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Gene		Primer sequence (5′-3′)	Amplification length/bp
Actin	Forward:	CTGGCACCTAGCACAATGAA	123
Reverse:	CTGCTTGCTGATCCACATCT
VEGFR2	Forward:	GACTTTCAGGAGAGCACACG	89
Reverse:	CCATCGGAAGCCTCTGTCTT

Gene

Primer sequence (5′-3′)

Amplification
length/bp

Actin

Forward:

CTGGCACCTAGCACAATGAA

123

Reverse:

CTGCTTGCTGATCCACATCT

VEGFR2

Forward:

GACTTTCAGGAGAGCACACG

Reverse:

CCATCGGAAGCCTCTGTCTT

Gene		Primer sequence (5′-3′)	Amplification length/bp
Actin	Forward:	CTGGCACCTAGCACAATGAA	123
Reverse:	CTGCTTGCTGATCCACATCT
VEGFR2	Forward:	GACTTTCAGGAGAGCACACG	89
Reverse:	CCATCGGAAGCCTCTGTCTT

Gene

Primer sequence (5′-3′)

Amplification
length/bp

Actin

Forward:

CTGGCACCTAGCACAATGAA

123

Reverse:

CTGCTTGCTGATCCACATCT

VEGFR2

Forward:

GACTTTCAGGAGAGCACACG

Reverse:

CCATCGGAAGCCTCTGTCTT

Source	Component	Formula	Mode	m/z	MS/MS
HL	Magnoflorine	C₂₀H₂₃NO₄	[M+H]⁺	342.170 0	342.170 2	297.112 2, 282.088 9, 265.086 0
HL	Coptisine	C₁₉H₁₃NO₄	[M+H]⁺	320.091 7	320.091 9	305.068 8, 292.096 8, 262.086 0, 249.078 4
HL	Epiberberine	C₂₀H₁₇NO₄	[M+H]⁺	336.123 0	336.122 9	320.091 8, 308.091 1, 292.096 7
HL	Jatrorrhizine	C₂₀H₂₀NO₄	[M]⁺	338.139 2	338.138 8	323.114 7, 294.112 3
HL	Berberine	C₂₀H₁₇NO₄	[M+H]⁺	336.123 0	336.123 0	320.091 7, 292.096 7
HL	Columbamine	C₂₀H₁₉NO₄	[M+H]⁺	338.138 7	338.138 7	322.107 5, 294.112 3
HL	Thalmineline	C₁₁H₁₃NO₃	[M+H]⁺	208.096 8	208.097 0	165.091 2, 150.067 7
HL	Berberrubine	C₁₉H₁₆NO₄	[M+H]⁺	322.107 9	322.107 5	279.089 1
HL	Noroxyhydrastinine	C₁₀H₉NO₃	[M+H]⁺	192.065 5	192.065 7	149.059 9
HL	Oxyberberine	C₂₀H₁₇NO₅	[M+H]⁺	352.117 9	352.117 9	337.093 6, 308.091 6
HL	Palmatine	C₂₁H₂₂NO₄	[M]⁺	352.154 9	352.157 9	337.093 6, 308.091 6
HL	Worenine	C₂₀H₁₅NO₄	[M+H]⁺	335.115 2	335.077 9	291.086 1
HL	Chlorogenic acid	C₁₆H₁₈O₉	[M-H]^-	353.087 8	353.087 8	191.056 4, 179.039 1, 161.024 8
HL	Lariciresinol 4-O-glucoside	C₂₆H₃₄O₁₁	[M-H]^-	521.202 8	521.203 5	329.103 9
YHS	Taxilamine	C₂₀H₁₉NO₆	[M+H]⁺	370.128 5	370.129 6	190.086 3
YHS	Palmatine	C₂₁H₂₂NO₄	[M]⁺	352.154 3	352.117 8	294.076 2
YHS	D-Lirioferine	C₂₀H₂₃NO₄	[M+H]⁺	341.162 2	342.169 0	192.102 1
YHS	Tetrahydrocoptisine	C₁₉H₁₇NO₄	[M+H]⁺	324.123 0	324.123 2	176.070 7, 119.049 0
YHS	Bicuculline	C₂₀H₁₇NO₆	[M+H]⁺	368.112 8	368.112 3	353.125 9, 338.021 0
YHS	Jatrorrhizine	C₂₀H₂₀NO₄	[M+H]⁺	338.138 7	338.138 7	279.088 9, 265.072 9
YHS	Tetrahydropalmatine	C₂₁H₂₅NO₄	[M+H]⁺	356.185 6	356.185 8	356.185 8, 192.102 1
YHS	N-De-Me-N-Methylsecoglaucine	C₂₁H₂₅NO₄	[M+H]⁺	356.185 6	356.185 9	178.086 5, 151.075 6
YHS	Yuanhunine	C₂₁H₂₅NO₄	[M+H]⁺	356.185 6	356.185 6	165.091 3
YHS	D-Glaucine	C₂₁H₂₅NO₄	[M+H]⁺	356.185 6	356.185 7	279.101 6, 251.106 6, 220.883 0
YHS	Isocorynoline	C₂₁H₂₅NO₄	[M+H]⁺	355.177 8	355.177 3	340.141 9, 192.102 1
YHS	N-Methyltetrahydrocolumbamine	C₂₁H₂₁NO₄	[M+H]⁺	352.154 3	352.157 0	190.086 4
YHS	Canadine	C₂₀H₂₁NO₄	[M+H]⁺	340.154 3	340.154 5	176.708 0, 149.059 8
YHS	Corydaline	C₂₂H₂₇NO₄	[M+H]⁺	370.201 3	370.201 7	192.102 1, 165.091 3
YHS	Dehydrocavidine	C₂₁H₂₂NO₄	[M+H]⁺	353.162 2	353.161 7	190.086 3
YHS	Berberine	C₂₀H₁₈NO₄	[M]⁺	336.123 0	336.123 1	320.091 9, 278.080 9
YHS	Dehydrocorydaline	C₂₂H₂₄NO₄	[M]⁺	366.169 9	366.170 3	350.138 8, 308.128 1

Source

Component

Formula

Mode

m/z

MS/MS

Calculated
mass

Measured
mass

Magnoflorine

C₂₀H₂₃NO₄

[M+H]⁺

342.170 0

342.170 2

297.112 2, 282.088 9, 265.086 0

Coptisine

C₁₉H₁₃NO₄

[M+H]⁺

320.091 7

320.091 9

305.068 8, 292.096 8, 262.086 0, 249.078 4

Epiberberine

C₂₀H₁₇NO₄

[M+H]⁺

336.123 0

336.122 9

320.091 8, 308.091 1, 292.096 7

Jatrorrhizine

C₂₀H₂₀NO₄

[M]⁺

338.139 2

338.138 8

323.114 7, 294.112 3

Berberine

C₂₀H₁₇NO₄

[M+H]⁺

336.123 0

320.091 7, 292.096 7

Columbamine

C₂₀H₁₉NO₄

[M+H]⁺

338.138 7

322.107 5, 294.112 3

Thalmineline

C₁₁H₁₃NO₃

[M+H]⁺

208.096 8

208.097 0

165.091 2, 150.067 7

Berberrubine

C₁₉H₁₆NO₄

[M+H]⁺

322.107 9

322.107 5

279.089 1

Noroxyhydrastinine

C₁₀H₉NO₃

[M+H]⁺

192.065 5

192.065 7

149.059 9

Oxyberberine

C₂₀H₁₇NO₅

[M+H]⁺

352.117 9

337.093 6, 308.091 6

Palmatine

C₂₁H₂₂NO₄

[M]⁺

352.154 9

352.157 9

337.093 6, 308.091 6

Worenine

C₂₀H₁₅NO₄

[M+H]⁺

335.115 2

335.077 9

291.086 1

Chlorogenic acid

C₁₆H₁₈O₉

[M-H]^-

353.087 8

191.056 4, 179.039 1, 161.024 8

Lariciresinol 4-O-glucoside

C₂₆H₃₄O₁₁

[M-H]^-

521.202 8

521.203 5

329.103 9

YHS

Taxilamine

C₂₀H₁₉NO₆

[M+H]⁺

370.128 5

370.129 6

190.086 3

YHS

Palmatine

C₂₁H₂₂NO₄

[M]⁺

352.154 3

352.117 8

294.076 2

YHS

D-Lirioferine

C₂₀H₂₃NO₄

[M+H]⁺

341.162 2

342.169 0

192.102 1

YHS

Tetrahydrocoptisine

C₁₉H₁₇NO₄

[M+H]⁺

324.123 0

324.123 2

176.070 7, 119.049 0

YHS

Bicuculline

C₂₀H₁₇NO₆

[M+H]⁺

368.112 8

368.112 3

353.125 9, 338.021 0

YHS

Jatrorrhizine

C₂₀H₂₀NO₄

[M+H]⁺

338.138 7

279.088 9, 265.072 9

YHS

Tetrahydropalmatine

C₂₁H₂₅NO₄

[M+H]⁺

356.185 6

356.185 8

356.185 8, 192.102 1

YHS

N-De-Me-N-Methylsecoglaucine

C₂₁H₂₅NO₄

[M+H]⁺

356.185 6

356.185 9

178.086 5, 151.075 6

YHS

Yuanhunine

C₂₁H₂₅NO₄

[M+H]⁺

356.185 6

165.091 3

YHS

D-Glaucine

C₂₁H₂₅NO₄

[M+H]⁺

356.185 6

356.185 7

279.101 6, 251.106 6, 220.883 0

YHS

Isocorynoline

C₂₁H₂₅NO₄

[M+H]⁺

355.177 8

355.177 3

340.141 9, 192.102 1

YHS

N-Methyltetrahydrocolumbamine

C₂₁H₂₁NO₄

[M+H]⁺

352.154 3

352.157 0

190.086 4

YHS

Canadine

C₂₀H₂₁NO₄

[M+H]⁺

340.154 3

340.154 5

176.708 0, 149.059 8

YHS

Corydaline

C₂₂H₂₇NO₄

[M+H]⁺

370.201 3

370.201 7

192.102 1, 165.091 3

YHS

Dehydrocavidine

C₂₁H₂₂NO₄

[M+H]⁺

353.162 2

353.161 7

190.086 3

YHS

Berberine

C₂₀H₁₈NO₄

[M]⁺

336.123 0

336.123 1

320.091 9, 278.080 9

YHS

Dehydrocorydaline

C₂₂H₂₄NO₄

[M]⁺

366.169 9

366.170 3

350.138 8, 308.128 1

Source	Component	Formula	Mode	m/z	MS/MS
HL	Magnoflorine	C₂₀H₂₃NO₄	[M+H]⁺	342.170 0	342.170 2	297.112 2, 282.088 9, 265.086 0
HL	Coptisine	C₁₉H₁₃NO₄	[M+H]⁺	320.091 7	320.091 9	305.068 8, 292.096 8, 262.086 0, 249.078 4
HL	Epiberberine	C₂₀H₁₇NO₄	[M+H]⁺	336.123 0	336.122 9	320.091 8, 308.091 1, 292.096 7
HL	Jatrorrhizine	C₂₀H₂₀NO₄	[M]⁺	338.139 2	338.138 8	323.114 7, 294.112 3
HL	Berberine	C₂₀H₁₇NO₄	[M+H]⁺	336.123 0	336.123 0	320.091 7, 292.096 7
HL	Columbamine	C₂₀H₁₉NO₄	[M+H]⁺	338.138 7	338.138 7	322.107 5, 294.112 3
HL	Thalmineline	C₁₁H₁₃NO₃	[M+H]⁺	208.096 8	208.097 0	165.091 2, 150.067 7
HL	Berberrubine	C₁₉H₁₆NO₄	[M+H]⁺	322.107 9	322.107 5	279.089 1
HL	Noroxyhydrastinine	C₁₀H₉NO₃	[M+H]⁺	192.065 5	192.065 7	149.059 9
HL	Oxyberberine	C₂₀H₁₇NO₅	[M+H]⁺	352.117 9	352.117 9	337.093 6, 308.091 6
HL	Palmatine	C₂₁H₂₂NO₄	[M]⁺	352.154 9	352.157 9	337.093 6, 308.091 6
HL	Worenine	C₂₀H₁₅NO₄	[M+H]⁺	335.115 2	335.077 9	291.086 1
HL	Chlorogenic acid	C₁₆H₁₈O₉	[M-H]^-	353.087 8	353.087 8	191.056 4, 179.039 1, 161.024 8
HL	Lariciresinol 4-O-glucoside	C₂₆H₃₄O₁₁	[M-H]^-	521.202 8	521.203 5	329.103 9
YHS	Taxilamine	C₂₀H₁₉NO₆	[M+H]⁺	370.128 5	370.129 6	190.086 3
YHS	Palmatine	C₂₁H₂₂NO₄	[M]⁺	352.154 3	352.117 8	294.076 2
YHS	D-Lirioferine	C₂₀H₂₃NO₄	[M+H]⁺	341.162 2	342.169 0	192.102 1
YHS	Tetrahydrocoptisine	C₁₉H₁₇NO₄	[M+H]⁺	324.123 0	324.123 2	176.070 7, 119.049 0
YHS	Bicuculline	C₂₀H₁₇NO₆	[M+H]⁺	368.112 8	368.112 3	353.125 9, 338.021 0
YHS	Jatrorrhizine	C₂₀H₂₀NO₄	[M+H]⁺	338.138 7	338.138 7	279.088 9, 265.072 9
YHS	Tetrahydropalmatine	C₂₁H₂₅NO₄	[M+H]⁺	356.185 6	356.185 8	356.185 8, 192.102 1
YHS	N-De-Me-N-Methylsecoglaucine	C₂₁H₂₅NO₄	[M+H]⁺	356.185 6	356.185 9	178.086 5, 151.075 6
YHS	Yuanhunine	C₂₁H₂₅NO₄	[M+H]⁺	356.185 6	356.185 6	165.091 3
YHS	D-Glaucine	C₂₁H₂₅NO₄	[M+H]⁺	356.185 6	356.185 7	279.101 6, 251.106 6, 220.883 0
YHS	Isocorynoline	C₂₁H₂₅NO₄	[M+H]⁺	355.177 8	355.177 3	340.141 9, 192.102 1
YHS	N-Methyltetrahydrocolumbamine	C₂₁H₂₁NO₄	[M+H]⁺	352.154 3	352.157 0	190.086 4
YHS	Canadine	C₂₀H₂₁NO₄	[M+H]⁺	340.154 3	340.154 5	176.708 0, 149.059 8
YHS	Corydaline	C₂₂H₂₇NO₄	[M+H]⁺	370.201 3	370.201 7	192.102 1, 165.091 3
YHS	Dehydrocavidine	C₂₁H₂₂NO₄	[M+H]⁺	353.162 2	353.161 7	190.086 3
YHS	Berberine	C₂₀H₁₈NO₄	[M]⁺	336.123 0	336.123 1	320.091 9, 278.080 9
YHS	Dehydrocorydaline	C₂₂H₂₄NO₄	[M]⁺	366.169 9	366.170 3	350.138 8, 308.128 1

Source

Component

Formula

Mode

m/z

MS/MS

Calculated
mass

Measured
mass

Magnoflorine

C₂₀H₂₃NO₄

[M+H]⁺

342.170 0

342.170 2

297.112 2, 282.088 9, 265.086 0

Coptisine

C₁₉H₁₃NO₄

[M+H]⁺

320.091 7

320.091 9

305.068 8, 292.096 8, 262.086 0, 249.078 4

Epiberberine

C₂₀H₁₇NO₄

[M+H]⁺

336.123 0

336.122 9

320.091 8, 308.091 1, 292.096 7

Jatrorrhizine

C₂₀H₂₀NO₄

[M]⁺

338.139 2

338.138 8

323.114 7, 294.112 3

Berberine

C₂₀H₁₇NO₄

[M+H]⁺

336.123 0

320.091 7, 292.096 7

Columbamine

C₂₀H₁₉NO₄

[M+H]⁺

338.138 7

322.107 5, 294.112 3

Thalmineline

C₁₁H₁₃NO₃

[M+H]⁺

208.096 8

208.097 0

165.091 2, 150.067 7

Berberrubine

C₁₉H₁₆NO₄

[M+H]⁺

322.107 9

322.107 5

279.089 1

Noroxyhydrastinine

C₁₀H₉NO₃

[M+H]⁺

192.065 5

192.065 7

149.059 9

Oxyberberine

C₂₀H₁₇NO₅

[M+H]⁺

352.117 9

337.093 6, 308.091 6

Palmatine

C₂₁H₂₂NO₄

[M]⁺

352.154 9

352.157 9

337.093 6, 308.091 6

Worenine

C₂₀H₁₅NO₄

[M+H]⁺

335.115 2

335.077 9

291.086 1

Chlorogenic acid

C₁₆H₁₈O₉

[M-H]^-

353.087 8

191.056 4, 179.039 1, 161.024 8

Lariciresinol 4-O-glucoside

C₂₆H₃₄O₁₁

[M-H]^-

521.202 8

521.203 5

329.103 9

YHS

Taxilamine

C₂₀H₁₉NO₆

[M+H]⁺

370.128 5

370.129 6

190.086 3

YHS

Palmatine

C₂₁H₂₂NO₄

[M]⁺

352.154 3

352.117 8

294.076 2

YHS

D-Lirioferine

C₂₀H₂₃NO₄

[M+H]⁺

341.162 2

342.169 0

192.102 1

YHS

Tetrahydrocoptisine

C₁₉H₁₇NO₄

[M+H]⁺

324.123 0

324.123 2

176.070 7, 119.049 0

YHS

Bicuculline

C₂₀H₁₇NO₆

[M+H]⁺

368.112 8

368.112 3

353.125 9, 338.021 0

YHS

Jatrorrhizine

C₂₀H₂₀NO₄

[M+H]⁺

338.138 7

279.088 9, 265.072 9

YHS

Tetrahydropalmatine

C₂₁H₂₅NO₄

[M+H]⁺

356.185 6

356.185 8

356.185 8, 192.102 1

YHS

N-De-Me-N-Methylsecoglaucine

C₂₁H₂₅NO₄

[M+H]⁺

356.185 6

356.185 9

178.086 5, 151.075 6

YHS

Yuanhunine

C₂₁H₂₅NO₄

[M+H]⁺

356.185 6

165.091 3

YHS

D-Glaucine

C₂₁H₂₅NO₄

[M+H]⁺

356.185 6

356.185 7

279.101 6, 251.106 6, 220.883 0

YHS

Isocorynoline

C₂₁H₂₅NO₄

[M+H]⁺

355.177 8

355.177 3

340.141 9, 192.102 1

YHS

N-Methyltetrahydrocolumbamine

C₂₁H₂₁NO₄

[M+H]⁺

352.154 3

352.157 0

190.086 4

YHS

Canadine

C₂₀H₂₁NO₄

[M+H]⁺

340.154 3

340.154 5

176.708 0, 149.059 8

YHS

Corydaline

C₂₂H₂₇NO₄

[M+H]⁺

370.201 3

370.201 7

192.102 1, 165.091 3

YHS

Dehydrocavidine

C₂₁H₂₂NO₄

[M+H]⁺

353.162 2

353.161 7

190.086 3

YHS

Berberine

C₂₀H₁₈NO₄

[M]⁺

336.123 0

336.123 1

320.091 9, 278.080 9

YHS

Dehydrocorydaline

C₂₂H₂₄NO₄

[M]⁺

366.169 9

366.170 3

350.138 8, 308.128 1

Component	Formula	Adduction	m/z	FC	P-value	VIP
Triethylamine N-oxide	C₆H₁₅NO	[M+H]⁺	118.087 0	2.05	0.000 789	4.77
Xymedon	C₈H₁₂N₂O₂	[M+H]⁺	169.047 8	2.89	0.000 674	5.34
2-(Diaminomethylideneamino)ethylsulfanylmethanimidamide	C₄H₁₁N₅S	[M+Na]⁺	184.066 9	3.80	0.000 107	2.70
Thiostatin	C₈H₁₇NO₂S	[M+H]⁺	192.123 5	2.81	0.000 004	5.46
Loxanast	C₁₄H₂₆O₂	[M+H]⁺	227.222 9	3.85	0.000 020	2.80
Heptyl ketone	C₁₅H₃₀O	[M+H]⁺	227.279 3	3.04	0.000 088	2.37
Dimethylmethoxy chromanol	C₁₂H₁₆O₃	[M+Na]⁺	231.084 4	5.27	0.000 005	1.67
2-(4-Methoxyphenyl)ethyl hydrogen sulfate	C₉H₁₂O₅S	[M+H]⁺	233.079 1	2.87	0.000 135	1.54
(8R, 9S, 13S, 14S)-3-Hydroxy-13-methyl-4, 6, 7, 8, 9, 11, 12, 14, 15, 16- decahydro-3H-cyclopenta[a]phenanthren-17-one	C₁₈H₂₄O₂	[M+H]⁺	273.167 6	2.32	0.000 157	1.07
(2S, 3R)-2-Amino-4-octadecene-3-ol	C₁₈H₃₇NO	[M+H]⁺	284.295 8	2.47	0.009 044	1.31
13-Azaprostanoic acid	C₁₉H₃₇NO₂	[M+H]⁺	312.326 7	2.48	0.003 354	1.06
Xylamidine	C₁₉H₂₄N₂O₂	[M+H]⁺	313.234 7	3.68	0.000 642	1.05
(1S, 2R, 3S, 7R, 10S, 13S, 14R)-1-Methyl-14-propan-2-yl-2-propyl-12-azapentacyclo[8.6.0.02, 13.03, 7.07, 12]hexadecane	C₂₂H₃₇N	[M+H]⁺	316.321 3	2.44	0.002 713	1.39
(3-(tert-Butoxyimino-methyl)-4-chloro-phenyl)-thiocarbamic acid, O-isopropyl ester	C₁₅H₂₁ClN₂O₂S	[M+H]⁺	329.156 2	2.61	0.000 038	1.09
N, N-Diisopropyl-N'-isoamyl-N'-diethylaminoethylurea	C₁₈H₃₉N₃O	[M+Na]⁺	336.290 1	4.01	0.001 945	1.12
(5alpha)-23-Methyl-4-aza-21-norchol-1-ene-3, 20-dione	C₂₃H₃₅NO₂	[M+H]⁺	358.244 1	0.37	0.000 853	2.44
(5Z, 8Z, 11Z, 14Z)-N-(4-Hydroxy-2-methylphenyl)-5, 8, 11, 14-eicosatetraenamide	C₂₇H₃₉NO₂	[M+Na]⁺	432.280 2	0.50	0.000 215	1.88
(2S, 3S, 5S, 8S, 9S, 10S, 13S, 14S, 17S)-17-Acetyl-2-(2, 2- dimethylmorpholino)-3-hydroxy-10, 13-dimethylhexadecahydro- 11H-cyclopenta[a]phenanthren-11-one	C₂₇H₄₃NO₄	[M+H]⁺	446.298 1	0.36	0.003 866	2.86
Mofarotene	C₂₉H₃₉NO₂	[M+Na]⁺	456.280 3	0.47	0.004 535	1.21
Z-LLNle-CHO	C₂₆H₄₁N₃O₅	[M+H]⁺	476.306 2	0.48	0.002 434	1.81
(8S, 9S, 10S, 11S, 13S, 14S, 17R)-11, 17-Dihydroxy-17-(2-hydroxyacetyl)- 10, 13-dimethyl-9-nonyl-1, 2, 6, 7, 8, 11, 12, 14, 15, 16-decahydrocyclopenta [a]phenanthren-3-one	C₃₀H₄₈O₅	[M+H]⁺	489.338 1	2.62	0.000 275	1.17
(1S, 2S, 6R, 15S, 16R)-5-(Cyclopropylmethyl)-16-(2-hydroxy-3, 3-dimethylbutan-2-yl)-15-methoxy-13-oxa-5-azahexacyclo [13.2.2.12, 8.01, 6.02, 14.012, 20]icosa-8(20), 9, 11-trien-11-ol	C₂₉H₄₁NO₄	[M+Na]⁺	490.323 7	0.31	0.001 417	2.82
(S)-N-((S)-1-Amino-3, 3-dimethyl-1-oxobutan-2-yl)-2-((S)-2- mercapto-4-(3, 4, 4-trimethyl-2, 5-dioxoimidazolidin-1-yl) butanamido)-N, 4-dimethylpentanamide	C₂₃H₄₁N₅O₅S	[M+H]⁺	500.306 7	0.43	0.000 222	1.39
Vicriviroc	C₂₈H₃₈F₃N₅O₂	[M+H]⁺	534.349 9	0.37	0.000 247	2.27
PC(18:1(9Z)-O(12, 13)/2:0)	C₂₈H₅₂NO₉P	[M+H]⁺	578.377 0	0.46	0.007 740	1.50
Quinoline, 6-(1-methyl-1-(methylsulfonyl)ethyl)-8-(3-((1E)-2-(3-methyl- 1, 2, 4-oxadiazol-5-yl)-2-(4-(methylsulfonyl)phenyl)ethenyl)phenyl)	C₃₁H₂₉N₃O₅S₂	[M+Na]⁺	610.182 4	8.92	0.007 600	1.61
Ethyl 5-[[[4-(3-methylsulfonylphenyl)phenyl]methyl-(2, 4, 6-trimethylphenyl)sulfonylamino]methyl]furan-2-carboxylate	C₃₁H₃₃NO₇S₂	[M+Na]⁺	618.135 0	2.68	0.000 182	1.03
1, 2-Dilauroyl-sn-glycero-3-phosphocholine	C₃₂H₆₄NO₈P	[M+H]⁺	622.401 7	0.42	0.000 477	1.26
PA(PGD1/8:0)	C₃₁H₅₅O₁₁P	[M+H]⁺	635.308 8	0.39	0.003 257	1.19
DG(LTE4/0:0/i-16:0)	C₄₂H₇₃NO₈S	[M+H]⁺	752.513 5	0.48	0.001 041	1.49
SM(d19:1/20:4(5Z, 7E, 11Z, 14Z)-OH(9))	C₄₄H₈₁N₂O₇P	[M+Na]⁺	803.541 7	0.16	0.000 140	1.65

Component

Formula

Adduction

m/z

P-value

VIP

Triethylamine N-oxide

C₆H₁₅NO

[M+H]⁺

118.087 0

2.05

0.000 789

4.77

Xymedon

C₈H₁₂N₂O₂

[M+H]⁺

169.047 8

2.89

0.000 674

5.34

2-(Diaminomethylideneamino)ethylsulfanylmethanimidamide

C₄H₁₁N₅S

[M+Na]⁺

184.066 9

3.80

0.000 107

2.70

Thiostatin

C₈H₁₇NO₂S

[M+H]⁺

192.123 5

2.81

0.000 004

5.46

Loxanast

C₁₄H₂₆O₂

[M+H]⁺

227.222 9

3.85

0.000 020

2.80

Heptyl ketone

C₁₅H₃₀O

[M+H]⁺

227.279 3

3.04

0.000 088

2.37

Dimethylmethoxy chromanol

C₁₂H₁₆O₃

[M+Na]⁺

231.084 4

5.27

0.000 005

1.67

2-(4-Methoxyphenyl)ethyl hydrogen sulfate

C₉H₁₂O₅S

[M+H]⁺

233.079 1

2.87

0.000 135

1.54

(8R, 9S, 13S, 14S)-3-Hydroxy-13-methyl-4, 6, 7, 8, 9, 11, 12, 14, 15, 16- decahydro-3H-cyclopenta[a]phenanthren-17-one

C₁₈H₂₄O₂

[M+H]⁺

273.167 6

2.32

0.000 157

1.07

(2S, 3R)-2-Amino-4-octadecene-3-ol

C₁₈H₃₇NO

[M+H]⁺

284.295 8

2.47

0.009 044

1.31

13-Azaprostanoic acid

C₁₉H₃₇NO₂

[M+H]⁺

312.326 7

2.48

0.003 354

1.06

Xylamidine

C₁₉H₂₄N₂O₂

[M+H]⁺

313.234 7

3.68

0.000 642

1.05

(1S, 2R, 3S, 7R, 10S, 13S, 14R)-1-Methyl-14-propan-2-yl-2-propyl-12-azapentacyclo[8.6.0.02, 13.03, 7.07, 12]hexadecane

C₂₂H₃₇N

[M+H]⁺

316.321 3

2.44

0.002 713

1.39

(3-(tert-Butoxyimino-methyl)-4-chloro-phenyl)-thiocarbamic acid, O-isopropyl ester

C₁₅H₂₁ClN₂O₂S

[M+H]⁺

329.156 2

2.61

0.000 038

1.09

N, N-Diisopropyl-N'-isoamyl-N'-diethylaminoethylurea

C₁₈H₃₉N₃O

[M+Na]⁺

336.290 1

4.01

0.001 945

1.12

(5alpha)-23-Methyl-4-aza-21-norchol-1-ene-3, 20-dione

C₂₃H₃₅NO₂

[M+H]⁺

358.244 1

0.37

0.000 853

2.44

(5Z, 8Z, 11Z, 14Z)-N-(4-Hydroxy-2-methylphenyl)-5, 8, 11, 14-eicosatetraenamide

C₂₇H₃₉NO₂

[M+Na]⁺

432.280 2

0.50

0.000 215

1.88

(2S, 3S, 5S, 8S, 9S, 10S, 13S, 14S, 17S)-17-Acetyl-2-(2, 2- dimethylmorpholino)-3-hydroxy-10, 13-dimethylhexadecahydro- 11H-cyclopenta[a]phenanthren-11-one

C₂₇H₄₃NO₄

[M+H]⁺

446.298 1

0.36

0.003 866

2.86

Mofarotene

C₂₉H₃₉NO₂

[M+Na]⁺

456.280 3

0.47

0.004 535

1.21

Z-LLNle-CHO

C₂₆H₄₁N₃O₅

[M+H]⁺

476.306 2

0.48

0.002 434

1.81

(8S, 9S, 10S, 11S, 13S, 14S, 17R)-11, 17-Dihydroxy-17-(2-hydroxyacetyl)- 10, 13-dimethyl-9-nonyl-1, 2, 6, 7, 8, 11, 12, 14, 15, 16-decahydrocyclopenta [a]phenanthren-3-one

C₃₀H₄₈O₅

[M+H]⁺

489.338 1

2.62

0.000 275

1.17

(1S, 2S, 6R, 15S, 16R)-5-(Cyclopropylmethyl)-16-(2-hydroxy-3, 3-dimethylbutan-2-yl)-15-methoxy-13-oxa-5-azahexacyclo [13.2.2.12, 8.01, 6.02, 14.012, 20]icosa-8(20), 9, 11-trien-11-ol

C₂₉H₄₁NO₄

[M+Na]⁺

490.323 7

0.31

0.001 417

2.82

(S)-N-((S)-1-Amino-3, 3-dimethyl-1-oxobutan-2-yl)-2-((S)-2- mercapto-4-(3, 4, 4-trimethyl-2, 5-dioxoimidazolidin-1-yl) butanamido)-N, 4-dimethylpentanamide

C₂₃H₄₁N₅O₅S

[M+H]⁺

500.306 7

0.43

0.000 222

1.39

Vicriviroc

C₂₈H₃₈F₃N₅O₂

[M+H]⁺

534.349 9

0.37

0.000 247

2.27

PC(18:1(9Z)-O(12, 13)/2:0)

C₂₈H₅₂NO₉P

[M+H]⁺

578.377 0

0.46

0.007 740

1.50

Quinoline, 6-(1-methyl-1-(methylsulfonyl)ethyl)-8-(3-((1E)-2-(3-methyl- 1, 2, 4-oxadiazol-5-yl)-2-(4-(methylsulfonyl)phenyl)ethenyl)phenyl)

C₃₁H₂₉N₃O₅S₂

[M+Na]⁺

610.182 4

8.92

0.007 600

1.61

Ethyl 5-[[[4-(3-methylsulfonylphenyl)phenyl]methyl-(2, 4, 6-trimethylphenyl)sulfonylamino]methyl]furan-2-carboxylate

C₃₁H₃₃NO₇S₂

[M+Na]⁺

618.135 0

2.68

0.000 182

1.03

1, 2-Dilauroyl-sn-glycero-3-phosphocholine

C₃₂H₆₄NO₈P

[M+H]⁺

622.401 7

0.42

0.000 477

1.26

PA(PGD1/8:0)

C₃₁H₅₅O₁₁P

[M+H]⁺

635.308 8

0.39

0.003 257

1.19

DG(LTE4/0:0/i-16:0)

C₄₂H₇₃NO₈S

[M+H]⁺

752.513 5

0.48

0.001 041

1.49

SM(d19:1/20:4(5Z, 7E, 11Z, 14Z)-OH(9))

C₄₄H₈₁N₂O₇P

[M+Na]⁺

803.541 7

0.16

0.000 140

1.65

Component	Formula	Adduction	m/z	FC	P-value	VIP
Triethylamine N-oxide	C₆H₁₅NO	[M+H]⁺	118.087 0	2.05	0.000 789	4.77
Xymedon	C₈H₁₂N₂O₂	[M+H]⁺	169.047 8	2.89	0.000 674	5.34
2-(Diaminomethylideneamino)ethylsulfanylmethanimidamide	C₄H₁₁N₅S	[M+Na]⁺	184.066 9	3.80	0.000 107	2.70
Thiostatin	C₈H₁₇NO₂S	[M+H]⁺	192.123 5	2.81	0.000 004	5.46
Loxanast	C₁₄H₂₆O₂	[M+H]⁺	227.222 9	3.85	0.000 020	2.80
Heptyl ketone	C₁₅H₃₀O	[M+H]⁺	227.279 3	3.04	0.000 088	2.37
Dimethylmethoxy chromanol	C₁₂H₁₆O₃	[M+Na]⁺	231.084 4	5.27	0.000 005	1.67
2-(4-Methoxyphenyl)ethyl hydrogen sulfate	C₉H₁₂O₅S	[M+H]⁺	233.079 1	2.87	0.000 135	1.54
(8R, 9S, 13S, 14S)-3-Hydroxy-13-methyl-4, 6, 7, 8, 9, 11, 12, 14, 15, 16- decahydro-3H-cyclopenta[a]phenanthren-17-one	C₁₈H₂₄O₂	[M+H]⁺	273.167 6	2.32	0.000 157	1.07
(2S, 3R)-2-Amino-4-octadecene-3-ol	C₁₈H₃₇NO	[M+H]⁺	284.295 8	2.47	0.009 044	1.31
13-Azaprostanoic acid	C₁₉H₃₇NO₂	[M+H]⁺	312.326 7	2.48	0.003 354	1.06
Xylamidine	C₁₉H₂₄N₂O₂	[M+H]⁺	313.234 7	3.68	0.000 642	1.05
(1S, 2R, 3S, 7R, 10S, 13S, 14R)-1-Methyl-14-propan-2-yl-2-propyl-12-azapentacyclo[8.6.0.02, 13.03, 7.07, 12]hexadecane	C₂₂H₃₇N	[M+H]⁺	316.321 3	2.44	0.002 713	1.39
(3-(tert-Butoxyimino-methyl)-4-chloro-phenyl)-thiocarbamic acid, O-isopropyl ester	C₁₅H₂₁ClN₂O₂S	[M+H]⁺	329.156 2	2.61	0.000 038	1.09
N, N-Diisopropyl-N'-isoamyl-N'-diethylaminoethylurea	C₁₈H₃₉N₃O	[M+Na]⁺	336.290 1	4.01	0.001 945	1.12
(5alpha)-23-Methyl-4-aza-21-norchol-1-ene-3, 20-dione	C₂₃H₃₅NO₂	[M+H]⁺	358.244 1	0.37	0.000 853	2.44
(5Z, 8Z, 11Z, 14Z)-N-(4-Hydroxy-2-methylphenyl)-5, 8, 11, 14-eicosatetraenamide	C₂₇H₃₉NO₂	[M+Na]⁺	432.280 2	0.50	0.000 215	1.88
(2S, 3S, 5S, 8S, 9S, 10S, 13S, 14S, 17S)-17-Acetyl-2-(2, 2- dimethylmorpholino)-3-hydroxy-10, 13-dimethylhexadecahydro- 11H-cyclopenta[a]phenanthren-11-one	C₂₇H₄₃NO₄	[M+H]⁺	446.298 1	0.36	0.003 866	2.86
Mofarotene	C₂₉H₃₉NO₂	[M+Na]⁺	456.280 3	0.47	0.004 535	1.21
Z-LLNle-CHO	C₂₆H₄₁N₃O₅	[M+H]⁺	476.306 2	0.48	0.002 434	1.81
(8S, 9S, 10S, 11S, 13S, 14S, 17R)-11, 17-Dihydroxy-17-(2-hydroxyacetyl)- 10, 13-dimethyl-9-nonyl-1, 2, 6, 7, 8, 11, 12, 14, 15, 16-decahydrocyclopenta [a]phenanthren-3-one	C₃₀H₄₈O₅	[M+H]⁺	489.338 1	2.62	0.000 275	1.17
(1S, 2S, 6R, 15S, 16R)-5-(Cyclopropylmethyl)-16-(2-hydroxy-3, 3-dimethylbutan-2-yl)-15-methoxy-13-oxa-5-azahexacyclo [13.2.2.12, 8.01, 6.02, 14.012, 20]icosa-8(20), 9, 11-trien-11-ol	C₂₉H₄₁NO₄	[M+Na]⁺	490.323 7	0.31	0.001 417	2.82
(S)-N-((S)-1-Amino-3, 3-dimethyl-1-oxobutan-2-yl)-2-((S)-2- mercapto-4-(3, 4, 4-trimethyl-2, 5-dioxoimidazolidin-1-yl) butanamido)-N, 4-dimethylpentanamide	C₂₃H₄₁N₅O₅S	[M+H]⁺	500.306 7	0.43	0.000 222	1.39
Vicriviroc	C₂₈H₃₈F₃N₅O₂	[M+H]⁺	534.349 9	0.37	0.000 247	2.27
PC(18:1(9Z)-O(12, 13)/2:0)	C₂₈H₅₂NO₉P	[M+H]⁺	578.377 0	0.46	0.007 740	1.50
Quinoline, 6-(1-methyl-1-(methylsulfonyl)ethyl)-8-(3-((1E)-2-(3-methyl- 1, 2, 4-oxadiazol-5-yl)-2-(4-(methylsulfonyl)phenyl)ethenyl)phenyl)	C₃₁H₂₉N₃O₅S₂	[M+Na]⁺	610.182 4	8.92	0.007 600	1.61
Ethyl 5-[[[4-(3-methylsulfonylphenyl)phenyl]methyl-(2, 4, 6-trimethylphenyl)sulfonylamino]methyl]furan-2-carboxylate	C₃₁H₃₃NO₇S₂	[M+Na]⁺	618.135 0	2.68	0.000 182	1.03
1, 2-Dilauroyl-sn-glycero-3-phosphocholine	C₃₂H₆₄NO₈P	[M+H]⁺	622.401 7	0.42	0.000 477	1.26
PA(PGD1/8:0)	C₃₁H₅₅O₁₁P	[M+H]⁺	635.308 8	0.39	0.003 257	1.19
DG(LTE4/0:0/i-16:0)	C₄₂H₇₃NO₈S	[M+H]⁺	752.513 5	0.48	0.001 041	1.49
SM(d19:1/20:4(5Z, 7E, 11Z, 14Z)-OH(9))	C₄₄H₈₁N₂O₇P	[M+Na]⁺	803.541 7	0.16	0.000 140	1.65

Component

Formula

Adduction

m/z

P-value

VIP

Triethylamine N-oxide

C₆H₁₅NO

[M+H]⁺

118.087 0

2.05

0.000 789

4.77

Xymedon

C₈H₁₂N₂O₂

[M+H]⁺

169.047 8

2.89

0.000 674

5.34

2-(Diaminomethylideneamino)ethylsulfanylmethanimidamide

C₄H₁₁N₅S

[M+Na]⁺

184.066 9

3.80

0.000 107

2.70

Thiostatin

C₈H₁₇NO₂S

[M+H]⁺

192.123 5

2.81

0.000 004

5.46

Loxanast

C₁₄H₂₆O₂

[M+H]⁺

227.222 9

3.85

0.000 020

2.80

Heptyl ketone

C₁₅H₃₀O

[M+H]⁺

227.279 3

3.04

0.000 088

2.37

Dimethylmethoxy chromanol

C₁₂H₁₆O₃

[M+Na]⁺

231.084 4

5.27

0.000 005

1.67

2-(4-Methoxyphenyl)ethyl hydrogen sulfate

C₉H₁₂O₅S

[M+H]⁺

233.079 1

2.87

0.000 135

1.54

(8R, 9S, 13S, 14S)-3-Hydroxy-13-methyl-4, 6, 7, 8, 9, 11, 12, 14, 15, 16- decahydro-3H-cyclopenta[a]phenanthren-17-one

C₁₈H₂₄O₂

[M+H]⁺

273.167 6

2.32

0.000 157

1.07

(2S, 3R)-2-Amino-4-octadecene-3-ol

C₁₈H₃₇NO

[M+H]⁺

284.295 8

2.47

0.009 044

1.31

13-Azaprostanoic acid

C₁₉H₃₇NO₂

[M+H]⁺

312.326 7

2.48

0.003 354

1.06

Xylamidine

C₁₉H₂₄N₂O₂

[M+H]⁺

313.234 7

3.68

0.000 642

1.05

(1S, 2R, 3S, 7R, 10S, 13S, 14R)-1-Methyl-14-propan-2-yl-2-propyl-12-azapentacyclo[8.6.0.02, 13.03, 7.07, 12]hexadecane

C₂₂H₃₇N

[M+H]⁺

316.321 3

2.44

0.002 713

1.39

(3-(tert-Butoxyimino-methyl)-4-chloro-phenyl)-thiocarbamic acid, O-isopropyl ester

C₁₅H₂₁ClN₂O₂S

[M+H]⁺

329.156 2

2.61

0.000 038

1.09

N, N-Diisopropyl-N'-isoamyl-N'-diethylaminoethylurea

C₁₈H₃₉N₃O

[M+Na]⁺

336.290 1

4.01

0.001 945

1.12

(5alpha)-23-Methyl-4-aza-21-norchol-1-ene-3, 20-dione

C₂₃H₃₅NO₂

[M+H]⁺

358.244 1

0.37

0.000 853

2.44

(5Z, 8Z, 11Z, 14Z)-N-(4-Hydroxy-2-methylphenyl)-5, 8, 11, 14-eicosatetraenamide

C₂₇H₃₉NO₂

[M+Na]⁺

432.280 2

0.50

0.000 215

1.88

(2S, 3S, 5S, 8S, 9S, 10S, 13S, 14S, 17S)-17-Acetyl-2-(2, 2- dimethylmorpholino)-3-hydroxy-10, 13-dimethylhexadecahydro- 11H-cyclopenta[a]phenanthren-11-one

C₂₇H₄₃NO₄

[M+H]⁺

446.298 1

0.36

0.003 866

2.86

Mofarotene

C₂₉H₃₉NO₂

[M+Na]⁺

456.280 3

0.47

0.004 535

1.21

Z-LLNle-CHO

C₂₆H₄₁N₃O₅

[M+H]⁺

476.306 2

0.48

0.002 434

1.81

(8S, 9S, 10S, 11S, 13S, 14S, 17R)-11, 17-Dihydroxy-17-(2-hydroxyacetyl)- 10, 13-dimethyl-9-nonyl-1, 2, 6, 7, 8, 11, 12, 14, 15, 16-decahydrocyclopenta [a]phenanthren-3-one

C₃₀H₄₈O₅

[M+H]⁺

489.338 1

2.62

0.000 275

1.17

(1S, 2S, 6R, 15S, 16R)-5-(Cyclopropylmethyl)-16-(2-hydroxy-3, 3-dimethylbutan-2-yl)-15-methoxy-13-oxa-5-azahexacyclo [13.2.2.12, 8.01, 6.02, 14.012, 20]icosa-8(20), 9, 11-trien-11-ol

C₂₉H₄₁NO₄

[M+Na]⁺

490.323 7

0.31

0.001 417

2.82

(S)-N-((S)-1-Amino-3, 3-dimethyl-1-oxobutan-2-yl)-2-((S)-2- mercapto-4-(3, 4, 4-trimethyl-2, 5-dioxoimidazolidin-1-yl) butanamido)-N, 4-dimethylpentanamide

C₂₃H₄₁N₅O₅S

[M+H]⁺

500.306 7

0.43

0.000 222

1.39

Vicriviroc

C₂₈H₃₈F₃N₅O₂

[M+H]⁺

534.349 9

0.37

0.000 247

2.27

PC(18:1(9Z)-O(12, 13)/2:0)

C₂₈H₅₂NO₉P

[M+H]⁺

578.377 0

0.46

0.007 740

1.50

Quinoline, 6-(1-methyl-1-(methylsulfonyl)ethyl)-8-(3-((1E)-2-(3-methyl- 1, 2, 4-oxadiazol-5-yl)-2-(4-(methylsulfonyl)phenyl)ethenyl)phenyl)

C₃₁H₂₉N₃O₅S₂

[M+Na]⁺

610.182 4

8.92

0.007 600

1.61

Ethyl 5-[[[4-(3-methylsulfonylphenyl)phenyl]methyl-(2, 4, 6-trimethylphenyl)sulfonylamino]methyl]furan-2-carboxylate

C₃₁H₃₃NO₇S₂

[M+Na]⁺

618.135 0

2.68

0.000 182

1.03

1, 2-Dilauroyl-sn-glycero-3-phosphocholine

C₃₂H₆₄NO₈P

[M+H]⁺

622.401 7

0.42

0.000 477

1.26

PA(PGD1/8:0)

C₃₁H₅₅O₁₁P

[M+H]⁺

635.308 8

0.39

0.003 257

1.19

DG(LTE4/0:0/i-16:0)

C₄₂H₇₃NO₈S

[M+H]⁺

752.513 5

0.48

0.001 041

1.49

SM(d19:1/20:4(5Z, 7E, 11Z, 14Z)-OH(9))

C₄₄H₈₁N₂O₇P

[M+Na]⁺

803.541 7

0.16

0.000 140

1.65

Pathway	Total	Hits	Raw P	Impact
Glutamine and glutamic acid metabolism	6	3	0.132 91	0.222 05
Arginine and ornithine metabolism	4	2	0.221 73	0.000 00
Valine, leucine, and isoleucine biosynthesis	8	3	0.262 46	0.000 00
Arginine biosynthesis	13	4	0.335 35	0.089 74

Pathway

Total

Hits

Raw P

Impact

Glutamine and glutamic
acid metabolism

0.132 91

0.222 05

Arginine and ornithine
metabolism

0.221 73

0.000 00

Valine, leucine, and
isoleucine biosynthesis

0.262 46

0.000 00

Arginine biosynthesis

0.335 35

0.089 74

Pathway	Total	Hits	Raw P	Impact
Glutamine and glutamic acid metabolism	6	3	0.132 91	0.222 05
Arginine and ornithine metabolism	4	2	0.221 73	0.000 00
Valine, leucine, and isoleucine biosynthesis	8	3	0.262 46	0.000 00
Arginine biosynthesis	13	4	0.335 35	0.089 74

Pathway

Total

Hits

Raw P

Impact

Glutamine and glutamic
acid metabolism

0.132 91

0.222 05

Arginine and ornithine
metabolism

0.221 73

0.000 00

Valine, leucine, and
isoleucine biosynthesis

0.262 46

0.000 00

Arginine biosynthesis

0.335 35

0.089 74

Component	VEGFR2	JAK2	EGFR
Berberine	-9.94	-9.51	-8.2
Oxyberberine	-9.84	-10.15	-8.4
Tetrahydropalmatine	-8.26	-7.91	-7.4

Component

VEGFR2

JAK2

EGFR

Berberine

-9.94

-9.51

-8.2

Oxyberberine

-9.84

-10.15

-8.4

Tetrahydropalmatine

-8.26

-7.91

-7.4

Component	VEGFR2	JAK2	EGFR
Berberine	-9.94	-9.51	-8.2
Oxyberberine	-9.84	-10.15	-8.4
Tetrahydropalmatine	-8.26	-7.91	-7.4

Component

VEGFR2

JAK2

EGFR

Berberine

-9.94

-9.51

-8.2

Oxyberberine

-9.84

-10.15

-8.4

Tetrahydropalmatine

-8.26

-7.91

-7.4

原小檗碱型生物碱干预血管生成活性评价与代谢调控机制研究

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陈可点 ¹^,² , 崔鹤蓉 ¹^,^* , 雷海民 ¹^,^*

药学学报 | 研究论文 2025,60(11): 3507-3517

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药学学报 |研究论文 2025 , 60 (11) : 3507 -3517

原小檗碱型生物碱干预血管生成活性评价与代谢调控机制研究

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陈可点¹^,², 崔鹤蓉¹^,^*, 雷海民¹^,^*

作者信息

¹北京中医药大学中药学院, 北京 102488

²中国中医科学院中药研究所, 北京 100700

通讯作者:

崔鹤蓉, E-mail: herongcui@outlook.com

雷海民, E-mail: leihaimin@126.com

作者简介:

作者贡献:

陈可点负责实验开展、数据分析和文章撰写; 崔鹤蓉负责整体研究方案设计以及论文审阅指导; 雷海民负责研究经费支持和论文审阅指导。

Evaluation of angiogenic activity and metabolic regulation mechanism of protoberberine alkaloids

Ke-dian CHEN¹^,², He-rong CUI¹^,^*, Hai-min LEI¹^,^*

Affiliations

¹School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China

²Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China

出版时间: 2025-11-12 doi: 10.16438/j.0513-4870.2025-0387

文章导航

摘要

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原小檗碱型生物碱具有显著的抗肿瘤及血管生成调节活性, 但其干预血管生成的具体效应与代谢调控机制尚未系统阐明。本研究采用超高效液相色谱-四极杆/静电场轨道阱高分辨质谱(UHPLC-Q Exactive Orbitrap HRMS) 鉴定黄连与延胡索中的化学成分谱, 结合鹌鹑胚绒毛尿囊膜(quail chorioallantoic membrane, qCAM) 模型与人脐静脉内皮细胞(human umbilical vein endothelial cells, HUVEC) 增殖实验评价主要原小檗碱型生物碱类成分的抗血管生成效应, 并通过qPCR实验检测血管内皮细胞生长因子受体2 (vascular endothelial growth factor receptor 2, VEGFR2) mRNA水平。进一步通过解吸电喷雾电离-质谱成像(DESI-MSI) 技术对主要抗血管生成成分干预后引起的代谢轮廓改变进行分析, 通过结合网络药理学与分子对接技术对其与血管生成关键靶点互作进行表征并开展“构-效”分析。黄连中共鉴定得到13种生物碱类成分, 延胡索中鉴定得到17种生物碱类成分, 其中均以原小檗碱型生物碱为主, 其中, qCAM模型与HUVEC实验共同表明, 氧化小檗碱抗血管生成活性最为显著。代谢组学结果表明, 氧化小檗碱干预后主要引起D-谷氨酰胺、D-谷氨酸代谢等氨基酸合成与代谢通路改变代谢轮廓, 且引起脂质代谢抑制, 这种由能量与脂质代谢抑制的代谢轮廓异常可能通过影响细胞膜结构(磷脂酸、鞘磷脂、磷脂酰胆碱)、信号传导、氧化应激及炎症反应抑制血管生成。而C-8位置的氧化使氧化小檗碱在与EGFR、JAK2的互作中表现出更低的结合能以及更多的弱相互作用, 从而表现出相对小檗碱更加显著的抗血管生成活性。

关键词

原小檗碱型生物碱 / 氧化小檗碱 / 血管生成 / 鹌鹑胚绒毛尿囊膜模型 / 代谢组学

Abstract

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Protoberberine alkaloids exhibit significant antitumor and angiogenesis-regulating activities, yet their specific effects on angiogenesis intervention and metabolic regulatory mechanisms remain systematically elucidated. In this study, ultra-high performance liquid chromatography coupled with quadrupole/orbitrap high-resolution mass spectrometry (UHPLC-Q Exactive Orbitrap HRMS) was employed to identify the chemical composition profiles of Coptidis Rhizoma and Corydalis yanhusuo. The anti-angiogenic effects of the major protoberberine-type alkaloid components were evaluated using the quail chorioallantoic membrane (qCAM) model and human umbilical vein endothelial cell (HUVEC) proliferation assays, while vascular endothelial growth factor receptor 2 (VEGFR2) mRNA levels were detected via qPCR experiments. Further analysis was conducted using desorption electrospray ionization-mass spectrometry imaging (DESI-MSI) technology to examine the metabolic profile changes induced by the intervention of key anti-angiogenic components. The interaction between these components and critical angiogenesis targets was characterized by integrating network pharmacology with molecular docking technology, followed by a "structure-activity" analysis. A total of 13 alkaloid components were identified in Coptidis Rhizoma, and 17 alkaloid components were identified in Corydalis yanhusuo, with protoberberine-type alkaloids being the predominant type in both. Both the qCAM model and HUVEC experiments demonstrated that oxyberberine exhibited the most significant anti-angiogenic activity. These metabolic abnormalities characterized by suppressed energy and lipid metabolism, may inhibit angiogenesis by affecting cell membrane structure (phosphatidic acid, sphingomyelin, phosphatidylcholine), signal transduction (VEGFR2), oxidative stress, and inflammatory responses. Molecular docking and network pharmacology analyses demonstrated that C-8 oxidation enhances oxyberberine's binding affinity to EGFR and JAK2 through reduced binding energy and increased weak interactions, ultimately conferring superior anti-angiogenic efficacy compared to berberine. These findings systematically elucidate the structure-activity relationship and metabolic basis of protoberberine-type alkaloids in angiogenesis modulation, providing novel insights for anti-angiogenic drug development.

Key words

protoberberine alkoloid / oxyberberine / angiogenesis / quail chorioallantoic membrane / metabolomics

引用本文

陈可点, 崔鹤蓉, 雷海民. 原小檗碱型生物碱干预血管生成活性评价与代谢调控机制研究. 药学学报, 2025 , 60 (11) : 3507 -3517 . DOI: 10.16438/j.0513-4870.2025-0387

Ke-dian CHEN, He-rong CUI, Hai-min LEI. Evaluation of angiogenic activity and metabolic regulation mechanism of protoberberine alkaloids[J]. Acta Pharmaceutica Sinica, 2025 , 60 (11) : 3507 -3517 . DOI: 10.16438/j.0513-4870.2025-0387

正文

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血管生成(angiogenesis) 作为血管系统形成与重塑的核心过程^[1], 在胚胎发育、组织修复等生理活动中不可或缺, 但其异常激活或失衡亦是肿瘤生长转移、糖尿病视网膜病变、类风湿性关节炎及动脉粥样硬化等重大疾病的共同病理特征^{[2, 3]}。目前, 针对血管生成的调控已成为疾病治疗的重要靶点, 临床应用的抗血管生成药物(如贝伐珠单抗) 虽取得一定疗效, 但仍存在靶向性不足、耐药性及毒副作用显著等问题。因此, 从天然药物中挖掘具有多靶点、低毒性的血管生成调节剂, 成为当前研究的热点方向。

近年来, 天然产物因其结构多样性和多靶点作用特性, 在抗血管生成药物开发中展现出独特优势。其中, 原小檗碱型生物碱作为一类具有四氢异喹啉骨架的植物次生代谢产物, 因其显著的抗血管生成活性和丰富的药理作用而备受关注^[4-6]。然而, 目前关于原小檗碱型生物碱干预血管生成的构效关系仍缺乏系统性研究。不同结构修饰(如C-8、C-13位取代、季铵盐的N-甲基化、D环的饱和程度等) 如何影响其抗血管生成活性尚不明确。深入探究原小檗碱型生物碱的结构特征与抗血管生成活性之间的关联, 以及其对代谢的调节, 对于指导该类化合物的结构优化和临床合理应用具有重要意义。

因此, 本研究旨在系统探究原小檗碱型生物碱干预血管生成的构效关系与代谢机制, 首先通过超高效液相色谱-四极杆/静电场轨道阱高分辨质谱法(UHPLC-Q-Exactive Orbitrap HRMS) 系统鉴定含原小檗碱型生物碱代表性中药黄连和延胡索中的成分, 基于细胞实验与鹌鹑胚绒毛尿囊膜(qCAM) 模型筛选具有显著调控作用的关键成分, 进一步通过网络药理学、非靶向代谢组学及分子对接技术, 基于“成分-靶点-通路”多维关联分析, 阐明黄连干预血管生成的主要物质基础及其调控代谢的整合机制。系统考察原小檗碱型生物碱结构多样性与其抗血管生成活性的关联, 并阐明其代谢调节机制, 亦为开发基于天然产物的血管生成调控药物奠定理论基础, 同时推动中医药理论从经验医学向精准医学的范式转化。

材料与方法

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试剂与材料 小檗碱(CAS: 2086-83-1)、巴马汀(CAS: 10605-02-4)、氧化小檗碱(CAS: 549-21-3)、表小檗碱(CAS: 6873-09-2)、四氢黄连碱(CAS: 7461-02-1) 购自上海源叶生物科技有限公司。黄连碱(CAS: 3486-66-6) 和甲基黄连碱(CAS: 38763-29-0) 购自成都瑞芬思生物科技有限公司。TRIzol Reagent (货号: DP424) 购自北京天根生化科技; 荧光定量PCR检测试剂盒(货号: AOPR-1200) 购自美国Genecopies公司; DEPC (货号: V900882) 购自德国Vetec公司。内皮细胞培养基(ECM, 货号: 1001) 购自美国ScienCell公司; 特级胎牛血清(货号: 164210) 购自武汉普诺赛公司; 胰酶TRYPSIN 0.25% EDTA (货号: 25200056) 购自美国Invitrogen公司; 乙腈(CAS: 75-05-8) 购自美国Thermo Fisher公司; 无水乙醇(CAS: 64-17-5) 购自上海麦克林公司; 异丙醇(CAS: 67-63-0) 购自北京伊诺凯科技有限公司; 甲酸(CAS: 64-18-6) 购自瑞士Fluka公司。医用止血明胶海绵购自广州市快康医疗器械有限公司。

实验细胞与鹌鹑胚蛋 日本黄羽鹌鹑胚蛋购买于江苏省连云港市赣榆区金山鹌鹑养殖基地。人脐静脉内皮细胞(HUVEC) 购自中国医学科学院基础医学研究所北京协和医学院细胞资源中心。鹌鹑胚蛋培养、给药及取材参考课题组前期研究^{[7, 8]}。

药材提取与冻干 黄连药材称取10 g, 加8倍去离子水浸泡30 min后加热回流提取1 h后, 倒出药液, 加8倍水回流提取40 min, 合并两次提取的药液, 放入冻干机进行冻干, 72 h后取出待成分分析。

UHPLC-Q Exactive Orbitrap HRMS分析 Waters ACQUITY UPLC BEH C18色谱柱(150 mm × 2.1 mm, 1.7 µm), 流动相A为0.1%甲酸水, 流动相B为乙腈。色谱梯度洗脱条件设置如下: 0~30 min, 90% A。电喷雾离子源(ESI), 扫描范围m/z 100~1 500。柱温设置为25 ℃, 进样量设置为5 µL, 流速设置为0.30 mL·min^-1。紫外检测波长345 nm。数据采集范围设置为m/z 100~1 500。裂解电压(DP): 100 V, 碰撞能量(CE): 25 eV, 碰撞电压差(CES): 15 eV。通过对SciFinder、CNKI、Chemspider、PubChem等在线数据库汇总和文献的检索, 建立黄连化学成分数据库, 收录化合物的名称、化学结构、分子量和分子式信息。将以上信息导入Xcalibur软件平台数据库中, 对比文献资料分析不同类型化合物的分子量、保留时间与质谱裂解规律, 推测黄连所含化学成分。

定量聚合酶链式反应(quantitative polymerase chain reaction, qPCR) 实验参数参考课题组前期研究^{[8, 9]}, 用RNAzol法提取鹌鹑胚组织总RNA, 参照说明书进行qPCR反应体系配置, 检测VEGFR2 mRNA表达水平, Actin为内参基因, 2^–ΔΔCt法计算mRNA相对表达量。引物信息见表1。

DESI-MSI非靶向代谢组学 实验步骤参考课题组前期研究^[10]。通过解吸电喷雾电离源(DESI) 进行质谱相关分析。喷雾溶液采用90%甲醇, 流量为1.5 μL·min^-1, 电喷雾电压为5.0 kV。空间分辨率为50~200 μm。雾化器技术参数设置为100 pis。质量范围设定为m/z 80~1 000。MarkerLynx (Waters, MA, USA) 用于数据预处理。使用MetaboAlalyst 3.0获得数据过滤、缺失值计、倍数变化、数据归一化和结果数据矩阵。通过t检验(P < 0.05)、方差分析(P < 0.05) 和倍数变化值(> 1.5) 的结果过滤显著差异。具有显著变化的变量被确定为潜在的生物标志物, 用于使用在线METLIN数据库基于已识别的生物标志物进行初步鉴定。使用MetaboAnalyst 3.0进行通路分析。通过OPLS-DA模型, 以VIP > 1、|p(corr)| ≥ 0.58为标准筛选组间差异相关变量, 差异代谢物筛选则采用单因素方差分析(ANOVA)、t检验和变化倍数(fold change, FC > 2或 < 0.5) 和显著性(P < 0.05)。采用METLIN数据库(http://www.metlin.scipps.edu/), 基于变量的同位素丰度信息和精确分子量指认关键代谢物, 质量误差设置为≤ 10 ppm。

基于网络药理学的关键靶点筛选 从Pubchem数据库(https://pubchem.ncbi.nlm.nih.gov/) 下载成分结构SDF文件, 采用Chem3D软件进行能量最小化(MM2) 后导出为mol2文件格式, 上传至Pharmmapper数据库(http://www.lilab-ecust.cn/pharmmapper/), 筛选收集氧化小檗碱映射的靶点, 同时从ETCM 2.0数据库(http://www.tcmip.cn/ETCM2/front/) 下载氧化小檗碱靶点。采用Uniprot数据库(https://www.uniprot.org/) 将靶点的基因名称进行整理。靶点整合后上传蛋白质相互作用分析平台STRING (https://cn.string-db.org/) 构建靶点群蛋白相互作用网络(PPI network), 将得到的基因导入STRING数据库, 设置种属为“Homo sapiens”, 将分析得到的TSV文件导入Cytoscape3.10.0, 应用其中的cytoHubba插件通过拓扑网络算法给每个基因赋值, 基于最大集团中心性(MCC) 排序挖掘关键基因(hub gene), 选择得分前10位的基因作为氧化小檗碱的关键靶标。

分子对接 从PDB数据库(http://www.rcsb.org) 关键靶点的PBD文件, 包括EGFR、JAK2、KDR (VEGFR2), 采用Pymol软件删除配体后, 导入Autodock 4.2.6后进行去水、加氢、添加原子类型(Edit-Atoms-Assign AD4 type)、计算电荷(compute gasteiger), 后输出蛋白文件为PDBQT格式。对上述优化受体可能结合的区域通过POCASA 1.1网站(https://g6altair.sci.hokudai.ac.jp/g6/service/pocasa/Grids) 获得, 然后通过Grid功能预测结合部位。将优化后的配体与蛋白导入Autodock4.2.6后, genetic algorithm中Number of GA Runs设置为100, number of generations for picking worst individual设置为100后采用Lamarckin进行分子对接。对接完成后, 通过Discovery Studio和Pymol进行结果分析与可视化, 即最低结合能与配体与靶点之间的相互作用分析。

生化指标检测 按照试剂盒说明, 匀浆提取稀释(1∶10) 后鹌鹑胚样本, 离心(4 ℃, 13 000 r·min^-1, 10 min) 取上清, 采用微板法检测组织样本中ATP含量、Ca²⁺-Mg²⁺-ATP酶活性、Na⁺-K⁺-ATP酶活性、琥珀酸脱氢酶(SDH) 活力、丙酮酸(PA) 含量及一氧化氮(NO) 含量。ATP含量试剂盒(货号: A095-1-1)、PA测试盒(货号: A081)、SDH测试盒(货号: A022-1-1)、超微量Ca²⁺-Mg²⁺-ATP酶测试盒(货号: A070-3)、超微量Na⁺-K⁺-ATP酶测试盒(货号: A070-2)、NO测定试剂盒(货号: A013-2-1) 购自南京建成。

统计学分析 统计数据采用SPSS Statistics 20软件分析。实验数据均以平均数±标准差(

$ \stackrel{-}{x} $

± s) 表示。血管生成面积、qPCR及生化指标检测结果多组间比较采用(one-way ANOVA), P < 0.05表示差异有统计学意义。代谢组实验结果使用t检验进行显著性分析。

结果

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1　黄连与延胡索的化学成分分析

黄连中共分析得到14种成分(表2), 其中12种为生物碱成分, 其中, 主要以原小檗碱型生物碱为主, 包括小檗碱、表小檗碱、黄连碱、药根碱、巴马汀、氧化小檗碱等。延胡索化学成分定性分析得到17种生物碱成分(表2), 其中主要分为原小檗碱型生物碱, 包括叔胺类延胡索甲素、延胡索乙素等和季铵类小檗碱、巴马汀等, 其中, 延胡索中所含的特异性原小檗碱型生物碱延胡索乙素、延胡索甲素、脱氢紫堇碱、四氢黄连碱与黄连中所含的原小檗碱型生物碱具有骨架相同、结构相似的特点, 因此, 选择黄连中的原小檗碱型成分小檗碱、表小檗碱、巴马汀、黄连碱、甲基黄连碱、氧化小檗碱和延胡索中的原小檗碱型成分延胡索乙素、延胡索甲素、脱氢紫堇碱、四氢黄连碱进一步活性实验。

2　黄连中原小檗碱型生物碱血管生成药效评价

采用qCAM模型对黄连和延胡索水提物血管生成作用进行评价。结果表明, 黄连水提物能够显著抑制qCAM血管生成，延胡索水提物显著抑制其血管生成(图1A)。进一步对黄连与延胡索中的原小檗碱型成分干预血管生成的药效进行评价。基于前期实验中有效性与存活率评价, 选择10、20、40、80 μmol·L^-1作为实验剂量, 统计各种成分干预48 h后qCAM血管生成面积。qCAM模型评价结果表明(图1A、B), 黄连中干预血管生成效果最为明显的成分为氧化小檗碱与小檗碱, 其中氧化小檗碱在10、20、40、80 μmol·L^-1浓度下降低血管生成面积均具有显著性差异(P < 0.01, P < 0.01, P < 0.001, P < 0.001)。20、40、80 μmol·L^-1延胡索乙素显著促进血管生成(P < 0.01, P < 0.001, P < 0.001), 基于qCAM模型干预结果, 选择小檗碱、氧化小檗碱及延胡索乙素作为后续研究的备选成分, 20与40 μmol·L^-1作为实验剂量。

3　qPCR实验检测鹌鹑胚VEGFR2 mRNA水平

qPCR实验结果显示(图1C), 20和40 μmol·L^-1小檗碱干预48 h能够显著(均P < 0.01) 降低鹌鹑胚VEGFR2 mRNA水平, 20和40 μmol·L^-1氧化小檗碱干预显著降低鹌鹑胚VEGFR2 mRNA水平(P < 0.01, P < 0.001), 说明VEGFR2的转录受到抑制, 表达在一定程度受到抑制。

4　HUVEC细胞活力实验

通过HUVEC细胞活力实验验证黄连与延胡索中原小檗碱型生物碱对qCAM模型血管生成的干预作用。选定1.25、2.5、5、10、20、40、80、160 μmol·L^-1作为实验剂量。图2显示, 氧化小檗碱、小檗碱处理24 h能够显著抑制HUVEC增殖, 其中, 氧化小檗碱的抑制作用最为明显, 且在实验剂量范围内具有剂量依赖性。主要原小檗碱型生物碱成分在HUVEC实验中的结果与其干预qCAM模型的效果基本一致。

5　基于非靶向代谢组学揭示黄连关键药效成分调节的代谢通路

基于DESI-MSI的非靶向代谢组学分析氧化小檗碱抑制鹌鹑胚样本的差异代谢物与代谢通路, 样本分析采用正离子模式, 对代谢产物建立PCA和OPLS-DA模型, 模型判别R²Y = 0.806, 模型预测能力Q²Y = 0.947表明拟合模型的准确度和预测度良好(图3A、B)。在此基础上, 通过S-plot分析OPLS-DA模型的差异性变量, 将差异性变量作为候选生物标志物(图3C、D), 具体筛选条件为: P < 0.05、FC > 2或 < 0.5以及VIP > 1、|p (corr)| ≥ 0.58。采用METLIN与HMDB数据库鉴定候选标志物共31个(表3), 其中13个下调, 18个上调。采用MetaboAnalyst和KEGG数据库对关键代谢产物预测关键代谢通路。结果显示, 氧化小檗碱显著上调了dimethylmethoxy chromanol、N, N-diisopropyl-N'-isoamyl- N'-diethylaminoethylurea、xylamidine等水平, 显著下调PA (PGD1/8:0)、PC (18:1(9Z)-O(12, 13)/2:0)、PA (22:6(4Z, 7Z, 11E, 13Z, 15E, 19Z)-2OH(10S, 17)/8:0)、SM (d19:1/20:4 (5Z, 7E, 11Z, 14Z)-OH(9))、DG (LTE4/0:0/I-16:0) 脂质类代谢物水平等。差异通路分析结果显示(表4), 氧化小檗碱主要引起了谷氨酰胺和谷氨酸代谢、精氨酸和鸟氨酸代谢、缬氨酸、亮氨酸和异亮氨酸的生物合成、精氨酸生物合成代谢通路的改变(raw P < 0.5, impact > 0)。

6　原小檗碱型生物碱对能量代谢生化指标的影响

由图4可见, 与对照组相比, 40 μmol·L^-1小檗碱干预能够后降低鹌鹑胚NO、SDH、ATP含量(P < 0.05, P < 0.05, P < 0.01) 及Ca²⁺-Mg²⁺-ATP酶活力(P < 0.05)。20及40 μmol·L^-1氧化小檗碱干预48 h后, 鹌鹑胚样本中NO (P < 0.05, P < 0.01)、SDH (P < 0.01, P < 0.001)、ATP (P < 0.05, P < 0.01) 含量显著降低, Na⁺-K⁺-ATP酶活力显著降低(P < 0.05, P < 0.01)。40 μmol·L^-1延胡索乙素干预后, NO、SDH水平(P < 0.01, P < 0.05) 及Na⁺-K⁺-ATP酶活力显著上升(P < 0.01)。

7　氧化小檗碱与血管生成关键靶标互作分析

通过cytoHubba插件分析PPI网络中的关键基因(图5), 进一步通过分子对接技术验证网络药理学预测关键基因与小檗碱、氧化小檗碱和延胡索乙素的结合作用。图6显示了关键基因VEGFR2、JAK2、EGFR与小檗碱、氧化小檗碱以及延胡索乙素的结合, 蛋白质和小分子通过各种弱相互作用(范德华力、氢键、静电相互作用、疏水作用等) 驱动的非共价相互作用。表5列出了互作的具体参数。小檗碱与VEGFR2、JAK2、EGFR分别与对接蛋白的氨基酸形成了1、2和1个氢键, 结合能分别为-9.94、-9.51、-8.2 kcal·mol^-1, 氧化小檗碱与VEGFR2、JAK2、EGFR分别与对接蛋白的氨基酸形成了1、4和1个氢键, 结合能分别为-9.84、-10.15、-8.4 kcal·mol^-1, 以上结合都位于配体结合结构域的开口处。氧化小檗碱与小檗碱结合部位基本相同, 而8位的氧化使氧化小檗碱在与JAK2结合中具有更多氢键形成与更低结合能。延胡索乙素与VEGFR2、JAK2、EGFR分别与对接蛋白氨基酸形成了1、1和0个氢键, 结合能分别为-8.26、-7.91、-7.4 kcal·mol^-1。以上结合能均低于-5 kcal·mol^-1, 说明其结合自发进行且较为稳定^[11]。

讨论

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原小檗碱型广泛存在于毛茛科、罂粟科等中药中, 是以异喹啉或四氢异喹啉为基本母核的一类化合物, 其生物来源为苯丙氨酸和酪氨酸^[12]。有研究表明, 这类生物碱成分在抗菌^[13]、抗炎^[14]、抗肿瘤^[15]、调节心脑血管^[10]等血管生成相关疾病上具有显著疗效。课题组前期采用共词分析方法分析血管生成领域的研究热点表明^[16], 含原小檗碱型生物碱的中药多为清热解毒药, 所含共有成分多为小檗碱、药根碱、巴马汀等, 并推测原小檗碱型生物碱共有的骨架是此类成分作用于血管的重要活性中心。

基于课题组前期研究^[7-9], qCAM模型的应用在为血管生成双向干预活性方面能够提供一定方法学参考, 其具有快速、客观、直观、低成本等优势。与鸡胚绒毛尿囊膜模型(CAM) 相比, qCAM模型的优点在于其成本更低、单次评价数量更大、世代间隔时间短、敏感性好、给药方便等^[9]。不同于啮齿类实验动物, 鹌鹑具有静脉属性、血管结构和血液微环境等与人类相似等独特的生物学特性, 其血浆游离脂肪酸、胆固醇、三酰甘油的水平以及极低密度脂蛋白、低密度脂蛋白的脂质构成与人类相似, 被广泛应用于高脂血症等疾病模型的研究中^[8]。经过课题组多因素平行实验考察, qCAM模型根据血管发育情况, 能相对可靠地评价受试因素/对象对血管生成的干预作用, 结合血管内皮细胞经典实验和组学技术, 为血管生成药效物质基础筛选及其机制研究提供新的思路。课题组前期也基于这一“动物‒细胞‒代谢”多层次模式的血管生成干预药物筛选及活性检测技术平台对莪术、延胡索及其血管生成药效物质基础及其作用机制进行了探索。

本研究基于qCAM模型与HUVEC对黄连中的原小檗碱型生物碱成分的血管生成干预作用进行了初步探索与验证, 有研究表明小檗碱能够降低TCA循环活性, 从而降低能量代谢, 抑制血管生成^{[17, 18]}。本研究中, 氧化小檗碱在qCAM模型中表现出比小檗碱更为显著的血管生成抑制作用, 其对TCA循环关键酶SDH活性、中间产物丙酮酸含量及ATP含量的抑制更为显著, 这一发现尚未见研究报道。差异代谢通路分析表明, 氧化小檗碱主要以调节谷氨酰胺和谷氨酸代谢来改变代谢轮廓。谷氨酰胺和谷氨酸代谢与三羧酸循环(TCA循环) 密切相关, 其通过提供碳骨架和氮源, 直接参与能量生成、生物合成及细胞稳态调控, 这一代谢通路的抑制将导致其代谢产物α-酮戊二酸^[19]减少, 抑制TCA循环导致能量代谢障碍。能量代谢的抑制使脂肪酸和胆固醇合成的关键辅因子NADPH和乙酰辅酶A减少, 引起多种脂质代谢异常^[20], 本研究中具体表现为磷脂酸[PA (PGD1/8:0)]和PA [22:6(4Z, 7Z, 11E, 13Z, 15E, 19Z)-2OH(10S, 17)/8:0)]、磷脂酰胆碱[PC(18:1(9Z)-O(12, 13)/2:0)] 以及二酰基甘油[DG (LTE4/0:0/I-16:0)] 含量降低, 这些脂质分子的含量降低反映了整体脂质代谢的异常抑制, 以上代谢物合成与降解均依赖于共同的脂肪酸代谢、甘油磷脂代谢和鞘脂代谢等。已有研究表明, 甘油磷脂代谢及D-谷氨酰胺和D-谷氨酸代谢是EGFR干预的重要代谢途径, EGFR能够通过抑制谷氨酰胺酶靶向抑制谷氨酰胺代谢^{[21, 22]}而显著影响细胞能量代谢。同时, EGFR通过磷脂酰肌醇激酶信号传导、AKT激活以及磷酸二酯酶依赖的环腺苷酸降解, 抑制由胰高血糖素等激素启动的分解代谢信号级联反应, 由此增加脂肪酸酯化和甘油三酯分泌, 还生成复杂的脂肪酸衍生物, 包括神经酰胺和鞘磷脂等^{[23, 24]}, 且EGFR-JAK轴的异常调控能够导致脂质代谢和线粒体功能改变, 影响细胞膜和线粒体膜功能, 对有效的三羧酸循环功能产生负面影响, 并可能导致脂质氧化与转运异常^[25], 由此可见, EGFR是同时参与并调控能量与脂质代谢的枢纽。基于本研究中网络药理学与代谢组学整合分析推测, 氧化小檗碱能够通过调控EGFR-JAK轴介导的能量、脂质代谢抑制影响细胞膜结构(磷脂酸、鞘磷脂、磷脂酰胆碱) 和直接参与血管生成的信号传导(EGFR-VEGFR2轴) 抑制血管生成。

黄连和延胡索主要含有的生物碱同属原小檗碱型生物碱, 具有共同的生源前体——酪氨酸^[12], 但两者的化学结构存在关键性差异, 这些差异直接影响它们的理化性质和生物活性。骨架上来看, 黄连中所含的原小檗碱型生物碱以季铵型为主, 由两个异喹啉环稠合而成, 形成的四环骨架系统, 在C-2和C-3位存在亚甲基双氧桥环状结构, C-7位带正电的季铵离子以及C-9、10位的甲氧基是其重要的药效团, 这种结构使小檗碱及其结构类似物具有显著的平面性和正电荷特性, 利于与DNA、蛋白质等生物大分子相互作用。氧化小檗碱保留了小檗碱的基本骨架, 但氧化引入的羰基增加了分子的极性, 可能影响其膜通透性和靶点结合特性, 因此, 推测C-8位的氧化修饰可以增强如抗血管生成和抗氧化等作用, 但也可能降低其他活性如抗菌效果。延胡索乙素为叔胺类生物碱, 其D环为饱和环状结构, 这使得分子刚性降低, 平面性减弱; N原子为叔胺形式, 不带永久正电荷, 仅在质子化条件下带正电, 这一物质基础特点可能决定了黄连及延胡索及其主要成分在干预血管生成以及代谢相关指标的相反趋势。黄连中原小檗碱型生物碱, 分别在C-2、C-3、C-9、C-10位连接不同的取代基团, 使其具有不同的化学结构。其中, C-2、C-3位多连接-OMe、-OH或形成-OCH₂O-环状结构, C-9、C-10位多连接-OMe、-OH或形成-OCH₂O-环状结构^[26-28]。研究发现, 原小檗碱型生物碱的抗菌活性增强与C-8位引入烷基, C-9位引入苯氧丁基、酰氧基或苯甲酰氧基等脂溶性基团, C-12位卤素取代, C-13位引入烷基有关^[29-33]; 调节血脂活性增强与C-9或C-10位短链烷基取代, C-10或C-11位甲氧基修饰有关^{[33, 34]}。本研究中, 分子对接互作结果显示小檗碱与氧化小檗碱与靶点结合的氨基酸部位相同, 结合能有一定差异, 8位的氧化减弱了小檗碱的阳离子特性, 进而影响其药理活性及其与生物大分子的相互作用模式。小檗碱的季铵盐结构是其与DNA相互作用的重要基础, 正电荷的N原子能够与DNA磷酸骨架形成静电相互作用, 而芳香环系统则通过插入作用与碱基对结合。这种作用模式使小檗碱能够干扰DNA复制和转录过程, 进而发挥抗肿瘤和抗菌作用。氧化小檗碱由于D环的氧化修饰, 改变了分子的电子分布和空间构象, 成了不同的分子识别模式。例如, D环上引入的羰基可能提供新的氢键受体, 使氧化小檗碱能够与EGFR、JAK2等血管生成过程中的关键靶点的特定氨基酸残基形成氢键网络, 并可能导致其对拓扑异构酶抑制选择性改变^[35], 进而能够使这类化合物与部分关键靶点的结合能降低, 因此推断这一结构改变能够通过直接与血管生成相关靶点作用, 发挥其抑制血管生成功能。延胡索乙素的饱和环系增加了分子的柔性和三维特性, 这种结构差异导致延胡索乙素表现出与季铵类原小檗碱型生物碱不同的生物活性谱, 如更显著的镇痛和镇静作用, 以及相对较弱的抗菌和降糖活性^[36]。此外, 延胡索乙素的手性中心对其生物活性也有重要影响。天然存在的延胡索乙素通常为消旋体, 而不同对映体可能表现出不同的药理活性和靶点选择性。研究表明, 左旋延胡索乙素和右旋延胡索乙素在镇痛、镇静和血管活性方面可能存在差异, 这种立体选择性也可能延伸至其对血管生成的调节作用。未来研究应进一步阐明不同立体构型延胡索乙素干预血管生成的效果差异, 为开发更精准的血管调节药物提供依据。

综上, 基于qCAM模型能够快速、直观评价黄连与延胡索中原小檗碱型生物碱成分干预血管生成的药效作用及构效关系, 并能够用于评价外源物质对于鹌鹑胚的代谢的影响。但目前qCAM模型还存在血管表征及计数方面的不足, 后续将通过采用活体微循环检测系统, 进行光学相干断层扫描血管及血流成像, 完善血管评价与表征。同时, 基于网络药理学与代谢组学通路整合分析结果, 氧化小檗碱对血管生成的调控机制中“基因表达-代谢差异”的具体互作关系还有待进一步研究, 其中, 关键靶点表达相关的具体调控机制及其对代谢的影响, 以及代谢物改变对关键靶点的表达乃至是否涉及表观遗传修饰相关作用均有待通过后续深入探索, 且氧化小檗碱对“能量-脂质”代谢的串扰机制有待相关实验进行研究。

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2025年第60卷第11期

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doi: 10.16438/j.0513-4870.2025-0387

接收时间：2025-04-07
首发时间：2026-09-20
出版时间：2025-11-12

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收稿日期：2025-04-07
修回日期：2025-08-03

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¹北京中医药大学中药学院, 北京 102488

²中国中医科学院中药研究所, 北京 100700

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崔鹤蓉, E-mail: herongcui@outlook.com

雷海民, E-mail: leihaimin@126.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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TxT

Gene		Primer sequence (5′-3′)	Amplification length/bp
Actin	Forward:	CTGGCACCTAGCACAATGAA	123
Reverse:	CTGCTTGCTGATCCACATCT
VEGFR2	Forward:	GACTTTCAGGAGAGCACACG	89
Reverse:	CCATCGGAAGCCTCTGTCTT

Gene

Primer sequence (5′-3′)

Amplification
length/bp

Actin

Forward:

CTGGCACCTAGCACAATGAA

123

Reverse:

CTGCTTGCTGATCCACATCT

VEGFR2

Forward:

GACTTTCAGGAGAGCACACG

Reverse:

CCATCGGAAGCCTCTGTCTT

Source	Component	Formula	Mode	m/z	MS/MS
HL	Magnoflorine	C₂₀H₂₃NO₄	[M+H]⁺	342.170 0	342.170 2	297.112 2, 282.088 9, 265.086 0
HL	Coptisine	C₁₉H₁₃NO₄	[M+H]⁺	320.091 7	320.091 9	305.068 8, 292.096 8, 262.086 0, 249.078 4
HL	Epiberberine	C₂₀H₁₇NO₄	[M+H]⁺	336.123 0	336.122 9	320.091 8, 308.091 1, 292.096 7
HL	Jatrorrhizine	C₂₀H₂₀NO₄	[M]⁺	338.139 2	338.138 8	323.114 7, 294.112 3
HL	Berberine	C₂₀H₁₇NO₄	[M+H]⁺	336.123 0	336.123 0	320.091 7, 292.096 7
HL	Columbamine	C₂₀H₁₉NO₄	[M+H]⁺	338.138 7	338.138 7	322.107 5, 294.112 3
HL	Thalmineline	C₁₁H₁₃NO₃	[M+H]⁺	208.096 8	208.097 0	165.091 2, 150.067 7
HL	Berberrubine	C₁₉H₁₆NO₄	[M+H]⁺	322.107 9	322.107 5	279.089 1
HL	Noroxyhydrastinine	C₁₀H₉NO₃	[M+H]⁺	192.065 5	192.065 7	149.059 9
HL	Oxyberberine	C₂₀H₁₇NO₅	[M+H]⁺	352.117 9	352.117 9	337.093 6, 308.091 6
HL	Palmatine	C₂₁H₂₂NO₄	[M]⁺	352.154 9	352.157 9	337.093 6, 308.091 6
HL	Worenine	C₂₀H₁₅NO₄	[M+H]⁺	335.115 2	335.077 9	291.086 1
HL	Chlorogenic acid	C₁₆H₁₈O₉	[M-H]^-	353.087 8	353.087 8	191.056 4, 179.039 1, 161.024 8
HL	Lariciresinol 4-O-glucoside	C₂₆H₃₄O₁₁	[M-H]^-	521.202 8	521.203 5	329.103 9
YHS	Taxilamine	C₂₀H₁₉NO₆	[M+H]⁺	370.128 5	370.129 6	190.086 3
YHS	Palmatine	C₂₁H₂₂NO₄	[M]⁺	352.154 3	352.117 8	294.076 2
YHS	D-Lirioferine	C₂₀H₂₃NO₄	[M+H]⁺	341.162 2	342.169 0	192.102 1
YHS	Tetrahydrocoptisine	C₁₉H₁₇NO₄	[M+H]⁺	324.123 0	324.123 2	176.070 7, 119.049 0
YHS	Bicuculline	C₂₀H₁₇NO₆	[M+H]⁺	368.112 8	368.112 3	353.125 9, 338.021 0
YHS	Jatrorrhizine	C₂₀H₂₀NO₄	[M+H]⁺	338.138 7	338.138 7	279.088 9, 265.072 9
YHS	Tetrahydropalmatine	C₂₁H₂₅NO₄	[M+H]⁺	356.185 6	356.185 8	356.185 8, 192.102 1
YHS	N-De-Me-N-Methylsecoglaucine	C₂₁H₂₅NO₄	[M+H]⁺	356.185 6	356.185 9	178.086 5, 151.075 6
YHS	Yuanhunine	C₂₁H₂₅NO₄	[M+H]⁺	356.185 6	356.185 6	165.091 3
YHS	D-Glaucine	C₂₁H₂₅NO₄	[M+H]⁺	356.185 6	356.185 7	279.101 6, 251.106 6, 220.883 0
YHS	Isocorynoline	C₂₁H₂₅NO₄	[M+H]⁺	355.177 8	355.177 3	340.141 9, 192.102 1
YHS	N-Methyltetrahydrocolumbamine	C₂₁H₂₁NO₄	[M+H]⁺	352.154 3	352.157 0	190.086 4
YHS	Canadine	C₂₀H₂₁NO₄	[M+H]⁺	340.154 3	340.154 5	176.708 0, 149.059 8
YHS	Corydaline	C₂₂H₂₇NO₄	[M+H]⁺	370.201 3	370.201 7	192.102 1, 165.091 3
YHS	Dehydrocavidine	C₂₁H₂₂NO₄	[M+H]⁺	353.162 2	353.161 7	190.086 3
YHS	Berberine	C₂₀H₁₈NO₄	[M]⁺	336.123 0	336.123 1	320.091 9, 278.080 9
YHS	Dehydrocorydaline	C₂₂H₂₄NO₄	[M]⁺	366.169 9	366.170 3	350.138 8, 308.128 1

Source

Component

Formula

Mode

m/z

MS/MS

Calculated
mass

Measured
mass

Magnoflorine

C₂₀H₂₃NO₄

[M+H]⁺

342.170 0

342.170 2

297.112 2, 282.088 9, 265.086 0

Coptisine

C₁₉H₁₃NO₄

[M+H]⁺

320.091 7

320.091 9

305.068 8, 292.096 8, 262.086 0, 249.078 4

Epiberberine

C₂₀H₁₇NO₄

[M+H]⁺

336.123 0

336.122 9

320.091 8, 308.091 1, 292.096 7

Jatrorrhizine

C₂₀H₂₀NO₄

[M]⁺

338.139 2

338.138 8

323.114 7, 294.112 3

Berberine

C₂₀H₁₇NO₄

[M+H]⁺

336.123 0

320.091 7, 292.096 7

Columbamine

C₂₀H₁₉NO₄

[M+H]⁺

338.138 7

322.107 5, 294.112 3

Thalmineline

C₁₁H₁₃NO₃

[M+H]⁺

208.096 8

208.097 0

165.091 2, 150.067 7

Berberrubine

C₁₉H₁₆NO₄

[M+H]⁺

322.107 9

322.107 5

279.089 1

Noroxyhydrastinine

C₁₀H₉NO₃

[M+H]⁺

192.065 5

192.065 7

149.059 9

Oxyberberine

C₂₀H₁₇NO₅

[M+H]⁺

352.117 9

337.093 6, 308.091 6

Palmatine

C₂₁H₂₂NO₄

[M]⁺

352.154 9

352.157 9

337.093 6, 308.091 6

Worenine

C₂₀H₁₅NO₄

[M+H]⁺

335.115 2

335.077 9

291.086 1

Chlorogenic acid

C₁₆H₁₈O₉

[M-H]^-

353.087 8

191.056 4, 179.039 1, 161.024 8

Lariciresinol 4-O-glucoside

C₂₆H₃₄O₁₁

[M-H]^-

521.202 8

521.203 5

329.103 9

YHS

Taxilamine

C₂₀H₁₉NO₆

[M+H]⁺

370.128 5

370.129 6

190.086 3

YHS

Palmatine

C₂₁H₂₂NO₄

[M]⁺

352.154 3

352.117 8

294.076 2

YHS

D-Lirioferine

C₂₀H₂₃NO₄

[M+H]⁺

341.162 2

342.169 0

192.102 1

YHS

Tetrahydrocoptisine

C₁₉H₁₇NO₄

[M+H]⁺

324.123 0

324.123 2

176.070 7, 119.049 0

YHS

Bicuculline

C₂₀H₁₇NO₆

[M+H]⁺

368.112 8

368.112 3

353.125 9, 338.021 0

YHS

Jatrorrhizine

C₂₀H₂₀NO₄

[M+H]⁺

338.138 7

279.088 9, 265.072 9

YHS

Tetrahydropalmatine

C₂₁H₂₅NO₄

[M+H]⁺

356.185 6

356.185 8

356.185 8, 192.102 1

YHS

N-De-Me-N-Methylsecoglaucine

C₂₁H₂₅NO₄

[M+H]⁺

356.185 6

356.185 9

178.086 5, 151.075 6

YHS

Yuanhunine

C₂₁H₂₅NO₄

[M+H]⁺

356.185 6

165.091 3

YHS

D-Glaucine

C₂₁H₂₅NO₄

[M+H]⁺

356.185 6

356.185 7

279.101 6, 251.106 6, 220.883 0

YHS

Isocorynoline

C₂₁H₂₅NO₄

[M+H]⁺

355.177 8

355.177 3

340.141 9, 192.102 1

YHS

N-Methyltetrahydrocolumbamine

C₂₁H₂₁NO₄

[M+H]⁺

352.154 3

352.157 0

190.086 4

YHS

Canadine

C₂₀H₂₁NO₄

[M+H]⁺

340.154 3

340.154 5

176.708 0, 149.059 8

YHS

Corydaline

C₂₂H₂₇NO₄

[M+H]⁺

370.201 3

370.201 7

192.102 1, 165.091 3

YHS

Dehydrocavidine

C₂₁H₂₂NO₄

[M+H]⁺

353.162 2

353.161 7

190.086 3

YHS

Berberine

C₂₀H₁₈NO₄

[M]⁺

336.123 0

336.123 1

320.091 9, 278.080 9

YHS

Dehydrocorydaline

C₂₂H₂₄NO₄

[M]⁺

366.169 9

366.170 3

350.138 8, 308.128 1

Component	Formula	Adduction	m/z	FC	P-value	VIP
Triethylamine N-oxide	C₆H₁₅NO	[M+H]⁺	118.087 0	2.05	0.000 789	4.77
Xymedon	C₈H₁₂N₂O₂	[M+H]⁺	169.047 8	2.89	0.000 674	5.34
2-(Diaminomethylideneamino)ethylsulfanylmethanimidamide	C₄H₁₁N₅S	[M+Na]⁺	184.066 9	3.80	0.000 107	2.70
Thiostatin	C₈H₁₇NO₂S	[M+H]⁺	192.123 5	2.81	0.000 004	5.46
Loxanast	C₁₄H₂₆O₂	[M+H]⁺	227.222 9	3.85	0.000 020	2.80
Heptyl ketone	C₁₅H₃₀O	[M+H]⁺	227.279 3	3.04	0.000 088	2.37
Dimethylmethoxy chromanol	C₁₂H₁₆O₃	[M+Na]⁺	231.084 4	5.27	0.000 005	1.67
2-(4-Methoxyphenyl)ethyl hydrogen sulfate	C₉H₁₂O₅S	[M+H]⁺	233.079 1	2.87	0.000 135	1.54
(8R, 9S, 13S, 14S)-3-Hydroxy-13-methyl-4, 6, 7, 8, 9, 11, 12, 14, 15, 16- decahydro-3H-cyclopenta[a]phenanthren-17-one	C₁₈H₂₄O₂	[M+H]⁺	273.167 6	2.32	0.000 157	1.07
(2S, 3R)-2-Amino-4-octadecene-3-ol	C₁₈H₃₇NO	[M+H]⁺	284.295 8	2.47	0.009 044	1.31
13-Azaprostanoic acid	C₁₉H₃₇NO₂	[M+H]⁺	312.326 7	2.48	0.003 354	1.06
Xylamidine	C₁₉H₂₄N₂O₂	[M+H]⁺	313.234 7	3.68	0.000 642	1.05
(1S, 2R, 3S, 7R, 10S, 13S, 14R)-1-Methyl-14-propan-2-yl-2-propyl-12-azapentacyclo[8.6.0.02, 13.03, 7.07, 12]hexadecane	C₂₂H₃₇N	[M+H]⁺	316.321 3	2.44	0.002 713	1.39
(3-(tert-Butoxyimino-methyl)-4-chloro-phenyl)-thiocarbamic acid, O-isopropyl ester	C₁₅H₂₁ClN₂O₂S	[M+H]⁺	329.156 2	2.61	0.000 038	1.09
N, N-Diisopropyl-N'-isoamyl-N'-diethylaminoethylurea	C₁₈H₃₉N₃O	[M+Na]⁺	336.290 1	4.01	0.001 945	1.12
(5alpha)-23-Methyl-4-aza-21-norchol-1-ene-3, 20-dione	C₂₃H₃₅NO₂	[M+H]⁺	358.244 1	0.37	0.000 853	2.44
(5Z, 8Z, 11Z, 14Z)-N-(4-Hydroxy-2-methylphenyl)-5, 8, 11, 14-eicosatetraenamide	C₂₇H₃₉NO₂	[M+Na]⁺	432.280 2	0.50	0.000 215	1.88
(2S, 3S, 5S, 8S, 9S, 10S, 13S, 14S, 17S)-17-Acetyl-2-(2, 2- dimethylmorpholino)-3-hydroxy-10, 13-dimethylhexadecahydro- 11H-cyclopenta[a]phenanthren-11-one	C₂₇H₄₃NO₄	[M+H]⁺	446.298 1	0.36	0.003 866	2.86
Mofarotene	C₂₉H₃₉NO₂	[M+Na]⁺	456.280 3	0.47	0.004 535	1.21
Z-LLNle-CHO	C₂₆H₄₁N₃O₅	[M+H]⁺	476.306 2	0.48	0.002 434	1.81
(8S, 9S, 10S, 11S, 13S, 14S, 17R)-11, 17-Dihydroxy-17-(2-hydroxyacetyl)- 10, 13-dimethyl-9-nonyl-1, 2, 6, 7, 8, 11, 12, 14, 15, 16-decahydrocyclopenta [a]phenanthren-3-one	C₃₀H₄₈O₅	[M+H]⁺	489.338 1	2.62	0.000 275	1.17
(1S, 2S, 6R, 15S, 16R)-5-(Cyclopropylmethyl)-16-(2-hydroxy-3, 3-dimethylbutan-2-yl)-15-methoxy-13-oxa-5-azahexacyclo [13.2.2.12, 8.01, 6.02, 14.012, 20]icosa-8(20), 9, 11-trien-11-ol	C₂₉H₄₁NO₄	[M+Na]⁺	490.323 7	0.31	0.001 417	2.82
(S)-N-((S)-1-Amino-3, 3-dimethyl-1-oxobutan-2-yl)-2-((S)-2- mercapto-4-(3, 4, 4-trimethyl-2, 5-dioxoimidazolidin-1-yl) butanamido)-N, 4-dimethylpentanamide	C₂₃H₄₁N₅O₅S	[M+H]⁺	500.306 7	0.43	0.000 222	1.39
Vicriviroc	C₂₈H₃₈F₃N₅O₂	[M+H]⁺	534.349 9	0.37	0.000 247	2.27
PC(18:1(9Z)-O(12, 13)/2:0)	C₂₈H₅₂NO₉P	[M+H]⁺	578.377 0	0.46	0.007 740	1.50
Quinoline, 6-(1-methyl-1-(methylsulfonyl)ethyl)-8-(3-((1E)-2-(3-methyl- 1, 2, 4-oxadiazol-5-yl)-2-(4-(methylsulfonyl)phenyl)ethenyl)phenyl)	C₃₁H₂₉N₃O₅S₂	[M+Na]⁺	610.182 4	8.92	0.007 600	1.61
Ethyl 5-[[[4-(3-methylsulfonylphenyl)phenyl]methyl-(2, 4, 6-trimethylphenyl)sulfonylamino]methyl]furan-2-carboxylate	C₃₁H₃₃NO₇S₂	[M+Na]⁺	618.135 0	2.68	0.000 182	1.03
1, 2-Dilauroyl-sn-glycero-3-phosphocholine	C₃₂H₆₄NO₈P	[M+H]⁺	622.401 7	0.42	0.000 477	1.26
PA(PGD1/8:0)	C₃₁H₅₅O₁₁P	[M+H]⁺	635.308 8	0.39	0.003 257	1.19
DG(LTE4/0:0/i-16:0)	C₄₂H₇₃NO₈S	[M+H]⁺	752.513 5	0.48	0.001 041	1.49
SM(d19:1/20:4(5Z, 7E, 11Z, 14Z)-OH(9))	C₄₄H₈₁N₂O₇P	[M+Na]⁺	803.541 7	0.16	0.000 140	1.65

Component

Formula

Adduction

m/z

P-value

VIP

Triethylamine N-oxide

C₆H₁₅NO

[M+H]⁺

118.087 0

2.05

0.000 789

4.77

Xymedon

C₈H₁₂N₂O₂

[M+H]⁺

169.047 8

2.89

0.000 674

5.34

2-(Diaminomethylideneamino)ethylsulfanylmethanimidamide

C₄H₁₁N₅S

[M+Na]⁺

184.066 9

3.80

0.000 107

2.70

Thiostatin

C₈H₁₇NO₂S

[M+H]⁺

192.123 5

2.81

0.000 004

5.46

Loxanast

C₁₄H₂₆O₂

[M+H]⁺

227.222 9

3.85

0.000 020

2.80

Heptyl ketone

C₁₅H₃₀O

[M+H]⁺

227.279 3

3.04

0.000 088

2.37

Dimethylmethoxy chromanol

C₁₂H₁₆O₃

[M+Na]⁺

231.084 4

5.27

0.000 005

1.67

2-(4-Methoxyphenyl)ethyl hydrogen sulfate

C₉H₁₂O₅S

[M+H]⁺

233.079 1

2.87

0.000 135

1.54

(8R, 9S, 13S, 14S)-3-Hydroxy-13-methyl-4, 6, 7, 8, 9, 11, 12, 14, 15, 16- decahydro-3H-cyclopenta[a]phenanthren-17-one

C₁₈H₂₄O₂

[M+H]⁺

273.167 6

2.32

0.000 157

1.07

(2S, 3R)-2-Amino-4-octadecene-3-ol

C₁₈H₃₇NO

[M+H]⁺

284.295 8

2.47

0.009 044

1.31

13-Azaprostanoic acid

C₁₉H₃₇NO₂

[M+H]⁺

312.326 7

2.48

0.003 354

1.06

Xylamidine

C₁₉H₂₄N₂O₂

[M+H]⁺

313.234 7

3.68

0.000 642

1.05

(1S, 2R, 3S, 7R, 10S, 13S, 14R)-1-Methyl-14-propan-2-yl-2-propyl-12-azapentacyclo[8.6.0.02, 13.03, 7.07, 12]hexadecane

C₂₂H₃₇N

[M+H]⁺

316.321 3

2.44

0.002 713

1.39

(3-(tert-Butoxyimino-methyl)-4-chloro-phenyl)-thiocarbamic acid, O-isopropyl ester

C₁₅H₂₁ClN₂O₂S

[M+H]⁺

329.156 2

2.61

0.000 038

1.09

N, N-Diisopropyl-N'-isoamyl-N'-diethylaminoethylurea

C₁₈H₃₉N₃O

[M+Na]⁺

336.290 1

4.01

0.001 945

1.12

(5alpha)-23-Methyl-4-aza-21-norchol-1-ene-3, 20-dione

C₂₃H₃₅NO₂

[M+H]⁺

358.244 1

0.37

0.000 853

2.44

(5Z, 8Z, 11Z, 14Z)-N-(4-Hydroxy-2-methylphenyl)-5, 8, 11, 14-eicosatetraenamide

C₂₇H₃₉NO₂

[M+Na]⁺

432.280 2

0.50

0.000 215

1.88

(2S, 3S, 5S, 8S, 9S, 10S, 13S, 14S, 17S)-17-Acetyl-2-(2, 2- dimethylmorpholino)-3-hydroxy-10, 13-dimethylhexadecahydro- 11H-cyclopenta[a]phenanthren-11-one

C₂₇H₄₃NO₄

[M+H]⁺

446.298 1

0.36

0.003 866

2.86

Mofarotene

C₂₉H₃₉NO₂

[M+Na]⁺

456.280 3

0.47

0.004 535

1.21

Z-LLNle-CHO

C₂₆H₄₁N₃O₅

[M+H]⁺

476.306 2

0.48

0.002 434

1.81

(8S, 9S, 10S, 11S, 13S, 14S, 17R)-11, 17-Dihydroxy-17-(2-hydroxyacetyl)- 10, 13-dimethyl-9-nonyl-1, 2, 6, 7, 8, 11, 12, 14, 15, 16-decahydrocyclopenta [a]phenanthren-3-one

C₃₀H₄₈O₅

[M+H]⁺

489.338 1

2.62

0.000 275

1.17

(1S, 2S, 6R, 15S, 16R)-5-(Cyclopropylmethyl)-16-(2-hydroxy-3, 3-dimethylbutan-2-yl)-15-methoxy-13-oxa-5-azahexacyclo [13.2.2.12, 8.01, 6.02, 14.012, 20]icosa-8(20), 9, 11-trien-11-ol

C₂₉H₄₁NO₄

[M+Na]⁺

490.323 7

0.31

0.001 417

2.82

(S)-N-((S)-1-Amino-3, 3-dimethyl-1-oxobutan-2-yl)-2-((S)-2- mercapto-4-(3, 4, 4-trimethyl-2, 5-dioxoimidazolidin-1-yl) butanamido)-N, 4-dimethylpentanamide

C₂₃H₄₁N₅O₅S

[M+H]⁺

500.306 7

0.43

0.000 222

1.39

Vicriviroc

C₂₈H₃₈F₃N₅O₂

[M+H]⁺

534.349 9

0.37

0.000 247

2.27

PC(18:1(9Z)-O(12, 13)/2:0)

C₂₈H₅₂NO₉P

[M+H]⁺

578.377 0

0.46

0.007 740

1.50

Quinoline, 6-(1-methyl-1-(methylsulfonyl)ethyl)-8-(3-((1E)-2-(3-methyl- 1, 2, 4-oxadiazol-5-yl)-2-(4-(methylsulfonyl)phenyl)ethenyl)phenyl)

C₃₁H₂₉N₃O₅S₂

[M+Na]⁺

610.182 4

8.92

0.007 600

1.61

Ethyl 5-[[[4-(3-methylsulfonylphenyl)phenyl]methyl-(2, 4, 6-trimethylphenyl)sulfonylamino]methyl]furan-2-carboxylate

C₃₁H₃₃NO₇S₂

[M+Na]⁺

618.135 0

2.68

0.000 182

1.03

1, 2-Dilauroyl-sn-glycero-3-phosphocholine

C₃₂H₆₄NO₈P

[M+H]⁺

622.401 7

0.42

0.000 477

1.26

PA(PGD1/8:0)

C₃₁H₅₅O₁₁P

[M+H]⁺

635.308 8

0.39

0.003 257

1.19

DG(LTE4/0:0/i-16:0)

C₄₂H₇₃NO₈S

[M+H]⁺

752.513 5

0.48

0.001 041

1.49

SM(d19:1/20:4(5Z, 7E, 11Z, 14Z)-OH(9))

C₄₄H₈₁N₂O₇P

[M+Na]⁺

803.541 7

0.16

0.000 140

1.65

Pathway	Total	Hits	Raw P	Impact
Glutamine and glutamic acid metabolism	6	3	0.132 91	0.222 05
Arginine and ornithine metabolism	4	2	0.221 73	0.000 00
Valine, leucine, and isoleucine biosynthesis	8	3	0.262 46	0.000 00
Arginine biosynthesis	13	4	0.335 35	0.089 74

Pathway

Total

Hits

Raw P

Impact

Glutamine and glutamic
acid metabolism

0.132 91

0.222 05

Arginine and ornithine
metabolism

0.221 73

0.000 00

Valine, leucine, and
isoleucine biosynthesis

0.262 46

0.000 00

Arginine biosynthesis

0.335 35

0.089 74

Component	VEGFR2	JAK2	EGFR
Berberine	-9.94	-9.51	-8.2
Oxyberberine	-9.84	-10.15	-8.4
Tetrahydropalmatine	-8.26	-7.91	-7.4

Component

VEGFR2

JAK2

EGFR

Berberine

-9.94

-9.51

-8.2

Oxyberberine

-9.84

-10.15

-8.4

Tetrahydropalmatine

-8.26

-7.91

-7.4