,the shorter the time between vomiting and eating,the higher the position of the blockage;⑥Abdominal distension,stomach disease is more common,stomach qi is reversed,can not eat and vomit;⑦ Stomach dryness becomes solid,and stomach qi is blocked,stomach qi does not descend,and stomach qi is still able to pass through.When descending,we can see the evidence of Yangming Fu and the ability to eat;⑧Liver failure to disperse,wood stagnation and soil,liver and stomach disharmony,lack of appetite and depression;⑨ No fever or slight fever after normal eating,prolonged If the sick person has a slight heat after eating,it may be a manifestation of stomach qi coming back and forth.If it is a severe fever,it means that the stomach qi has deteriorated,and the absolute yang qi is exposed to the outside,and the prognosis is poor.Both depression and liver-stomach discord syndrome can be caused by long-term external negative stimuli.Liver-stomach discord syndrome manifests as emotional depression,decreased food intake,depressed and loss of appetite,which is similar in symptoms to depression.Preliminary studies have shown that DA neurons in the VTA area of depression model rats have changed,and Shugan Hewei Decoction,which treats liver-stomach disharmony,can increase the body weight of CUMS rats and improve HPA axis hyperfunction.The contents of DA,5-HT,5-HIAA,NE,GABA and other neurotransmitters in the body,regulating the PFC-NAc-VTA neural circuit and other pathways play an antidepressant effect,indicating that the liver-stomach disharmony syndrome and depression are similar in the etiology,symptoms and treatment.2 Systems pharmacology research152 potential target genes were obtained by searching the active ingredients and target information of Shugan Hewei Decoction in TCMSP database.A total of 10,067 genes related to major depression were obtained by collecting major depressive disorder-related disease genes.Using the depression-related dataset of the GEO database,3213 differential genes were identified based on depression samples and Control samples.The obtained active ingredient target genes,disease genes and differential genes were intersected,and a total of 40 intersecting genes were obtained as key target genes.The gene differential expression analysis of depression patients and control samples（Control）showed that the expression of LEP,which is directly related to feeding,was up-regulated,and the Leptin protein encoded by LEP could antagonize the feeding effect of Ghrelin by inhibiting the activation of NPY neurons.For 874 papers in the field of depression and brain-gut peptides from 2000 to 2022,the Duplicates Removal function of CiteSpace software was used to exclude 56 papers,including proofreading notices,editing materials,conference papers and retraction notices,and a total of 818 papers were included.Using CiteSpace software to sort out high-frequency shared keywords in 818 literatures in the field of depression and brain-gut peptides,it is found that food intake in the somatic symptoms of depression is concerned by researchers;the brain-gut peptide keyword with the highest centrality is Ghrelin,indicating that Ghrelin closely related to depression.The above studies indicated that both Leptin and Ghrelin acted on the changes of food intake and body weight in depression model rats.3 Experimental studiesExperiment 1 Effects of Shugan Hewei Decoction on the changes of behavior and body weight in depression model rats①Effect of Shugan Hewei Decoction on the body weight of depression model rats:After 6 weeks of modeling,compared with the blank group,the body weight of the model group was significantly decreased（P<0.01）;The body weight of the low-dose and high-dose groups increased（P<0.05 or P<0.01）;compared with the anamorelin group,the body weight of the Shuganheweitang high-dose group increased（P<0.05）.It shows that the body weight of rats decreases after modeling,and Shugan Hewei Decoction can promote the body weight of depression model rats,and its effect is better than that of anamorelin at high doses.② The effect of Shugan Hewei Decoction on the change of sugar water preference rate in depression model rats:Compared with the blank group,the sugar water preference rate of the rats in the model group decreased（P<0.01）;The preference rate of sugar water increased in the dose group（P<0.01 or P<0.05）;compared with the anamorelin group,there was no significant difference in the preference rate of sugar water between the low and high dose groups of Shugan Hewei Decoction.It shows that Shugan Hewei Decoction can improve the preference of sugar water in depression model rats,and its effect is not significantly different from that of anamorelin.③The effect of Shugan Hewei Decoction on the open field distance of depression model rats:Compared with the blank group,the open field distance of the rats in the model group decreased（P<0.01）;compared with the model group,the high dose of Shugan Hewei Decoction Compared with the anamorelin group,the low-dose and high-dose Shuganheweitang groups increased the active distance（P<0.01 or P<0.05）.It shows that Shugan Hewei Decoction can increase the activity distance of depression model rats in an open box within 5 minutes,and its effect is better than that of anamorelin.④The effect of Shugan Hewei Decoction on the immobility time of forced swimming in depression model rats:Compared with the blank group,the immobility time of forced swimming in the model group increased（P<0.01）;Compared with the blank group,the immobility time of forced swimming in the high and low dose group were decreased（P<0.01）.Compared with the anamorelin group,the immobility time in the high-dose Shuganheweitang group decreased（P<0.05）.It is indicated that Shugan Hewei Decoction can shorten the forced swimming immobility time of depression model rats,and its effect is better than that of anamorelin at high dose.Experiment 2 Effect of Shugan Hewei Decoction on Serum Ghrelin Acylation in Depressed Model Rats①The effect of Shugan Hewei Decoction on the content of AG in serum:Compared with the blank group,the serum AG content of the rats in the model group was significantly decreased（P<0.01）;Serum AG content was increased（P<0.01）;compared with anamorelin group,serum AG content of Shuganheweitang low and high dose groups was increased（P<0.01）.It shows that the serum AG content of rats decreases after modeling,and Shugan Hewei Decoction can increase the serum AG content of depression model rats,and its effect is better than that of anamorelin.②The effect of Shugan Hewei Decoction on the content of UAG in serum:Compared with the blank group,the serum UAG content of the depression model rats was significantly decreased（P<0.01）;Compared with the model group,the serum UAG content was higher than that in the model group（P<0.01 or P<0.05）;compared with the anamorelin group,the serum UAG content of the Shuganheweitang low and high-dose groups were all higher than those of the model group（P<0.01 or P<0.05）.It shows that the content of UAG in serum of rats decreases after modeling,and Shugan Hewei Decoction can increase the content of UAG in depression model rats,and its effect is better than that of anamorelin.③The effect of Shugan Hewei Decoction on the ratio of AG to total Ghrelin in serum:Calculate the ratio of AG to total Ghrelin（the sum of AG and UAG content）,compared with the blank group,the ratio of the model group decreased（P<0.05）;compared with the model group,high dose group showed increase in the ratio（P<0.05）.Compared with the anamorelin group,the ratio of the high-dose Shuganheweitang group increased（P<0.05）.It showed that the acylation of Ghrelin in rat serum was weakened after modeling,and Shugan Hewei Decoction could promote the acylation of UAG,and its effect was better than that of anamorelin at high doses.Experiment 3 Effects of Shuganhewei Decoction on the expression and content of GOAT mRNA in the gastric fundus of rats①Effects of Shugan Hewei Decoction on the expression of GOAT mRNA in the gastric fundus of the depression model rats:Compared with the blank group,the expression of GOAT mRNA in the gastric fundus of the depression model rats was significantly decreased（P<0.01）;The expression of GOAT mRNA in gastric fundus was significantly increased in the low-dose and high-dose decoction groups（P<0.01）;compared with the anamorelin group,the expression of GOAT mRNA in the gastric fundus in the Shuganheweitang group was increased（P<0.01 or P<0.05）.It shows that the expression of GOAT mRNA in the gastric fundus of rats is reduced after modeling,and Shugan Hewei Decoction can increase the expression of GOAT mRNA in the gastric fundus of depression model rats,and its effect is better than that of anamorelin.② Effect of Shugan Hewei Decoction on the content of GOAT in the gastric fundus of the depression model rats:Compared with the blank group,the GOAT content in the gastric fundus of the depression model rats was significantly lower（P<0.01）;Compared with the model group,the GOAT content in the gastric fundus of rats in the high-dose group increased（P<0.05）;compared with the anamorelin group,the GOAT content in the low-dose and high-dose Shuganheweitang groups increased（P<0.05）.It shows that modeling can reduce the content of GOAT in the gastric fundus of rats,and Shugan Hewei Decoction can increase the content of GOAT in the gastric fundus of depression model rats,and its effect is better than that of anamorelin.Experiment 4 Effects of Shugan Hewei Decoction on the expression and content of LEAP2 in rat liver①The effect of Shugan Hewei Decoction on the expression of LEAP2 in the liver of rats:Compared with the blank group,the expression of LEAP2 mRNA in the liver of the model group was significantly increased（P<0.01）;compared with the model group,the low and high doses of Shugan Hewei Decoction The hepatic LEAP2 mRNA expression in the group was significantly decreased（P<0.01）;compared with the anamorelin group,the hepatic LEAP2 mRNA expression in the Shuganheweitang low and high-dose groups were both decreased（P<0.01,P<0.05）.Experiments showed that the expression of LEAP2 mRNA in the liver of rats increased after modeling,and Shugan Hewei Decoction could reduce the expression of LEAP2 mRNA in depression model rats,and its effect was better than that of anamorelin.②The effect of Shugan Hewei Decoction on the content of LEAP2 in the liver of rats:Compared with the blank group,the content of LEAP2 in the liver of the rats in the model group increased significantly（P<0.01）;Compared with the model group,the content of LEAP2 in the liver of high and low dose group are significantly decreased（P<0.01）;compared with the anamorelin group,the content in the high-dose group was lower（P<0.05）.The results showed that modeling could increase LEAP2 content in rat liver,Shugan Hewei Decoction could reduce LEAP2 content in depression model rats,and its effect was better than anamorelin at high dose.Experiment 5 Effects of Shugan Hewei Decoction on the expression of NPY and c-Fos in hypothalamus Arc of depression model rats①The effect of Shugan Hewei Decoction on the average optical density of NPY in the hypothalamus Arc area of hypothalamus of the depression model rats:Compared with the blank group,the average optical density of NPY in the hypothalamus Arc area of hypothalamus of the rats in the model group was significantly decreased（P<0.01）;Compared with the model group,the average optical density of NPY in the high-dose Shuganheweitang group was significantly increased（P<0.01）;compared with the anamorelin group,the average optical density of NPY in the high-dose Shuganheweitang group was significantly increased（P<0.01）..It showed that the average optical density of NPY in the Arc area of the hypothalamus decreased after modeling,and the high dose of Shugan Hewei Decoction could increase the average optical density of NPY in the Arc area of the hypothalamus,and its effect was better than that of anamorelin.②The effect of Shugan Hewei Decoction on the average optical density of c-Fos in the Arc area of the hypothalamus of rats:Compared with the blank group,the average optical density of c-Fos in the Arc area of the hypothalamus of the rats in the model group decreased significantly（P<0.01）;Compared with the model group,the average optical density of c-Fos in the low-dose and high-dose Shuganheweitang groups increased（P<0.05 or P<0.01）;compared with the anamorelin group,the high-dose Shuganheweitang group c-Fos mean optical density value increased（P<0.05）.The results showed that the model reduced the average optical density of c-Fos in the Arc area of the hypothalamus,and Shugan Hewei Decoction could increase the average optical density of c-Fos in the Arc area of the hypothalamus,and its effect was better than that of anamorelin at high doses.Conclusion1 The normal function of the spleen and stomach is the basis for the normal food intake of the body.If the spleen and stomach can not transport and transform food and water,the absorption of the stomach will be decomposed and the qi of the stomach will be disturbed.Symptoms of abnormal eating,such as eating" and"inability to eat".heat pathogen invading the stomach leads to stomach heat,and there may be abnormal feeding performance of swift digestion and rapid hungering.The normality of the liver’s dredging function has an important influence on the coordination of the rise and fall of the spleen and stomach qi.Regardless of the cause of "not wanting to eat" or "can’t eat",the spleen and stomach will be deficient,which will lead to soil（spleen）deficiencyr.2.The causes of depression and liver-stomach discord syndrome are both feeling negative external stimuli.Liver-stomach discord syndrome manifests emotional depression,decreased food intake,depressed mood,and silent desire to eat,which is related to depression.Decreased food intake has certain symptoms.similarity.Shugan Hewei Decoction can regulate DA neurons in the VTA region of depression model rats,indicating that there is a high similarity in etiology,symptoms and treatment between liver and stomach discord syndrome and depression.3 Through the gene differential expression analysis of depression patients and control samples（Control）,it was found that the expression of LEP,which is directly related to food intake,was up-regulated.Leptin encoded by LEP has the effect of inhibiting food intake and reducing body weight,and can also antagonize ghrelin by inhibiting the activation of NPY neurons.Ghrelin is closely related to the change of food intake in depression,and Shugan Hewei Decoction may regulate the mutual antagonism The neuropeptides exert antidepressant and food intake regulation effects.4 Shugan Hewei Decoction may improve the abnormal feeding through the following four aspects:①increase the expression and synthesis of Ghrelin;②promote the acylation of Ghrelin and increase the relative level of AG;③reduce the expression of LEAP2 and reduce the GSH-The inhibition of Rla promotes the activation of NPY neurons;④reduces the level of Leptin and increases the synthesis of NPY.Based on the above results,it shows that Shugan Hewei Decoction may play an antidepressant,improve abnormal feeding and increase body weight by regulating the Ghrelin/GOAT/GHS-Rla system and participating in the synthesis and secretion of LEAP2 and Leptin. |
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