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No.	t_R/min	Formula	Theoretical m/z	Practical m/z	Ion	Product ion (m/z)	Identification
1	0.62	C₉H₁₀O₄	182.057 4	183.004 1	[M+H]⁺	123.007 1, 95.012 5	Syringaldehyde
2	0.65	C₅H₈N₂O₅	176.042 8	174.955 3	[M-H]^-	146.960 0, 118.964 9	Dencichine
3	0.76	C₇H₇NO₂	137.047 1	138.055 0	[M+H]⁺	110.060 5	Trigonelline
4	0.85	C₆H₆O₃	126.031 1	127.039 2	[M+H]⁺	108.044 8, 81.034 2, 69.034 3	5-Hydroxymethylfurfura
5	0.86	C₅H₉NO₂	115.062 8	116.070 9	[M+H]⁺	70.065 9	L-Proline
6	1.11	C₆H₈O₇	192.026 5	191.018 9	[M-H]^-	111.007 4, 85.027 9	Citric acid
7	1.83	C₁₂H₂₂O₁₁	342.115 7	341.109 1	[M-H]^-	179.054 9, 89.022 9	Sucrose
8	2.68	C₅H₉NO₄	147.052 6	146.023 6	[M-H]^-	128.033 3, 128.033 3, 75.006 9	L-Glutamic acid
9	3.67	C₁₁H₁₂N₂O₂	204.089 3	203.082 1	[M-H]^-	142.065 1, 116.049 2	L-Tryptophan
10	4.42	C₁₆H₁₈O₉	354.094 5	353.087 8	[M-H]^-	191.055 4, 179.034 2, 135.043 9	1-Caffeoylquinic acid
11	4.45	C₇H₆O₃	138.031 1	137.023 2	[M-H]^-	108.020 1	3,4-Dihydroxybenzaldehyde
12	4.68	C₉H₁₁NO₃	181.073 3	182.081 1	[M+H]⁺	165.054 7	L-Tyrosine
13	4.74	C₇H₆O₂	122.036 2	121.028 2	[M-H]^-	91.017 6	4-Hydroxybenzaldehyde
14	4.90	C₉H₆O₄	178.026 1	177.018 2	[M-H]^-	115.038 7, 85.064 2	Esculetine
15	5.41	C₁₉H₂₄O₁₃	460.121 1	459.115 6	[M-H]^-	111.007 3	Parishin E
16	5.52	C₈H₈O₃	152.046 8	153.054 2	[M+H]⁺	93.033 0	4-Mthoxysalicylaldehyde
17	5.59	C₁₅H₁₆O₉	340.078 9	339.073 2	[M-H]^-	177.018 5, 133.028 3	Esculin
18	6.39	C₁₆H₁₈O₉	354.094 5	353.088 4	[M-H]^-	191.055 4, 173.044 7, 135.043 9	Cryptochlorogenic acid
19	6.41	C₇H₆O₄	154.026 1	153.018 3	[M-H]^-	109.028 1	Protocatechuic acid
20	6.87	C₉H₈O₄	180.041 7	179.034 1	[M-H]^-	135.043 9, 107.048 9	Caffeic acid
21	7.04	C₁₅H₁₂O₄	256.073 0	257.080 6	[M+H]⁺	239.071 2, 211.074 4, 147.044 1, 137.023 4, 119.049 4	Isoliquiritigenin
22	7.20	C₁₀H₈O₃	176.046 8	177.054 3	[M+H]⁺	145.028 4, 117.033 8, 89.039 2	7-Methoxycoumarin
23	8.17	C₂₆H₂₈O₁₄	564.147 4	563.145 3	[M-H]^-	353.068 2, 297.077 0	Isoschaftoside
24	8.27	C₃₃H₄₀O₁₉	740.215 8	741.223 7	[M+H]⁺	271.059 9	Apigenin-7-O-(2G-rhamnosyl) gentiobioside
25	8.38	C₂₁H₂₀O₁₁	448.100 0	447.094 3	[M-H]^-	429.083 0, 285.040 4, 133.028 4	Isoorientin
26	8.55	C₂₁H₂₀O₁₁	448.100 0	447.096 2	[M-H]^-	327.052 3	Orientin
27	8.79	C₁₅H₁₂O₄	256.073 0	255.066 3	[M-H]^-	135.007 5, 119.048 8, 91.017 4	Liquiritigenin
28	8.91	C₂₁H₂₂O₉	418.125 8	417.120 3	[M-H]^-	255.066 4, 135.007 5, 119.048 9	Liquiritin
29	9.03	C₂₁H₂₀O₁₀	432.105 1	433.113 0	[M+H]⁺	415.100 4, 397.092 4, 271.060 0	Isovitexin
30	9.23	C₂₇H₃₀O₁₅	594.157 9	593.154 7	[M-H]^-	285.040 6	Kaempferol-3-O-rutinoside
31	9.24	C₇H₆O₃	138.031 1	137.023 2	[M-H]^-	93.033 1	Salicylic acid
32	9.70	C₂₇H₃₂O₁₄	580.178 7	579.172 4	[M-H]^-	271.062 5, 151.002 5, 119.048 8, 107.012 4	Narigin
33	9.79	C₂₇H₃₀O₁₄	578.163 0	579.170 8	[M+H]⁺	271.059 6, 153.018 1	Isorhoifolin
34	9.87	C₁₆H₁₂O₆	300.062 8	299.056 6	[M-H]^-	284.032 4, 255.066 1, 255.066 1, 240.042 5	Tectorigenin
35	9.91	C₁₅H₁₆O₄	260.104 3	261.112 2	[M+H]⁺	189.054 7, 131.049 3	Isomeranzin
36	10.09	C₁₅H₁₂O₆	288.062 8	287.056 9	[M-H]^-	151.002 7	Eriodictyol
37	10.32	C₉H₆O₂	146.036 2	147.044 2	[M+H]⁺	119.049 4, 91.054 8	Coumarin
38	10.33	C₉H₈O₃	164.046 8	163.039 0	[M-H]^-	119.048 8, 93.032 8	p-Hydroxycinnamic acid
39	10.76	C₂₆H₃₀O₁₃	550.168 1	549.163 4	[M-H]^-	549.161 4, 135.007 5, 119.049 0	Liquiritigenin-7-O-β-D-apiofuranosyl-4′-O-β-D-glucopyranoside
40	10.82	C₁₅H₂₀O₃	248.140 7	249.148 1	[M+H]⁺	185.132 3	Parthenolide
41	10.95	C₁₆H₁₄O₅	286.083 6	285.077 3	[M-H]^-	270.053 8, 150.031 1	Licochalcone B
42	11.13	C₁₆H₁₂O₇	316.057 8	317.065 4	[M+H]⁺	302.041 2, 274.047 1, 153.018 2	Isorhamnetin
43	11.21	C₁₅H₁₀O₆	286.047 2	285.041 1	[M-H]^-	133.028 2	Luteolin
44	11.46	C₁₆H₁₂O₅	284.067 9	285.075 7	[M+H]⁺	270.052 3	Glycitein
45	11.47	C₁₆H₁₂O₅	284.067 9	283.061 7	[M-H]^-	268.038 3, 239.034 7, 211.040 2	Calycosin
46	11.62	C₁₆H₁₄O₆	302.078 5	301.036 0	[M-H]^-	151.002 5	Hesperetin
47	12.18	C₁₅H₁₀O₄	254.057 4	253.050 7	[M-H]^-	209.056 4	Daidzein
48	12.29	C₉H₆O₄	178.026 1	179.033 8	[M+H]⁺	133.028 4	5,7-Dihydroxychromone
49	12.30	C₁₅H₁₂O₅	272.067 9	271.061 6	[M-H]^-	227.159 0, 151.002 5, 145.027 8	Naringenin chalcone
50	12.51	C₁₆H₁₄O₄	270.088 7	271.096 8	[M+H]⁺	153.018 3	Echinatin
51	12.59	C₁₅H₁₀O₅	270.052 3	271.060 0	[M+H]⁺	243.065 2, 153.018 2, 119.049 4	Genistein
52	12.79	C₇H₁₂O₆	192.062 8	191.055 3	[M-H]^-	127.039 0, 85.028 0	Quinic acid
53	12.79	C₁₅H₁₀O₅	270.052 3	269.046 1	[M-H]^-	151.002 6	Apigenin
54	12.81	C₃₀H₄₆O₅	486.334 0	487.341 8	[M+H]⁺	173.132 5	Quillaic acid
55	13.16	C₃₀H₄₆O₃	454.344 1	455.353 9	[M+H]⁺	95.086 4	Wilforlide A
56	13.17	C₁₆H₁₂O₆	300.062 8	299.057 0	[M-H]^-	284.032 9, 255.029 4, 227.034 5	Hydroxygenkwanin
57	13.67	C₁₆H₁₂O₄	268.073 0	267.066 6	[M-H]^-	267.066 6, 223.039 4	Formononetin
58	13.96	C₃₀H₄₄O₄	468.323 4	469.331 4	[M+H]⁺	451.320 1, 439.321 6	Glabrolide
59	14.11	C₁₇H₁₄O₆	314.078 5	313.072 4	[M-H]^-	298.048 1, 283.024 8, 255.030 6	Pectolinarigenin
60	14.22	C₃₀H₄₆O₄	470.339 1	471.346 9	[M+H]⁺	453.336 5, 189.164 0	Glycyrrhetinic acid
61	14.22	C₉H₆O₃	162.031 1	161.023 6	[M-H]^-	117.033 5, 89.022 9	7-Hydroxycoumarin
62	14.35	C₂₁H₂₀O₆	368.125 4	367.119 0	[M-H]^-	309.041 2, 269.042 3	Icaritin
63	14.46	C₁₅H₂₀O₃	248.140 7	249.148 6	[M+H]⁺	231.138 0, 203.143 1, 175.075 1, 119.085 9, 105.070 4	Atractylenolide Ⅲ
64	14.94	C₄₂H₆₂O₁₆	822.403 2	821.398 0	[M-H]^-	351.057 2, 193.034 7	Diammonium glycyrrhizinate
65	15.15	C₂₀H₁₈O₄	322.120 0	321.113 9	[M-H]^-	117.033 3	Licoflavone A
66	15.41	C₁₆H₁₂O₅	284.067 9	283.061 4	[M-H]^-	283.061 4	Acacetin
67	15.63	C₁₆H₁₂O₅	284.067 9	285.075 5	[M+H]⁺	270.052 2	Wogonin
68	15.80	C₁₁H₆O₃	186.031 1	187.039 0	[M+H]⁺	131.049 3, 103.054 6	Isopsoralen
69	15.84	C₁₅H₁₈O₂	230.130 1	231.137 9	[M+H]⁺	185.132 6, 157.101 2	Atractylodes Ⅰ
70	15.87	C₁₆H₁₄O₄	270.088 7	269.082 2	[M-H]^-	254.058 4, 225.055 3, 210.068 2	Medicarpin
71	15.93	C₂₀H₂₀O₅	340.130 5	341.136 8	[M+H]⁺	341.136 8, 341.136 8	8-Prenylnaringenin
72	16.70	C₂₁H₂₂O₄	338.151 3	339.158 8	[M+H]⁺	121.028 7	Glycyrrhiza chalcone C
73	16.90	C₁₂H₁₄O₂	190.098 8	191.106 9	[M+H]⁺	119.049 1, 107.049 5	Ligustilide
74	17.02	C₁₈H₃₀O₂	278.224 0	279.231 7	[M+H]⁺	243.100 9	α-Linolenic acid
75	17.35	C₂₀H₁₆O₅	336.099 2	335.092 8	[M-H]^-	320.067 9, 291.103 4, 199.075 8	Photoglycyrrhizinone
76	17.61	C₁₀H₁₀O₄	194.057 4	191.055 3	[M-H]^-	178.025 8	Ferulic acid
77	18.00	C₁₅H₂₀O₂	232.145 8	233.153 6	[M+H]⁺	215.143 3, 151.075 5, 131.085 7	Atractylodes Ⅱ
78	19.88	C₅H₁₁NO₂	117.078 4	118.086 6	[M+H]⁺	91.054 7, 72.081 5	L-Valine

No.	t_R/min	Formula	Theoretical m/z	Practical m/z	Ion	Product ion (m/z)	Identification
1	0.62	C₉H₁₀O₄	182.057 4	183.004 1	[M+H]⁺	123.007 1, 95.012 5	Syringaldehyde
2	0.65	C₅H₈N₂O₅	176.042 8	174.955 3	[M-H]^-	146.960 0, 118.964 9	Dencichine
3	0.76	C₇H₇NO₂	137.047 1	138.055 0	[M+H]⁺	110.060 5	Trigonelline
4	0.85	C₆H₆O₃	126.031 1	127.039 2	[M+H]⁺	108.044 8, 81.034 2, 69.034 3	5-Hydroxymethylfurfura
5	0.86	C₅H₉NO₂	115.062 8	116.070 9	[M+H]⁺	70.065 9	L-Proline
6	1.11	C₆H₈O₇	192.026 5	191.018 9	[M-H]^-	111.007 4, 85.027 9	Citric acid
7	1.83	C₁₂H₂₂O₁₁	342.115 7	341.109 1	[M-H]^-	179.054 9, 89.022 9	Sucrose
8	2.68	C₅H₉NO₄	147.052 6	146.023 6	[M-H]^-	128.033 3, 128.033 3, 75.006 9	L-Glutamic acid
9	3.67	C₁₁H₁₂N₂O₂	204.089 3	203.082 1	[M-H]^-	142.065 1, 116.049 2	L-Tryptophan
10	4.42	C₁₆H₁₈O₉	354.094 5	353.087 8	[M-H]^-	191.055 4, 179.034 2, 135.043 9	1-Caffeoylquinic acid
11	4.45	C₇H₆O₃	138.031 1	137.023 2	[M-H]^-	108.020 1	3,4-Dihydroxybenzaldehyde
12	4.68	C₉H₁₁NO₃	181.073 3	182.081 1	[M+H]⁺	165.054 7	L-Tyrosine
13	4.74	C₇H₆O₂	122.036 2	121.028 2	[M-H]^-	91.017 6	4-Hydroxybenzaldehyde
14	4.90	C₉H₆O₄	178.026 1	177.018 2	[M-H]^-	115.038 7, 85.064 2	Esculetine
15	5.41	C₁₉H₂₄O₁₃	460.121 1	459.115 6	[M-H]^-	111.007 3	Parishin E
16	5.52	C₈H₈O₃	152.046 8	153.054 2	[M+H]⁺	93.033 0	4-Mthoxysalicylaldehyde
17	5.59	C₁₅H₁₆O₉	340.078 9	339.073 2	[M-H]^-	177.018 5, 133.028 3	Esculin
18	6.39	C₁₆H₁₈O₉	354.094 5	353.088 4	[M-H]^-	191.055 4, 173.044 7, 135.043 9	Cryptochlorogenic acid
19	6.41	C₇H₆O₄	154.026 1	153.018 3	[M-H]^-	109.028 1	Protocatechuic acid
20	6.87	C₉H₈O₄	180.041 7	179.034 1	[M-H]^-	135.043 9, 107.048 9	Caffeic acid
21	7.04	C₁₅H₁₂O₄	256.073 0	257.080 6	[M+H]⁺	239.071 2, 211.074 4, 147.044 1, 137.023 4, 119.049 4	Isoliquiritigenin
22	7.20	C₁₀H₈O₃	176.046 8	177.054 3	[M+H]⁺	145.028 4, 117.033 8, 89.039 2	7-Methoxycoumarin
23	8.17	C₂₆H₂₈O₁₄	564.147 4	563.145 3	[M-H]^-	353.068 2, 297.077 0	Isoschaftoside
24	8.27	C₃₃H₄₀O₁₉	740.215 8	741.223 7	[M+H]⁺	271.059 9	Apigenin-7-O-(2G-rhamnosyl) gentiobioside
25	8.38	C₂₁H₂₀O₁₁	448.100 0	447.094 3	[M-H]^-	429.083 0, 285.040 4, 133.028 4	Isoorientin
26	8.55	C₂₁H₂₀O₁₁	448.100 0	447.096 2	[M-H]^-	327.052 3	Orientin
27	8.79	C₁₅H₁₂O₄	256.073 0	255.066 3	[M-H]^-	135.007 5, 119.048 8, 91.017 4	Liquiritigenin
28	8.91	C₂₁H₂₂O₉	418.125 8	417.120 3	[M-H]^-	255.066 4, 135.007 5, 119.048 9	Liquiritin
29	9.03	C₂₁H₂₀O₁₀	432.105 1	433.113 0	[M+H]⁺	415.100 4, 397.092 4, 271.060 0	Isovitexin
30	9.23	C₂₇H₃₀O₁₅	594.157 9	593.154 7	[M-H]^-	285.040 6	Kaempferol-3-O-rutinoside
31	9.24	C₇H₆O₃	138.031 1	137.023 2	[M-H]^-	93.033 1	Salicylic acid
32	9.70	C₂₇H₃₂O₁₄	580.178 7	579.172 4	[M-H]^-	271.062 5, 151.002 5, 119.048 8, 107.012 4	Narigin
33	9.79	C₂₇H₃₀O₁₄	578.163 0	579.170 8	[M+H]⁺	271.059 6, 153.018 1	Isorhoifolin
34	9.87	C₁₆H₁₂O₆	300.062 8	299.056 6	[M-H]^-	284.032 4, 255.066 1, 255.066 1, 240.042 5	Tectorigenin
35	9.91	C₁₅H₁₆O₄	260.104 3	261.112 2	[M+H]⁺	189.054 7, 131.049 3	Isomeranzin
36	10.09	C₁₅H₁₂O₆	288.062 8	287.056 9	[M-H]^-	151.002 7	Eriodictyol
37	10.32	C₉H₆O₂	146.036 2	147.044 2	[M+H]⁺	119.049 4, 91.054 8	Coumarin
38	10.33	C₉H₈O₃	164.046 8	163.039 0	[M-H]^-	119.048 8, 93.032 8	p-Hydroxycinnamic acid
39	10.76	C₂₆H₃₀O₁₃	550.168 1	549.163 4	[M-H]^-	549.161 4, 135.007 5, 119.049 0	Liquiritigenin-7-O-β-D-apiofuranosyl-4′-O-β-D-glucopyranoside
40	10.82	C₁₅H₂₀O₃	248.140 7	249.148 1	[M+H]⁺	185.132 3	Parthenolide
41	10.95	C₁₆H₁₄O₅	286.083 6	285.077 3	[M-H]^-	270.053 8, 150.031 1	Licochalcone B
42	11.13	C₁₆H₁₂O₇	316.057 8	317.065 4	[M+H]⁺	302.041 2, 274.047 1, 153.018 2	Isorhamnetin
43	11.21	C₁₅H₁₀O₆	286.047 2	285.041 1	[M-H]^-	133.028 2	Luteolin
44	11.46	C₁₆H₁₂O₅	284.067 9	285.075 7	[M+H]⁺	270.052 3	Glycitein
45	11.47	C₁₆H₁₂O₅	284.067 9	283.061 7	[M-H]^-	268.038 3, 239.034 7, 211.040 2	Calycosin
46	11.62	C₁₆H₁₄O₆	302.078 5	301.036 0	[M-H]^-	151.002 5	Hesperetin
47	12.18	C₁₅H₁₀O₄	254.057 4	253.050 7	[M-H]^-	209.056 4	Daidzein
48	12.29	C₉H₆O₄	178.026 1	179.033 8	[M+H]⁺	133.028 4	5,7-Dihydroxychromone
49	12.30	C₁₅H₁₂O₅	272.067 9	271.061 6	[M-H]^-	227.159 0, 151.002 5, 145.027 8	Naringenin chalcone
50	12.51	C₁₆H₁₄O₄	270.088 7	271.096 8	[M+H]⁺	153.018 3	Echinatin
51	12.59	C₁₅H₁₀O₅	270.052 3	271.060 0	[M+H]⁺	243.065 2, 153.018 2, 119.049 4	Genistein
52	12.79	C₇H₁₂O₆	192.062 8	191.055 3	[M-H]^-	127.039 0, 85.028 0	Quinic acid
53	12.79	C₁₅H₁₀O₅	270.052 3	269.046 1	[M-H]^-	151.002 6	Apigenin
54	12.81	C₃₀H₄₆O₅	486.334 0	487.341 8	[M+H]⁺	173.132 5	Quillaic acid
55	13.16	C₃₀H₄₆O₃	454.344 1	455.353 9	[M+H]⁺	95.086 4	Wilforlide A
56	13.17	C₁₆H₁₂O₆	300.062 8	299.057 0	[M-H]^-	284.032 9, 255.029 4, 227.034 5	Hydroxygenkwanin
57	13.67	C₁₆H₁₂O₄	268.073 0	267.066 6	[M-H]^-	267.066 6, 223.039 4	Formononetin
58	13.96	C₃₀H₄₄O₄	468.323 4	469.331 4	[M+H]⁺	451.320 1, 439.321 6	Glabrolide
59	14.11	C₁₇H₁₄O₆	314.078 5	313.072 4	[M-H]^-	298.048 1, 283.024 8, 255.030 6	Pectolinarigenin
60	14.22	C₃₀H₄₆O₄	470.339 1	471.346 9	[M+H]⁺	453.336 5, 189.164 0	Glycyrrhetinic acid
61	14.22	C₉H₆O₃	162.031 1	161.023 6	[M-H]^-	117.033 5, 89.022 9	7-Hydroxycoumarin
62	14.35	C₂₁H₂₀O₆	368.125 4	367.119 0	[M-H]^-	309.041 2, 269.042 3	Icaritin
63	14.46	C₁₅H₂₀O₃	248.140 7	249.148 6	[M+H]⁺	231.138 0, 203.143 1, 175.075 1, 119.085 9, 105.070 4	Atractylenolide Ⅲ
64	14.94	C₄₂H₆₂O₁₆	822.403 2	821.398 0	[M-H]^-	351.057 2, 193.034 7	Diammonium glycyrrhizinate
65	15.15	C₂₀H₁₈O₄	322.120 0	321.113 9	[M-H]^-	117.033 3	Licoflavone A
66	15.41	C₁₆H₁₂O₅	284.067 9	283.061 4	[M-H]^-	283.061 4	Acacetin
67	15.63	C₁₆H₁₂O₅	284.067 9	285.075 5	[M+H]⁺	270.052 2	Wogonin
68	15.80	C₁₁H₆O₃	186.031 1	187.039 0	[M+H]⁺	131.049 3, 103.054 6	Isopsoralen
69	15.84	C₁₅H₁₈O₂	230.130 1	231.137 9	[M+H]⁺	185.132 6, 157.101 2	Atractylodes Ⅰ
70	15.87	C₁₆H₁₄O₄	270.088 7	269.082 2	[M-H]^-	254.058 4, 225.055 3, 210.068 2	Medicarpin
71	15.93	C₂₀H₂₀O₅	340.130 5	341.136 8	[M+H]⁺	341.136 8, 341.136 8	8-Prenylnaringenin
72	16.70	C₂₁H₂₂O₄	338.151 3	339.158 8	[M+H]⁺	121.028 7	Glycyrrhiza chalcone C
73	16.90	C₁₂H₁₄O₂	190.098 8	191.106 9	[M+H]⁺	119.049 1, 107.049 5	Ligustilide
74	17.02	C₁₈H₃₀O₂	278.224 0	279.231 7	[M+H]⁺	243.100 9	α-Linolenic acid
75	17.35	C₂₀H₁₆O₅	336.099 2	335.092 8	[M-H]^-	320.067 9, 291.103 4, 199.075 8	Photoglycyrrhizinone
76	17.61	C₁₀H₁₀O₄	194.057 4	191.055 3	[M-H]^-	178.025 8	Ferulic acid
77	18.00	C₁₅H₂₀O₂	232.145 8	233.153 6	[M+H]⁺	215.143 3, 151.075 5, 131.085 7	Atractylodes Ⅱ
78	19.88	C₅H₁₁NO₂	117.078 4	118.086 6	[M+H]⁺	91.054 7, 72.081 5	L-Valine

Group	Before intervention/g	Intervention for 8 weeks/g
C	17.36 ± 0.03	15.91 ± 0.03
M	11.38 ± 0.19^*	11.23 ± 0.41^*
BBT	10.41 ± 0.65^*	16.18 ± 1.53^#

Group	Before intervention/g	Intervention for 8 weeks/g
C	17.36 ± 0.03	15.91 ± 0.03
M	11.38 ± 0.19^*	11.23 ± 0.41^*
BBT	10.41 ± 0.65^*	16.18 ± 1.53^#

Group	SBP/mmHg		DBP/mmHg
C	112.7 ± 7.6	114.4 ± 8.3	112.8 ± 3.5		75.1 ± 6.1	79.2 ± 4.2	79.6 ± 2.8
M	129.3 ± 2.8^**	128.4 ± 3.2^**	124.0 ± 2.9^**	85.8 ± 2.2^**	86.6 ± 1.5^**	82.5 ± 1.1^*
BBT	129.0 ± 3.9^**	117.0 ± 4.9^##	118.6 ± 4.3^*#	85.7 ± 4.1^**	80.2 ± 3.8^##	78.4 ± 1.8^##

Group	SBP/mmHg		DBP/mmHg
C	112.7 ± 7.6	114.4 ± 8.3	112.8 ± 3.5		75.1 ± 6.1	79.2 ± 4.2	79.6 ± 2.8
M	129.3 ± 2.8^**	128.4 ± 3.2^**	124.0 ± 2.9^**	85.8 ± 2.2^**	86.6 ± 1.5^**	82.5 ± 1.1^*
BBT	129.0 ± 3.9^**	117.0 ± 4.9^##	118.6 ± 4.3^*#	85.7 ± 4.1^**	80.2 ± 3.8^##	78.4 ± 1.8^##

Group	TG/mmol·L^-1	TC/mmol·L^-1	HDL-C/mmol·L^-1	LDL-C/mmol·L^-1
C	0.34 ± 0.06	3.19 ± 0.27	2.21 ± 0.20	0.79 ± 0.08
M	1.13 ± 0.27^**	3.61 ± 0.35^*	1.72 ± 0.09	0.98 ± 0.16^*
BBT	0.38 ± 0.04^##	3.00 ± 0.27^##	1.89 ± 0.17^#	0.64 ± 0.06^**##

Group	TG/mmol·L^-1	TC/mmol·L^-1	HDL-C/mmol·L^-1	LDL-C/mmol·L^-1
C	0.34 ± 0.06	3.19 ± 0.27	2.21 ± 0.20	0.79 ± 0.08
M	1.13 ± 0.27^**	3.61 ± 0.35^*	1.72 ± 0.09	0.98 ± 0.16^*
BBT	0.38 ± 0.04^##	3.00 ± 0.27^##	1.89 ± 0.17^#	0.64 ± 0.06^**##

Mode	Principal component	R²	Q²
+	5	0.99	0.84
-	5	0.99	0.82

Mode	Principal component	R²	Q²
+	5	0.99	0.84
-	5	0.99	0.82

Formula	Metabolite	t_R/min	m/z	M vs C		BBT vs M
C₂₀H₃₂O₂	Arachidonic acid	14.91	305.247 6	1.53	↑^*		2.6	↓^##
C₂₄H₄₀O₅	Cholic acid	8.98	407.280 7	9.89	↓^*	1.5	↑^#
C₂₆H₄₃NO₅	Glycodeoxycholic acid	8.31	450.322 7	1.21	↑^**	2.92	↓^#
C₂₉H₄₁NO₄	N-Arachidonoyl tyrosine	8.98	468.311 6	2.42	↓^**	0.11	↑^#
C₆H₁₄N₄O₂	Arginine	0.80	175.119 2	1.57	↑^*	0.65	↓^#
C₂₅H₅₂NO₇P	LysoPE(20:0/0:0)	10.27	510.356 1	2.58	↓^**	2.26	↑^##
C₂₆H₅₄NO₆P	LysoPC(P-18:0)	11.00	508.377	2.39	↑^**	0.82	↓^##
C₂₆H₅₆NO₆P	LysoPC(18:0)	12.40	510.392 7	2.53	↑^**	1.48	↓^##
C₃₀H₅₂NO₇P	LysoPC(22:5(7Z, 10Z, 13Z, 16Z, 19Z))	11.40	570.356 1	2.33	↑^**	0.6	↓^##

Formula	Metabolite	t_R/min	m/z	M vs C		BBT vs M
C₂₀H₃₂O₂	Arachidonic acid	14.91	305.247 6	1.53	↑^*		2.6	↓^##
C₂₄H₄₀O₅	Cholic acid	8.98	407.280 7	9.89	↓^*	1.5	↑^#
C₂₆H₄₃NO₅	Glycodeoxycholic acid	8.31	450.322 7	1.21	↑^**	2.92	↓^#
C₂₉H₄₁NO₄	N-Arachidonoyl tyrosine	8.98	468.311 6	2.42	↓^**	0.11	↑^#
C₆H₁₄N₄O₂	Arginine	0.80	175.119 2	1.57	↑^*	0.65	↓^#
C₂₅H₅₂NO₇P	LysoPE(20:0/0:0)	10.27	510.356 1	2.58	↓^**	2.26	↑^##
C₂₆H₅₄NO₆P	LysoPC(P-18:0)	11.00	508.377	2.39	↑^**	0.82	↓^##
C₂₆H₅₆NO₆P	LysoPC(18:0)	12.40	510.392 7	2.53	↑^**	1.48	↓^##
C₃₀H₅₂NO₇P	LysoPC(22:5(7Z, 10Z, 13Z, 16Z, 19Z))	11.40	570.356 1	2.33	↑^**	0.6	↓^##

基于代谢组学技术探究半夏白术天麻汤对正常高值血压痰湿壅盛证大鼠的干预机制

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叶建桥 ¹ , 郭晓庆 ¹ , 李淑敏 ² , 蒋海强 ¹^,³^,⁴ , 齐冬梅 ²^,³^,⁴^,^* , 齐于辰 ⁵^,^*

药学学报 | 研究论文 2023,58(7): 1822-1832

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药学学报 | 研究论文 2023, 58(7): 1822-1832

基于代谢组学技术探究半夏白术天麻汤对正常高值血压痰湿壅盛证大鼠的干预机制

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叶建桥¹, 郭晓庆¹, 李淑敏², 蒋海强¹^,³^,⁴, 齐冬梅²^,³^,⁴^,^*, 齐于辰⁵^,^*

作者信息

1.山东中医药大学中医药创新研究院, 山东济南 250355

2.山东中医药大学实验中心, 山东济南 250355

3.山东省中医药基础研究重点实验室, 山东济南 250355

4.山东中医药大学, 教育部中医药经典理论重点实验室, 山东济南 250355

5.山东中医药大学健康学院, 山东济南 250355

通讯作者:

*齐冬梅, Tel: 15805316081, E-mail: qidm119@163.com;

齐于辰, Tel: 13287011229, E-mail: qiyuchenbzy@163.com

Mechanism of Banxia Baizhu Tianma decoction to prevent the development of prehypertension and excessive phlegm-dampness syndrome in rats based on metabonomics technology

Jian-qiao YE¹, Xiao-qing GUO¹, Shu-min LI², Hai-qiang JIANG¹^,³^,⁴, Dong-mei QI²^,³^,⁴^,^*, Yu-chen QI⁵^,^*

Affiliations

1. Institute of Innovation in Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250355, China

2. Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan 250355, China

3. Shandong Provincial Key Laboratory of Traditional Chinese Medicine for Basic Research, Jinan 250355, China

4. Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan 250355, China

5. Faculty of Health, Shandong University of Traditional Chinese Medicine, Jinan 250355, China

出版时间: 2023-07-12 doi: 10.16438/j.0513-4870.2022-1216

文章导航

摘要

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通过血清代谢组学分析半夏白术天麻汤(Banxia Baizhu Tianma decoction, BBT) 干预正常高值血压(prehypertension, PHT) 痰湿壅盛证大鼠血清生物内源性物质的变化, 明确BBT的代谢调控途径。复制正常高值血痰湿壅盛证大鼠模型, 采集大鼠的血压、行为学指标、血清生化指标, 评估BBT的调节血压和血脂的药效, 利用超高效液相色谱-四极杆/静电场轨道阱高分辨质谱联用(UPLC-Q-orbitrap-MS) 代谢组学技术, 测定大鼠血清中内源性小分子物质变化, 寻找潜在的生物标志物。结果显示, BBT可以对其中9个代谢物进行调控, 主要包括花生四烯酸、胆酸、甘脱氧胆酸、N-腺苷酪氨酸、精氨酸、溶血磷脂酰乙醇胺(20:0/0:0)、溶血磷脂(P-18:0)、溶血磷脂(18:0)、溶血磷脂[22:5(7Z, 10Z, 13Z, 16Z, 19Z)]。通过MetaboAnalyst进行代谢通路分析, 共有7条代谢通路与大鼠血压的改变密切相关, 其中花生四烯酸代谢通路最为关键。模型大鼠体内代谢差异物有向正常水平回调的趋势, 从代谢组学角度为BBT的作用机制提供了研究依据。本研究已获得山东中医药大学实验动物福利伦理审查委员会批准(批准号: SDUTCM20211103001)。

关键词

半夏白术天麻汤 / 正常高值血压 / 痰湿壅盛证大鼠 / 代谢组学

Abstract

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The alterations of serum biological endogenous chemicals in rats with phlegm dampness accumulation syndrome of prehypertension (PHT) were interfered by Banxia Baizhu Tianma decoction (BBT), and the metabolic regulatory pathway of BBT was clarified using serum metabonomics analysis. To replicate the rat model of prehypertension phlegm dampness syndrome, blood pressure, behavioral markers, and serum biochemical markers of rats were collected. BBT's effectiveness in controlling blood pressure and blood lipids was assessed, and changes in endogenous small molecules in rat serum were determined using UPLC-Q-Orbitrap MS metabolic analysis. The results showed that BBT could regulate 9 metabolites, including arachidonic acid, cholic acid, glycodeoxycholic acid, N-adenosyltyrosine, arginine, lysophosphatidylethanolamine (20:0/0:00), lysophospholipid (P-18:0), lysophospholipid (18:0), lysophospholipid (22:5(7Z, 10Z, 13Z, 16Z, 19Z)). MetaboAnalyst was used to analyze the metabolic pathway. There were 7 metabolic pathways closely related to the change of blood pressure in rats, among which arachidonic acid metabolic pathway was the most critical. The metabolism difference foreign body in the model rats tends to return to the normal level, which provides a research basis for the mechanism of BBT from the perspective of metabonomics. This study was approved by the Experimental Animal Welfare Ethics Review Committee of Shandong University of Traditional Chinese Medicine (approval number: SDUTCM20211103001).

Key words

Banxia Baizhu Tianma decoction / prehypertension / phlegm-dampness syndrome / metabonomics

引用本文

叶建桥, 郭晓庆, 李淑敏, 蒋海强, 齐冬梅, 齐于辰. 基于代谢组学技术探究半夏白术天麻汤对正常高值血压痰湿壅盛证大鼠的干预机制. 药学学报, 2023 , 58 (7) : 1822 -1832 . DOI: 10.16438/j.0513-4870.2022-1216

Jian-qiao YE, Xiao-qing GUO, Shu-min LI, Hai-qiang JIANG, Dong-mei QI, Yu-chen QI. Mechanism of Banxia Baizhu Tianma decoction to prevent the development of prehypertension and excessive phlegm-dampness syndrome in rats based on metabonomics technology[J]. Acta Pharmaceutica Sinica, 2023 , 58 (7) : 1822 -1832 . DOI: 10.16438/j.0513-4870.2022-1216

正文

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中国约有4.35亿人口血压处于正常高值血压(120~139/80~89 mmHg), 且半数将进展为临床高血压^[1-3]。课题组前期研究表明, 正常高值血压人群可分为五类: 无症状组、痰湿壅盛证、阴虚阳亢证、肝火炽盛证和肾阳虚证, 其中痰湿壅盛证是PHT的主要临床证候, 临床表现有肥胖、呕吐痰涎、头重、口淡、舌体胖、脉象或沉、或细、或弱^[4-6]。中医认为“肥人多痰湿”, 素日饮食不节, 恣食肥甘厚味或因脾虚致脾运化失常, 水湿停聚, 虚则生痰, 上蒙神窍, 清阳不升, 浊阴不降, 引发血压升高^[7]。

半夏白术天麻汤源自《医学心悟》是临床治疗痰湿壅盛证高血压的主要方剂, 由半夏、白术、天麻、茯苓、橘红和甘草组成, 具有燥湿化痰、平肝熄风之功、主治风痰眩晕^[8]。临床研究表明, BBT可显著提高降压效果, 并能维持患者血压稳定^[9], 改善CD3⁺、CD4⁺及CD4⁺/CD8⁺和IgM、IgG等免疫指标的表达^[10], 血脂控制效果较好^[11], 患者眩晕、失眠、头重如裹等中医症状积分明显降低^[12]。现代药理学研究表明, BBT可调节血清NO浓度和内皮素-1水平, 通过调节内分泌系统, 改善血管内皮功能而降低血压^[13]。BBT可调节肾素-血管紧张素系统各因子mRNA的表达, 从而降低动脉压^[14]。姜月华等^[15]发现BBT通过上调miRNA-217, 促进内皮细胞增殖, 发挥内皮保护作用。姜玲宇等^[16]通过蛋白组学技术发现11个与细胞形态、氧化应激及能量代谢等有关的差异蛋白可能是BBT降压作用靶点。

BBT的降压机制研究比较全面, 但对于高血压前期的PHT阶段, 目前研究尚为不足, 仍需要新角度去研究。代谢组学技术(metabolomics) 作为系统生物学新技术, 以生物体内代谢产物为研究对象, 从整体角度出发, 研究代谢物与机体生理病理变化之间的关系。课题组前期通过代谢组学发现脂质代谢通路可能是高血压发生发展的主要影响通路^[17]。为进一步探究PHT阶段痰湿壅盛证的代谢机制, 本实验利用超高效液相色谱-四极杆/静电场轨道阱高分辨质谱联用(UPLC-Q-orbitrap-MS) 分析给药前后PHT痰湿壅盛证大鼠血清代谢组变化, 探讨差异代谢通路, 明确BBT降低痰湿壅盛型正常高值血压的作用机制。利用代谢组学技术从新的角度理解PHT, 诠释中医证候的内在机制和方证相关作用, 探究BBT降血压作用机制, 为其临床应用提供实验依据。

材料与方法

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实验动物 正常雄性WKY大鼠(SPF级), 体质量为80 ± 10 g, 购自北京维通利华实验动物技术有限公司[生产许可证号: SCXK (京) 2021-0006], 饲养于山东中医药大学动物实验中心SPF级实验室动物, 使用许可证号: SYXK (鲁) 20170022。饲养条件: 温度22~24 ℃, 湿度45%~65%。本研究已获得山东中医药大学实验动物福利伦理审查委员会批准(批准号: SDUTCM20211103001)。

仪器及试剂 BP-2010A型大小鼠智能无创血压仪(北京软隆生物技术有限公司); SuperMaze动物行为分析系统、XR-XG201型大鼠高架十字迷宫、XR-XZ301型旷场实验系统(上海欣软信息科技有限公司); 赛默飞Ultimate3000-Q-Exactive型高效液相-四级杆-傅里叶变换质谱仪(静电轨道阱液质联用仪)、Heraeus Biofuge Primo R型通用台式离心机、乙腈、甲醇、甲酸(试剂批号: 203023、172010、186935, 美国Thermo Fisher Scientific公司); URIT-8026型全自动生化分析仪、甘油三酯(triglyceride, TG)、总胆固醇(total cholesterol, TC)、高密度脂蛋白胆固醇(high-density lipoprotein cholesterol, HDL-C) 和低密度脂蛋白胆固醇(low-density lipoprotein cholesterol, LDL-C) 测定试剂盒(试剂批号: 22010322M1、22020441M1、2202029M1、22010519M1, 桂林优利特医疗电子有限公司)。法半夏、麸炒白术、天麻、茯苓、化橘红、甘草(批号: 2111260052、2110200043、2201050012、2112220052、2203190032、2201050112, 亳州市沪谯药业有限公司)、大枣(批号: 20211107009, 通化市济参药业有限公司) 均购于山东省中医院, 生姜(产地: 山东) 购于山东济南银座购物广场(长清大学城店)。经山东中医药大学实验中心刘红燕教授鉴定, 法半夏为天南星科植物半夏Pinellia ternata (Thunb.) Breit.的干燥块茎的炮制加工品“法半夏”, 炒白术为菊科植物白术Atractylodes macrocephala Koidz.的干燥根茎的炮制加工品, 天麻为兰科植物天麻Gastrodia elata BI.的干燥块茎, 茯苓为多孔菌科真菌茯苓Poria cocos (Schw.) Wolf的干燥菌核, 化橘红为芸香科植物化州柚Citrus grandis ‘Tomentosa’或柚Citrus grandis (L.) Osbeck的未成熟或近成熟的干燥外层果皮, 甘草为豆科植物甘草Glycyrrhiza uralensis Fisch.、胀果甘草Glycyrrhiza inflata Bat.或光果甘草Glycyrrhiza glabra L.的干燥根和根茎, 大枣为鼠李科植物枣Zixiphus jujuba Mill.的干燥成熟果实, 生姜为姜科植物姜Zingiber officinale Rosc.的新鲜根茎。D12492高脂饲料(美国Research Diets公司, 批号: 21111502), 由60% kcal脂肪、20% kcal碳水化合物和20% kcal蛋白质组成^[18]; 维持饲料(北京科澳协力饲料有限公司, 批号: 21113213)。

药物制备方法 按照处方比例(3∶6∶2∶2∶2∶1∶1∶1) 称取法半夏饮片、炒白术饮片、天麻饮片、茯苓饮片、化橘红饮片、甘草饮片、大枣饮片、生姜, 加入饮片量10倍的水浸泡60 min, 煎煮两次, 一煎武火煮沸后文火继续煎煮30 min, 滤布趁热过滤; 药渣加入饮片量8倍的水煮沸后煎煮20 min, 趁热过滤, 合并滤液。滤液减压浓缩(60 ℃) 成相当于原生药材1.0 g·mL^-1的药液, 冷却后用无菌瓶密封包装, 冷冻保存备用。

BBT提取物化学成分研究 将100 mg的BBT水提物冻干粉充分溶于100 mL的75%甲醇溶液, 离心(12 000 r·min^-1, 10 min), 0.22 μm滤膜过滤后置于液相小瓶中。使用UPLC-Q-Orbitrap-MS分析, HALO C18色谱柱(100 mm × 2.1 mm, 2.7 μm), 柱温: 45 ℃, 进样量: 5 μL; 流速: 0.3 mL·min^-1。流动相由0.05%甲酸水溶液(A) 和0.05%甲酸乙腈溶液(B) 组成。洗脱梯度: 0~4 min, 2% B; 4~10 min, 2%~25% B; 10~18 min, 25%~100% B; 3 min平衡。质谱条件: 毛细管温度350 ℃; 正离子模式和负离子模式毛细管电压: 3.5 kV和3.5 kV; 鞘气45 arb; 辅助气10 arb; 质量扫描范围m/z 80~1 000; 全扫描分辨率70 000; S-Lens电压50 V。

分组及给药方法 结合实验组前期工作^{[17, 19]}, 适应性喂养1周后, 将大鼠按体质量随机分为正常组(C, n = 10)、模型组(M, n = 10) 和半夏白术天麻汤组(BBT, n = 10)。M组和BBT组大鼠给予高脂+高盐饮食, C组大鼠给予正常维持饲料; 20周后, BBT灌胃8周。按人与动物等效剂量换算公式^[20], 大鼠灌胃剂量为12.60 g·kg^-1·d^-1。C和M组给予等量的蒸馏水灌胃。

血压数据测定 采用套尾无创血压仪检测大鼠的血压, 将仪器初始敏感度设置为4, 将大鼠专用鼠网罩住并置入保温桶中(温度调至37 ℃), 并用鼠袋包裹, 令大鼠尾部完全暴露, 将加压感应器套住大鼠尾部并置于尾根处, 待大鼠稳定5~10 min后, 开始血压测定, 血压图像波动平稳时记录数据, 重复测量3次取均值。

行为学观察和处理 给药前和取材前1周, 分别开展行为学观测。①高架十字迷宫实验: 大鼠放置于中央开放区域(5 cm × 5 cm), 用视频跟踪系统记录大鼠6 min内进入开放臂与闭合臂(5 cm × 15 cm × 35 cm) 的次数OE (open arm entry)、CE (close arm entry) 和时间OT (open arm time)、CT (close arm time), 并计算开放臂进入次数百分比OE% [OE% = OE/(OE+OT)] 和开放臂停留时间百分比OT% [OT% = OT/(OT+OE)]。②旷场实验: 大鼠单独放入黑色内壁的旷场箱(100 cm × 100 cm × 40 cm) 的中央区域中, 自由探索6 min。用视频跟踪系统记录大鼠的运动距离、进入中央区域次数、站立次数等指标。收集实验所得运动坐标, 采用MATLAB R2021b软件(美国MathWorks公司) 绘制大鼠运动轨迹图。

血清采集与处理 取材前, 大鼠12 h禁食不禁水, 以1.5%戊巴比妥钠30 mg·kg^-1腹下注射麻醉, 腹主动脉取血静置30 min, 离心(4 ℃, 4 500 r·min^-1, 15 min), 取上清液, 分装, -80 ℃冷冻备用。

血脂水平测定 血清80 μL, 全自动生化分析仪测定血清TG、TC、HDL-C和LDL-C水平。

血清代谢组学样品处理 血清200 μL, 加入200 μL乙腈, 涡旋60 s, 离心(4 ℃, 12 000 r·min^-1, 10 min)。取200 μL上清液置于2 mL EP管中, 氮气吹干, 用初始流动相(水∶乙腈, 95∶5) 复溶, 离心(4 ℃, 12 000 r·min^-1, 10 min), 0.22 μm微孔滤膜滤过, 置于液相小瓶中。所有血清样本取等量制成质量控制(quality control, QC) 样本。

使用UPLC-Q-Orbitrap-MS分析, HALO C18色谱柱, 柱温: 45 ℃, 进样量: 5 μL; 流速: 0.3 mL·min^-1。流动相由0.05%甲酸水溶液(A) 和0.05%甲酸乙腈溶液(B) 组成。洗脱梯度: 0~1 min, 2% B; 1~5 min, 2%~20% B; 5~7 min, 20%~45% B; 7~15 min, 45%~90% B; 15~17 min, 90% B; 3 min平衡。

数据分析 质谱数据以Compound Discoverer 3.3软件(美国Thermo Fisher Scientific公司) 进行峰对齐、峰提取、归一化等预处理后, 将数据导入SIMCA-P 14.1 (瑞典Umetrics公司) 进行分析, 并采用无监督的主成分分析(principal component analysis, PCA) 及有监督的偏最小二乘判别分析(partial leasts quares discriminant analysis, PLS-DA), 筛选投影变量重要性VIP > 1, P < 0.05的变量作为潜在差异代谢物。通过HMDB数据库(http://www.hmdb.ca/)、KEGG数据库(https://www.kegg.jp/) 和MetaboAnalyst 5.0 (https://www.metaboanalyst.ca/) 平台确定内源性差异代谢物和代谢通路。

统计分析 GraphPad Prism 8.0.1软件(美国GraphPad Software公司), 结果以$\bar{x}$ ± s表示, 多组间比较采用单因素方差分析, P < 0.05为差异有统计学意义。

结果

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1 半夏白术天麻汤化学成分表征

运用所建立的液相色谱-高分辨质谱进行分析, 初步鉴定了78个化合物(表 1), 包括38个黄酮类化合物、17个苯丙素类化合物、8个萜类化合物、6个氨基酸类化合物、1个生物碱类化合物和8个其他类化合物。

2 一般指标观察

与C组相比, 大鼠造模1周后, 开始出现饮食量减少, 见表 2, 暴躁; 造模20周后, M组和BBT组出现皮毛污秽、懒动、纳呆、便溏、精神不佳、舌象白胖、抓取时口中分泌口水等情况; 给药干预8周后, BBT组大鼠与M组比较, 饮食量增加、便溏改善、活动度增加、抓取时口水分泌减少。

3 BBT对体重的影响

图 1可见, 和C组比较, 干预前M、BBT组大鼠体重和C组有显著性差异。M组与BBT组体重之间无差异。在干预4周后, BBT组大鼠体重下降明显, 与M组比较有显著性差异。干预8周后, C、M组大鼠体重持续稳定增加, 而BBT组体重基本平稳, 且和M组有显著性差异。

4 BBT对血压的干预影响

图 2A中, 20周喂养中, C组大鼠的收缩压维持在120 mmHg之下; 而高脂高盐造模的M组和BBT组大鼠血压在稳步增加, 在第10周, 血压均值已经高于120 mmHg, 且在之后的10周里都能正常维持在120~140 mmHg之间。第20周开始用BBT干预后, 干预组大鼠的收缩压开始下降, 而M组大鼠血压仍然维持在正常高值。图 2B中, 喂养的20周里, C组大鼠的血压小于80 mmHg, M组和BBT组在第10周后舒张压高于80 mmHg, 且在之后的10周里都能正常维持在80~90 mmHg之间。第20周开始用BBT干预后, 干预组大鼠的舒张压开始下降, 而M组大鼠血压仍然维持在正常高值。表 3可见, 干预前、模型组和半夏白术天麻汤组的大鼠收缩压和舒张压与正常组比较有显著性差异。第20周开始用BBT干预, 干预4周后, 大鼠血压下降显著, 干预8周后血压下降趋势不多, 但仍然与M组有显著差异。

5 BBT对大鼠行为学影响

图 3是药物干预前大鼠高架十字迷宫试验和旷场试验的各项指标数据图。图 3A~C中分别展示了C组、M组和BBT组中典型的大鼠在高架十字迷宫中的运动轨迹, 可以看到C组大鼠的运动总距离和开放臂的运动距离都比M和BBT组多。图 3D表明C组大鼠与M组、BBT组在十字迷宫中所运动的总距离上有显著差异。图 3E是大鼠进入开放臂次数(OE) 和封闭臂次数(CE) 之和, C组显著大于M组和BBT组。说明正常组大鼠在体力和探索欲上都明显好于模型组。但是在焦虑评分上, C组与M组、BBT组无差异, 如图 3F、G所示。

图 3H~J展示了C组、M组和BBT组中的一只大鼠在给药前旷场试验的轨迹图, 可见C组大鼠在运动距离上多于M组和BBT组, 从图 3K可知在旷场运动的总距离方面, C组和M组、BBT组有显著性差异。另外在进入中央区域的次数(图 3L)、中央区的运动距离(图 3M)、在中央区停留的时间(图 3N) 和站立次数(图 3O) 这几个反映大鼠探索欲的指标中, C组和M组、BBT组大鼠有显著性差异。

图 4为给药8周后大鼠旷场试验的结果汇总, C组大鼠(图 4A) 活动度明显高于M组大鼠(图 4B), 而BBT组大鼠的活动度较M组又有所回升(图 4C), 线路越粗, 亮度越偏黄, 表明大鼠在该区域停留时间越长。从D也可见在运动的总距离方面, 经过药物干预后, BBT组大鼠有显著性增加。在进入中央区域的次数(图 4E)、中央区的运动距离(图 4F) 方面, 给药组的大鼠表现相较于模型组都有所好转。但在中央区停留的时间(图 4G) 上, 虽有所增加, 但是并未有显著性。图 4整体可以看出, BBT对于痰湿壅盛证大鼠活动度的干预有显著作用, 可以改善大鼠因痰湿证候所导致的慵懒的状态。

6 BBT对血脂指标的影响

通过表 4可知, C组和M组在TG、TC、LDL-C有显著性差异, 给药后BBT组和M组对比, TG、TC、LDL-C均有显著性降低, HDL-C值显著性升高。

7 代谢组学分析

7.1 血清代谢物轮廓分析

通过血压、血脂四项和行为学指标的观察, 可见BBT的干预效果明显, 进一步进行代谢组学分析。C组、M组、BBT组大鼠血清样本在正、负离子模式下的总离子流图, 如图 5所示, 可知各组轮廓大致相似, 但代谢物含量有差异。

7.2 血清样本的PCA和PLS-DA分析

对各组样本进行PCA分析, 如图 6A、B所示, PCA结果显示QC样本聚集度高, 说明实验建立的方法重复性和稳定性较好, 在正、负离子模式下, 各组间有聚集分离趋势。为了进一步突出组间差异, 需采用PLS-DA分析。去除QC样本后, 对C组、M组及BBT组进行PLS-DA分析, 结果如图 6C、D所示, C组与M组、M组与BBT组之间分离效果较好, 组内样本在一定范围内聚集良好, 说明C组与M组、M组与BBT组之间存在着明显的差异代谢物。BBT组的样品点逐渐接近C组的样品点, 说明BBT影响了PHT痰湿壅盛证大鼠血清代谢, 并使之趋向于正常大鼠。经10-fold循环交叉验证(10-fold cross validation) 得到的模型评价参数(R², Q²) 交叉验证列于表 5, 本实验正、负离子模式数据建立的PLS-DA模型R²和Q²值均较大(R²、Q²均大于0.7), 说明模型稳定可靠^[21]。

7.3 差异代谢物筛选

BBT干预PHT痰湿壅盛证大鼠的主要差异代谢物结果如表 6所示, 进一步筛选各组间内源性差异代谢物, 通过一、二级质谱信息, 并结合HMDB、KEGG数据库查询和相关文献报道进行鉴定, 最终在正、负离子模式下共筛选出9个血清差异代谢物, 分别是: 花生四烯酸(arachidonic acid, AA)、胆酸、甘脱氧胆酸、N-腺苷酪氨酸、精氨酸、溶血磷脂酰乙醇胺(20:0/0:0)、溶血磷脂(P-18:0)、溶血磷脂(18:0)、溶血磷脂[22:5(7Z, 10Z, 13Z, 16Z, 19Z)]。

7.4 代谢通路分析

造模和用药干预后, 大鼠血压的上升和回调, 所涉及到的代谢通路有7条: 精氨酸生物合成、不饱和脂肪酸的生物合成、甘油磷脂代谢、花生四烯酸代谢、精氨酸和脯氨酸代谢、初级胆汁酸生物合成和氨酰tRNA生物合成, 如图 7所示。

讨论

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根据临床表现, 中医常将正常高值血压分为两类, 一类“逸病”范畴, 仅仅血压略有升高而无临床症状; 另一类属于“头痛”“眩晕”的范畴^[22]。正常高值血压在中医上的分型有肝阳上亢、肝郁气滞、痰浊中阻、肝肾亏虚证^[23]。通过患者脉象特点和临床表现, 将正常高值血压分为脾虚湿盛证、肝肾阴亏证、肾阴阳两虚证、肝郁气滞证^[24]。作为高血压前期最主要的证型之一, 真实临床上痰湿壅盛证更偏于“逸病”。患者因饮食不节、劳逸失常而导致的脾虚而生痰致使血压升高^[25]。

本研究根据临床经验, 采用高脂+高盐方法制备PHT痰湿壅盛证模型, 使大鼠长期的饮食不节, 从而引发痰湿壅盛型的血压升高。前期课题组实验发现WKY大鼠经过造模8周后, 血压开始符合PHT, 10~12周趋于稳定^[19]。为进一步观察模型大鼠的生理、病理形态的改变。采取加长喂养时间, 另外增加行为学测试, 来验证模型成立的可信度。模型组大鼠的体重增加明显, 在给药之后, 随着证候的改善, 大鼠体重迅速下降。说明BBT对于大鼠体重的干预效果显著, 同时也可以观察到大鼠的收缩压和舒张压也在逐步下降。有学者统计^[26-28], 人体血压上升与肥胖密切相关。结果可以看到, BBT可以显著改善大鼠的血脂四项指标数据, 与学者研究中医药对于预防和治疗高脂血症的研究结果一致^[29]。

另外, 行为学指标与临床表现相一致, 动物行为学数据表明动物^[30-32]痰湿壅盛证模型动物懒动倦乏。采用旷场实验和高架十字迷宫实验检测模型动物的运动情况与临床上痰湿壅盛所致的胖人懒动的表现相一致。图 3、4可见, 模型组在长期高脂高盐的喂养下, 造模20周的模型组大鼠和正常组大鼠比较, 自主活动度下降、便溏等脾虚痰湿等症状, 用BBT干预后, 大鼠体重下降, 血脂自主活动度上升。本文以方测证, 比较大鼠造模以及用药前后指标改变, 反证“痰湿壅盛证”模型建立, 以行为学实验量化动物的懒动情况^[33]。

BBT的化学成分鉴定中, 发现多种化合物, 其中黄酮类化合物是BBT中最主要的成分。有研究表明^[34], 黄酮类成分是广泛存在于中药的一类多酚类化合物, 具有调节糖脂代谢、抗炎等作用。另外, 有研究表明中药营养物质利用和心血管疾病密切相关^[35], 利用好中药可以间接改善血压状况, 通过本实验可以为临床提供实验基础。

本研究进一步用代谢组学研究表明, PHT痰湿壅盛证大鼠血清内9个内源性代谢物发生了波动, 半夏白术天麻汤可使代谢物发生回调, 分别是: 花生四烯酸、胆酸、甘脱氧胆酸、N-腺苷酪氨酸、精氨酸、溶血磷脂酰乙醇胺(20:0/0:0)、溶血磷脂(P-18:0)、溶血磷脂(18:0)、溶血磷脂[22:5(7Z, 10Z, 13Z, 16Z, 19Z)]。所涉及到的代谢通路有7条: 精氨酸生物合成、不饱和脂肪酸的生物合成、甘油磷脂代谢、花生四烯酸代谢、精氨酸和脯氨酸代谢、初级胆汁酸生物合成和氨酰tRNA生物合成。

课题组之前发现钩藤调节高血压与AA的调节通路密切相关^[36]。AA是人体内含量丰富的一种不饱和脂肪酸, 其代谢产物参与调节多种病理生理过程。AA经细胞色素P450 (cytochrome P450, CYP) 途径代谢, 且其CYPω-羟化酶代谢产物20-羟基二十碳四烯酸(20-hydroxyeicosatetraenoic acid, 20-HETE) 会影响心脑血管疾病的发展^[37]。P450酶代谢途径产生的环氧二十碳三烯酸(epoxyeicosatrienoic acids, EETs) 主要体现为舒张血管和抑制血管炎症^[38]。在本研究中模型组和用药组的大鼠血压调整, 可能与AA释放具有血压调节作用的代谢物相关。

胆汁酸是胆酸的主要组成部分, 参与体内脂类物质的代谢, 具有重要的生理功能。胆汁酸通过肝脏由胆固醇转化而来, 主要存在于肠肝循环系统中发挥功能。有学者通过网络分析和生物学验证结果表明, 高血压前期的发生与胆汁酸和芳香族氨基酸代谢异常引起的血管炎症有关; 胆汁酸代谢通过调节血管炎症反应在高血压前期的发生发展中起重要作用^[39]。在本研究中胆酸代谢和血压呈负相关趋势, 说明BBT对于血压的调节可能和胆酸相关代谢有关。

综上所述, 本文通过代谢组学技术探究半夏白术天麻汤对于正常高值血压痰湿壅盛证大鼠的干预可能在通过花生四烯酸代谢通路和胆汁生物合成通路来释放相关代谢物, 从而调节血压。为阐明高血压的发生发展机制做出新的探索, 以期为延缓高血压的发生发展提供可靠的实验依据。

作者贡献: 叶建桥负责实验操作、数据处理和文章撰写; 蒋海强负责指导代谢组学实验、文章设计及修改; 齐冬梅、齐于辰负责整体设计及文章修改; 李淑敏协助指导实验和数据处理; 郭晓庆协助完成动物实验。

利益冲突: 本文无利益冲突。

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国家自然科学基金资助项目(81974555)

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2023年第58卷第7期

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doi: 10.16438/j.0513-4870.2022-1216

接收时间：2022-11-15
首发时间：2025-11-21
出版时间：2023-07-12

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收稿日期：2022-11-15
修回日期：2023-03-12

基金

国家自然科学基金资助项目(81974555)

作者信息

1.山东中医药大学中医药创新研究院, 山东济南 250355

2.山东中医药大学实验中心, 山东济南 250355

3.山东省中医药基础研究重点实验室, 山东济南 250355

4.山东中医药大学, 教育部中医药经典理论重点实验室, 山东济南 250355

5.山东中医药大学健康学院, 山东济南 250355

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*齐冬梅, Tel: 15805316081, E-mail: qidm119@163.com;

齐于辰, Tel: 13287011229, E-mail: qiyuchenbzy@163.com

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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No.	t_R/min	Formula	Theoretical m/z	Practical m/z	Ion	Product ion (m/z)	Identification
1	0.62	C₉H₁₀O₄	182.057 4	183.004 1	[M+H]⁺	123.007 1, 95.012 5	Syringaldehyde
2	0.65	C₅H₈N₂O₅	176.042 8	174.955 3	[M-H]^-	146.960 0, 118.964 9	Dencichine
3	0.76	C₇H₇NO₂	137.047 1	138.055 0	[M+H]⁺	110.060 5	Trigonelline
4	0.85	C₆H₆O₃	126.031 1	127.039 2	[M+H]⁺	108.044 8, 81.034 2, 69.034 3	5-Hydroxymethylfurfura
5	0.86	C₅H₉NO₂	115.062 8	116.070 9	[M+H]⁺	70.065 9	L-Proline
6	1.11	C₆H₈O₇	192.026 5	191.018 9	[M-H]^-	111.007 4, 85.027 9	Citric acid
7	1.83	C₁₂H₂₂O₁₁	342.115 7	341.109 1	[M-H]^-	179.054 9, 89.022 9	Sucrose
8	2.68	C₅H₉NO₄	147.052 6	146.023 6	[M-H]^-	128.033 3, 128.033 3, 75.006 9	L-Glutamic acid
9	3.67	C₁₁H₁₂N₂O₂	204.089 3	203.082 1	[M-H]^-	142.065 1, 116.049 2	L-Tryptophan
10	4.42	C₁₆H₁₈O₉	354.094 5	353.087 8	[M-H]^-	191.055 4, 179.034 2, 135.043 9	1-Caffeoylquinic acid
11	4.45	C₇H₆O₃	138.031 1	137.023 2	[M-H]^-	108.020 1	3,4-Dihydroxybenzaldehyde
12	4.68	C₉H₁₁NO₃	181.073 3	182.081 1	[M+H]⁺	165.054 7	L-Tyrosine
13	4.74	C₇H₆O₂	122.036 2	121.028 2	[M-H]^-	91.017 6	4-Hydroxybenzaldehyde
14	4.90	C₉H₆O₄	178.026 1	177.018 2	[M-H]^-	115.038 7, 85.064 2	Esculetine
15	5.41	C₁₉H₂₄O₁₃	460.121 1	459.115 6	[M-H]^-	111.007 3	Parishin E
16	5.52	C₈H₈O₃	152.046 8	153.054 2	[M+H]⁺	93.033 0	4-Mthoxysalicylaldehyde
17	5.59	C₁₅H₁₆O₉	340.078 9	339.073 2	[M-H]^-	177.018 5, 133.028 3	Esculin
18	6.39	C₁₆H₁₈O₉	354.094 5	353.088 4	[M-H]^-	191.055 4, 173.044 7, 135.043 9	Cryptochlorogenic acid
19	6.41	C₇H₆O₄	154.026 1	153.018 3	[M-H]^-	109.028 1	Protocatechuic acid
20	6.87	C₉H₈O₄	180.041 7	179.034 1	[M-H]^-	135.043 9, 107.048 9	Caffeic acid
21	7.04	C₁₅H₁₂O₄	256.073 0	257.080 6	[M+H]⁺	239.071 2, 211.074 4, 147.044 1, 137.023 4, 119.049 4	Isoliquiritigenin
22	7.20	C₁₀H₈O₃	176.046 8	177.054 3	[M+H]⁺	145.028 4, 117.033 8, 89.039 2	7-Methoxycoumarin
23	8.17	C₂₆H₂₈O₁₄	564.147 4	563.145 3	[M-H]^-	353.068 2, 297.077 0	Isoschaftoside
24	8.27	C₃₃H₄₀O₁₉	740.215 8	741.223 7	[M+H]⁺	271.059 9	Apigenin-7-O-(2G-rhamnosyl) gentiobioside
25	8.38	C₂₁H₂₀O₁₁	448.100 0	447.094 3	[M-H]^-	429.083 0, 285.040 4, 133.028 4	Isoorientin
26	8.55	C₂₁H₂₀O₁₁	448.100 0	447.096 2	[M-H]^-	327.052 3	Orientin
27	8.79	C₁₅H₁₂O₄	256.073 0	255.066 3	[M-H]^-	135.007 5, 119.048 8, 91.017 4	Liquiritigenin
28	8.91	C₂₁H₂₂O₉	418.125 8	417.120 3	[M-H]^-	255.066 4, 135.007 5, 119.048 9	Liquiritin
29	9.03	C₂₁H₂₀O₁₀	432.105 1	433.113 0	[M+H]⁺	415.100 4, 397.092 4, 271.060 0	Isovitexin
30	9.23	C₂₇H₃₀O₁₅	594.157 9	593.154 7	[M-H]^-	285.040 6	Kaempferol-3-O-rutinoside
31	9.24	C₇H₆O₃	138.031 1	137.023 2	[M-H]^-	93.033 1	Salicylic acid
32	9.70	C₂₇H₃₂O₁₄	580.178 7	579.172 4	[M-H]^-	271.062 5, 151.002 5, 119.048 8, 107.012 4	Narigin
33	9.79	C₂₇H₃₀O₁₄	578.163 0	579.170 8	[M+H]⁺	271.059 6, 153.018 1	Isorhoifolin
34	9.87	C₁₆H₁₂O₆	300.062 8	299.056 6	[M-H]^-	284.032 4, 255.066 1, 255.066 1, 240.042 5	Tectorigenin
35	9.91	C₁₅H₁₆O₄	260.104 3	261.112 2	[M+H]⁺	189.054 7, 131.049 3	Isomeranzin
36	10.09	C₁₅H₁₂O₆	288.062 8	287.056 9	[M-H]^-	151.002 7	Eriodictyol
37	10.32	C₉H₆O₂	146.036 2	147.044 2	[M+H]⁺	119.049 4, 91.054 8	Coumarin
38	10.33	C₉H₈O₃	164.046 8	163.039 0	[M-H]^-	119.048 8, 93.032 8	p-Hydroxycinnamic acid
39	10.76	C₂₆H₃₀O₁₃	550.168 1	549.163 4	[M-H]^-	549.161 4, 135.007 5, 119.049 0	Liquiritigenin-7-O-β-D-apiofuranosyl-4′-O-β-D-glucopyranoside
40	10.82	C₁₅H₂₀O₃	248.140 7	249.148 1	[M+H]⁺	185.132 3	Parthenolide
41	10.95	C₁₆H₁₄O₅	286.083 6	285.077 3	[M-H]^-	270.053 8, 150.031 1	Licochalcone B
42	11.13	C₁₆H₁₂O₇	316.057 8	317.065 4	[M+H]⁺	302.041 2, 274.047 1, 153.018 2	Isorhamnetin
43	11.21	C₁₅H₁₀O₆	286.047 2	285.041 1	[M-H]^-	133.028 2	Luteolin
44	11.46	C₁₆H₁₂O₅	284.067 9	285.075 7	[M+H]⁺	270.052 3	Glycitein
45	11.47	C₁₆H₁₂O₅	284.067 9	283.061 7	[M-H]^-	268.038 3, 239.034 7, 211.040 2	Calycosin
46	11.62	C₁₆H₁₄O₆	302.078 5	301.036 0	[M-H]^-	151.002 5	Hesperetin
47	12.18	C₁₅H₁₀O₄	254.057 4	253.050 7	[M-H]^-	209.056 4	Daidzein
48	12.29	C₉H₆O₄	178.026 1	179.033 8	[M+H]⁺	133.028 4	5,7-Dihydroxychromone
49	12.30	C₁₅H₁₂O₅	272.067 9	271.061 6	[M-H]^-	227.159 0, 151.002 5, 145.027 8	Naringenin chalcone
50	12.51	C₁₆H₁₄O₄	270.088 7	271.096 8	[M+H]⁺	153.018 3	Echinatin
51	12.59	C₁₅H₁₀O₅	270.052 3	271.060 0	[M+H]⁺	243.065 2, 153.018 2, 119.049 4	Genistein
52	12.79	C₇H₁₂O₆	192.062 8	191.055 3	[M-H]^-	127.039 0, 85.028 0	Quinic acid
53	12.79	C₁₅H₁₀O₅	270.052 3	269.046 1	[M-H]^-	151.002 6	Apigenin
54	12.81	C₃₀H₄₆O₅	486.334 0	487.341 8	[M+H]⁺	173.132 5	Quillaic acid
55	13.16	C₃₀H₄₆O₃	454.344 1	455.353 9	[M+H]⁺	95.086 4	Wilforlide A
56	13.17	C₁₆H₁₂O₆	300.062 8	299.057 0	[M-H]^-	284.032 9, 255.029 4, 227.034 5	Hydroxygenkwanin
57	13.67	C₁₆H₁₂O₄	268.073 0	267.066 6	[M-H]^-	267.066 6, 223.039 4	Formononetin
58	13.96	C₃₀H₄₄O₄	468.323 4	469.331 4	[M+H]⁺	451.320 1, 439.321 6	Glabrolide
59	14.11	C₁₇H₁₄O₆	314.078 5	313.072 4	[M-H]^-	298.048 1, 283.024 8, 255.030 6	Pectolinarigenin
60	14.22	C₃₀H₄₆O₄	470.339 1	471.346 9	[M+H]⁺	453.336 5, 189.164 0	Glycyrrhetinic acid
61	14.22	C₉H₆O₃	162.031 1	161.023 6	[M-H]^-	117.033 5, 89.022 9	7-Hydroxycoumarin
62	14.35	C₂₁H₂₀O₆	368.125 4	367.119 0	[M-H]^-	309.041 2, 269.042 3	Icaritin
63	14.46	C₁₅H₂₀O₃	248.140 7	249.148 6	[M+H]⁺	231.138 0, 203.143 1, 175.075 1, 119.085 9, 105.070 4	Atractylenolide Ⅲ
64	14.94	C₄₂H₆₂O₁₆	822.403 2	821.398 0	[M-H]^-	351.057 2, 193.034 7	Diammonium glycyrrhizinate
65	15.15	C₂₀H₁₈O₄	322.120 0	321.113 9	[M-H]^-	117.033 3	Licoflavone A
66	15.41	C₁₆H₁₂O₅	284.067 9	283.061 4	[M-H]^-	283.061 4	Acacetin
67	15.63	C₁₆H₁₂O₅	284.067 9	285.075 5	[M+H]⁺	270.052 2	Wogonin
68	15.80	C₁₁H₆O₃	186.031 1	187.039 0	[M+H]⁺	131.049 3, 103.054 6	Isopsoralen
69	15.84	C₁₅H₁₈O₂	230.130 1	231.137 9	[M+H]⁺	185.132 6, 157.101 2	Atractylodes Ⅰ
70	15.87	C₁₆H₁₄O₄	270.088 7	269.082 2	[M-H]^-	254.058 4, 225.055 3, 210.068 2	Medicarpin
71	15.93	C₂₀H₂₀O₅	340.130 5	341.136 8	[M+H]⁺	341.136 8, 341.136 8	8-Prenylnaringenin
72	16.70	C₂₁H₂₂O₄	338.151 3	339.158 8	[M+H]⁺	121.028 7	Glycyrrhiza chalcone C
73	16.90	C₁₂H₁₄O₂	190.098 8	191.106 9	[M+H]⁺	119.049 1, 107.049 5	Ligustilide
74	17.02	C₁₈H₃₀O₂	278.224 0	279.231 7	[M+H]⁺	243.100 9	α-Linolenic acid
75	17.35	C₂₀H₁₆O₅	336.099 2	335.092 8	[M-H]^-	320.067 9, 291.103 4, 199.075 8	Photoglycyrrhizinone
76	17.61	C₁₀H₁₀O₄	194.057 4	191.055 3	[M-H]^-	178.025 8	Ferulic acid
77	18.00	C₁₅H₂₀O₂	232.145 8	233.153 6	[M+H]⁺	215.143 3, 151.075 5, 131.085 7	Atractylodes Ⅱ
78	19.88	C₅H₁₁NO₂	117.078 4	118.086 6	[M+H]⁺	91.054 7, 72.081 5	L-Valine

No.

t_R/min

Formula

Theoretical m/z

Practical m/z

Ion

Product ion (m/z)

Identification

0.62

C₉H₁₀O₄

182.057 4

183.004 1

[M+H]⁺

123.007 1, 95.012 5

Syringaldehyde

0.65

C₅H₈N₂O₅

176.042 8

174.955 3

[M-H]^-

146.960 0, 118.964 9

Dencichine

0.76

C₇H₇NO₂

137.047 1

138.055 0

[M+H]⁺

110.060 5

Trigonelline

0.85

C₆H₆O₃

126.031 1

127.039 2

[M+H]⁺

108.044 8, 81.034 2, 69.034 3

5-Hydroxymethylfurfura

0.86

C₅H₉NO₂

115.062 8

116.070 9

[M+H]⁺

70.065 9

L-Proline

1.11

C₆H₈O₇

192.026 5

191.018 9

[M-H]^-

111.007 4, 85.027 9

Citric acid

1.83

C₁₂H₂₂O₁₁

342.115 7

341.109 1

[M-H]^-

179.054 9, 89.022 9

Sucrose

2.68

C₅H₉NO₄

147.052 6

146.023 6

[M-H]^-

128.033 3, 128.033 3, 75.006 9

L-Glutamic acid

3.67

C₁₁H₁₂N₂O₂

204.089 3

203.082 1

[M-H]^-

142.065 1, 116.049 2

L-Tryptophan

4.42

C₁₆H₁₈O₉

354.094 5

353.087 8

[M-H]^-

191.055 4, 179.034 2, 135.043 9

1-Caffeoylquinic acid

4.45

C₇H₆O₃

138.031 1

137.023 2

[M-H]^-

108.020 1

3,4-Dihydroxybenzaldehyde

4.68

C₉H₁₁NO₃

181.073 3

182.081 1

[M+H]⁺

165.054 7

L-Tyrosine

4.74

C₇H₆O₂

122.036 2

121.028 2

[M-H]^-

91.017 6

4-Hydroxybenzaldehyde

4.90

C₉H₆O₄

178.026 1

177.018 2

[M-H]^-

115.038 7, 85.064 2

Esculetine

5.41

C₁₉H₂₄O₁₃

460.121 1

459.115 6

[M-H]^-

111.007 3

Parishin E

5.52

C₈H₈O₃

152.046 8

153.054 2

[M+H]⁺

93.033 0

4-Mthoxysalicylaldehyde

5.59

C₁₅H₁₆O₉

340.078 9

339.073 2

[M-H]^-

177.018 5, 133.028 3

Esculin

6.39

C₁₆H₁₈O₉

354.094 5

353.088 4

[M-H]^-

191.055 4, 173.044 7, 135.043 9

Cryptochlorogenic acid

6.41

C₇H₆O₄

154.026 1

153.018 3

[M-H]^-

109.028 1

Protocatechuic acid

6.87

C₉H₈O₄

180.041 7

179.034 1

[M-H]^-

135.043 9, 107.048 9

Caffeic acid

7.04

C₁₅H₁₂O₄

256.073 0

257.080 6

[M+H]⁺

239.071 2, 211.074 4, 147.044 1, 137.023 4, 119.049 4

Isoliquiritigenin

7.20

C₁₀H₈O₃

176.046 8

177.054 3

[M+H]⁺

145.028 4, 117.033 8, 89.039 2

7-Methoxycoumarin

8.17

C₂₆H₂₈O₁₄

564.147 4

563.145 3

[M-H]^-

353.068 2, 297.077 0

Isoschaftoside

8.27

C₃₃H₄₀O₁₉

740.215 8

741.223 7

[M+H]⁺

271.059 9

Apigenin-7-O-(2G-rhamnosyl) gentiobioside

8.38

C₂₁H₂₀O₁₁

448.100 0

447.094 3

[M-H]^-

429.083 0, 285.040 4, 133.028 4

Isoorientin

8.55

C₂₁H₂₀O₁₁

448.100 0

447.096 2

[M-H]^-

327.052 3

Orientin

8.79

C₁₅H₁₂O₄

256.073 0

255.066 3

[M-H]^-

135.007 5, 119.048 8, 91.017 4

Liquiritigenin

8.91

C₂₁H₂₂O₉

418.125 8

417.120 3

[M-H]^-

255.066 4, 135.007 5, 119.048 9

Liquiritin

9.03

C₂₁H₂₀O₁₀

432.105 1

433.113 0

[M+H]⁺

415.100 4, 397.092 4, 271.060 0

Isovitexin

9.23

C₂₇H₃₀O₁₅

594.157 9

593.154 7

[M-H]^-

285.040 6

Kaempferol-3-O-rutinoside

9.24

C₇H₆O₃

138.031 1

137.023 2

[M-H]^-

93.033 1

Salicylic acid

9.70

C₂₇H₃₂O₁₄

580.178 7

579.172 4

[M-H]^-

271.062 5, 151.002 5, 119.048 8, 107.012 4

Narigin

9.79

C₂₇H₃₀O₁₄

578.163 0

579.170 8

[M+H]⁺

271.059 6, 153.018 1

Isorhoifolin

9.87

C₁₆H₁₂O₆

300.062 8

299.056 6

[M-H]^-

284.032 4, 255.066 1, 255.066 1, 240.042 5

Tectorigenin

9.91

C₁₅H₁₆O₄

260.104 3

261.112 2

[M+H]⁺

189.054 7, 131.049 3

Isomeranzin

10.09

C₁₅H₁₂O₆

288.062 8

287.056 9

[M-H]^-

151.002 7

Eriodictyol

10.32

C₉H₆O₂

146.036 2

147.044 2

[M+H]⁺

119.049 4, 91.054 8

Coumarin

10.33

C₉H₈O₃

164.046 8

163.039 0

[M-H]^-

119.048 8, 93.032 8

p-Hydroxycinnamic acid

10.76

C₂₆H₃₀O₁₃

550.168 1

549.163 4

[M-H]^-

549.161 4, 135.007 5, 119.049 0

Liquiritigenin-7-O-β-D-apiofuranosyl-4′-O-β-D-glucopyranoside

10.82

C₁₅H₂₀O₃

248.140 7

249.148 1

[M+H]⁺

185.132 3

Parthenolide

10.95

C₁₆H₁₄O₅

286.083 6

285.077 3

[M-H]^-

270.053 8, 150.031 1

Licochalcone B

11.13

C₁₆H₁₂O₇

316.057 8

317.065 4

[M+H]⁺

302.041 2, 274.047 1, 153.018 2

Isorhamnetin

11.21

C₁₅H₁₀O₆

286.047 2

285.041 1

[M-H]^-

133.028 2

Luteolin

11.46

C₁₆H₁₂O₅

284.067 9

285.075 7

[M+H]⁺

270.052 3

Glycitein

11.47

C₁₆H₁₂O₅

284.067 9

283.061 7

[M-H]^-

268.038 3, 239.034 7, 211.040 2

Calycosin

11.62

C₁₆H₁₄O₆

302.078 5

301.036 0

[M-H]^-

151.002 5

Hesperetin

12.18

C₁₅H₁₀O₄

254.057 4

253.050 7

[M-H]^-

209.056 4

Daidzein

12.29

C₉H₆O₄

178.026 1

179.033 8

[M+H]⁺

133.028 4

5,7-Dihydroxychromone

12.30

C₁₅H₁₂O₅

272.067 9

271.061 6

[M-H]^-

227.159 0, 151.002 5, 145.027 8

Naringenin chalcone

12.51

C₁₆H₁₄O₄

270.088 7

271.096 8

[M+H]⁺

153.018 3

Echinatin

12.59

C₁₅H₁₀O₅

270.052 3

271.060 0

[M+H]⁺

243.065 2, 153.018 2, 119.049 4

Genistein

12.79

C₇H₁₂O₆

192.062 8

191.055 3

[M-H]^-

127.039 0, 85.028 0

Quinic acid

12.79

C₁₅H₁₀O₅

270.052 3

269.046 1

[M-H]^-

151.002 6

Apigenin

12.81

C₃₀H₄₆O₅

486.334 0

487.341 8

[M+H]⁺

173.132 5

Quillaic acid

13.16

C₃₀H₄₆O₃

454.344 1

455.353 9

[M+H]⁺

95.086 4

Wilforlide A

13.17

C₁₆H₁₂O₆

300.062 8

299.057 0

[M-H]^-

284.032 9, 255.029 4, 227.034 5

Hydroxygenkwanin

13.67

C₁₆H₁₂O₄

268.073 0

267.066 6

[M-H]^-

267.066 6, 223.039 4

Formononetin

13.96

C₃₀H₄₄O₄

468.323 4

469.331 4

[M+H]⁺

451.320 1, 439.321 6

Glabrolide

14.11

C₁₇H₁₄O₆

314.078 5

313.072 4

[M-H]^-

298.048 1, 283.024 8, 255.030 6

Pectolinarigenin

14.22

C₃₀H₄₆O₄

470.339 1

471.346 9

[M+H]⁺

453.336 5, 189.164 0

Glycyrrhetinic acid

14.22

C₉H₆O₃

162.031 1

161.023 6

[M-H]^-

117.033 5, 89.022 9

7-Hydroxycoumarin

14.35

C₂₁H₂₀O₆

368.125 4

367.119 0

[M-H]^-

309.041 2, 269.042 3

Icaritin

14.46

C₁₅H₂₀O₃

248.140 7

249.148 6

[M+H]⁺

231.138 0, 203.143 1, 175.075 1, 119.085 9, 105.070 4

Atractylenolide Ⅲ

14.94

C₄₂H₆₂O₁₆

822.403 2

821.398 0

[M-H]^-

351.057 2, 193.034 7

Diammonium glycyrrhizinate

15.15

C₂₀H₁₈O₄

322.120 0

321.113 9

[M-H]^-

117.033 3

Licoflavone A

15.41

C₁₆H₁₂O₅

284.067 9

283.061 4

[M-H]^-

283.061 4

Acacetin

15.63

C₁₆H₁₂O₅

284.067 9

285.075 5

[M+H]⁺

270.052 2

Wogonin

15.80

C₁₁H₆O₃

186.031 1

187.039 0

[M+H]⁺

131.049 3, 103.054 6

Isopsoralen

15.84

C₁₅H₁₈O₂

230.130 1

231.137 9

[M+H]⁺

185.132 6, 157.101 2

Atractylodes Ⅰ

15.87

C₁₆H₁₄O₄

270.088 7

269.082 2

[M-H]^-

254.058 4, 225.055 3, 210.068 2

Medicarpin

15.93

C₂₀H₂₀O₅

340.130 5

341.136 8

[M+H]⁺

341.136 8, 341.136 8

8-Prenylnaringenin

16.70

C₂₁H₂₂O₄

338.151 3

339.158 8

[M+H]⁺

121.028 7

Glycyrrhiza chalcone C

16.90

C₁₂H₁₄O₂

190.098 8

191.106 9

[M+H]⁺

119.049 1, 107.049 5

Ligustilide

17.02

C₁₈H₃₀O₂

278.224 0

279.231 7

[M+H]⁺

243.100 9

α-Linolenic acid

17.35

C₂₀H₁₆O₅

336.099 2

335.092 8

[M-H]^-

320.067 9, 291.103 4, 199.075 8

Photoglycyrrhizinone

17.61

C₁₀H₁₀O₄

194.057 4

191.055 3

[M-H]^-

178.025 8

Ferulic acid

18.00

C₁₅H₂₀O₂

232.145 8

233.153 6

[M+H]⁺

215.143 3, 151.075 5, 131.085 7

Atractylodes Ⅱ

19.88

C₅H₁₁NO₂

117.078 4

118.086 6

[M+H]⁺

91.054 7, 72.081 5

L-Valine

Group	Before intervention/g	Intervention for 8 weeks/g
C	17.36 ± 0.03	15.91 ± 0.03
M	11.38 ± 0.19^*	11.23 ± 0.41^*
BBT	10.41 ± 0.65^*	16.18 ± 1.53^#

Group

Before intervention/g

Intervention for 8 weeks/g

17.36 ± 0.03

15.91 ± 0.03

11.38 ± 0.19^*

11.23 ± 0.41^*

BBT

10.41 ± 0.65^*

16.18 ± 1.53^#

Group	SBP/mmHg		DBP/mmHg
C	112.7 ± 7.6	114.4 ± 8.3	112.8 ± 3.5		75.1 ± 6.1	79.2 ± 4.2	79.6 ± 2.8
M	129.3 ± 2.8^**	128.4 ± 3.2^**	124.0 ± 2.9^**	85.8 ± 2.2^**	86.6 ± 1.5^**	82.5 ± 1.1^*
BBT	129.0 ± 3.9^**	117.0 ± 4.9^##	118.6 ± 4.3^*#	85.7 ± 4.1^**	80.2 ± 3.8^##	78.4 ± 1.8^##

Group

SBP/mmHg

DBP/mmHg

Before intervention

Intervention for 4 weeks

Intervention for 8 weeks

Before intervention

Intervention for 4 weeks

Intervention for 8weeks

112.7 ± 7.6

114.4 ± 8.3

112.8 ± 3.5

75.1 ± 6.1

79.2 ± 4.2

79.6 ± 2.8

129.3 ± 2.8^**

128.4 ± 3.2^**

124.0 ± 2.9^**

85.8 ± 2.2^**

86.6 ± 1.5^**

82.5 ± 1.1^*

BBT

129.0 ± 3.9^**

117.0 ± 4.9^##

118.6 ± 4.3^*#

85.7 ± 4.1^**

80.2 ± 3.8^##

78.4 ± 1.8^##

Group	TG/mmol·L^-1	TC/mmol·L^-1	HDL-C/mmol·L^-1	LDL-C/mmol·L^-1
C	0.34 ± 0.06	3.19 ± 0.27	2.21 ± 0.20	0.79 ± 0.08
M	1.13 ± 0.27^**	3.61 ± 0.35^*	1.72 ± 0.09	0.98 ± 0.16^*
BBT	0.38 ± 0.04^##	3.00 ± 0.27^##	1.89 ± 0.17^#	0.64 ± 0.06^**##

Group

TG/mmol·L^-1

TC/mmol·L^-1

HDL-C/mmol·L^-1

LDL-C/mmol·L^-1

0.34 ± 0.06

3.19 ± 0.27

2.21 ± 0.20

0.79 ± 0.08

1.13 ± 0.27^**

3.61 ± 0.35^*

1.72 ± 0.09

0.98 ± 0.16^*

BBT

0.38 ± 0.04^##

3.00 ± 0.27^##

1.89 ± 0.17^#

0.64 ± 0.06^**##

Mode	Principal component	R²	Q²
+	5	0.99	0.84
-	5	0.99	0.82

Mode

Principal component

R²

Q²

0.99

0.84

0.99

0.82

Formula	Metabolite	t_R/min	m/z	M vs C		BBT vs M
C₂₀H₃₂O₂	Arachidonic acid	14.91	305.247 6	1.53	↑^*		2.6	↓^##
C₂₄H₄₀O₅	Cholic acid	8.98	407.280 7	9.89	↓^*	1.5	↑^#
C₂₆H₄₃NO₅	Glycodeoxycholic acid	8.31	450.322 7	1.21	↑^**	2.92	↓^#
C₂₉H₄₁NO₄	N-Arachidonoyl tyrosine	8.98	468.311 6	2.42	↓^**	0.11	↑^#
C₆H₁₄N₄O₂	Arginine	0.80	175.119 2	1.57	↑^*	0.65	↓^#
C₂₅H₅₂NO₇P	LysoPE(20:0/0:0)	10.27	510.356 1	2.58	↓^**	2.26	↑^##
C₂₆H₅₄NO₆P	LysoPC(P-18:0)	11.00	508.377	2.39	↑^**	0.82	↓^##
C₂₆H₅₆NO₆P	LysoPC(18:0)	12.40	510.392 7	2.53	↑^**	1.48	↓^##
C₃₀H₅₂NO₇P	LysoPC(22:5(7Z, 10Z, 13Z, 16Z, 19Z))	11.40	570.356 1	2.33	↑^**	0.6	↓^##

Formula

Metabolite

t_R/min

m/z

M vs C

BBT vs M

VIP

Trend

VIP

Trend

C₂₀H₃₂O₂

Arachidonic acid

14.91

305.247 6

1.53

↑^*

2.6

↓^##

C₂₄H₄₀O₅

Cholic acid

8.98

407.280 7

9.89

↓^*

1.5

↑^#

C₂₆H₄₃NO₅

Glycodeoxycholic acid

8.31

450.322 7

1.21

↑^**

2.92

↓^#

C₂₉H₄₁NO₄

N-Arachidonoyl tyrosine

8.98

468.311 6

2.42

↓^**

0.11

↑^#

C₆H₁₄N₄O₂

Arginine

0.80

175.119 2

1.57

↑^*

0.65

↓^#

C₂₅H₅₂NO₇P

LysoPE(20:0/0:0)

10.27

510.356 1

2.58

↓^**

2.26

↑^##

C₂₆H₅₄NO₆P

LysoPC(P-18:0)

11.00

508.377

2.39

↑^**

0.82

↓^##

C₂₆H₅₆NO₆P

LysoPC(18:0)

12.40

510.392 7

2.53

↑^**

1.48

↓^##

C₃₀H₅₂NO₇P

LysoPC(22:5(7Z, 10Z, 13Z, 16Z, 19Z))

11.40

570.356 1

2.33

↑^**

0.6

↓^##