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Metabolite	Formula	Measured m/z	Theoretical m/z	RT /min	VIP value	ESI mode	Error /ppm	Variation trend
Fumaric acid	C₄H₄O₄	115.003 7	115.003 7	1.05	1.376 6	-	0.00	↑^**	↓^#	↓^##	↓^##
Malic acid	C₄H₆O₅	133.014 2	133.014 2	0.87	1.834 0	+/-	0.00	↓^**	↑^##	↑^##	↑^##
Vanylglycol	C₉H₁₂O₄	134.071 2	134.070 6	0.85	1.544 7	+	4.33	↑^**	↓^##	↓^##	↓^##
4-Trimethylammoniobutanoic acid	C₇H₁₅NO₂	144.102 9	144.103 0	13.05	1.335 6	-	-0.69	↓^**	/	↑^##	↑^##
L-Phenylalanine	C₉H₁₁NO₂	164.071 9	164.071 7	2.08	1.800 1	-	1.28	↑^**	↓^##	↓^##	↓^##
L-Tyrosine	C₉H₁₁NO₃	182.080 4	182.081 2	0.88	1.576 3	+	-4.39	↓^**	/	↑^##	↑^##
17alpha, 21-Dihydroxypregnenolone	C₂₁H₃₂O₄	186.114 1	186.113 3	6.33	1.774 4	+	4.03	↑^**	↓^##	↓^##	↓^##
Taurine	C₂H₇NO₃S	191.994 6	191.994 9	0.78	1.760 4	+/-	-1.56	↓^**	↑^##	↑^##	↑^##
4-Hydroxy-2-oxoglutaric acid	C₅H₆O₆	245.075 8	245.076 8	1.16	1.787 2	+	-4.20	↓^**	/	/	↑^##
Androstenedione	C₁₉H₂₆O₂	251.179 8	251.180 6	10.15	1.778 4	+	-3.03	↑^**	↓^##	↓^##	↓^##
Androsterone	C₁₉H₃₀O₂	271.207 0	271.206 2	9.57	1.852 8	-	2.95	↑^**	↓^##	↓^##	↓^##
PE(22:2(13Z, 16Z)/18:1(9Z))	C₄₅H₈₄NO₈P	274.198 8	274.199 1	8.77	1.326 9	+	-1.09	↓^**	↑^##	↑^##	↑^##
Oleic acid	C₁₈H₃₄O₂	281.248 1	281.248 6	13.35	1.613 4	-	-1.78	↓^**	↑^##	↑^##	↑^##
3-O-Sulfogalactosylceramide (D18:1/18:0)	C₄₂H₈₁NO₁₁S	292.172 4	292.173 6	13.19	1.492 7	+	-4.11	↓^**	/	/	↑^##
Sphingosine	C₁₈H₃₇NO₂	300.288 5	300.289 7	11.81	1.593 1	+	-4.13	↓^**	↑^##	↑^##	↑^##
LysoPC(22:0/0:0)	C₃₀H₆₂NO₇P	311.234 3	311.233 7	15.83	1.509 3	+	1.93	↓^**	↑^##	↑^##	↑^##
Linoleic acid	C₁₈H₃₂O₂	313.272 5	313.273 7	15.10	1.224 3	+	-3.83	↓^**	/	↑^##	↑^##
4-Trimethylammoniobutanal	C₇H₁₆NO	322.247 1	322.2476	5.36	1.334 9	+	-1.68	↓^**	↑^#	↑^#	↑^##
Glucose 1-phosphate	C₆H₁₃O₉P	327.009 8	327.009 9	0.73	1.497 6	-	-0.31	↑^**	↓^##	↓^##	↓^##
Docosahexaenoic acid	C₂₂H₃₂O₂	327.232 5	327.233 0	12.72	1.061 1	-	-1.53	↑^**	↓^##	↓^##	↓^##
Leukotriene A4	C₂₀H₃₀O₃	360.253 8	360.253 3	6.76	1.832 7	+	1.39	↓^**	↑^##	↑^##	↑^##
Vitamin D3	C₂₇H₄₄O	367.338 1	367.336 5	13.12	1.599 5	+	4.36	↑^**	/	/	↓^##
Sphingosine 1-phosphate	C₁₈H₃₈NO₅P	378.239 9	378.241 5	11.85	1.308 5	-	-4.23	↑^**	↓^##	↓^##	↓^##
PE(15:0/14:1(9Z))	C₃₄H₆₆NO₈P	386.273 6	386.273 4	14.18	1.653 6	+	0.44	↓^**	↑^##	↑^##	↑^##
PE(14:0/P-16:0)	C₃₅H₇₀NO₇P	386.293 0	386.291 6	14.18	1.425 5	+	3.62	↑^**	↓^#	↓^#	↓^##
15-HETE	C₂₀H₃₂O₃	387.214 7	387.215 3	14.32	1.710 3	-	-1.55	↓^**	↑^##	↑^##	↑^##
PE(22:2(13Z, 16Z)/P-18:0)	C₄₅H₈₆NO₇P	403.806 0	403.805 3	7.29	1.426 7	+	1.83	↑^**	↓^##	↓^##	↓^##
PC(22:5(7Z, 10Z, 13Z, 16Z, 19Z)/P-16:0)	C₄₆H₈₂NO₇P	407.790 2	407.789 7	7.01	1.728 8	+	1.18	↓^**	/	↑^##	↑^##
4a-Carboxy-4b-methyl-5a-cholesta-8, 24-dien-3b-ol	C₂₉H₄₆O₃	425.343 9	425.342 0	12.73	1.841 5	+	4.51	↓^**	↑^##	↑^##	↑^##
PC(22:5(7Z, 10Z, 13Z, 16Z, 19Z)/18:1(11Z))	C₄₈H₈₄NO₈P	438.318 0	438.317 3	12.73	1.601 8	+	1.60	↑^**	/	/	↓^##
Folinic acid	C₂₀H₂₃N₇O₇	456.164 8	456.163 2	15.87	1.642 1	+	3.53	↓^**	↑^##	↑^##	↑^##
LysoPC(15:0/0:0)	C₂₃H₄₈NO₇P	462.296 9	462.298 4	12.77	1.105 8	+/-	-3.20	↑^**	↓^##	↓^##	↓^##
Cholesterol sulfate	C₂₇H₄₆O₄S	499.343 8	499.345 2	13.49	1.851 9	+	-2.76	↑^**	↓^##	↓^##	↓^##
3-O-Sulfogalactosylceramide (D18:1/24:0)	C₄₈H₉₃NO₁₁S	508.372 1	508.370 6	14.31	1.778 0	+	2.97	↓^**	↑^##	↑^##	↑^##
LysoPC(18:0/0:0)	C₂₆H₅₄NO₇P	524.369 0	524.371 1	14.91	1.090 3	+	-3.97	↓^**	/	↑^#	↑^##
LysoPC(18:1(9Z)/0:0)	C₂₆H₅₂NO₇P	588.329 9	588.328 3	13.00	1.042 3	-	2.72	↑^**	/	/	↓^##
LysoPC(20:3(8Z, 11Z, 14Z)/0:0)	C₂₈H₅₂NO₇P	590.318 0	590.319 3	12.77	1.620 9	+	-2.20	↓^**	↑^##	↑^##	↑^##

Metabolite

Formula

Measured m/z

Theoretical m/z

RT /min

VIP value

ESI mode

Error /ppm

Variation trend

Normal/Model

Model/PD-L

Model/PD-M

Model/PD-H

Fumaric acid

C₄H₄O₄

115.003 7

1.05

1.376 6

0.00

↑^**

↓^#

↓^##

Malic acid

C₄H₆O₅

133.014 2

0.87

1.834 0

+/-

0.00

↓^**

↑^##

Vanylglycol

C₉H₁₂O₄

134.071 2

134.070 6

0.85

1.544 7

4.33

↑^**

↓^##

4-Trimethylammoniobutanoic acid

C₇H₁₅NO₂

144.102 9

144.103 0

13.05

1.335 6

-0.69

↓^**

↑^##

L-Phenylalanine

C₉H₁₁NO₂

164.071 9

164.071 7

2.08

1.800 1

1.28

↑^**

↓^##

L-Tyrosine

C₉H₁₁NO₃

182.080 4

182.081 2

0.88

1.576 3

-4.39

↓^**

↑^##

17alpha, 21-Dihydroxypregnenolone

C₂₁H₃₂O₄

186.114 1

186.113 3

6.33

1.774 4

4.03

↑^**

↓^##

Taurine

C₂H₇NO₃S

191.994 6

191.994 9

0.78

1.760 4

+/-

-1.56

↓^**

↑^##

4-Hydroxy-2-oxoglutaric acid

C₅H₆O₆

245.075 8

245.076 8

1.16

1.787 2

-4.20

↓^**

↑^##

Androstenedione

C₁₉H₂₆O₂

251.179 8

251.180 6

10.15

1.778 4

-3.03

↑^**

↓^##

Androsterone

C₁₉H₃₀O₂

271.207 0

271.206 2

9.57

1.852 8

2.95

↑^**

↓^##

PE(22:2(13Z, 16Z)/18:1(9Z))

C₄₅H₈₄NO₈P

274.198 8

274.199 1

8.77

1.326 9

-1.09

↓^**

↑^##

Oleic acid

C₁₈H₃₄O₂

281.248 1

281.248 6

13.35

1.613 4

-1.78

↓^**

↑^##

3-O-Sulfogalactosylceramide (D18:1/18:0)

C₄₂H₈₁NO₁₁S

292.172 4

292.173 6

13.19

1.492 7

-4.11

↓^**

↑^##

Sphingosine

C₁₈H₃₇NO₂

300.288 5

300.289 7

11.81

1.593 1

-4.13

↓^**

↑^##

LysoPC(22:0/0:0)

C₃₀H₆₂NO₇P

311.234 3

311.233 7

15.83

1.509 3

1.93

↓^**

↑^##

Linoleic acid

C₁₈H₃₂O₂

313.272 5

313.273 7

15.10

1.224 3

-3.83

↓^**

↑^##

4-Trimethylammoniobutanal

C₇H₁₆NO

322.247 1

322.2476

5.36

1.334 9

-1.68

↓^**

↑^#

↑^##

Glucose 1-phosphate

C₆H₁₃O₉P

327.009 8

327.009 9

0.73

1.497 6

-0.31

↑^**

↓^##

Docosahexaenoic acid

C₂₂H₃₂O₂

327.232 5

327.233 0

12.72

1.061 1

-1.53

↑^**

↓^##

Leukotriene A4

C₂₀H₃₀O₃

360.253 8

360.253 3

6.76

1.832 7

1.39

↓^**

↑^##

Vitamin D3

C₂₇H₄₄O

367.338 1

367.336 5

13.12

1.599 5

4.36

↑^**

↓^##

Sphingosine 1-phosphate

C₁₈H₃₈NO₅P

378.239 9

378.241 5

11.85

1.308 5

-4.23

↑^**

↓^##

PE(15:0/14:1(9Z))

C₃₄H₆₆NO₈P

386.273 6

386.273 4

14.18

1.653 6

0.44

↓^**

↑^##

PE(14:0/P-16:0)

C₃₅H₇₀NO₇P

386.293 0

386.291 6

14.18

1.425 5

3.62

↑^**

↓^#

↓^##

15-HETE

C₂₀H₃₂O₃

387.214 7

387.215 3

14.32

1.710 3

-1.55

↓^**

↑^##

PE(22:2(13Z, 16Z)/P-18:0)

C₄₅H₈₆NO₇P

403.806 0

403.805 3

7.29

1.426 7

1.83

↑^**

↓^##

PC(22:5(7Z, 10Z, 13Z, 16Z, 19Z)/P-16:0)

C₄₆H₈₂NO₇P

407.790 2

407.789 7

7.01

1.728 8

1.18

↓^**

↑^##

4a-Carboxy-4b-methyl-5a-cholesta-8, 24-dien-3b-ol

C₂₉H₄₆O₃

425.343 9

425.342 0

12.73

1.841 5

4.51

↓^**

↑^##

PC(22:5(7Z, 10Z, 13Z, 16Z, 19Z)/18:1(11Z))

C₄₈H₈₄NO₈P

438.318 0

438.317 3

12.73

1.601 8

1.60

↑^**

↓^##

Folinic acid

C₂₀H₂₃N₇O₇

456.164 8

456.163 2

15.87

1.642 1

3.53

↓^**

↑^##

LysoPC(15:0/0:0)

C₂₃H₄₈NO₇P

462.296 9

462.298 4

12.77

1.105 8

+/-

-3.20

↑^**

↓^##

Cholesterol sulfate

C₂₇H₄₆O₄S

499.343 8

499.345 2

13.49

1.851 9

-2.76

↑^**

↓^##

3-O-Sulfogalactosylceramide (D18:1/24:0)

C₄₈H₉₃NO₁₁S

508.372 1

508.370 6

14.31

1.778 0

2.97

↓^**

↑^##

LysoPC(18:0/0:0)

C₂₆H₅₄NO₇P

524.369 0

524.371 1

14.91

1.090 3

-3.97

↓^**

↑^#

↑^##

LysoPC(18:1(9Z)/0:0)

C₂₆H₅₂NO₇P

588.329 9

588.328 3

13.00

1.042 3

2.72

↑^**

↓^##

LysoPC(20:3(8Z, 11Z, 14Z)/0:0)

C₂₈H₅₂NO₇P

590.318 0

590.319 3

12.77

1.620 9

-2.20

↓^**

↑^##

Metabolite	Formula	Measured m/z	Theoretical m/z	RT /min	VIP value	ESI mode	Error /ppm	Variation trend
Fumaric acid	C₄H₄O₄	115.003 7	115.003 7	1.05	1.376 6	-	0.00	↑^**	↓^#	↓^##	↓^##
Malic acid	C₄H₆O₅	133.014 2	133.014 2	0.87	1.834 0	+/-	0.00	↓^**	↑^##	↑^##	↑^##
Vanylglycol	C₉H₁₂O₄	134.071 2	134.070 6	0.85	1.544 7	+	4.33	↑^**	↓^##	↓^##	↓^##
4-Trimethylammoniobutanoic acid	C₇H₁₅NO₂	144.102 9	144.103 0	13.05	1.335 6	-	-0.69	↓^**	/	↑^##	↑^##
L-Phenylalanine	C₉H₁₁NO₂	164.071 9	164.071 7	2.08	1.800 1	-	1.28	↑^**	↓^##	↓^##	↓^##
L-Tyrosine	C₉H₁₁NO₃	182.080 4	182.081 2	0.88	1.576 3	+	-4.39	↓^**	/	↑^##	↑^##
17alpha, 21-Dihydroxypregnenolone	C₂₁H₃₂O₄	186.114 1	186.113 3	6.33	1.774 4	+	4.03	↑^**	↓^##	↓^##	↓^##
Taurine	C₂H₇NO₃S	191.994 6	191.994 9	0.78	1.760 4	+/-	-1.56	↓^**	↑^##	↑^##	↑^##
4-Hydroxy-2-oxoglutaric acid	C₅H₆O₆	245.075 8	245.076 8	1.16	1.787 2	+	-4.20	↓^**	/	/	↑^##
Androstenedione	C₁₉H₂₆O₂	251.179 8	251.180 6	10.15	1.778 4	+	-3.03	↑^**	↓^##	↓^##	↓^##
Androsterone	C₁₉H₃₀O₂	271.207 0	271.206 2	9.57	1.852 8	-	2.95	↑^**	↓^##	↓^##	↓^##
PE(22:2(13Z, 16Z)/18:1(9Z))	C₄₅H₈₄NO₈P	274.198 8	274.199 1	8.77	1.326 9	+	-1.09	↓^**	↑^##	↑^##	↑^##
Oleic acid	C₁₈H₃₄O₂	281.248 1	281.248 6	13.35	1.613 4	-	-1.78	↓^**	↑^##	↑^##	↑^##
3-O-Sulfogalactosylceramide (D18:1/18:0)	C₄₂H₈₁NO₁₁S	292.172 4	292.173 6	13.19	1.492 7	+	-4.11	↓^**	/	/	↑^##
Sphingosine	C₁₈H₃₇NO₂	300.288 5	300.289 7	11.81	1.593 1	+	-4.13	↓^**	↑^##	↑^##	↑^##
LysoPC(22:0/0:0)	C₃₀H₆₂NO₇P	311.234 3	311.233 7	15.83	1.509 3	+	1.93	↓^**	↑^##	↑^##	↑^##
Linoleic acid	C₁₈H₃₂O₂	313.272 5	313.273 7	15.10	1.224 3	+	-3.83	↓^**	/	↑^##	↑^##
4-Trimethylammoniobutanal	C₇H₁₆NO	322.247 1	322.2476	5.36	1.334 9	+	-1.68	↓^**	↑^#	↑^#	↑^##
Glucose 1-phosphate	C₆H₁₃O₉P	327.009 8	327.009 9	0.73	1.497 6	-	-0.31	↑^**	↓^##	↓^##	↓^##
Docosahexaenoic acid	C₂₂H₃₂O₂	327.232 5	327.233 0	12.72	1.061 1	-	-1.53	↑^**	↓^##	↓^##	↓^##
Leukotriene A4	C₂₀H₃₀O₃	360.253 8	360.253 3	6.76	1.832 7	+	1.39	↓^**	↑^##	↑^##	↑^##
Vitamin D3	C₂₇H₄₄O	367.338 1	367.336 5	13.12	1.599 5	+	4.36	↑^**	/	/	↓^##
Sphingosine 1-phosphate	C₁₈H₃₈NO₅P	378.239 9	378.241 5	11.85	1.308 5	-	-4.23	↑^**	↓^##	↓^##	↓^##
PE(15:0/14:1(9Z))	C₃₄H₆₆NO₈P	386.273 6	386.273 4	14.18	1.653 6	+	0.44	↓^**	↑^##	↑^##	↑^##
PE(14:0/P-16:0)	C₃₅H₇₀NO₇P	386.293 0	386.291 6	14.18	1.425 5	+	3.62	↑^**	↓^#	↓^#	↓^##
15-HETE	C₂₀H₃₂O₃	387.214 7	387.215 3	14.32	1.710 3	-	-1.55	↓^**	↑^##	↑^##	↑^##
PE(22:2(13Z, 16Z)/P-18:0)	C₄₅H₈₆NO₇P	403.806 0	403.805 3	7.29	1.426 7	+	1.83	↑^**	↓^##	↓^##	↓^##
PC(22:5(7Z, 10Z, 13Z, 16Z, 19Z)/P-16:0)	C₄₆H₈₂NO₇P	407.790 2	407.789 7	7.01	1.728 8	+	1.18	↓^**	/	↑^##	↑^##
4a-Carboxy-4b-methyl-5a-cholesta-8, 24-dien-3b-ol	C₂₉H₄₆O₃	425.343 9	425.342 0	12.73	1.841 5	+	4.51	↓^**	↑^##	↑^##	↑^##
PC(22:5(7Z, 10Z, 13Z, 16Z, 19Z)/18:1(11Z))	C₄₈H₈₄NO₈P	438.318 0	438.317 3	12.73	1.601 8	+	1.60	↑^**	/	/	↓^##
Folinic acid	C₂₀H₂₃N₇O₇	456.164 8	456.163 2	15.87	1.642 1	+	3.53	↓^**	↑^##	↑^##	↑^##
LysoPC(15:0/0:0)	C₂₃H₄₈NO₇P	462.296 9	462.298 4	12.77	1.105 8	+/-	-3.20	↑^**	↓^##	↓^##	↓^##
Cholesterol sulfate	C₂₇H₄₆O₄S	499.343 8	499.345 2	13.49	1.851 9	+	-2.76	↑^**	↓^##	↓^##	↓^##
3-O-Sulfogalactosylceramide (D18:1/24:0)	C₄₈H₉₃NO₁₁S	508.372 1	508.370 6	14.31	1.778 0	+	2.97	↓^**	↑^##	↑^##	↑^##
LysoPC(18:0/0:0)	C₂₆H₅₄NO₇P	524.369 0	524.371 1	14.91	1.090 3	+	-3.97	↓^**	/	↑^#	↑^##
LysoPC(18:1(9Z)/0:0)	C₂₆H₅₂NO₇P	588.329 9	588.328 3	13.00	1.042 3	-	2.72	↑^**	/	/	↓^##
LysoPC(20:3(8Z, 11Z, 14Z)/0:0)	C₂₈H₅₂NO₇P	590.318 0	590.319 3	12.77	1.620 9	+	-2.20	↓^**	↑^##	↑^##	↑^##

Metabolite

Formula

Measured m/z

Theoretical m/z

RT /min

VIP value

ESI mode

Error /ppm

Variation trend

Normal/Model

Model/PD-L

Model/PD-M

Model/PD-H

Fumaric acid

C₄H₄O₄

115.003 7

1.05

1.376 6

0.00

↑^**

↓^#

↓^##

Malic acid

C₄H₆O₅

133.014 2

0.87

1.834 0

+/-

0.00

↓^**

↑^##

Vanylglycol

C₉H₁₂O₄

134.071 2

134.070 6

0.85

1.544 7

4.33

↑^**

↓^##

4-Trimethylammoniobutanoic acid

C₇H₁₅NO₂

144.102 9

144.103 0

13.05

1.335 6

-0.69

↓^**

↑^##

L-Phenylalanine

C₉H₁₁NO₂

164.071 9

164.071 7

2.08

1.800 1

1.28

↑^**

↓^##

L-Tyrosine

C₉H₁₁NO₃

182.080 4

182.081 2

0.88

1.576 3

-4.39

↓^**

↑^##

17alpha, 21-Dihydroxypregnenolone

C₂₁H₃₂O₄

186.114 1

186.113 3

6.33

1.774 4

4.03

↑^**

↓^##

Taurine

C₂H₇NO₃S

191.994 6

191.994 9

0.78

1.760 4

+/-

-1.56

↓^**

↑^##

4-Hydroxy-2-oxoglutaric acid

C₅H₆O₆

245.075 8

245.076 8

1.16

1.787 2

-4.20

↓^**

↑^##

Androstenedione

C₁₉H₂₆O₂

251.179 8

251.180 6

10.15

1.778 4

-3.03

↑^**

↓^##

Androsterone

C₁₉H₃₀O₂

271.207 0

271.206 2

9.57

1.852 8

2.95

↑^**

↓^##

PE(22:2(13Z, 16Z)/18:1(9Z))

C₄₅H₈₄NO₈P

274.198 8

274.199 1

8.77

1.326 9

-1.09

↓^**

↑^##

Oleic acid

C₁₈H₃₄O₂

281.248 1

281.248 6

13.35

1.613 4

-1.78

↓^**

↑^##

3-O-Sulfogalactosylceramide (D18:1/18:0)

C₄₂H₈₁NO₁₁S

292.172 4

292.173 6

13.19

1.492 7

-4.11

↓^**

↑^##

Sphingosine

C₁₈H₃₇NO₂

300.288 5

300.289 7

11.81

1.593 1

-4.13

↓^**

↑^##

LysoPC(22:0/0:0)

C₃₀H₆₂NO₇P

311.234 3

311.233 7

15.83

1.509 3

1.93

↓^**

↑^##

Linoleic acid

C₁₈H₃₂O₂

313.272 5

313.273 7

15.10

1.224 3

-3.83

↓^**

↑^##

4-Trimethylammoniobutanal

C₇H₁₆NO

322.247 1

322.2476

5.36

1.334 9

-1.68

↓^**

↑^#

↑^##

Glucose 1-phosphate

C₆H₁₃O₉P

327.009 8

327.009 9

0.73

1.497 6

-0.31

↑^**

↓^##

Docosahexaenoic acid

C₂₂H₃₂O₂

327.232 5

327.233 0

12.72

1.061 1

-1.53

↑^**

↓^##

Leukotriene A4

C₂₀H₃₀O₃

360.253 8

360.253 3

6.76

1.832 7

1.39

↓^**

↑^##

Vitamin D3

C₂₇H₄₄O

367.338 1

367.336 5

13.12

1.599 5

4.36

↑^**

↓^##

Sphingosine 1-phosphate

C₁₈H₃₈NO₅P

378.239 9

378.241 5

11.85

1.308 5

-4.23

↑^**

↓^##

PE(15:0/14:1(9Z))

C₃₄H₆₆NO₈P

386.273 6

386.273 4

14.18

1.653 6

0.44

↓^**

↑^##

PE(14:0/P-16:0)

C₃₅H₇₀NO₇P

386.293 0

386.291 6

14.18

1.425 5

3.62

↑^**

↓^#

↓^##

15-HETE

C₂₀H₃₂O₃

387.214 7

387.215 3

14.32

1.710 3

-1.55

↓^**

↑^##

PE(22:2(13Z, 16Z)/P-18:0)

C₄₅H₈₆NO₇P

403.806 0

403.805 3

7.29

1.426 7

1.83

↑^**

↓^##

PC(22:5(7Z, 10Z, 13Z, 16Z, 19Z)/P-16:0)

C₄₆H₈₂NO₇P

407.790 2

407.789 7

7.01

1.728 8

1.18

↓^**

↑^##

4a-Carboxy-4b-methyl-5a-cholesta-8, 24-dien-3b-ol

C₂₉H₄₆O₃

425.343 9

425.342 0

12.73

1.841 5

4.51

↓^**

↑^##

PC(22:5(7Z, 10Z, 13Z, 16Z, 19Z)/18:1(11Z))

C₄₈H₈₄NO₈P

438.318 0

438.317 3

12.73

1.601 8

1.60

↑^**

↓^##

Folinic acid

C₂₀H₂₃N₇O₇

456.164 8

456.163 2

15.87

1.642 1

3.53

↓^**

↑^##

LysoPC(15:0/0:0)

C₂₃H₄₈NO₇P

462.296 9

462.298 4

12.77

1.105 8

+/-

-3.20

↑^**

↓^##

Cholesterol sulfate

C₂₇H₄₆O₄S

499.343 8

499.345 2

13.49

1.851 9

-2.76

↑^**

↓^##

3-O-Sulfogalactosylceramide (D18:1/24:0)

C₄₈H₉₃NO₁₁S

508.372 1

508.370 6

14.31

1.778 0

2.97

↓^**

↑^##

LysoPC(18:0/0:0)

C₂₆H₅₄NO₇P

524.369 0

524.371 1

14.91

1.090 3

-3.97

↓^**

↑^#

↑^##

LysoPC(18:1(9Z)/0:0)

C₂₆H₅₂NO₇P

588.329 9

588.328 3

13.00

1.042 3

2.72

↑^**

↓^##

LysoPC(20:3(8Z, 11Z, 14Z)/0:0)

C₂₈H₅₂NO₇P

590.318 0

590.319 3

12.77

1.620 9

-2.20

↓^**

↑^##

Metabolite	Formula	Measured m/z	Theoretical m/z	RT /min	VIP value	ESI mode	Error /ppm	Variation trend
Glyoxylic acid	C₂H₂O₃	72.993 3	72.993 1	1.25	1.408 4	-	2.74	↓^**	/	↑^##	↑^##
Estrone	C₁₈H₂₂O₂	134.074 3	134.073 7	12.62	1.436 2	-	4.48	↓^**	/	/	↑^##
Hydroxypropionic acid	C₃H₆O₃	135.030 1	135.029 9	0.83	1.525 1	-	1.48	↓^**	↑^##	↑^##	↑^##
Glyceric acid	C₃H₆O₄	142.975 1	142.975 2	0.74	1.469 4	-	-0.70	↑^**	/	↓^##	↓^##
Allantoic acid	C₄H₈N₄O₄	157.036 7	157.036 2	1.14	1.410 5	-	3.18	↓^**	/	/	↑^##
Orotidylic acid	C₁₀H₁₃N₂O₁₁P	183.006 2	183.005 6	0.85	1.401 0	-	3.28	↓^**	↑^##	↑^##	↑^##
4-Hydroxyphenylpyruvic acid	C₉H₈O₄	213.076 4	213.075 7	15.65	1.413 9	+	3.29	↑^**	↓^##	↓^##	↓^##
5-Acetylamino-6-formylamino-3-methyluracil	C₈H₁₀N₄O₄	225.063 0	225.062 9	3.76	1.546 8	-	0.44	↑^**	/	/	↓^##
CE(20:1(11Z))	C₄₇H₈2O₂	225.203 8	225.203 2	15.91	1.492 7	-	2.66	↓^**	↑^##	↑^##	↑^##
Thymidine	C₁₀H₁₄N₂O₅	241.082 4	241.083 0	1.90	1.460 7	-	-2.49	↑^**	/	↓^##	↓^##
Serotonin	C₁₀H₁₂N₂O	259.155 3	259.155 3	15.64	1.409 2	+	0.00	↑^**	↓^##	↓^##	↓^##
Citric acid	C₆H₈O₇	261.021 4	261.021 6	1.08	1.468 0	+	-0.77	↑^**	↓^##	↓^##	↓^##
5-Hydroxykynurenine	C₁₀H₁₂N₂O₄	269.077 4	269.077 9	1.21	1.092 1	-	-1.86	↓^*	/	↑^#	↑^#
Linoleic acid	C₁₈H₃₂O₂	313.274 9	313.273 7	15.12	1.354 7	+	3.83	↓^**	/	↑^#	↑^##
Prostaglandin H3	C₂₀H₃₀O₅	331.191 1	331.190 9	8.56	1.377 5	-	0.60	↓^**	/	↑^##	↑^##
Dihomo-gamma-linolenic acid	C₂₀H₃₄O₂	339.290 7	339.289 4	13.11	1.043 7	+	3.83	↓^**	/	↑^#	↑^##
19-Hydroxytestosterone	C₁₉H₂₈O₃	349.200 8	349.202 0	9.90	1.144 5	-	-3.44	↓^**	↑^##	↑^##	↑^##
14-Hydroxy-E4-neuroprostane	C₂₂H₃₂O₅	357.207 6	357.206 6	13.14	1.449 0	-	2.80	↓^**	/	↑^##	↑^##
12(13)-EpOME	C₁₈H₃₂O₃	363.215 9	363.215 3	13.06	1.089 4	-	1.65	↓^**	/	/	↑^##
Cyclic GMP	C₁₀H₁₂N₅O₇P	380.015 0	380.016 8	0.72	1.430 4	-	-4.74	↓^**	↑^##	↑^##	↑^##
Palmitoylcarnitine	C₂₃H₄₅NO₄	398.327 7	398.327 6	12.63	1.430 1	-	0.25	↓^**	↑^##	↑^##	↑^##
Thiamine pyrophosphate	C₁₂H₁₉N₄O₇P₂S	405.019 8	405.019 3	0.98	1.384 0	-	1.23	↑^**	/	↓^##	↓^##
Cortisone	C₂₁H₂₈O₅	405.190 2	405.191 9	5.25	1.120 0	-	-4.20	↓^**	↑^##	↑^##	↑^##
LysoPA(0:0/16:0)	C₁₉H₃₉O₇P	409.235 5	409.236 1	13.94	1.467 6	-	-1.47	↑^**	/	/	↓^##
PE(16:0/P-18:0)	C₃₉H₇₈NO₇P	414.321 6	414.322 9	10.32	1.041 8	+	-3.14	↓^**	/	↑^##	↑^##
PE(20:1(11Z)/P-18:1(11Z))	C₄₃H₈₂NO₇P	440.337 2	440.338 5	10.63	1.230 6	+	-2.95	↓^**	/	/	↑^##
LysoPA(0:0/18:1(9Z))	C₂₁H₄₁O₇P	478.294 3	478.292 8	12.20	1.033 8	+	3.14	↓^**	↑^##	↑^##	↑^##
LysoPA(18:0/0:0)	C₂₁H₄₃O₇P	480.309 7	480.308 5	13.12	1.050 2	+	2.50	↓^**	↑^##	↑^##	↑^##
24R, 25-Dihydroxyvitamin D3	C₂₇H₄₄O₃	483.310 3	483.309 2	13.62	1.028 6	-	2.28	↑^**	/	↓^##	↓^##
LysoPC(18:3(6Z, 9Z, 12Z)/0:0)	C₂₆H₄₈NO₇P	518.323 3	518.324 1	12.65	1.179 4	+	-1.54	↓^**	↑^##	↑^##	↑^##
LysoPC(18:2(9Z, 12Z)/0:0)	C₂₆H₅₀NO₇P	542.323 2	542.321 7	12.16	1.157 3	+	2.77	↓^**	/	↑^#	↑^#
LysoPC(20:4(8Z, 11Z, 14Z, 17Z)/0:0)	C₂₈H₅₀NO₇P	544.341 0	544.339 8	12.35	1.270 1	+	2.20	↓^**	↑^##	↑^##	↑^##
LysoPC(18:1(11Z)/0:0)	C₂₆H₅₂NO₇P	556.315 7	556.317 5	13.01	1.562 4	-	-3.24	↓^**	/	↑^#	↑^##
LysoPC(22:6(4Z, 7Z, 10Z, 13Z, 16Z, 19Z)/0:0)	C₃₀H₅₀NO₇P	568.341 3	568.339 8	12.29	1.036 1	+	2.64	↓^**	↑^##	↑^##	↑^##
LysoPC(22:5(4Z, 7Z, 10Z, 13Z, 16Z)/0:0)	C₃₀H₅₂NO₇P	570.357 3	570.355 4	12.67	1.208 3	+/-	3.33	↓^**	↑^##	↑^##	↑^##
LysoPC(20:5(5Z, 8Z, 11Z, 14Z, 17Z)/0:0)	C₂₈H₄₈NO₇P	586.316 9	586.315 0	12.03	1.431 4	-	3.24	↓^**	↑^##	↑^##	↑^##

Metabolite

Formula

Measured m/z

Theoretical m/z

RT /min

VIP value

ESI mode

Error /ppm

Variation trend

Normal/Model

Model/PD-L

Model/PD-M

Model/PD-H

Glyoxylic acid

C₂H₂O₃

72.993 3

72.993 1

1.25

1.408 4

2.74

↓^**

↑^##

Estrone

C₁₈H₂₂O₂

134.074 3

134.073 7

12.62

1.436 2

4.48

↓^**

↑^##

Hydroxypropionic acid

C₃H₆O₃

135.030 1

135.029 9

0.83

1.525 1

1.48

↓^**

↑^##

Glyceric acid

C₃H₆O₄

142.975 1

142.975 2

0.74

1.469 4

-0.70

↑^**

↓^##

Allantoic acid

C₄H₈N₄O₄

157.036 7

157.036 2

1.14

1.410 5

3.18

↓^**

↑^##

Orotidylic acid

C₁₀H₁₃N₂O₁₁P

183.006 2

183.005 6

0.85

1.401 0

3.28

↓^**

↑^##

4-Hydroxyphenylpyruvic acid

C₉H₈O₄

213.076 4

213.075 7

15.65

1.413 9

3.29

↑^**

↓^##

5-Acetylamino-6-formylamino-3-methyluracil

C₈H₁₀N₄O₄

225.063 0

225.062 9

3.76

1.546 8

0.44

↑^**

↓^##

CE(20:1(11Z))

C₄₇H₈2O₂

225.203 8

225.203 2

15.91

1.492 7

2.66

↓^**

↑^##

Thymidine

C₁₀H₁₄N₂O₅

241.082 4

241.083 0

1.90

1.460 7

-2.49

↑^**

↓^##

Serotonin

C₁₀H₁₂N₂O

259.155 3

15.64

1.409 2

0.00

↑^**

↓^##

Citric acid

C₆H₈O₇

261.021 4

261.021 6

1.08

1.468 0

-0.77

↑^**

↓^##

5-Hydroxykynurenine

C₁₀H₁₂N₂O₄

269.077 4

269.077 9

1.21

1.092 1

-1.86

↓^*

↑^#

Linoleic acid

C₁₈H₃₂O₂

313.274 9

313.273 7

15.12

1.354 7

3.83

↓^**

↑^#

↑^##

Prostaglandin H3

C₂₀H₃₀O₅

331.191 1

331.190 9

8.56

1.377 5

0.60

↓^**

↑^##

Dihomo-gamma-linolenic acid

C₂₀H₃₄O₂

339.290 7

339.289 4

13.11

1.043 7

3.83

↓^**

↑^#

↑^##

19-Hydroxytestosterone

C₁₉H₂₈O₃

349.200 8

349.202 0

9.90

1.144 5

-3.44

↓^**

↑^##

14-Hydroxy-E4-neuroprostane

C₂₂H₃₂O₅

357.207 6

357.206 6

13.14

1.449 0

2.80

↓^**

↑^##

12(13)-EpOME

C₁₈H₃₂O₃

363.215 9

363.215 3

13.06

1.089 4

1.65

↓^**

↑^##

Cyclic GMP

C₁₀H₁₂N₅O₇P

380.015 0

380.016 8

0.72

1.430 4

-4.74

↓^**

↑^##

Palmitoylcarnitine

C₂₃H₄₅NO₄

398.327 7

398.327 6

12.63

1.430 1

0.25

↓^**

↑^##

Thiamine pyrophosphate

C₁₂H₁₉N₄O₇P₂S

405.019 8

405.019 3

0.98

1.384 0

1.23

↑^**

↓^##

Cortisone

C₂₁H₂₈O₅

405.190 2

405.191 9

5.25

1.120 0

-4.20

↓^**

↑^##

LysoPA(0:0/16:0)

C₁₉H₃₉O₇P

409.235 5

409.236 1

13.94

1.467 6

-1.47

↑^**

↓^##

PE(16:0/P-18:0)

C₃₉H₇₈NO₇P

414.321 6

414.322 9

10.32

1.041 8

-3.14

↓^**

↑^##

PE(20:1(11Z)/P-18:1(11Z))

C₄₃H₈₂NO₇P

440.337 2

440.338 5

10.63

1.230 6

-2.95

↓^**

↑^##

LysoPA(0:0/18:1(9Z))

C₂₁H₄₁O₇P

478.294 3

478.292 8

12.20

1.033 8

3.14

↓^**

↑^##

LysoPA(18:0/0:0)

C₂₁H₄₃O₇P

480.309 7

480.308 5

13.12

1.050 2

2.50

↓^**

↑^##

24R, 25-Dihydroxyvitamin D3

C₂₇H₄₄O₃

483.310 3

483.309 2

13.62

1.028 6

2.28

↑^**

↓^##

LysoPC(18:3(6Z, 9Z, 12Z)/0:0)

C₂₆H₄₈NO₇P

518.323 3

518.324 1

12.65

1.179 4

-1.54

↓^**

↑^##

LysoPC(18:2(9Z, 12Z)/0:0)

C₂₆H₅₀NO₇P

542.323 2

542.321 7

12.16

1.157 3

2.77

↓^**

↑^#

LysoPC(20:4(8Z, 11Z, 14Z, 17Z)/0:0)

C₂₈H₅₀NO₇P

544.341 0

544.339 8

12.35

1.270 1

2.20

↓^**

↑^##

LysoPC(18:1(11Z)/0:0)

C₂₆H₅₂NO₇P

556.315 7

556.317 5

13.01

1.562 4

-3.24

↓^**

↑^#

↑^##

LysoPC(22:6(4Z, 7Z, 10Z, 13Z, 16Z, 19Z)/0:0)

C₃₀H₅₀NO₇P

568.341 3

568.339 8

12.29

1.036 1

2.64

↓^**

↑^##

LysoPC(22:5(4Z, 7Z, 10Z, 13Z, 16Z)/0:0)

C₃₀H₅₂NO₇P

570.357 3

570.355 4

12.67

1.208 3

+/-

3.33

↓^**

↑^##

LysoPC(20:5(5Z, 8Z, 11Z, 14Z, 17Z)/0:0)

C₂₈H₄₈NO₇P

586.316 9

586.315 0

12.03

1.431 4

3.24

↓^**

↑^##

Metabolite	Formula	Measured m/z	Theoretical m/z	RT /min	VIP value	ESI mode	Error /ppm	Variation trend
Glyoxylic acid	C₂H₂O₃	72.993 3	72.993 1	1.25	1.408 4	-	2.74	↓^**	/	↑^##	↑^##
Estrone	C₁₈H₂₂O₂	134.074 3	134.073 7	12.62	1.436 2	-	4.48	↓^**	/	/	↑^##
Hydroxypropionic acid	C₃H₆O₃	135.030 1	135.029 9	0.83	1.525 1	-	1.48	↓^**	↑^##	↑^##	↑^##
Glyceric acid	C₃H₆O₄	142.975 1	142.975 2	0.74	1.469 4	-	-0.70	↑^**	/	↓^##	↓^##
Allantoic acid	C₄H₈N₄O₄	157.036 7	157.036 2	1.14	1.410 5	-	3.18	↓^**	/	/	↑^##
Orotidylic acid	C₁₀H₁₃N₂O₁₁P	183.006 2	183.005 6	0.85	1.401 0	-	3.28	↓^**	↑^##	↑^##	↑^##
4-Hydroxyphenylpyruvic acid	C₉H₈O₄	213.076 4	213.075 7	15.65	1.413 9	+	3.29	↑^**	↓^##	↓^##	↓^##
5-Acetylamino-6-formylamino-3-methyluracil	C₈H₁₀N₄O₄	225.063 0	225.062 9	3.76	1.546 8	-	0.44	↑^**	/	/	↓^##
CE(20:1(11Z))	C₄₇H₈2O₂	225.203 8	225.203 2	15.91	1.492 7	-	2.66	↓^**	↑^##	↑^##	↑^##
Thymidine	C₁₀H₁₄N₂O₅	241.082 4	241.083 0	1.90	1.460 7	-	-2.49	↑^**	/	↓^##	↓^##
Serotonin	C₁₀H₁₂N₂O	259.155 3	259.155 3	15.64	1.409 2	+	0.00	↑^**	↓^##	↓^##	↓^##
Citric acid	C₆H₈O₇	261.021 4	261.021 6	1.08	1.468 0	+	-0.77	↑^**	↓^##	↓^##	↓^##
5-Hydroxykynurenine	C₁₀H₁₂N₂O₄	269.077 4	269.077 9	1.21	1.092 1	-	-1.86	↓^*	/	↑^#	↑^#
Linoleic acid	C₁₈H₃₂O₂	313.274 9	313.273 7	15.12	1.354 7	+	3.83	↓^**	/	↑^#	↑^##
Prostaglandin H3	C₂₀H₃₀O₅	331.191 1	331.190 9	8.56	1.377 5	-	0.60	↓^**	/	↑^##	↑^##
Dihomo-gamma-linolenic acid	C₂₀H₃₄O₂	339.290 7	339.289 4	13.11	1.043 7	+	3.83	↓^**	/	↑^#	↑^##
19-Hydroxytestosterone	C₁₉H₂₈O₃	349.200 8	349.202 0	9.90	1.144 5	-	-3.44	↓^**	↑^##	↑^##	↑^##
14-Hydroxy-E4-neuroprostane	C₂₂H₃₂O₅	357.207 6	357.206 6	13.14	1.449 0	-	2.80	↓^**	/	↑^##	↑^##
12(13)-EpOME	C₁₈H₃₂O₃	363.215 9	363.215 3	13.06	1.089 4	-	1.65	↓^**	/	/	↑^##
Cyclic GMP	C₁₀H₁₂N₅O₇P	380.015 0	380.016 8	0.72	1.430 4	-	-4.74	↓^**	↑^##	↑^##	↑^##
Palmitoylcarnitine	C₂₃H₄₅NO₄	398.327 7	398.327 6	12.63	1.430 1	-	0.25	↓^**	↑^##	↑^##	↑^##
Thiamine pyrophosphate	C₁₂H₁₉N₄O₇P₂S	405.019 8	405.019 3	0.98	1.384 0	-	1.23	↑^**	/	↓^##	↓^##
Cortisone	C₂₁H₂₈O₅	405.190 2	405.191 9	5.25	1.120 0	-	-4.20	↓^**	↑^##	↑^##	↑^##
LysoPA(0:0/16:0)	C₁₉H₃₉O₇P	409.235 5	409.236 1	13.94	1.467 6	-	-1.47	↑^**	/	/	↓^##
PE(16:0/P-18:0)	C₃₉H₇₈NO₇P	414.321 6	414.322 9	10.32	1.041 8	+	-3.14	↓^**	/	↑^##	↑^##
PE(20:1(11Z)/P-18:1(11Z))	C₄₃H₈₂NO₇P	440.337 2	440.338 5	10.63	1.230 6	+	-2.95	↓^**	/	/	↑^##
LysoPA(0:0/18:1(9Z))	C₂₁H₄₁O₇P	478.294 3	478.292 8	12.20	1.033 8	+	3.14	↓^**	↑^##	↑^##	↑^##
LysoPA(18:0/0:0)	C₂₁H₄₃O₇P	480.309 7	480.308 5	13.12	1.050 2	+	2.50	↓^**	↑^##	↑^##	↑^##
24R, 25-Dihydroxyvitamin D3	C₂₇H₄₄O₃	483.310 3	483.309 2	13.62	1.028 6	-	2.28	↑^**	/	↓^##	↓^##
LysoPC(18:3(6Z, 9Z, 12Z)/0:0)	C₂₆H₄₈NO₇P	518.323 3	518.324 1	12.65	1.179 4	+	-1.54	↓^**	↑^##	↑^##	↑^##
LysoPC(18:2(9Z, 12Z)/0:0)	C₂₆H₅₀NO₇P	542.323 2	542.321 7	12.16	1.157 3	+	2.77	↓^**	/	↑^#	↑^#
LysoPC(20:4(8Z, 11Z, 14Z, 17Z)/0:0)	C₂₈H₅₀NO₇P	544.341 0	544.339 8	12.35	1.270 1	+	2.20	↓^**	↑^##	↑^##	↑^##
LysoPC(18:1(11Z)/0:0)	C₂₆H₅₂NO₇P	556.315 7	556.317 5	13.01	1.562 4	-	-3.24	↓^**	/	↑^#	↑^##
LysoPC(22:6(4Z, 7Z, 10Z, 13Z, 16Z, 19Z)/0:0)	C₃₀H₅₀NO₇P	568.341 3	568.339 8	12.29	1.036 1	+	2.64	↓^**	↑^##	↑^##	↑^##
LysoPC(22:5(4Z, 7Z, 10Z, 13Z, 16Z)/0:0)	C₃₀H₅₂NO₇P	570.357 3	570.355 4	12.67	1.208 3	+/-	3.33	↓^**	↑^##	↑^##	↑^##
LysoPC(20:5(5Z, 8Z, 11Z, 14Z, 17Z)/0:0)	C₂₈H₄₈NO₇P	586.316 9	586.315 0	12.03	1.431 4	-	3.24	↓^**	↑^##	↑^##	↑^##

Metabolite

Formula

Measured m/z

Theoretical m/z

RT /min

VIP value

ESI mode

Error /ppm

Variation trend

Normal/Model

Model/PD-L

Model/PD-M

Model/PD-H

Glyoxylic acid

C₂H₂O₃

72.993 3

72.993 1

1.25

1.408 4

2.74

↓^**

↑^##

Estrone

C₁₈H₂₂O₂

134.074 3

134.073 7

12.62

1.436 2

4.48

↓^**

↑^##

Hydroxypropionic acid

C₃H₆O₃

135.030 1

135.029 9

0.83

1.525 1

1.48

↓^**

↑^##

Glyceric acid

C₃H₆O₄

142.975 1

142.975 2

0.74

1.469 4

-0.70

↑^**

↓^##

Allantoic acid

C₄H₈N₄O₄

157.036 7

157.036 2

1.14

1.410 5

3.18

↓^**

↑^##

Orotidylic acid

C₁₀H₁₃N₂O₁₁P

183.006 2

183.005 6

0.85

1.401 0

3.28

↓^**

↑^##

4-Hydroxyphenylpyruvic acid

C₉H₈O₄

213.076 4

213.075 7

15.65

1.413 9

3.29

↑^**

↓^##

5-Acetylamino-6-formylamino-3-methyluracil

C₈H₁₀N₄O₄

225.063 0

225.062 9

3.76

1.546 8

0.44

↑^**

↓^##

CE(20:1(11Z))

C₄₇H₈2O₂

225.203 8

225.203 2

15.91

1.492 7

2.66

↓^**

↑^##

Thymidine

C₁₀H₁₄N₂O₅

241.082 4

241.083 0

1.90

1.460 7

-2.49

↑^**

↓^##

Serotonin

C₁₀H₁₂N₂O

259.155 3

15.64

1.409 2

0.00

↑^**

↓^##

Citric acid

C₆H₈O₇

261.021 4

261.021 6

1.08

1.468 0

-0.77

↑^**

↓^##

5-Hydroxykynurenine

C₁₀H₁₂N₂O₄

269.077 4

269.077 9

1.21

1.092 1

-1.86

↓^*

↑^#

Linoleic acid

C₁₈H₃₂O₂

313.274 9

313.273 7

15.12

1.354 7

3.83

↓^**

↑^#

↑^##

Prostaglandin H3

C₂₀H₃₀O₅

331.191 1

331.190 9

8.56

1.377 5

0.60

↓^**

↑^##

Dihomo-gamma-linolenic acid

C₂₀H₃₄O₂

339.290 7

339.289 4

13.11

1.043 7

3.83

↓^**

↑^#

↑^##

19-Hydroxytestosterone

C₁₉H₂₈O₃

349.200 8

349.202 0

9.90

1.144 5

-3.44

↓^**

↑^##

14-Hydroxy-E4-neuroprostane

C₂₂H₃₂O₅

357.207 6

357.206 6

13.14

1.449 0

2.80

↓^**

↑^##

12(13)-EpOME

C₁₈H₃₂O₃

363.215 9

363.215 3

13.06

1.089 4

1.65

↓^**

↑^##

Cyclic GMP

C₁₀H₁₂N₅O₇P

380.015 0

380.016 8

0.72

1.430 4

-4.74

↓^**

↑^##

Palmitoylcarnitine

C₂₃H₄₅NO₄

398.327 7

398.327 6

12.63

1.430 1

0.25

↓^**

↑^##

Thiamine pyrophosphate

C₁₂H₁₉N₄O₇P₂S

405.019 8

405.019 3

0.98

1.384 0

1.23

↑^**

↓^##

Cortisone

C₂₁H₂₈O₅

405.190 2

405.191 9

5.25

1.120 0

-4.20

↓^**

↑^##

LysoPA(0:0/16:0)

C₁₉H₃₉O₇P

409.235 5

409.236 1

13.94

1.467 6

-1.47

↑^**

↓^##

PE(16:0/P-18:0)

C₃₉H₇₈NO₇P

414.321 6

414.322 9

10.32

1.041 8

-3.14

↓^**

↑^##

PE(20:1(11Z)/P-18:1(11Z))

C₄₃H₈₂NO₇P

440.337 2

440.338 5

10.63

1.230 6

-2.95

↓^**

↑^##

LysoPA(0:0/18:1(9Z))

C₂₁H₄₁O₇P

478.294 3

478.292 8

12.20

1.033 8

3.14

↓^**

↑^##

LysoPA(18:0/0:0)

C₂₁H₄₃O₇P

480.309 7

480.308 5

13.12

1.050 2

2.50

↓^**

↑^##

24R, 25-Dihydroxyvitamin D3

C₂₇H₄₄O₃

483.310 3

483.309 2

13.62

1.028 6

2.28

↑^**

↓^##

LysoPC(18:3(6Z, 9Z, 12Z)/0:0)

C₂₆H₄₈NO₇P

518.323 3

518.324 1

12.65

1.179 4

-1.54

↓^**

↑^##

LysoPC(18:2(9Z, 12Z)/0:0)

C₂₆H₅₀NO₇P

542.323 2

542.321 7

12.16

1.157 3

2.77

↓^**

↑^#

LysoPC(20:4(8Z, 11Z, 14Z, 17Z)/0:0)

C₂₈H₅₀NO₇P

544.341 0

544.339 8

12.35

1.270 1

2.20

↓^**

↑^##

LysoPC(18:1(11Z)/0:0)

C₂₆H₅₂NO₇P

556.315 7

556.317 5

13.01

1.562 4

-3.24

↓^**

↑^#

↑^##

LysoPC(22:6(4Z, 7Z, 10Z, 13Z, 16Z, 19Z)/0:0)

C₃₀H₅₀NO₇P

568.341 3

568.339 8

12.29

1.036 1

2.64

↓^**

↑^##

LysoPC(22:5(4Z, 7Z, 10Z, 13Z, 16Z)/0:0)

C₃₀H₅₂NO₇P

570.357 3

570.355 4

12.67

1.208 3

+/-

3.33

↓^**

↑^##

LysoPC(20:5(5Z, 8Z, 11Z, 14Z, 17Z)/0:0)

C₂₈H₄₈NO₇P

586.316 9

586.315 0

12.03

1.431 4

3.24

↓^**

↑^##

No.	KEGG pathway	Total	Hit	Impact	P value	Hit compound
1	Phenylalanine, tyrosine and tryptophan biosynthesis	4	2	1.000 0	0.001 8	L-Tyrosine; L-phenylalanine
2	Linoleic acid metabolism	5	2	1.000 0	0.003 0	Linoleic acid; PC
3	Taurine and hypotaurine metabolism	8	1	0.428 6	0.136 0	Taurine
4	Phenylalanine metabolism	10	2	0.357 1	0.013 0	L-Tyrosine; L-phenylalanine
5	Glycerophospholipid metabolism	36	3	0.216 3	0.025 3	PC; LysoPC; PE
6	Tyrosine metabolism	42	3	0.164 4	0.041 4	Vanylglycol; L-tyrosine; fumaric acid
7	Starch and sucrose metabolism	18	1	0.134 9	0.281 1	Glucose 1-phosphate
8	Steroid hormone biosynthesis	85	4	0.128 6	0.063 0	Androstenedione; cholesterol sulfate; androsterone; 17alpha, 21-dihydroxypregnenolone

No.

KEGG pathway

Total

Hit

Impact

P value

Hit compound

Phenylalanine, tyrosine and tryptophan biosynthesis

1.000 0

0.001 8

L-Tyrosine; L-phenylalanine

Linoleic acid metabolism

1.000 0

0.003 0

Linoleic acid; PC

Taurine and hypotaurine metabolism

0.428 6

0.136 0

Taurine

Phenylalanine metabolism

0.357 1

0.013 0

L-Tyrosine; L-phenylalanine

Glycerophospholipid metabolism

0.216 3

0.025 3

PC; LysoPC; PE

Tyrosine metabolism

0.164 4

0.041 4

Vanylglycol; L-tyrosine; fumaric acid

Starch and sucrose metabolism

0.134 9

0.281 1

Glucose 1-phosphate

Steroid hormone biosynthesis

0.128 6

0.063 0

Androstenedione; cholesterol sulfate; androsterone; 17alpha, 21-dihydroxypregnenolone

No.	KEGG pathway	Total	Hit	Impact	P value	Hit compound
1	Phenylalanine, tyrosine and tryptophan biosynthesis	4	2	1.000 0	0.001 8	L-Tyrosine; L-phenylalanine
2	Linoleic acid metabolism	5	2	1.000 0	0.003 0	Linoleic acid; PC
3	Taurine and hypotaurine metabolism	8	1	0.428 6	0.136 0	Taurine
4	Phenylalanine metabolism	10	2	0.357 1	0.013 0	L-Tyrosine; L-phenylalanine
5	Glycerophospholipid metabolism	36	3	0.216 3	0.025 3	PC; LysoPC; PE
6	Tyrosine metabolism	42	3	0.164 4	0.041 4	Vanylglycol; L-tyrosine; fumaric acid
7	Starch and sucrose metabolism	18	1	0.134 9	0.281 1	Glucose 1-phosphate
8	Steroid hormone biosynthesis	85	4	0.128 6	0.063 0	Androstenedione; cholesterol sulfate; androsterone; 17alpha, 21-dihydroxypregnenolone

No.

KEGG pathway

Total

Hit

Impact

P value

Hit compound

Phenylalanine, tyrosine and tryptophan biosynthesis

1.000 0

0.001 8

L-Tyrosine; L-phenylalanine

Linoleic acid metabolism

1.000 0

0.003 0

Linoleic acid; PC

Taurine and hypotaurine metabolism

0.428 6

0.136 0

Taurine

Phenylalanine metabolism

0.357 1

0.013 0

L-Tyrosine; L-phenylalanine

Glycerophospholipid metabolism

0.216 3

0.025 3

PC; LysoPC; PE

Tyrosine metabolism

0.164 4

0.041 4

Vanylglycol; L-tyrosine; fumaric acid

Starch and sucrose metabolism

0.134 9

0.281 1

Glucose 1-phosphate

Steroid hormone biosynthesis

0.128 6

0.063 0

Androstenedione; cholesterol sulfate; androsterone; 17alpha, 21-dihydroxypregnenolone

No.	KEGG pathway	Total	Hit	Impact	P value	Hit compound
1	Linoleic acid metabolism	5	2	1.000 0	0.003 3	Linoleic acid; 12(13)-EpOME
2	Ubiquinone and other terpenoid-quinone biosynthesis	9	1	1.000 0	0.156 7	4-Hydroxyphenylpyruvic acid
3	Thiamine metabolism	7	1	0.666 7	0.124 1	Thiamine pyrophosphate
4	Glyoxylate and dicarboxylate metabolism	32	3	0.386 3	0.020 3	Glyoxylic acid; glyceric acid; citric acid
5	Glycerophospholipid metabolism	36	3	0.261 7	0.027 8	PE; LysoPA; LysoPC
6	TCA cycle	20	2	0.147 4	0.052 2	Citric acid; thiamine pyrophosphate
7	Tryptophan metabolism	41	2	0.131 8	0.177 4	Serotonin; 5-hydroxykynurenine
8	Pyrimidine metabolism	39	2	0.129 5	0.163 9	Orotidylic acid; thymidine
9	Arachidonic acid metabolism	36	2	0.111 2	0.144 2	Prostaglandin H3; 14-hydroxy-E4-neuroprostane
10	Glycerolipid metabolism	16	2	0.105 9	0.034 5	Glyceric acid; LysoPA

No.

KEGG pathway

Total

Hit

Impact

P value

Hit compound

Linoleic acid metabolism

1.000 0

0.003 3

Linoleic acid; 12(13)-EpOME

Ubiquinone and other terpenoid-quinone biosynthesis

1.000 0

0.156 7

4-Hydroxyphenylpyruvic acid

Thiamine metabolism

0.666 7

0.124 1

Thiamine pyrophosphate

Glyoxylate and dicarboxylate metabolism

0.386 3

0.020 3

Glyoxylic acid; glyceric acid; citric acid

Glycerophospholipid metabolism

0.261 7

0.027 8

PE; LysoPA; LysoPC

TCA cycle

0.147 4

0.052 2

Citric acid; thiamine pyrophosphate

Tryptophan metabolism

0.131 8

0.177 4

Serotonin; 5-hydroxykynurenine

Pyrimidine metabolism

0.129 5

0.163 9

Orotidylic acid; thymidine

Arachidonic acid metabolism

0.111 2

0.144 2

Prostaglandin H3; 14-hydroxy-E4-neuroprostane

Glycerolipid metabolism

0.105 9

0.034 5

Glyceric acid; LysoPA

No.	KEGG pathway	Total	Hit	Impact	P value	Hit compound
1	Linoleic acid metabolism	5	2	1.000 0	0.003 3	Linoleic acid; 12(13)-EpOME
2	Ubiquinone and other terpenoid-quinone biosynthesis	9	1	1.000 0	0.156 7	4-Hydroxyphenylpyruvic acid
3	Thiamine metabolism	7	1	0.666 7	0.124 1	Thiamine pyrophosphate
4	Glyoxylate and dicarboxylate metabolism	32	3	0.386 3	0.020 3	Glyoxylic acid; glyceric acid; citric acid
5	Glycerophospholipid metabolism	36	3	0.261 7	0.027 8	PE; LysoPA; LysoPC
6	TCA cycle	20	2	0.147 4	0.052 2	Citric acid; thiamine pyrophosphate
7	Tryptophan metabolism	41	2	0.131 8	0.177 4	Serotonin; 5-hydroxykynurenine
8	Pyrimidine metabolism	39	2	0.129 5	0.163 9	Orotidylic acid; thymidine
9	Arachidonic acid metabolism	36	2	0.111 2	0.144 2	Prostaglandin H3; 14-hydroxy-E4-neuroprostane
10	Glycerolipid metabolism	16	2	0.105 9	0.034 5	Glyceric acid; LysoPA

No.

KEGG pathway

Total

Hit

Impact

P value

Hit compound

Linoleic acid metabolism

1.000 0

0.003 3

Linoleic acid; 12(13)-EpOME

Ubiquinone and other terpenoid-quinone biosynthesis

1.000 0

0.156 7

4-Hydroxyphenylpyruvic acid

Thiamine metabolism

0.666 7

0.124 1

Thiamine pyrophosphate

Glyoxylate and dicarboxylate metabolism

0.386 3

0.020 3

Glyoxylic acid; glyceric acid; citric acid

Glycerophospholipid metabolism

0.261 7

0.027 8

PE; LysoPA; LysoPC

TCA cycle

0.147 4

0.052 2

Citric acid; thiamine pyrophosphate

Tryptophan metabolism

0.131 8

0.177 4

Serotonin; 5-hydroxykynurenine

Pyrimidine metabolism

0.129 5

0.163 9

Orotidylic acid; thymidine

Arachidonic acid metabolism

0.111 2

0.144 2

Prostaglandin H3; 14-hydroxy-E4-neuroprostane

Glycerolipid metabolism

0.105 9

0.034 5

Glyceric acid; LysoPA

基于代谢组学的桔梗皂苷D镇咳祛痰活性及作用机制阐释研究

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张欣雨 , 钟渊涵 , 冯艳 , 张雪梅 , 张寿文 , 曾金祥 ^*

药学学报 | 研究论文 2024,59(3): 724-734

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药学学报 | 研究论文 2024, 59(3): 724-734

基于代谢组学的桔梗皂苷D镇咳祛痰活性及作用机制阐释研究

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张欣雨, 钟渊涵, 冯艳, 张雪梅, 张寿文, 曾金祥^*

作者信息

江西中医药大学, 中药资源与民族药研究中心, 江西南昌 330004

通讯作者:

^*曾金祥, E-mail: zjx@jxutcm.edu.cn

Study on the antitussive and expectorant activities and mechanism of platycodin D based on metabolomics method

Xin-yu ZHANG, Yuan-han ZHONG, Yan FENG, Xue-mei ZHANG, Shou-wen ZHANG, Jin-xiang ZENG^*

Affiliations

Research Center of Chinese Medicine Resources and Ethnic Minority Medicine, Jiangxi University of Chinese Medicine, Nanchang 330004, China

出版时间: 2024-03-12 doi: 10.16438/j.0513-4870.2023-0744

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摘要

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本文通过构建小鼠浓氨水引咳模型与小鼠气管酚红排泄模型研究桔梗皂苷D (platycodin D, PD) 的镇咳祛痰活性, 采用代谢组学方法研究并阐释PD的镇咳祛痰机制。动物实验经江西中医药大学动物伦理委员会批准(批准号: JZLLSC-20220739)。将小鼠随机分为正常组、模型组、阳性药、PD低、中、高剂量给药组, 通过浓氨水引咳和酚红排泄实验评估PD的镇咳与祛痰药效。采用UHPLC-LTQ-Orbitrap-MS对小鼠肺组织代谢物进行鉴定, 应用正交偏最小二乘判别分析(OPLS-DA) 分析方法, 通过变量投影重要性值(VIP) 和t检验结果筛选差异代谢物, 利用MetaboAnalyst平台富集差异性代谢产物的通路。采用比较学方法比较PD与桔梗总皂苷及去芹糖桔梗皂苷D (deapio-platycodin D, DPD) 的镇咳祛痰机制的异同。结果显示, 各浓度PD能显著延长(P < 0.05) 浓氨水引咳模型中小鼠的潜伏期, 减少咳嗽次数, 能显著增加(P < 0.05) 酚红排泄模型中小鼠的酚红排泄量。代谢组学分析结果显示其可调控苯丙氨酸、酪氨酸和色氨酸生物合成、亚油酸代谢、苯丙氨酸代谢、甘油磷脂代谢、酪氨酸代谢等6条代谢通路发挥镇咳作用; 可调控亚油酸代谢、乙醛酸和二羧酸代谢、甘油磷脂代谢、柠檬酸循环、花生四烯酸代谢等8条代谢通路发挥祛痰作用; 但受桔梗皂苷成分结构及其与肠道菌群双向调控作用影响, 仅亚油酸代谢和花生四烯酸代谢通路均可被桔梗总皂苷、PD及DPD所共同调控而发挥镇咳祛痰作用。生物信息功能分析显示, PD调控的代谢通路与抗炎、免疫功能调节、神经递质释放、细胞信号传导、能量代谢与细胞凋亡等调控机制密切相关。本研究显示PD具有良好的镇咳祛痰活性, PD与桔梗总皂苷及DPD镇咳祛痰机制的异同特性表明PD所含芹糖分子及桔梗皂苷成分与肠道菌群的双向调控作用对于PD及DPD等桔梗皂苷成分的镇咳祛痰机制具有重要影响。

关键词

桔梗皂苷D / 镇咳 / 祛痰 / 代谢组学 / 作用机制阐释

Abstract

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In this paper, the antitussive and expectorant activity of platycodin D (PD) were studied by constructing a mouse cough induced by concentrated ammonia water and a mouse trachea phenol red excretion model. The mechanism of antitussive and expectorant effect of PD was studied by metabolomics. The animal experiment was approved by the Animal Ethics Committee of Jiangxi University of Chinese Medicine (approval number: JZLLSC-20220739). Then mice were randomly divided into the normal, model, positive drug, PD low-dose, PD medium-dose and PD high-dose group. The antitussive and expectorant effects of PD were evaluated using a cough mouse model induced by concentrated ammonia water and a mouse tracheal phenol red excretion model, respectively. UHPLC-LTQ-Orbitrap-MS was used to identify the metabolites of mouse lung tissue, and multivariate statistical analysis method of orthogonal partial least squares discriminant analysis (OPLS-DA) was used for metabolites profile analysis. The differential metabolites were screened by variable projected importance value (VIP) and t-test results. Pathways for enrichment of differentiated metabolites were analyzed using the MetaboAnalyst platform. The comparative method was applied to analyze the differences in mechanisms of PD, Deapio-platycodin D (DPD) and total platycosides fraction. The results showed that PD at different concentrations could significantly prolong (P < 0.05) the incubation period of cough mice induced by ammonia water, reduce the coughs frequency, and significantly increase (P < 0.05) the amount of phenol red excretion in phenol red excretion model mice. PD could regulate 6 metabolic pathways of phenylalanine, tyrosine and tryptophan biosynthesis, linoleic acid metabolism, phenylalanine metabolism, glycerophospholipid metabolism, and tyrosine metabolism to exert antitussive effect. It could also regulate 8 metabolic pathways of linoleic acid metabolism, glyoxylic acid and dicarboxylic acid metabolism, glycerol phospholipid metabolism, citric acid cycle and arachidonic acid metabolism to exert an expectorant effect. However, only linoleic acid metabolism and glycerophospholipid metabolism could be regulated by the PD, total platycosides fraction and DPD, which may be ascribed to the structural difference of the platycosides and the interaction between platycosides and the intestinal microbiota. Functional analysis showed that these metabolic pathways are closely related to the regulatory mechanisms of anti-inflammatory response, immune function regulation, neurotransmitter release, cell signal transduction, energy metabolism and cell apoptosis. This study shows that PD possesses good antitussive and expectorant activities. In addition, the mechanism difference of PD, total platycosides fraction and DPD imply that the apiose in PD and the interaction between PD and intestinal microbiota could exert an important effect on the antitussive and expectorant mechanism of the platycosides.

Key words

platycodin D / antitussive / expectorant / metabolomics / explanation of mechanism of action

引用本文

张欣雨, 钟渊涵, 冯艳, 张雪梅, 张寿文, 曾金祥. 基于代谢组学的桔梗皂苷D镇咳祛痰活性及作用机制阐释研究. 药学学报, 2024 , 59 (3) : 724 -734 . DOI: 10.16438/j.0513-4870.2023-0744

Xin-yu ZHANG, Yuan-han ZHONG, Yan FENG, Xue-mei ZHANG, Shou-wen ZHANG, Jin-xiang ZENG. Study on the antitussive and expectorant activities and mechanism of platycodin D based on metabolomics method[J]. Acta Pharmaceutica Sinica, 2024 , 59 (3) : 724 -734 . DOI: 10.16438/j.0513-4870.2023-0744

正文

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咳嗽咳痰是许多呼吸系统疾病的常见症状, 2021年咳嗽治疗与诊断指南调查显示, 在我国, 感冒镇咳药年销售量位居零售药店榜首, 年销售额高达516亿元^{[1, 2]}。咳嗽、咳痰病因复杂, 现有镇咳、祛痰西药存在作用范围窄, 疗效不明显, 易产生肠道反应、嗜睡、抑制呼吸中枢等严重不良反应^[3]。因此研究开发新型安全有效的镇咳祛痰药物是咳嗽、咳痰安全防治的迫切要求。

中药用于治疗预防咳嗽咳痰等呼吸道疾病已有上千年的历史。桔梗为桔梗科植物桔梗Platycodon grandiflorum (Jacq.) A.DC.的干燥根, 具宣肺、利咽、祛痰、排脓等功效, 临床常用于咳嗽痰多、胸闷不畅、咽痛音哑、肺痈吐脓。桔梗皂苷成分是桔梗主要药效成分, 其中桔梗皂苷D (platycodin D, PD) 是桔梗皂苷中含量最高的成分, 也是2020版中国药典规定的桔梗药材指标成分。去芹糖桔梗皂苷D (deapio-platycodin D, DPD) 是桔梗中另一种重要的活性成分; 且与PD相比, 二者在结构上仅相差一分子芹糖。本课题组前期基于桔梗总皂苷部位^[4]及其肠道菌转化产物^[5]的镇咳祛痰谱效关系研究结果表明, PD、DPD及二者的肠道菌转化产物是潜在的镇咳祛痰活性成分^[6], 这表明PD、DPD均具有重要的镇咳祛痰新药研究开发价值。而进一步研究阐释PD的镇咳祛痰活性与机制, 并比较三者活性与机制的异同, 无疑能为基于桔梗皂苷成分的镇咳祛痰新药开发策略提供重要参考依据。

另一方面, 代谢组学是应用现代色谱质谱方法对基因、转录体、蛋白的代谢物进行研究, 探索代谢物与机体相应生理、病理状态的关系的一门新兴组学技术, 已被广泛用于中药药效物质及作用机制研究^[7]。课题组在前期已经基于代谢组学方法阐明了桔梗总皂苷^[4]及DPD^[8]的镇咳祛痰活性与机制。本研究在前期研究基础上进一步验证PD的镇咳祛痰活性, 并应用代谢组学技术阐释PD的镇咳祛痰作用机制; 且在此基础上比较其与桔梗总皂苷^[4]及DPD^[8]镇咳祛痰机制的异同, 进而为基于PD及桔梗皂苷成分安全有效的现代化镇咳祛痰药物开发策略提供参考依据。

材料与方法

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仪器 LTQ Orbitrap VELOS Pro型线性离子阱-静电场轨道阱联用质谱仪, 配备Ultimate 3000超高效液相色谱系统、808964-1601型超低温冰箱(美国赛默飞公司); ZORBAX RRHD Eclipse Plus C18色谱柱(100 mm × 2.1 mm, 1.8 µm; 美国安捷伦公司); DY89-II型匀浆机(宁波新芝生物科技股份有限公司); CP214型电子分析天平(上海奥豪斯仪器有限公司); Milli-Q水净化系统(美国Millipore公司); UV-1800型紫外分光光度计(日本Shimadzu公司); QL-901型涡旋仪(海门市其林贝尔仪器制造有限公司); 402AI型超声雾化器(江苏省鱼跃医疗设备股份有限公司)。

药物与试剂 桔梗皂苷D (纯度: 98.66%, 成都曼斯特生物科技有限公司, 批号: MUST-20051510); 苯酚红(天津市大茂化学试剂厂, 批号: 20170901); 枸橼酸喷托林片(每片含枸橼酸喷托维林25 mg, 河南国药集团荣生制药有限公司, 批号: 21032312); 乙腈(质谱级, 德国Merck公司); 甲酸、甲醇为色谱级, 浓氨水、氯化铵、碳酸氢钠为分析纯(西陇化工股份有限公司), 水为超纯水, 其他试剂为分析纯。

实验动物 96只SPF级雄性昆明小鼠(KM小鼠), 6~8周龄, 体重18~22 g, 购自江西中医药大学动物实验中心, 许可证号为SCXK (赣) 2018-0003。小鼠于SPF级环境和适宜条件下饲养, 可自由饮水与进食。正式实验前, 动物适应性喂养1周以适应实验室条件。动物实验按照《实验动物护理与使用指南》进行, 经江西中医药大学动物伦理委员会批准, 批准文号JZLLSC20220739。

镇咳实验 采用浓氨水引咳法研究PD的镇咳活性, 研究方案同DPD^[8]。简言之, 48只雄性KM小鼠, 随机分为正常组(normal)、模型组(model)、阳性对照组(枸橼酸喷托维林, pentoxyverine, Pen), PD低(platycodin D low dosage, PD-L)、中(platycodin D medium dosage, PD-M)、高剂量(platycodin D high dosage, PD-H) 组, 每组8只。小鼠灌胃给药剂量为10 mL·kg^-1·d^-1, 枸橼酸喷托维林剂量为100 mg·kg^-1·d^-1, PD-L、PD-M、PD-H组分别给药10、20、40 mg·kg^-1·d^-1, 正常组和模型组灌胃等量生理盐水。连续给药7天, 末次给药前所有小鼠禁食不禁水24 h, 末次给药1 h后, 除正常组外所有小鼠依次置于透明玻璃罩内, 浓氨水定量恒压喷雾20 s后立即取出, 记录小鼠从接受喷雾开始到出现咳嗽的潜伏期, 以及3 min内的咳嗽次数, 正常组小鼠恒压喷雾等量生理盐水。采集完咳嗽相关数据后立即摘眼球取血, 脱颈处死小鼠后在冰台上切取肺组织备用。

祛痰实验 采用酚红排泄法研究PD的祛痰活性^[8]。精确称量25.0 mg苯酚红, 用适量5%碳酸氢钠溶液溶解后转移到250 mL量瓶中, 加入5%的碳酸氢钠溶液至刻度线。然后将溶液稀释成0.1、0.2、0.5、1.0、1.5、2.0和3.0 μg·mL^-1酚红溶液, 分别用UV-1800分光光度计测定波长546 nm的吸光度。以酚红浓度(X) 为横坐标, 吸光度(Y) 为纵坐标绘制标准曲线, 得到线性回归方程: Y = 0.724 1X + 0.007 6, R² = 0.999 8。

祛痰实验研究方案同DPD^[8]: 48只雄性KM小鼠, 随机分为正常组(normal)、模型组(model)、阳性对照组(氯化铵, ammonium chloride, AmCh), PD-L、PD-M、PD-H组, 每组8只, 小鼠灌胃给药剂量为10 mL·kg^-1·d^-1, 氯化铵剂量为10 mg·kg^-1·d^-1, PD-L、PD-M、PD-H组分别给药10、20、40 mg·kg^-1·d^-1, 正常组和模型组灌胃等量生理盐水。连续给药7天, 末次给药前所有小鼠禁食不禁水24 h, 于末次给药30 min后, 除正常组外所有小鼠腹腔注射0.5%酚红生理盐水溶液(20 mL·kg^-1), 30 min后摘眼球取血, 脱颈处死小鼠后于冰台上切取肺组织备用。取血取肺后暴露气管, 剥去气管周围组织, 剪下自甲状软骨下至支气管分支处的一段气管, 气管放入装有2 mL生理盐水的离心管中, 旋涡振荡器振荡5 min后超声振荡洗涤20 min, 加入50 g·L^-1 NaHCO₃溶液1 mL, 1 500 r·min^-1离心10 min, 取上清液, 测量546 nm处吸光度, 与酚红标准曲线比较, 折算出酚红排泄量。

肺组织样品处理 镇咳和祛痰实验所得肺组织样品迅速从-80 ℃冰箱中取出, 称取100 mg肺组织置于的离心管中, 加入1 mL预冷的75%甲醇-水溶液, 将离心管放入组织研磨盘中研磨5 min, 于4 ℃摇床上振摇10 min, 混合物在4 ℃以12 000 r·min^-1离心15 min, 取上清液转移至新的离心管中, 用氮气吹干, 残渣用200 μL 75%甲醇-水溶液复溶, 在4 ℃下12 000 r·min^-1离心15 min, 取上清液过0.22 μm滤膜得到用于UHPLC LTQ Orbitrap MS分析的最终样品。质量控制(quality control, QC) 样品用于控制样品收集和制备方法的稳定性, 同组的每个样品中吸取2 μL混合均匀, 再从每组样品中收集15 μL混合组织样品并混匀以获得QC样品, 分析过程中每8个样品进行一次QC分析。

代谢组学样品分析方法 质谱正离子模式参数如下: 离子源温度(TEM), 500 ℃; 气帘气(CUR), 40 psi; 辅助气1 (GS1) 和辅助气2 (GS2), 50 psi; 离子喷雾电压(ISVF), 5.5 kV; 碰撞能量(CE), 35 V; 碰撞能量补充(CES), 15 V; 去簇电压(DP), 100 V。负离子模式参数如下: TEM, 550 ℃; CUR, 40 psi; GS1和GS2, 50 psi; ISVF, -4.5 kV; CE, 35 V; CES, 15 V; DP, -100 V。m/z 50~1 200 Da。色谱柱为Agilent ZORBAX RRHD Eclipse plus C18 (100 mm × 2.1 mm, 1.8 μm) 色谱柱。流动相为0.1%甲酸水(A) 和0.1%甲酸乙腈(B)。流速为0.3 mL·min^-1。洗脱梯度: 0~1 min, 5% B; 1.1~17 min, 5%~100% B; 17.1~18 min, 100% B; 18.1~20 min, 100%~5% B; 20.1~21 min, 5% B。进样量2 μL, 柱温箱40 ℃。

数据处理 药理实验数据以

$ \overline{x} $

± s表示, 多组数据比较采用SPSS数据统计分析软件进行单因素方差分析, P < 0.05为有统计学差异。质谱原始数据经过峰提取、峰匹配、峰识别及归一化处理得到数据矩阵, 所得数据矩阵导入软件SIMCA 14.1软件中进行正交偏最小二乘判别分析(OPLS-DA), 并对数据进行200次随机排列实验, 根据R²和Q²检验模型建立的准确性。OPLS-DA中正交偏最小二乘分析变量投影重要性值(variable importance in projection, VIP) 大于1, 且t检验的P值小于0.05 (P < 0.05) 的内源代谢物被视为与镇咳祛痰作用有关的差异性代谢物。差异性代谢物鉴定通过与METLIN和HMDB等数据库质荷比(m/z) 和二级碎裂参数信息比对, 限定误差范围为±5 ppm。代谢通路分析在MetaboAnalyst 5.0平台完成。

结果

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1 PD镇咳祛痰药效

一般而言, 咳嗽潜伏期越长, 咳嗽频率越低, 说明该药镇咳活性越强^{[8, 9]}。PD的镇咳祛痰活性结果见图 1。如图 1A、B所示, PD-L组咳嗽潜伏期显著延长(P < 0.05), PD-M组和PD-H组咳嗽潜伏期极显著延长(P < 0.01), 各PD给药组咳嗽频率均极显著降低(P < 0.01)。说明口服PD具有明显的镇咳作用, 且呈剂量依赖性。采用小鼠气管酚红排泄实验评价PD祛痰活性, 酚红排出量越多, 说明该药祛痰作用越强, PD祛痰活性见图 1C。如图所示, PD-M与PD-H组酚红分泌量极显著增加(P < 0.01), 说明PD同时具有明显的祛痰作用。这一结果与DPD^[8]及桔梗总皂苷^[9]的镇咳祛痰活性类似, 这提示PD与DPD均是桔梗总皂苷重要的镇咳祛痰活性成分。

2 代谢组学研究

2.1 镇咳、祛痰代谢产物轮廓分析

OPLS-DA可以在不降低模型预测能力的前提下, 有效减少模型的复杂性和增强模型的解释能力。课题组前期应用OPLS-DA技术发现桔梗总皂苷^[9]与DPD^[8]镇咳祛痰实验各组别小鼠代谢产物轮廓。在本研究中, 镇咳OPLS-DA模型正离子模式排列检验的R²和Q²分别为0.316和0.384, 负离子模式的R²和Q²分别为0.208和0.341; 祛痰OPLS-DA模型正离子模式的R²和Q²分别为0.461和0.358, 负离子模式的R²和Q²分别为0.201和0.341; 这说明PD镇咳祛痰OPLS-DA模型具有较好的拟合预测能力。另外, 镇咳祛痰实验QC样品在正离子模式和负离子模式下都在坐标中心区域紧密聚集, 表明仪器稳定性高, 方法重复性好。PD镇咳实验OPLS-DA最终结果见图 2A、B, 祛痰实验OPLS-DA结果见图 2C、D。由图可知, PD镇咳实验和祛痰实验的样品正、负离子模式下正常组与模型组、模型组与各给药组之间能被很好地分开, 组内样本在一定范围内聚集良好, 说明正常组与模型组、模型组与各给药组之间存在着明显的差异代谢物。这一现象与课题组前期的桔梗总皂苷及PD实验类似^{[8, 9]}, 说明PD同样能有效影响咳嗽咳痰小鼠内源性代谢产物的轮廓。

2.2 镇咳、祛痰差异性代谢物鉴定

正常组与模型组OPLS-DA分析中VIP > 1且t检验(P < 0.05) 的物质为与氨水致咳模型和酚红排泄模型的相关差异代谢物。基于OPLS-DA分析中的VIP值与差异倍数(fold change), 结合t检验的P值, 以log₂(fold change) 为横坐标, -lg(P) 为纵坐标绘制火山图, 快速直观地识别差异性代谢物, 模型组中log₂(fold change) ≤ -1的代谢物较正常组下调, log₂(fold change) ≥ 1的代谢物较正常组上调, 火山图结果见图 3。由火山图可知, 镇咳祛痰实验中正、负离子模式下差异性代谢产物既可被上调, 也可被下调, 通过HMDB数据库和METIN数据库质荷比和二级碎裂参数对差异代谢物进行鉴定。

镇咳实验差异性代谢产物鉴定结果见表 1。由表 1可知, 镇咳实验正常组与模型组之间共存在37个差异代谢物, 且与正常组相比, 模型组小鼠肺组织16种差异代谢物水平上调, 21种差异代谢物水平下调。与模型组相比, PD-L组3种代谢物水平显著回调(P < 0.05), 24种代谢物水平极显著回调(P < 0.01)。PD-M组3种代谢物水平显著回调(P < 0.05), 29种代谢物水平极显著回调(P < 0.01)。PD-H组37种代谢物水平极显著回调(P < 0.01)。

祛痰差异性代谢物鉴定结果见表 2。由表 2可知, 祛痰实验正常组与模型组共有36个差异代谢物, 与模型组比较, PD-L组、PD-M组和PD-H组分别有5种代谢物和2种代谢物水平显著回调(P < 0.05), 17种、25种和34种代谢物水平极显著回调(P < 0.01)。

2.3 镇咳、祛痰代谢通路富集分析

在前期研究中, 课题组应用MetaboAnalyst 5.0对桔梗总皂苷及DPD的镇咳祛痰代谢通路进行了富集分析。结果显示, 桔梗总皂苷可调控亚油酸代谢、花生四烯酸代谢和甘油磷脂代谢通路发挥镇咳作用, 亚油酸代谢, 苯丙氨酸、酪氨酸和色氨酸的生物合成, 花生四烯酸代谢, 苯丙氨酸代谢和α-亚麻酸代谢通路发挥祛痰作用^[4]。而DPD则可调控亚油酸代谢, 花生四烯酸代谢, 甘油磷脂代谢, 丙氨酸、天冬氨酸和谷氨酸代谢, 戊糖和葡萄糖醛酸相互转化与赖氨酸降解代谢通路发挥镇咳作用; 可调控亚油酸代谢, 牛磺酸与亚牛磺酸代谢, 甘油磷脂代谢, 嘌呤代谢, 嘧啶代谢, 花生四烯酸代谢与不饱和脂肪酸代谢通路发挥祛痰作用^[8]。在本研究中, 课题组使用MetaboAnalyst 5.0对PD镇咳祛痰实验中检测到的PD-H组差异代谢物进行通路分析^[10], 将显著通路的影响值(impact值) 设置为0.1^[11]。镇咳实验富集代谢通路名称、P值和impact值等信息见表 3与图 4A, 祛痰实验富集代谢通路名称、P值和impact值等信息见表 4与图 4B。

由表 3可知, 在镇咳实验中, PD所致的差异性代谢物主要富集于8条代谢途径, 即苯丙氨酸、酪氨酸和色氨酸生物合成(phenylalanine, tyrosine and tryptophan biosynthesis)、亚油酸代谢(linoleic acid metabolism)、牛磺酸和次牛磺酸代谢(taurine and hypotaurine metabolism)、苯丙氨酸代谢(phenylalanine metabolism)、甘油磷脂代谢(glycerophospholipid metabolism)、酪氨酸代谢(tyrosine metabolism)、淀粉和蔗糖代谢(starch and sucrose metabolism) 与类固醇激素生物合成(steroid hormone biosynthesis)。但牛磺酸和次牛磺酸代谢(taurine and hypotaurine metabolism) 及淀粉和蔗糖代谢(starch and sucrose metabolism) 代谢通路中只有一个代谢产物水平发生了变化, 这2条代谢通路的作用可能被高估^[5], 因此这2条代谢通路在后续的分析中被剔除。

而在祛痰实验中, PD所致的差异代谢物主要富集于10条代谢通路, 分别是亚油酸代谢、泛醌等萜类醌生物合成(ubiquinone and other terpenoid-quinone biosynthesis)、硫胺素代谢(thiamine metabolism)、乙醛酸和二羧酸代谢(glyoxylate and dicarboxylate metabolism)、甘油磷脂代谢、柠檬酸循环(citrate cycle, TCA cycle)、色氨酸代谢(tryptophan metabolism)、嘧啶代谢(pyrimidine metabolism)、花生四烯酸代谢(arachidonic acid metabolism) 和甘油脂代谢(glycerolipid metabolism)。但泛醌等萜类醌生物合成和硫胺素代谢中也只有1个差异代谢物水平发生了改变, 说明这2条代谢通路的作用同样可能被高估^[5], 因此这些代谢通路在后续的分析中被剔除。

讨论

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咳嗽、咳痰发病机制复杂, 缺少特异性的研究模型与检测指标, 通过监测机体代谢物的变化对疾病发病机制及中药治疗作用机制进行研究^[7], 因此, 特别适合于药物镇咳祛痰机制研究。本文药效结果显示各PD给药剂量均能显著延长浓氨水引咳模型中小鼠的咳嗽潜伏期和减少咳嗽次数, 能显著增加酚红排泄模型中小鼠的酚红排泄量。这一结果与桔梗总皂苷及DPD的镇咳祛痰活性研究结果是一致的, 说明PD与桔梗总皂苷^[4]及DPD^[8]一样具有重要的镇咳祛痰新药研究与开发价值。

对于镇咳代谢通路而言, 苯丙氨酸、酪氨酸和色氨酸生物合成, 苯丙氨酸代谢, 酪氨酸代谢和色氨酸代谢均为氨基酸代谢的重要环节, 对维持机体正常生理功能和生命活动有重要作用, 免疫和炎症反应可调节某些氨基酸代谢, 氨基酸水平的高低可以反映机体对感染或组织损伤的免疫反应^[12]。正常生理代谢过程中, 苯丙氨酸经苯丙氨酸羟化酶催化生成酪氨酸, 病理条件下苯丙氨酸向酪氨酸的转化受到抑制, 继而与酮戊二酸发生反应, 产生苯丙酮酸, 造成苯丙酮酸在体内的累积, 过量的苯丙酮酸累积通常会对机体的神经系统造成损伤^[13], 李露等^[14]研究发现急性肠道炎症大鼠盲肠内容物中苯丙酮酸含量过高, 提示苯丙氨酸代谢异常可能是炎症发生的标志。酪氨酸参与体内激素的合成, 酪氨酸可由酪氨酸羟化酶转化为多巴进而合成黑色素和儿茶酚胺类激素, 酪氨酸在机体中过度积累还可引起三羧酸循环中几种关键酶功能发生变化, 从而导致机体能量代谢紊乱, 引起线粒体的氧化应激^[15]。色氨酸是所有氨基酸中抗自由基活性最强的氨基酸^[16], 提示色氨酸水平与炎症水平负相关, 在小鼠支原体肺炎感染小鼠血清中色氨酸水平低于正常小鼠水平^[17], 另有研究表明支原体肺炎感染患者中存在氨基酸代谢紊乱现象, 肺炎患者色氨酸水平明显低于正常患者^[18]。

亚油酸代谢途径作为炎症介质广泛参与局部炎症, 亚油酸是人体必需脂肪酸, 同时是花生四烯酸的前体, 具有参与脂肪分解、维持正常新陈代谢、增强机体免疫力等多种生理功能, 其代谢物13S-羟基-9Z, 11E-十八碳二烯酸(13S-hydroxy-9Z, 11E-octadecadienoic acid, 13-S-HODE) 可导致线粒体功能紊乱、气道上皮细胞损伤^[19]; 亚油酸不仅可以促进成纤维细胞分泌NO、TNF、IL-1β、IL-8等炎症介质, 参与肺部炎症反应的发生, 而且对机体免疫功能及细胞因子水平有重要调节作用^[20]。

PCs和LysoPCs等甘油磷脂类化合物, 是细胞膜结构的重要组成部分, 同时也是一种重要的趋化介质, 可通过特定的G蛋白偶联受体介导免疫细胞的激活, 参与炎症过程。此外, PCs和PEs还是线粒体膜的重要组成部分, 线粒体膜磷脂水平变化可能影响关键跨膜蛋白活性, 引起线粒体功能障碍, 导致细胞凋亡^[21]。研究发现, 饱和的LysoPCs是有效的炎性介质, 可以诱导血浆渗漏、免疫细胞迁移和促炎细胞因子的释放, 相反, 多不饱和LysoPCs可以作为抗炎脂质介质, 减少血浆渗漏和炎症细胞活化, 抑制炎症介质(IL-6、NO、PGE等) 的产生, 并增加抗炎因子IL-10和IL-4含量^[22]。由此可见, 这些复杂的代谢通路彼此关联, 进而形成复杂的代谢通路网络(图 5)。PD可调控这种复杂的代谢网络发挥镇咳作用, 这提示PD具有很好的镇咳新药开发价值。

对于祛痰代谢通路而言, PD同样可调控亚油酸代谢通路与甘油磷脂代谢通路产生祛痰作用。此外, 花生四烯酸对肺的生理功能及病理过程具有极其重要的调节作用, 由磷脂酶释放的花生四烯酸的强效类花生酸脂介质, 如前列腺素、白三烯类等成分, 参与多种稳态生物学功能和炎症, 被视为先天免疫应答的促炎因子^[23]。这些代谢物对机体免疫功能、细胞信号转导、血管舒张等具有重要调节作用, 如这些代谢物可激活呼吸道感受器、改变肺的机械特性、促进炎症细胞聚集等, 进而发挥祛痰活性^{[24, 25]}。TCA循环与乙醛酸和二羧酸代谢都是机体能量代谢的重要环节。TCA循环也被称为三羧酸循环, 是需氧生物体内普遍存在的代谢途径, 乙醛酸和二羧酸代谢是脂肪酸进入三羧酸循环的关键步骤^[26], 为机体提供能量, 此外, 糖酵解和TCA循环等能量代谢途径在免疫细胞的分化和激活过程中发生变化, 并在免疫细胞的功能调节中发挥重要作用^[27], 柠檬酸和琥珀酸盐是TCA循环中的关键物质, 在先天性和适应性免疫的非代谢信号调节、脂质和核苷酸合成以及DNA甲基化中发挥重要作用^[28]。甘油酯是甘油和脂肪酸经酯化所生成的酯, 在机体内负责贮存能量与输送, 甘油作为重要小分子物质, 是甘油三酯的前体, 参与多条代谢通路如甘油酯类代谢、甘油磷脂类代谢等^[29]。嘧啶代谢能对细胞信号和能量代谢起到调节作用, 研究发现, 黄芪多糖可以通过嘧啶代谢发挥免疫抑制作用^[25]。由此可见, 这些复杂的代谢通路彼此关联, 进而形成复杂的代谢通路网络(图 6)。PD可调控这种复杂的代谢网络的祛痰作用, 这同样说明PD具有很好的祛痰新药开发价值。

另一方面, 由上述机制研究结果可知, PD与桔梗总皂苷既可调控相同的代谢通路如亚油酸代谢及甘油磷脂代谢发挥镇咳祛痰活性, 也可以调控其他不同的代谢通路分别发挥镇咳祛痰活性。这一结果与DPD的镇咳祛痰机制类似^[8], 其原因可能一方面是因为本文差异性代谢物来自肺部组织, 而桔梗总皂苷镇咳祛痰实验的差异性代谢物来自于血清样本, 且肺部组织差异性代谢物可能更能全面地反映PD的调控机制。另一方面是因为在本文给药剂量下, DPD及其肠道菌转化物的体内血药浓度可能与桔梗总皂苷部位中PD的血药浓度并不相同, 这可能导致潜在的活性成分群及其调控机制发生了变化^{[4, 8]}。虽然有研究显示, PD及DPD口服生物利用度低会被肠道菌转化进而通过肠道菌转化产物发挥镇咳祛痰活性^[5]。且由于其结构的相似性, 经肠道菌转化可产生大量相同的代谢产物^[5], 因而有可能具有相似的镇咳祛痰机制。但本研究结果显示, 虽然PD与DPD均基于肺部组织进行代谢组学研究, 且二者的给药剂量也相同^[8], 但二者的镇咳祛痰机制仍存在很大的不同, 推测可能与PD及DPD连接的糖链不同有关: 一方面PD分子中C-28位糖链末端的芹糖影响了其肠道菌转化, 进而导致相应的肠道菌转化速度、转化产物的种类以及进入血中的产物浓度与DPD并不完全相同; 另一方面, 不同的成分对肠道菌群的调控作用也不相同, 而不同的肠道菌群本身所产生的代谢产物也并不相同, 进而影响了PD的镇咳祛痰机制。这是合理的, 因为中草药成分与肠道菌群之间存在复杂的双向调控作用, 而其药效物质不仅可能包括源自中草药成分的代谢产物, 也可能包括源自肠道菌本身的代谢产物^[30]。PD与DPD均属于桔梗皂苷的重要活性成分, 且可产生部分相同的代谢产物, 但同时可产生不同的代谢产物, 这可能正是三者镇咳祛痰机制既存在共同之处, 也存在不同之处的重要原因。

总之, 本研究阐释了PD的镇咳祛痰活性与作用机制, 探讨了PD镇咳祛痰机制与桔梗总皂苷及DPD镇咳祛痰机制异同的潜在原因, 为基于PD及其他桔梗皂苷成分的镇咳祛痰新药的现代化开发提供了参考依据。

作者贡献: 张欣雨和曾金祥构思并设计了实验, 张欣雨、钟渊涵进行论文整体实验和数据分析, 冯艳、张雪梅、张寿文协助实验开展与数据分析, 张欣雨与曾金祥撰写并修改了论文。

利益冲突: 所有作者均声明不存在利益冲突。

基金

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国家自然科学基金资助项目(81860685)
国家自然科学基金资助项目(82160736)
江西中医药大学科技创新团队项目(CXTD22002)
江西中医药大学校级研究生创新专项资金项目(JZYC22S08)
江西中医药大学校级研究生创新专项资金项目(JZYC22S64)

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2024年第59卷第3期

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doi: 10.16438/j.0513-4870.2023-0744

接收时间：2023-06-15
首发时间：2025-11-28
出版时间：2024-03-12

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出版历史

收稿日期：2023-06-15
修回日期：2023-09-09

基金

国家自然科学基金资助项目(81860685)

国家自然科学基金资助项目(82160736)

江西中医药大学科技创新团队项目(CXTD22002)

江西中医药大学校级研究生创新专项资金项目(JZYC22S08)

江西中医药大学校级研究生创新专项资金项目(JZYC22S64)

作者信息

江西中医药大学, 中药资源与民族药研究中心, 江西南昌 330004

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^*曾金祥, E-mail: zjx@jxutcm.edu.cn

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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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Metabolite	Formula	Measured m/z	Theoretical m/z	RT /min	VIP value	ESI mode	Error /ppm	Variation trend
Fumaric acid	C₄H₄O₄	115.003 7	115.003 7	1.05	1.376 6	-	0.00	↑^**	↓^#	↓^##	↓^##
Malic acid	C₄H₆O₅	133.014 2	133.014 2	0.87	1.834 0	+/-	0.00	↓^**	↑^##	↑^##	↑^##
Vanylglycol	C₉H₁₂O₄	134.071 2	134.070 6	0.85	1.544 7	+	4.33	↑^**	↓^##	↓^##	↓^##
4-Trimethylammoniobutanoic acid	C₇H₁₅NO₂	144.102 9	144.103 0	13.05	1.335 6	-	-0.69	↓^**	/	↑^##	↑^##
L-Phenylalanine	C₉H₁₁NO₂	164.071 9	164.071 7	2.08	1.800 1	-	1.28	↑^**	↓^##	↓^##	↓^##
L-Tyrosine	C₉H₁₁NO₃	182.080 4	182.081 2	0.88	1.576 3	+	-4.39	↓^**	/	↑^##	↑^##
17alpha, 21-Dihydroxypregnenolone	C₂₁H₃₂O₄	186.114 1	186.113 3	6.33	1.774 4	+	4.03	↑^**	↓^##	↓^##	↓^##
Taurine	C₂H₇NO₃S	191.994 6	191.994 9	0.78	1.760 4	+/-	-1.56	↓^**	↑^##	↑^##	↑^##
4-Hydroxy-2-oxoglutaric acid	C₅H₆O₆	245.075 8	245.076 8	1.16	1.787 2	+	-4.20	↓^**	/	/	↑^##
Androstenedione	C₁₉H₂₆O₂	251.179 8	251.180 6	10.15	1.778 4	+	-3.03	↑^**	↓^##	↓^##	↓^##
Androsterone	C₁₉H₃₀O₂	271.207 0	271.206 2	9.57	1.852 8	-	2.95	↑^**	↓^##	↓^##	↓^##
PE(22:2(13Z, 16Z)/18:1(9Z))	C₄₅H₈₄NO₈P	274.198 8	274.199 1	8.77	1.326 9	+	-1.09	↓^**	↑^##	↑^##	↑^##
Oleic acid	C₁₈H₃₄O₂	281.248 1	281.248 6	13.35	1.613 4	-	-1.78	↓^**	↑^##	↑^##	↑^##
3-O-Sulfogalactosylceramide (D18:1/18:0)	C₄₂H₈₁NO₁₁S	292.172 4	292.173 6	13.19	1.492 7	+	-4.11	↓^**	/	/	↑^##
Sphingosine	C₁₈H₃₇NO₂	300.288 5	300.289 7	11.81	1.593 1	+	-4.13	↓^**	↑^##	↑^##	↑^##
LysoPC(22:0/0:0)	C₃₀H₆₂NO₇P	311.234 3	311.233 7	15.83	1.509 3	+	1.93	↓^**	↑^##	↑^##	↑^##
Linoleic acid	C₁₈H₃₂O₂	313.272 5	313.273 7	15.10	1.224 3	+	-3.83	↓^**	/	↑^##	↑^##
4-Trimethylammoniobutanal	C₇H₁₆NO	322.247 1	322.2476	5.36	1.334 9	+	-1.68	↓^**	↑^#	↑^#	↑^##
Glucose 1-phosphate	C₆H₁₃O₉P	327.009 8	327.009 9	0.73	1.497 6	-	-0.31	↑^**	↓^##	↓^##	↓^##
Docosahexaenoic acid	C₂₂H₃₂O₂	327.232 5	327.233 0	12.72	1.061 1	-	-1.53	↑^**	↓^##	↓^##	↓^##
Leukotriene A4	C₂₀H₃₀O₃	360.253 8	360.253 3	6.76	1.832 7	+	1.39	↓^**	↑^##	↑^##	↑^##
Vitamin D3	C₂₇H₄₄O	367.338 1	367.336 5	13.12	1.599 5	+	4.36	↑^**	/	/	↓^##
Sphingosine 1-phosphate	C₁₈H₃₈NO₅P	378.239 9	378.241 5	11.85	1.308 5	-	-4.23	↑^**	↓^##	↓^##	↓^##
PE(15:0/14:1(9Z))	C₃₄H₆₆NO₈P	386.273 6	386.273 4	14.18	1.653 6	+	0.44	↓^**	↑^##	↑^##	↑^##
PE(14:0/P-16:0)	C₃₅H₇₀NO₇P	386.293 0	386.291 6	14.18	1.425 5	+	3.62	↑^**	↓^#	↓^#	↓^##
15-HETE	C₂₀H₃₂O₃	387.214 7	387.215 3	14.32	1.710 3	-	-1.55	↓^**	↑^##	↑^##	↑^##
PE(22:2(13Z, 16Z)/P-18:0)	C₄₅H₈₆NO₇P	403.806 0	403.805 3	7.29	1.426 7	+	1.83	↑^**	↓^##	↓^##	↓^##
PC(22:5(7Z, 10Z, 13Z, 16Z, 19Z)/P-16:0)	C₄₆H₈₂NO₇P	407.790 2	407.789 7	7.01	1.728 8	+	1.18	↓^**	/	↑^##	↑^##
4a-Carboxy-4b-methyl-5a-cholesta-8, 24-dien-3b-ol	C₂₉H₄₆O₃	425.343 9	425.342 0	12.73	1.841 5	+	4.51	↓^**	↑^##	↑^##	↑^##
PC(22:5(7Z, 10Z, 13Z, 16Z, 19Z)/18:1(11Z))	C₄₈H₈₄NO₈P	438.318 0	438.317 3	12.73	1.601 8	+	1.60	↑^**	/	/	↓^##
Folinic acid	C₂₀H₂₃N₇O₇	456.164 8	456.163 2	15.87	1.642 1	+	3.53	↓^**	↑^##	↑^##	↑^##
LysoPC(15:0/0:0)	C₂₃H₄₈NO₇P	462.296 9	462.298 4	12.77	1.105 8	+/-	-3.20	↑^**	↓^##	↓^##	↓^##
Cholesterol sulfate	C₂₇H₄₆O₄S	499.343 8	499.345 2	13.49	1.851 9	+	-2.76	↑^**	↓^##	↓^##	↓^##
3-O-Sulfogalactosylceramide (D18:1/24:0)	C₄₈H₉₃NO₁₁S	508.372 1	508.370 6	14.31	1.778 0	+	2.97	↓^**	↑^##	↑^##	↑^##
LysoPC(18:0/0:0)	C₂₆H₅₄NO₇P	524.369 0	524.371 1	14.91	1.090 3	+	-3.97	↓^**	/	↑^#	↑^##
LysoPC(18:1(9Z)/0:0)	C₂₆H₅₂NO₇P	588.329 9	588.328 3	13.00	1.042 3	-	2.72	↑^**	/	/	↓^##
LysoPC(20:3(8Z, 11Z, 14Z)/0:0)	C₂₈H₅₂NO₇P	590.318 0	590.319 3	12.77	1.620 9	+	-2.20	↓^**	↑^##	↑^##	↑^##

Metabolite

Formula

Measured m/z

Theoretical m/z

RT /min

VIP value

ESI mode

Error /ppm

Variation trend

Normal/Model

Model/PD-L

Model/PD-M

Model/PD-H

Fumaric acid

C₄H₄O₄

115.003 7

1.05

1.376 6

0.00

↑^**

↓^#

↓^##

Malic acid

C₄H₆O₅

133.014 2

0.87

1.834 0

+/-

0.00

↓^**

↑^##

Vanylglycol

C₉H₁₂O₄

134.071 2

134.070 6

0.85

1.544 7

4.33

↑^**

↓^##

4-Trimethylammoniobutanoic acid

C₇H₁₅NO₂

144.102 9

144.103 0

13.05

1.335 6

-0.69

↓^**

↑^##

L-Phenylalanine

C₉H₁₁NO₂

164.071 9

164.071 7

2.08

1.800 1

1.28

↑^**

↓^##

L-Tyrosine

C₉H₁₁NO₃

182.080 4

182.081 2

0.88

1.576 3

-4.39

↓^**

↑^##

17alpha, 21-Dihydroxypregnenolone

C₂₁H₃₂O₄

186.114 1

186.113 3

6.33

1.774 4

4.03

↑^**

↓^##

Taurine

C₂H₇NO₃S

191.994 6

191.994 9

0.78

1.760 4

+/-

-1.56

↓^**

↑^##

4-Hydroxy-2-oxoglutaric acid

C₅H₆O₆

245.075 8

245.076 8

1.16

1.787 2

-4.20

↓^**

↑^##

Androstenedione

C₁₉H₂₆O₂

251.179 8

251.180 6

10.15

1.778 4

-3.03

↑^**

↓^##

Androsterone

C₁₉H₃₀O₂

271.207 0

271.206 2

9.57

1.852 8

2.95

↑^**

↓^##

PE(22:2(13Z, 16Z)/18:1(9Z))

C₄₅H₈₄NO₈P

274.198 8

274.199 1

8.77

1.326 9

-1.09

↓^**

↑^##

Oleic acid

C₁₈H₃₄O₂

281.248 1

281.248 6

13.35

1.613 4

-1.78

↓^**

↑^##

3-O-Sulfogalactosylceramide (D18:1/18:0)

C₄₂H₈₁NO₁₁S

292.172 4

292.173 6

13.19

1.492 7

-4.11

↓^**

↑^##

Sphingosine

C₁₈H₃₇NO₂

300.288 5

300.289 7

11.81

1.593 1

-4.13

↓^**

↑^##

LysoPC(22:0/0:0)

C₃₀H₆₂NO₇P

311.234 3

311.233 7

15.83

1.509 3

1.93

↓^**

↑^##

Linoleic acid

C₁₈H₃₂O₂

313.272 5

313.273 7

15.10

1.224 3

-3.83

↓^**

↑^##

4-Trimethylammoniobutanal

C₇H₁₆NO

322.247 1

322.2476

5.36

1.334 9

-1.68

↓^**

↑^#

↑^##

Glucose 1-phosphate

C₆H₁₃O₉P

327.009 8

327.009 9

0.73

1.497 6

-0.31

↑^**

↓^##

Docosahexaenoic acid

C₂₂H₃₂O₂

327.232 5

327.233 0

12.72

1.061 1

-1.53

↑^**

↓^##

Leukotriene A4

C₂₀H₃₀O₃

360.253 8

360.253 3

6.76

1.832 7

1.39

↓^**

↑^##

Vitamin D3

C₂₇H₄₄O

367.338 1

367.336 5

13.12

1.599 5

4.36

↑^**

↓^##

Sphingosine 1-phosphate

C₁₈H₃₈NO₅P

378.239 9

378.241 5

11.85

1.308 5

-4.23

↑^**

↓^##

PE(15:0/14:1(9Z))

C₃₄H₆₆NO₈P

386.273 6

386.273 4

14.18

1.653 6

0.44

↓^**

↑^##

PE(14:0/P-16:0)

C₃₅H₇₀NO₇P

386.293 0

386.291 6

14.18

1.425 5

3.62

↑^**

↓^#

↓^##

15-HETE

C₂₀H₃₂O₃

387.214 7

387.215 3

14.32

1.710 3

-1.55

↓^**

↑^##

PE(22:2(13Z, 16Z)/P-18:0)

C₄₅H₈₆NO₇P

403.806 0

403.805 3

7.29

1.426 7

1.83

↑^**

↓^##

PC(22:5(7Z, 10Z, 13Z, 16Z, 19Z)/P-16:0)

C₄₆H₈₂NO₇P

407.790 2

407.789 7

7.01

1.728 8

1.18

↓^**

↑^##

4a-Carboxy-4b-methyl-5a-cholesta-8, 24-dien-3b-ol

C₂₉H₄₆O₃

425.343 9

425.342 0

12.73

1.841 5

4.51

↓^**

↑^##

PC(22:5(7Z, 10Z, 13Z, 16Z, 19Z)/18:1(11Z))

C₄₈H₈₄NO₈P

438.318 0

438.317 3

12.73

1.601 8

1.60

↑^**

↓^##

Folinic acid

C₂₀H₂₃N₇O₇

456.164 8

456.163 2

15.87

1.642 1

3.53

↓^**

↑^##

LysoPC(15:0/0:0)

C₂₃H₄₈NO₇P

462.296 9

462.298 4

12.77

1.105 8

+/-

-3.20

↑^**

↓^##

Cholesterol sulfate

C₂₇H₄₆O₄S

499.343 8

499.345 2

13.49

1.851 9

-2.76

↑^**

↓^##

3-O-Sulfogalactosylceramide (D18:1/24:0)

C₄₈H₉₃NO₁₁S

508.372 1

508.370 6

14.31

1.778 0

2.97

↓^**

↑^##

LysoPC(18:0/0:0)

C₂₆H₅₄NO₇P

524.369 0

524.371 1

14.91

1.090 3

-3.97

↓^**

↑^#

↑^##

LysoPC(18:1(9Z)/0:0)

C₂₆H₅₂NO₇P

588.329 9

588.328 3

13.00

1.042 3

2.72

↑^**

↓^##

LysoPC(20:3(8Z, 11Z, 14Z)/0:0)

C₂₈H₅₂NO₇P

590.318 0

590.319 3

12.77

1.620 9

-2.20

↓^**

↑^##

Metabolite	Formula	Measured m/z	Theoretical m/z	RT /min	VIP value	ESI mode	Error /ppm	Variation trend
Glyoxylic acid	C₂H₂O₃	72.993 3	72.993 1	1.25	1.408 4	-	2.74	↓^**	/	↑^##	↑^##
Estrone	C₁₈H₂₂O₂	134.074 3	134.073 7	12.62	1.436 2	-	4.48	↓^**	/	/	↑^##
Hydroxypropionic acid	C₃H₆O₃	135.030 1	135.029 9	0.83	1.525 1	-	1.48	↓^**	↑^##	↑^##	↑^##
Glyceric acid	C₃H₆O₄	142.975 1	142.975 2	0.74	1.469 4	-	-0.70	↑^**	/	↓^##	↓^##
Allantoic acid	C₄H₈N₄O₄	157.036 7	157.036 2	1.14	1.410 5	-	3.18	↓^**	/	/	↑^##
Orotidylic acid	C₁₀H₁₃N₂O₁₁P	183.006 2	183.005 6	0.85	1.401 0	-	3.28	↓^**	↑^##	↑^##	↑^##
4-Hydroxyphenylpyruvic acid	C₉H₈O₄	213.076 4	213.075 7	15.65	1.413 9	+	3.29	↑^**	↓^##	↓^##	↓^##
5-Acetylamino-6-formylamino-3-methyluracil	C₈H₁₀N₄O₄	225.063 0	225.062 9	3.76	1.546 8	-	0.44	↑^**	/	/	↓^##
CE(20:1(11Z))	C₄₇H₈2O₂	225.203 8	225.203 2	15.91	1.492 7	-	2.66	↓^**	↑^##	↑^##	↑^##
Thymidine	C₁₀H₁₄N₂O₅	241.082 4	241.083 0	1.90	1.460 7	-	-2.49	↑^**	/	↓^##	↓^##
Serotonin	C₁₀H₁₂N₂O	259.155 3	259.155 3	15.64	1.409 2	+	0.00	↑^**	↓^##	↓^##	↓^##
Citric acid	C₆H₈O₇	261.021 4	261.021 6	1.08	1.468 0	+	-0.77	↑^**	↓^##	↓^##	↓^##
5-Hydroxykynurenine	C₁₀H₁₂N₂O₄	269.077 4	269.077 9	1.21	1.092 1	-	-1.86	↓^*	/	↑^#	↑^#
Linoleic acid	C₁₈H₃₂O₂	313.274 9	313.273 7	15.12	1.354 7	+	3.83	↓^**	/	↑^#	↑^##
Prostaglandin H3	C₂₀H₃₀O₅	331.191 1	331.190 9	8.56	1.377 5	-	0.60	↓^**	/	↑^##	↑^##
Dihomo-gamma-linolenic acid	C₂₀H₃₄O₂	339.290 7	339.289 4	13.11	1.043 7	+	3.83	↓^**	/	↑^#	↑^##
19-Hydroxytestosterone	C₁₉H₂₈O₃	349.200 8	349.202 0	9.90	1.144 5	-	-3.44	↓^**	↑^##	↑^##	↑^##
14-Hydroxy-E4-neuroprostane	C₂₂H₃₂O₅	357.207 6	357.206 6	13.14	1.449 0	-	2.80	↓^**	/	↑^##	↑^##
12(13)-EpOME	C₁₈H₃₂O₃	363.215 9	363.215 3	13.06	1.089 4	-	1.65	↓^**	/	/	↑^##
Cyclic GMP	C₁₀H₁₂N₅O₇P	380.015 0	380.016 8	0.72	1.430 4	-	-4.74	↓^**	↑^##	↑^##	↑^##
Palmitoylcarnitine	C₂₃H₄₅NO₄	398.327 7	398.327 6	12.63	1.430 1	-	0.25	↓^**	↑^##	↑^##	↑^##
Thiamine pyrophosphate	C₁₂H₁₉N₄O₇P₂S	405.019 8	405.019 3	0.98	1.384 0	-	1.23	↑^**	/	↓^##	↓^##
Cortisone	C₂₁H₂₈O₅	405.190 2	405.191 9	5.25	1.120 0	-	-4.20	↓^**	↑^##	↑^##	↑^##
LysoPA(0:0/16:0)	C₁₉H₃₉O₇P	409.235 5	409.236 1	13.94	1.467 6	-	-1.47	↑^**	/	/	↓^##
PE(16:0/P-18:0)	C₃₉H₇₈NO₇P	414.321 6	414.322 9	10.32	1.041 8	+	-3.14	↓^**	/	↑^##	↑^##
PE(20:1(11Z)/P-18:1(11Z))	C₄₃H₈₂NO₇P	440.337 2	440.338 5	10.63	1.230 6	+	-2.95	↓^**	/	/	↑^##
LysoPA(0:0/18:1(9Z))	C₂₁H₄₁O₇P	478.294 3	478.292 8	12.20	1.033 8	+	3.14	↓^**	↑^##	↑^##	↑^##
LysoPA(18:0/0:0)	C₂₁H₄₃O₇P	480.309 7	480.308 5	13.12	1.050 2	+	2.50	↓^**	↑^##	↑^##	↑^##
24R, 25-Dihydroxyvitamin D3	C₂₇H₄₄O₃	483.310 3	483.309 2	13.62	1.028 6	-	2.28	↑^**	/	↓^##	↓^##
LysoPC(18:3(6Z, 9Z, 12Z)/0:0)	C₂₆H₄₈NO₇P	518.323 3	518.324 1	12.65	1.179 4	+	-1.54	↓^**	↑^##	↑^##	↑^##
LysoPC(18:2(9Z, 12Z)/0:0)	C₂₆H₅₀NO₇P	542.323 2	542.321 7	12.16	1.157 3	+	2.77	↓^**	/	↑^#	↑^#
LysoPC(20:4(8Z, 11Z, 14Z, 17Z)/0:0)	C₂₈H₅₀NO₇P	544.341 0	544.339 8	12.35	1.270 1	+	2.20	↓^**	↑^##	↑^##	↑^##
LysoPC(18:1(11Z)/0:0)	C₂₆H₅₂NO₇P	556.315 7	556.317 5	13.01	1.562 4	-	-3.24	↓^**	/	↑^#	↑^##
LysoPC(22:6(4Z, 7Z, 10Z, 13Z, 16Z, 19Z)/0:0)	C₃₀H₅₀NO₇P	568.341 3	568.339 8	12.29	1.036 1	+	2.64	↓^**	↑^##	↑^##	↑^##
LysoPC(22:5(4Z, 7Z, 10Z, 13Z, 16Z)/0:0)	C₃₀H₅₂NO₇P	570.357 3	570.355 4	12.67	1.208 3	+/-	3.33	↓^**	↑^##	↑^##	↑^##
LysoPC(20:5(5Z, 8Z, 11Z, 14Z, 17Z)/0:0)	C₂₈H₄₈NO₇P	586.316 9	586.315 0	12.03	1.431 4	-	3.24	↓^**	↑^##	↑^##	↑^##

Metabolite

Formula

Measured m/z

Theoretical m/z

RT /min

VIP value

ESI mode

Error /ppm

Variation trend

Normal/Model

Model/PD-L

Model/PD-M

Model/PD-H

Glyoxylic acid

C₂H₂O₃

72.993 3

72.993 1

1.25

1.408 4

2.74

↓^**

↑^##

Estrone

C₁₈H₂₂O₂

134.074 3

134.073 7

12.62

1.436 2

4.48

↓^**

↑^##

Hydroxypropionic acid

C₃H₆O₃

135.030 1

135.029 9

0.83

1.525 1

1.48

↓^**

↑^##

Glyceric acid

C₃H₆O₄

142.975 1

142.975 2

0.74

1.469 4

-0.70

↑^**

↓^##

Allantoic acid

C₄H₈N₄O₄

157.036 7

157.036 2

1.14

1.410 5

3.18

↓^**

↑^##

Orotidylic acid

C₁₀H₁₃N₂O₁₁P

183.006 2

183.005 6

0.85

1.401 0

3.28

↓^**

↑^##

4-Hydroxyphenylpyruvic acid

C₉H₈O₄

213.076 4

213.075 7

15.65

1.413 9

3.29

↑^**

↓^##

5-Acetylamino-6-formylamino-3-methyluracil

C₈H₁₀N₄O₄

225.063 0

225.062 9

3.76

1.546 8

0.44

↑^**

↓^##

CE(20:1(11Z))

C₄₇H₈2O₂

225.203 8

225.203 2

15.91

1.492 7

2.66

↓^**

↑^##

Thymidine

C₁₀H₁₄N₂O₅

241.082 4

241.083 0

1.90

1.460 7

-2.49

↑^**

↓^##

Serotonin

C₁₀H₁₂N₂O

259.155 3

15.64

1.409 2

0.00

↑^**

↓^##

Citric acid

C₆H₈O₇

261.021 4

261.021 6

1.08

1.468 0

-0.77

↑^**

↓^##

5-Hydroxykynurenine

C₁₀H₁₂N₂O₄

269.077 4

269.077 9

1.21

1.092 1

-1.86

↓^*

↑^#

Linoleic acid

C₁₈H₃₂O₂

313.274 9

313.273 7

15.12

1.354 7

3.83

↓^**

↑^#

↑^##

Prostaglandin H3

C₂₀H₃₀O₅

331.191 1

331.190 9

8.56

1.377 5

0.60

↓^**

↑^##

Dihomo-gamma-linolenic acid

C₂₀H₃₄O₂

339.290 7

339.289 4

13.11

1.043 7

3.83

↓^**

↑^#

↑^##

19-Hydroxytestosterone

C₁₉H₂₈O₃

349.200 8

349.202 0

9.90

1.144 5

-3.44

↓^**

↑^##

14-Hydroxy-E4-neuroprostane

C₂₂H₃₂O₅

357.207 6

357.206 6

13.14

1.449 0

2.80

↓^**

↑^##

12(13)-EpOME

C₁₈H₃₂O₃

363.215 9

363.215 3

13.06

1.089 4

1.65

↓^**

↑^##

Cyclic GMP

C₁₀H₁₂N₅O₇P

380.015 0

380.016 8

0.72

1.430 4

-4.74

↓^**

↑^##

Palmitoylcarnitine

C₂₃H₄₅NO₄

398.327 7

398.327 6

12.63

1.430 1

0.25

↓^**

↑^##

Thiamine pyrophosphate

C₁₂H₁₉N₄O₇P₂S

405.019 8

405.019 3

0.98

1.384 0

1.23

↑^**

↓^##

Cortisone

C₂₁H₂₈O₅

405.190 2

405.191 9

5.25

1.120 0

-4.20

↓^**

↑^##

LysoPA(0:0/16:0)

C₁₉H₃₉O₇P

409.235 5

409.236 1

13.94

1.467 6

-1.47

↑^**

↓^##

PE(16:0/P-18:0)

C₃₉H₇₈NO₇P

414.321 6

414.322 9

10.32

1.041 8

-3.14

↓^**

↑^##

PE(20:1(11Z)/P-18:1(11Z))

C₄₃H₈₂NO₇P

440.337 2

440.338 5

10.63

1.230 6

-2.95

↓^**

↑^##

LysoPA(0:0/18:1(9Z))

C₂₁H₄₁O₇P

478.294 3

478.292 8

12.20

1.033 8

3.14

↓^**

↑^##

LysoPA(18:0/0:0)

C₂₁H₄₃O₇P

480.309 7

480.308 5

13.12

1.050 2

2.50

↓^**

↑^##

24R, 25-Dihydroxyvitamin D3

C₂₇H₄₄O₃

483.310 3

483.309 2

13.62

1.028 6

2.28

↑^**

↓^##

LysoPC(18:3(6Z, 9Z, 12Z)/0:0)

C₂₆H₄₈NO₇P

518.323 3

518.324 1

12.65

1.179 4

-1.54

↓^**

↑^##

LysoPC(18:2(9Z, 12Z)/0:0)

C₂₆H₅₀NO₇P

542.323 2

542.321 7

12.16

1.157 3

2.77

↓^**

↑^#

LysoPC(20:4(8Z, 11Z, 14Z, 17Z)/0:0)

C₂₈H₅₀NO₇P

544.341 0

544.339 8

12.35

1.270 1

2.20

↓^**

↑^##

LysoPC(18:1(11Z)/0:0)

C₂₆H₅₂NO₇P

556.315 7

556.317 5

13.01

1.562 4

-3.24

↓^**

↑^#

↑^##

LysoPC(22:6(4Z, 7Z, 10Z, 13Z, 16Z, 19Z)/0:0)

C₃₀H₅₀NO₇P

568.341 3

568.339 8

12.29

1.036 1

2.64

↓^**

↑^##

LysoPC(22:5(4Z, 7Z, 10Z, 13Z, 16Z)/0:0)

C₃₀H₅₂NO₇P

570.357 3

570.355 4

12.67

1.208 3

+/-

3.33

↓^**

↑^##

LysoPC(20:5(5Z, 8Z, 11Z, 14Z, 17Z)/0:0)

C₂₈H₄₈NO₇P

586.316 9

586.315 0

12.03

1.431 4

3.24

↓^**

↑^##

No.	KEGG pathway	Total	Hit	Impact	P value	Hit compound
1	Phenylalanine, tyrosine and tryptophan biosynthesis	4	2	1.000 0	0.001 8	L-Tyrosine; L-phenylalanine
2	Linoleic acid metabolism	5	2	1.000 0	0.003 0	Linoleic acid; PC
3	Taurine and hypotaurine metabolism	8	1	0.428 6	0.136 0	Taurine
4	Phenylalanine metabolism	10	2	0.357 1	0.013 0	L-Tyrosine; L-phenylalanine
5	Glycerophospholipid metabolism	36	3	0.216 3	0.025 3	PC; LysoPC; PE
6	Tyrosine metabolism	42	3	0.164 4	0.041 4	Vanylglycol; L-tyrosine; fumaric acid
7	Starch and sucrose metabolism	18	1	0.134 9	0.281 1	Glucose 1-phosphate
8	Steroid hormone biosynthesis	85	4	0.128 6	0.063 0	Androstenedione; cholesterol sulfate; androsterone; 17alpha, 21-dihydroxypregnenolone

No.

KEGG pathway

Total

Hit

Impact

P value

Hit compound

Phenylalanine, tyrosine and tryptophan biosynthesis

1.000 0

0.001 8

L-Tyrosine; L-phenylalanine

Linoleic acid metabolism

1.000 0

0.003 0

Linoleic acid; PC

Taurine and hypotaurine metabolism

0.428 6

0.136 0

Taurine

Phenylalanine metabolism

0.357 1

0.013 0

L-Tyrosine; L-phenylalanine

Glycerophospholipid metabolism

0.216 3

0.025 3

PC; LysoPC; PE

Tyrosine metabolism

0.164 4

0.041 4

Vanylglycol; L-tyrosine; fumaric acid

Starch and sucrose metabolism

0.134 9

0.281 1

Glucose 1-phosphate

Steroid hormone biosynthesis

0.128 6

0.063 0

Androstenedione; cholesterol sulfate; androsterone; 17alpha, 21-dihydroxypregnenolone

No.	KEGG pathway	Total	Hit	Impact	P value	Hit compound
1	Linoleic acid metabolism	5	2	1.000 0	0.003 3	Linoleic acid; 12(13)-EpOME
2	Ubiquinone and other terpenoid-quinone biosynthesis	9	1	1.000 0	0.156 7	4-Hydroxyphenylpyruvic acid
3	Thiamine metabolism	7	1	0.666 7	0.124 1	Thiamine pyrophosphate
4	Glyoxylate and dicarboxylate metabolism	32	3	0.386 3	0.020 3	Glyoxylic acid; glyceric acid; citric acid
5	Glycerophospholipid metabolism	36	3	0.261 7	0.027 8	PE; LysoPA; LysoPC
6	TCA cycle	20	2	0.147 4	0.052 2	Citric acid; thiamine pyrophosphate
7	Tryptophan metabolism	41	2	0.131 8	0.177 4	Serotonin; 5-hydroxykynurenine
8	Pyrimidine metabolism	39	2	0.129 5	0.163 9	Orotidylic acid; thymidine
9	Arachidonic acid metabolism	36	2	0.111 2	0.144 2	Prostaglandin H3; 14-hydroxy-E4-neuroprostane
10	Glycerolipid metabolism	16	2	0.105 9	0.034 5	Glyceric acid; LysoPA

No.

KEGG pathway

Total

Hit

Impact

P value

Hit compound

Linoleic acid metabolism

1.000 0

0.003 3

Linoleic acid; 12(13)-EpOME

Ubiquinone and other terpenoid-quinone biosynthesis

1.000 0

0.156 7

4-Hydroxyphenylpyruvic acid

Thiamine metabolism

0.666 7

0.124 1

Thiamine pyrophosphate

Glyoxylate and dicarboxylate metabolism

0.386 3

0.020 3

Glyoxylic acid; glyceric acid; citric acid

Glycerophospholipid metabolism

0.261 7

0.027 8

PE; LysoPA; LysoPC

TCA cycle

0.147 4

0.052 2

Citric acid; thiamine pyrophosphate

Tryptophan metabolism

0.131 8

0.177 4

Serotonin; 5-hydroxykynurenine

Pyrimidine metabolism

0.129 5

0.163 9

Orotidylic acid; thymidine

Arachidonic acid metabolism

0.111 2

0.144 2

Prostaglandin H3; 14-hydroxy-E4-neuroprostane

Glycerolipid metabolism

0.105 9

0.034 5

Glyceric acid; LysoPA