【摘要】：目的采用基于超高效液相色譜串聯(lián)四級(jí)桿軌道阱質(zhì)譜(UPLC-Q- Exactive Orbitrap-MS)的技術(shù)和方法研究針刺合募配穴對(duì)功能性消化不良(Functional Dyspepsia, FD)患者血漿中內(nèi)源性小分子(分子量1000)代謝物的影響,探討針刺合募配穴對(duì)效應(yīng)物質(zhì)基礎(chǔ)含量變化的影響及其規(guī)律,為揭示針刺合募配穴治療FD的代謝組學(xué)機(jī)制提供新的生物信息學(xué)依據(jù)和線索。方法1.FD患者的血漿代謝組學(xué)研究：采用UPLC-Q- Exactive Orbitrap-MS代謝組學(xué)技術(shù),通過(guò)與健康組比較,找出FD的血漿潛在生物標(biāo)志物,利用MetPA平臺(tái)分析潛在生物標(biāo)志物的代謝途徑。2.合募配穴治療FD的代謝組學(xué)研究：分別采用針刺合募配穴、下合穴、募穴治療FD,運(yùn)用UPLC-Q- Exactive Orbitrap-MS代謝組學(xué)技術(shù),通過(guò)與各組治療前比較,找出各組FD患者在針刺治療2個(gè)療程(10天)、4個(gè)療程(20天)后血漿中差異具有統(tǒng)計(jì)學(xué)意義的生物標(biāo)志物。3.各組血漿中差異標(biāo)志物的含量變化分析：以健康組的血漿標(biāo)志物的均值含量為參考標(biāo)準(zhǔn),對(duì)針刺合募配穴、下合穴、募穴治療FD的治療前、治療2個(gè)療程、治療4個(gè)療程后血漿中的差異標(biāo)志物的均值含量做整體比較,觀察各標(biāo)志物在各組中的均值含量變化趨勢(shì)及變化規(guī)律,探討針刺合募配穴對(duì)FD患者血漿代謝物的影響。結(jié)果1.與健康組相比,FD患者血漿中苯乙胺、(3R,7R)-1,3,7-Octanetriol含量明顯下降(P0.01);亞硝酸鹽、2-苯乙酰胺、L-別異亮氨酸含量明顯升高(P0.01);2-己基甘油、4-羥基-L-谷氨酸含量明顯下降(P0.05);1-二氫吡咯—2—羧酸酸、D-脯氨酸含量明顯升高(P0.05),是FD的潛在生物標(biāo)志物。與FD疾病相關(guān)的代謝通路是苯丙氨酸代謝、精氨酸和脯氨酸代謝。2.從針刺合募配穴(足三里、中脘)治療FD患者2個(gè)療程和4個(gè)療程后的血漿中,共篩選出15個(gè)具有統(tǒng)計(jì)學(xué)差異的標(biāo)志物(P0.05),并成功鑒定10個(gè),其中亞硝酸鹽、2-苯乙酰胺、D-脯氨酸、L-別異亮氨酸在針刺合募配穴治療后的血漿中均呈下調(diào)趨勢(shì)；2-己基甘油、氨基丙二酸、1-吡咯啉-2-羧酸、4-羥基-L-谷氨酸、3-甲基組氨酸、12酮脫氧膽酸在針刺合募配穴治療后的血漿中均呈上調(diào)趨勢(shì)。針刺合募配穴治療FD的相關(guān)調(diào)節(jié)通路是苯丙氨酸代謝、精氨酸和脯氨酸代謝。3.從針刺下合穴(足三里)治療FD患者2個(gè)療程和4個(gè)療程后的血漿中,共篩選出11個(gè)具有統(tǒng)計(jì)學(xué)差異的生物標(biāo)志物(P0.05),并成功鑒定9個(gè),其中亞硝酸鹽、2-苯乙酰胺、D-脯氨酸、(3R,7R)-1,3,7-Octanetriol.L-異亮氨酸在針刺足三里穴治療后的血漿中均呈下調(diào)趨勢(shì)；2-己基甘油、4-羥基-L-谷氨酸、12酮脫氧膽酸、煙酰胺在針刺足三里穴治療后的血漿中均呈上調(diào)趨勢(shì)。針刺下合穴治療FD的相關(guān)調(diào)節(jié)通路是苯丙氨酸代謝。4.從針刺募穴(中脘)治療FD患者2個(gè)療程和4個(gè)療程后的血漿中,共篩選出11個(gè)具有統(tǒng)計(jì)學(xué)差異的標(biāo)志物(P0.05),并成功鑒定10個(gè),其中亞硝酸鹽、2-苯乙酰胺、D-脯氨酸在針刺中脘穴治療后的血漿中均呈下調(diào)趨勢(shì)；2-己基甘油、氨基丙二酸、1-吡咯啉-2-羧酸、4-羥基-L-谷氨酸、3-甲基組氨酸、12酮脫氧膽酸、L-別蘇氨酸在針刺中脘穴治療后的血漿中均呈上調(diào)趨勢(shì)。針刺募穴治療FD的相關(guān)調(diào)節(jié)通路是苯丙氨酸代謝、精氨酸和脯氨酸代謝。結(jié)論1.一系列代謝物的含量變化異常是FD患者血漿代謝物的共同特點(diǎn),其中,血漿苯乙胺、亞硝酸鹽、2-苯乙酰胺、2-己基甘油、4-羥基-L-谷氨酸、1-吡咯啉-2-羧酸、D-脯氨酸、(3R,7R)-1,3,7-Octanetriol.L-別異亮氨酸,是FD潛在的生物標(biāo)志物。2.與FD疾病相關(guān)的潛在靶標(biāo)通路可能是苯丙氨酸代謝、精氨酸和脯氨酸代謝。3.針刺合募配穴治療FD的代謝組學(xué)機(jī)制可能與調(diào)控苯丙氨酸代謝、精氨酸和脯氨酸代謝有關(guān)。4.針刺合募配穴、下合穴、募穴對(duì)FD疾病相關(guān)代謝標(biāo)志物都有一定的良性調(diào)節(jié)作用,合募配穴的總體調(diào)節(jié)作用優(yōu)于下合穴和募穴。
[Abstract]:Objective To study the effect of acupuncture on the endogenous small molecule (molecular weight 1000) of functional dyspepsia (FD) in patients with functional dyspepsia (FD) by means of ultra-high performance liquid chromatography tandem quadrupole mass spectrometry (UPLC-Q-active Orbitrap-MS). To study the effect of acupuncture on the change of the material base content and the law, to provide a new bioinformatics basis and a clue for revealing the mechanism of the metabolic group of the acupuncture combined point treatment FD. Methods The plasma metabolic group of FD patients was studied by means of UPLC-Q-Exactive Orbitrap-MS, and the potential biomarkers of FD were found by comparison with the healthy group. The metabolic pathway of potential biomarkers was analyzed by the MetPA platform. In the study of the metabolic group of the treatment FD of the combined point, the treatment FD was treated by means of acupuncture combined with the points, the lower and the lower, and the point of raising, and by means of UPLC-Q-Exactive Orbitrap-MS, the group of FD patients were found to be treated with acupuncture for 2 courses of treatment (10 days). There was a statistically significant biomarker in plasma after 4 courses of treatment (20 days). the content of the difference marker in each group of plasma is analyzed, the mean content of the plasma mark in the healthy group is taken as the reference standard, the acupuncture combined point, the lower cavity and the point raising point are used for treating the treatment of the FD, and the two treatment courses are treated, The mean content of the difference markers in the plasma after 4 treatment courses was compared and the change of the mean content of the markers in each group was observed, and the effect of the acupuncture on the plasma metabolites in the FD patients was discussed. Results 1. Compared with the healthy group, the content of phenethylamine, (3R, 7R) -1, 3, 7-Octanetriol in the plasma of FD patients decreased significantly (P0.01), and the content of nitrite, 2-phenethyl amine and L-isoleucine increased significantly (P0.01), and the content of 4-hydroxy-L-glutamic acid in the 2-hexanyl glycerol, 4-hydroxy-L-glutamic acid decreased significantly (P0.05). The contents of D-proline and D-proline increased significantly (P0.05). The metabolic pathway associated with FD is phenylalanine metabolism, arginine and proline metabolism. A total of 15 markers of statistical difference (P0.05) were selected and 10 were successfully identified, including nitrite, 2-phenethyl amine and D-proline. L-isoleucine is down-regulated in plasma after acupuncture combined with point-in-point treatment; 2-hexyl glycerol, amino malonic acid, 1-methyl-2-coumaric acid, 4-hydroxy-L-glutamic acid, 3-methylhistidine and 12-ketodesodeoxycholic acid were up-regulated in plasma after acupuncture combined with the point-in-point treatment. The related regulatory pathway of the treatment of FD with the acupuncture combined point is phenylalanine metabolism, arginine and proline metabolism. A total of 11 biomarkers (P0.05) were selected and 9 were successfully identified, including nitrite, 2-phenethamine, D-proline, (3R, (R) -1, 3, 7-Octanetriol. L-isoleucine was down-regulated in the plasma after the treatment of the acupuncture and the third-point acupuncture point; 2-hexyl glycerol, 4-hydroxy-L-glutamic acid, and 12-one deoxycholic acid, and the smoke and the amine were all up-regulated in the plasma treated by the acupuncture and the three-point acupuncture point. The relevant regulatory pathway of the treatment of FD with acupuncture at the lower point of acupuncture is phenylalanine metabolism. A total of 11 markers of statistical difference (P0.05) were selected from the treatment of 2 treatment courses and 4 treatment courses of the FD patients from the acupuncture point-raising point (Zhongzi), and 10 were successfully identified, of which the nitrite, 2-phenylidenamine, D-proline is down-regulated in plasma after acupuncture, and 2-hexyl glycerol, amino malonic acid, 1-methyl-2-coumaric acid, 4-hydroxy-L-glutamic acid, 3-methylhistidine, and 12-one deoxycholic acid, L-non-threonine was up-regulated in plasma after acupuncture. The related regulatory pathway of the acupuncture point-raising treatment FD is the metabolism of phenylalanine, arginine and proline. Conclusion 1. The variation in the content of a series of metabolites is a common characteristic of the plasma metabolite of the FD patient, in which the plasma phenethylamine, the nitrite, the 2-phenylglyoxyamine, the 2-hexanyl glycerol, the 4-hydroxy-L-glutamic acid, the 1-ethanone-2-coumaric acid, the D-proline, (3R, 7R) -1,3,7-Octanetriol. L-Inisoleucine is a potential biomarker for FD. The potential target pathway associated with the FD disease may be phenylalanine metabolism, arginine and proline metabolism. The mechanism of the metabolic group in the treatment of FD by acupuncture combined with the acupoint may be related to the regulation of the metabolism of phenylalanine, arginine and proline. Acupuncture combined with the points of distribution, the lower combined point and the point-raising point have a certain benign regulation effect on the metabolic markers of the FD-related metabolic markers, and the overall regulation effect of the combined points is better than that of the lower and the point-raising points.
【學(xué)位授予單位】：成都中醫(yī)藥大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R246.1

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