| ObjectiveTo study experience of Ling-nan Liang’s spleen-stomach academic school in treating epigastric fullness(functional dyspepsia,FD),providing domestic and foreign gastroenterologists with clinical practice for the treatment of epigastric fullness(FD).To study the mechanism of Si-jun-zi decoction,which is the Liang’s academic school’s core prescription for Qi-nourishing and spleen-strengthening,to reveal the molecular mechanism of spleen-strengthening treatment for epigastric fullness(FD)and to provide new ideas and new targets for the study of the mechanism of traditional Chinese medicine.MethodsIn the literature review section,literature databases and ancient books were retrieved for reviewing the development of Liang’s academic school,the progress on pathogenesis of FD and the mechanism of Chinese medicine for gastrointestinal smooth muscle MLCK signaling pathway.In the academic school study section,data processing is performed on outpatient medical records of the second and third generation medical specialists of Liang’s academic school,and a standardized database is established for data mining.Frequency statistics,association rules analysis,factor analysis,etc.are used.The syndrome discrimination and treatment characteristic of the second generation physician Professor Huang Sui-ping and treatment characteristic of the third generation physician Professor Chen Yan and Professor Zhang Bei-ping were analyzed for summarizing the development and characteristic of the academic school treating epigastric fullness.In the experimental research section,the mechanism of the Calmodulin/MLCK signaling pathway was investigated in the model rats with spleen deficiency syndrome,which is the most common type of FD,and the core prescription Sijunzi decoction treating for the FD with the most common syndrome type spleen deficiency syndrome.Iodoacetamide gavage combined with irregulate eating,water environment platform standing method were used for spleen deficiency syndrome FD animal modeling,Model animals were given Si-jun-zi decoction and mosapride treatment.After the administration,gastric emptying was determined by semi-solid gastric emptying in each group.Western blotting and reverse transcription-polymerase chain reaction(RT-PCR)were used to detect changes in calmodulin and MLCK proteins and transcription levels in gastric fundus.In order to further verify the results of animal experiments,smooth muscle cells were isolated and cultured in vitro from the smooth muscle of the stomach of infant SD rats.Smooth muscle cells were treated with Si-jun-zi decoction in vitro and detect the changes of Calmodulin and MLCK protein and transcription levels by Western blotting and RT-PCR.ResultsThe results of the literature review indicate that Liang’s academic school started from Prof.Liang Nai-jin.After the development of the second and third generation of specialists,such as Prof.Huang Suiping,Prof.Chen Yan and Prof.Zhang Beiping,it gradually formed the characteristics of the Ling-nan region in the spleen-stomach theroy with unique academic therapies and excellent curative therapies.Functional dyspepsia has seen more progress in duodenal inflammation and intestinal microecology,which may be the breakout of FD pathogenesis research.There were only a few studies on the gastrointestinal smooth muscle MLCK signaling pathway in traditional Chinese medicine,or only targeting on gastric antrum and jejunum.There was no study on the mechanism of this pathway in proximal gastric smooth muscle cells.The research results of the academic school show that the specialists of the Liang’s academic school believe that “the weakness of the spleen-stomach and the disorder of Qi” are the core pathogenesis of epigastric fullness.Tonifying spleen-stomach treat the root and regulating Qi is the temporary solution.Codonopsis,Atractylodes,licorice,Astragalus always used for tonifying spleen Qi,and ginger for tonifying spleen Yang,Adenophora,Ophiopogon japonicus and Polygonatum odoratum tonifying for stomach Yin.Xiang-sha-liu-jun-zi decoction,Bu-zhong-yi-qi decoction,Huang sui-ping’s Jian-pi-li-qi decoction are frequently used based on Si-jun-zi decoction,Li-zhong decoction and Yi-wei decoction."elevating spleen Qi" and "descending stomach Qi" are the most common method for regulating spleen-stomach Qi.Astragalus,Cimicifuga,Bupleurum,Radix Astragali and Bu-zhong-yi-qi decoction,Sheng-yang-yi-wei decoction often for elevating spleen Qi,and Magnolia and Pinellia for descending stomach Qi,which can dry dampness and resolve phlegmas suitable for Ling-nan region as well.Clearing liver combining with adjusting stomach and strengthening spleen are commonly used for regulating liver’s Qi.For patients with hepatogastric disharmony and spleen deficiency and dampness,some of specialists of Liang’s school use Xiao-chai-hu decoction for treatment.For patients with liver depression and spleen deficiency,Chai-shao-liu-jun-zi decoction is used for treatment.Spleen and stomach are always cared,once the patient shows spleen deficiency,the cold and cool drugs are disabled immediately to prevent injurying the spleen and stomach.In addition,the Liang’s specialists like to use rhizoma corydalis and turmeric,which can relieve pain and regulate Qi.The experimental results showed that after the spleen-deficiency syndrome FD compounding model,the rats contracted,the response was dull,the back hair was dry,the fatigue was weak,the lazy movement,the food intake was reduced,the stool was not formed,and the body weight was significantly reduced compared with the normal group,consistent with the spleen deficiency syndrome.The body weight of the rats decreased significantly after modeling(P<0.001).There was no significant difference in body weight between the model groups(P=0.391).The rats’ food intake decreased significantly,and the difference was statistically significant(P<0.001)There was no significant difference in food intake between the model groups(P=0.569).After intervention of Si-jun-zi decoction and Mosapride,the activity of rats was more active than before,the response was more agile than before,and the stools returned to normal.The average weight of rats in Sijunzi decoction group increased,and the difference was statistically significant(P=0.006).The weight of the rats in the mosapride group were lower than those in the model group,and the difference was statistically significant(P=0.0015).The food intake in Sijunzi decoction group increased,and the difference was statistically significant(P<0.001).After the intervention of Sijunzi decoction,the gastric emptying rate of rats increased,and the difference was statistically significant(P=0.002).The gastric emptying rate of rats in the mosapride group also increased compared with the model group,and the difference was statistically significant.(P=0.007).The expression of Calmodulin and MLCK protein in gastric fundus smooth muscles of FD rats with spleen deficiency syndrome was higher than that in control group.The difference of MLCK expression was statistically significant(P<0.0001),but the difference of Calmodulin was not statistically significant(P=0.386);After Si-jun-zi decoction intervention,the expression of Calmodulin and MLCK decreased,and the difference of MLCK expression was statistically significant(P<0.0001).However,the difference of Calmodulin was not statistically significant(P=0.140).The results of the mosapride intervention group were similar to those of the Sijunzi decoction group.The difference between the MLCK and the model group was statistically significant(P<0.0001),while there was no significant difference between the Calmodulin(P=0.623).The relative expression of MLCK m RNA in the gastric fundus smooth muscles of spleen deficiency syndrome model rats was higher than that in the control group(P<0.0001).The expression of MLCK m RNA was decreased after Si-jun-zi decoction intervention(P=0.0002).Mosapride intervention also decreased the expression of MLCK m RNA in smooth muscle,and the difference was statistically significant(P=0.0001).The activity of Myosin ATPase in FD rats with spleen deficiency syndrome was increased,and the difference was statistically significant(P<0.0001).After the intervention of Si-jun-zi decoction,the activity of Myosin ATPase was decreased,and the difference was statistically significant(P<0.0001).After mosapride intervention,the decrease of ATPase activity was statistically significant(P=0.0019).In vitro,the effect of Si-jun-zi decoction on the expression of MLCK protein in smooth muscle cells(SMCs)of rat stomach was decreased,and the concentration of Sijunzi decoction solution was dose-dependent.The expression of MLCK was down-regulated when the concentration of Si-jun-zi decoction was higher,with a statistically significant difference in concentration of 12 mg/m L and 15 mg/m L(P=0.0474,0.0072).However,although the expression of Calmodulin decreased,the difference with the control group was not statistically significant(P>0.05).Si-jun-zi decoction decreased the expression of MLCK m RNA in SMCs of gastric fundus in rats,and was dose-dependent with the increase of Sijunzi decoction concentration.The higher concentration of Sijunzi decoction(12 mg/m L,15 mg/m L)decreased the expression of MLCK m RNA.Obviously,the difference was statistically significant(P=0.0173,<0.0001).ConclusionLing-nan Liang’s spleen-stomach academic school began with Prof.Liang Nai-jin.After the development of the second and third generation of disciples such as Prof.Huang Suiping,Prof.Chen Yan,and Professor Zhang Beiping,it gradually formed the characteristics of the Ling-nan region in the spleen-stomach theroy with unique academic therapies and excellent curative therapies.There is an abnormality of MLCK signaling pathway in spleen deficiency syndrome FD.Si-jun-zi decoction can improve food intake and gastric emptying capacity by adjusting this pathway,and reduce MLCK and myosin ATPase activity,which may be the mechanism of improvement in FD gastric fundus tolerance diastolic abnormalities and mitigation fullness,early satiety and other symptoms. |
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