药学学报

Number	Composition	Degree	Betweeness	OB/%	DL
TFA1^*	Calycosin-7-O-β-D-glycoside	20	0.030 817 68	-	-
TFA2^*	Apigenin-hex	21	0.033 418 38	-	-
TFA3^*	7, 2'-Dihydroxy-3', 4'-dimethoxy-isoflavan-7, 2'-di-O-β-D-glucoside	24	0.037 978 17	-	-
TFA4^*	Calycosin	19	0.016 360 85	47.75	0.24
TFA5^*	Pratensein-7-O-β-D-glucoside	28	0.056 452 29	-	-
TFA6^*	10-Hydroxy-9-methoxypterocarpan-3-O-β-D-glucoside	19	0.027 192 82	-	-
TFA7^*	6''-O-Acetyl calycosin-7-O-β-D-glycoside	20	0.023 329 57	-	-
TFA8^*	Glycyroside	22	0.030 656 15	37.25	0.79
TFA9^*	Ononin	20	0.035 375 44	11.52	0.78
TFA10^*	3-Hydroxy-9, 10-dimethoxypterocarpan-3-O-β-D-glucoside	21	0.022 477 57	-	-
TFA11^*#	7, 2'-Dihydroxy-3', 4'-dimethoxy-isoflavan-7-O-β-D-glucoside	16	0.015 809 63	16.16	0.86
TFA12^*#	Calycosin	26	0.051 131 86	47.75	0.24
TFA13^*	Dihydroxy-dimethoxyisoflavone	19	0.016 586 87	-	-
TFA14^*	6''-O-Acetyl ononin	25	0.036 401 27	-	-
TFA15^*	Dihydroxy-trimethoxy dihydroisoflavone	30	0.061 953 26	-	-
TFA16^*	3-Hydroxy-9, 10-dimethoxypterocarpan	21	0.026 405 55	-	-
TFA17^*	7, 2'-Dihydroxy-3', 4'-dimethoxy-isoflavan	23	0.032 532 35	-	-
TFA18^*	Formononetin	18	0.022 347 14	69.67	0.21
TFA19^*	7-Hydroxy-6, 4'-dimethoxyisoflavan	23	0.038 222 03	-	-
TFA20^#	(3R)-3-(2-Hydroxy-3, 4-dimethoxyphenyl)chroman-7-ol	14	0.040 249 27	67.67	0.26
TFA21^#	5'-Hydroxyiso-muronulatol-2', 5'-di-O-glucoside	11	0.036 514 41	41.72	0.69
TFA22^#	7-O-Methylisomucronulatol	12	0.036 690 85	74.69	0.3
TFA23^#	9, 10-Dimethoxypterocarpan-3-O-β-D-glucoside	8	0.011 433 53	36.74	0.92
TFA24^#	Isoflavanone	12	0.045 879 49	109.99	0.3
TFA25^#	Isomucronulatol-7, 2'-di-O-glucosiole	7	0.010 033 14	49.28	0.62
TFA26^#	Isorhamnetin	6	0.006 536 52	49.6	0.31
TFA27^#	Jaranol	7	0.011 916 39	50.83	0.29
TFA28^#	Kaempferol	5	0.004 295 97	41.88	0.24
TFA29^#	Quercetin	7	0.015 167 40	47.75	0.24

Number

Composition

Degree

Betweeness

OB/%

TFA1^*

Calycosin-7-O-β-D-glycoside

0.030 817 68

TFA2^*

Apigenin-hex

0.033 418 38

TFA3^*

7, 2'-Dihydroxy-3', 4'-dimethoxy-isoflavan-7, 2'-di-O-β-D-glucoside

0.037 978 17

TFA4^*

Calycosin

0.016 360 85

47.75

0.24

TFA5^*

Pratensein-7-O-β-D-glucoside

0.056 452 29

TFA6^*

10-Hydroxy-9-methoxypterocarpan-3-O-β-D-glucoside

0.027 192 82

TFA7^*

6''-O-Acetyl calycosin-7-O-β-D-glycoside

0.023 329 57

TFA8^*

Glycyroside

0.030 656 15

37.25

0.79

TFA9^*

Ononin

0.035 375 44

11.52

0.78

TFA10^*

3-Hydroxy-9, 10-dimethoxypterocarpan-3-O-β-D-glucoside

0.022 477 57

TFA11^*#

7, 2'-Dihydroxy-3', 4'-dimethoxy-isoflavan-7-O-β-D-glucoside

0.015 809 63

16.16

0.86

TFA12^*#

Calycosin

0.051 131 86

47.75

0.24

TFA13^*

Dihydroxy-dimethoxyisoflavone

0.016 586 87

TFA14^*

6''-O-Acetyl ononin

0.036 401 27

TFA15^*

Dihydroxy-trimethoxy dihydroisoflavone

0.061 953 26

TFA16^*

3-Hydroxy-9, 10-dimethoxypterocarpan

0.026 405 55

TFA17^*

7, 2'-Dihydroxy-3', 4'-dimethoxy-isoflavan

0.032 532 35

TFA18^*

Formononetin

0.022 347 14

69.67

0.21

TFA19^*

7-Hydroxy-6, 4'-dimethoxyisoflavan

0.038 222 03

TFA20^#

(3R)-3-(2-Hydroxy-3, 4-dimethoxyphenyl)chroman-7-ol

0.040 249 27

67.67

0.26

TFA21^#

5'-Hydroxyiso-muronulatol-2', 5'-di-O-glucoside

0.036 514 41

41.72

0.69

TFA22^#

7-O-Methylisomucronulatol

0.036 690 85

74.69

0.3

TFA23^#

9, 10-Dimethoxypterocarpan-3-O-β-D-glucoside

0.011 433 53

36.74

0.92

TFA24^#

Isoflavanone

0.045 879 49

109.99

0.3

TFA25^#

Isomucronulatol-7, 2'-di-O-glucosiole

0.010 033 14

49.28

0.62

TFA26^#

Isorhamnetin

0.006 536 52

49.6

0.31

TFA27^#

Jaranol

0.011 916 39

50.83

0.29

TFA28^#

Kaempferol

0.004 295 97

41.88

0.24

TFA29^#

Quercetin

0.015 167 40

47.75

0.24

Number	Composition	Degree	Betweeness	OB/%	DL
TFA1^*	Calycosin-7-O-β-D-glycoside	20	0.030 817 68	-	-
TFA2^*	Apigenin-hex	21	0.033 418 38	-	-
TFA3^*	7, 2'-Dihydroxy-3', 4'-dimethoxy-isoflavan-7, 2'-di-O-β-D-glucoside	24	0.037 978 17	-	-
TFA4^*	Calycosin	19	0.016 360 85	47.75	0.24
TFA5^*	Pratensein-7-O-β-D-glucoside	28	0.056 452 29	-	-
TFA6^*	10-Hydroxy-9-methoxypterocarpan-3-O-β-D-glucoside	19	0.027 192 82	-	-
TFA7^*	6''-O-Acetyl calycosin-7-O-β-D-glycoside	20	0.023 329 57	-	-
TFA8^*	Glycyroside	22	0.030 656 15	37.25	0.79
TFA9^*	Ononin	20	0.035 375 44	11.52	0.78
TFA10^*	3-Hydroxy-9, 10-dimethoxypterocarpan-3-O-β-D-glucoside	21	0.022 477 57	-	-
TFA11^*#	7, 2'-Dihydroxy-3', 4'-dimethoxy-isoflavan-7-O-β-D-glucoside	16	0.015 809 63	16.16	0.86
TFA12^*#	Calycosin	26	0.051 131 86	47.75	0.24
TFA13^*	Dihydroxy-dimethoxyisoflavone	19	0.016 586 87	-	-
TFA14^*	6''-O-Acetyl ononin	25	0.036 401 27	-	-
TFA15^*	Dihydroxy-trimethoxy dihydroisoflavone	30	0.061 953 26	-	-
TFA16^*	3-Hydroxy-9, 10-dimethoxypterocarpan	21	0.026 405 55	-	-
TFA17^*	7, 2'-Dihydroxy-3', 4'-dimethoxy-isoflavan	23	0.032 532 35	-	-
TFA18^*	Formononetin	18	0.022 347 14	69.67	0.21
TFA19^*	7-Hydroxy-6, 4'-dimethoxyisoflavan	23	0.038 222 03	-	-
TFA20^#	(3R)-3-(2-Hydroxy-3, 4-dimethoxyphenyl)chroman-7-ol	14	0.040 249 27	67.67	0.26
TFA21^#	5'-Hydroxyiso-muronulatol-2', 5'-di-O-glucoside	11	0.036 514 41	41.72	0.69
TFA22^#	7-O-Methylisomucronulatol	12	0.036 690 85	74.69	0.3
TFA23^#	9, 10-Dimethoxypterocarpan-3-O-β-D-glucoside	8	0.011 433 53	36.74	0.92
TFA24^#	Isoflavanone	12	0.045 879 49	109.99	0.3
TFA25^#	Isomucronulatol-7, 2'-di-O-glucosiole	7	0.010 033 14	49.28	0.62
TFA26^#	Isorhamnetin	6	0.006 536 52	49.6	0.31
TFA27^#	Jaranol	7	0.011 916 39	50.83	0.29
TFA28^#	Kaempferol	5	0.004 295 97	41.88	0.24
TFA29^#	Quercetin	7	0.015 167 40	47.75	0.24

Number

Composition

Degree

Betweeness

OB/%

TFA1^*

Calycosin-7-O-β-D-glycoside

0.030 817 68

TFA2^*

Apigenin-hex

0.033 418 38

TFA3^*

7, 2'-Dihydroxy-3', 4'-dimethoxy-isoflavan-7, 2'-di-O-β-D-glucoside

0.037 978 17

TFA4^*

Calycosin

0.016 360 85

47.75

0.24

TFA5^*

Pratensein-7-O-β-D-glucoside

0.056 452 29

TFA6^*

10-Hydroxy-9-methoxypterocarpan-3-O-β-D-glucoside

0.027 192 82

TFA7^*

6''-O-Acetyl calycosin-7-O-β-D-glycoside

0.023 329 57

TFA8^*

Glycyroside

0.030 656 15

37.25

0.79

TFA9^*

Ononin

0.035 375 44

11.52

0.78

TFA10^*

3-Hydroxy-9, 10-dimethoxypterocarpan-3-O-β-D-glucoside

0.022 477 57

TFA11^*#

7, 2'-Dihydroxy-3', 4'-dimethoxy-isoflavan-7-O-β-D-glucoside

0.015 809 63

16.16

0.86

TFA12^*#

Calycosin

0.051 131 86

47.75

0.24

TFA13^*

Dihydroxy-dimethoxyisoflavone

0.016 586 87

TFA14^*

6''-O-Acetyl ononin

0.036 401 27

TFA15^*

Dihydroxy-trimethoxy dihydroisoflavone

0.061 953 26

TFA16^*

3-Hydroxy-9, 10-dimethoxypterocarpan

0.026 405 55

TFA17^*

7, 2'-Dihydroxy-3', 4'-dimethoxy-isoflavan

0.032 532 35

TFA18^*

Formononetin

0.022 347 14

69.67

0.21

TFA19^*

7-Hydroxy-6, 4'-dimethoxyisoflavan

0.038 222 03

TFA20^#

(3R)-3-(2-Hydroxy-3, 4-dimethoxyphenyl)chroman-7-ol

0.040 249 27

67.67

0.26

TFA21^#

5'-Hydroxyiso-muronulatol-2', 5'-di-O-glucoside

0.036 514 41

41.72

0.69

TFA22^#

7-O-Methylisomucronulatol

0.036 690 85

74.69

0.3

TFA23^#

9, 10-Dimethoxypterocarpan-3-O-β-D-glucoside

0.011 433 53

36.74

0.92

TFA24^#

Isoflavanone

0.045 879 49

109.99

0.3

TFA25^#

Isomucronulatol-7, 2'-di-O-glucosiole

0.010 033 14

49.28

0.62

TFA26^#

Isorhamnetin

0.006 536 52

49.6

0.31

TFA27^#

Jaranol

0.011 916 39

50.83

0.29

TFA28^#

Kaempferol

0.004 295 97

41.88

0.24

TFA29^#

Quercetin

0.015 167 40

47.75

0.24

No.	Gene name	Protein name	UniProt ID	Degree	Betweenness
1	ACE	Angiotensin-converting enzyme	P12821	7	0.013 999 41
2	ACHE	Acetylcholinesterase	P22303	24	0.074 162 56
3	ADA	Adenosine deaminase	P00813	13	0.014 974 62
4	AKT1	RAC-alpha serine/threonine-protein kinase	P31749	8	0.017 560 56
5	ALB	Serum albumin	P02768	15	0.008 759 52
6	ALDH2	Aldehyde dehydrogenase, mitochondrial	P05091	5	0.000 869 00
7	ANXA5	Annexin A5	P08758	7	0.001 697 63
8	APOA2	Apolipoprotein A-Ⅱ	P02652	10	0.003 092 04
9	AQP1	Aquaporin-1	P29972	9	0.002 868 61
10	CCNA2	Cyclin-A2	P20248	17	0.011 603 99
11	CD38	ADP-ribosyl cyclase	P28907	7	0.001 958 75
12	DDC	Aromatic-L-amino-acid decarboxylase	P20711	9	0.013 839 84
13	F2	Prothrombin	P00734	20	0.032 690 05
14	FBP1	Fructose-1, 6-bisphosphatase 1	P09467	3	0.000 950 00
15	G6PD	Glucose-6-phosphate1-dehydrogenase	P11413	6	0.004 196 00
16	GC	Vitamin D-binding protein	P02774	13	0.021 355 00
17	GSR	Glutathione reductase, mitochondrial	P00390	14	0.012 622 60
18	GSTM1	Glutathione S-transferase Mu 1	P09488	8	0.008 155 00
19	GSTP1	Glutathione S-transferase P	P09211	13	0.010 657 50
20	HMGCR	3-Hydroxy-3-methylglutaryl-coenzyme A reductase	P04035	6	0.005 811 70
21	HPRT1	Hypoxanthine-guanine phosphoribosyltransferase	P00492	2	0.000 247 00
22	HSD11B1	Corticosteroid 11-beta-dehydrogenase isozyme 1	P28845	12	0.005 933 00
23	HSP90AA1	Heat shock protein HSP 90-alpha	P07900	15	0.009 452 50
24	INS	Insulin	P01308	21	0.039 836 80
25	KDR	Kinase insert domain receptor	P35968	10	0.004 099 40
26	LCN2	Neutrophil gelatinase-associated lipocalin	P80188	4	0.001 563 40
27	LTA4H	Leukotriene A-4 hydrolase	P09960	7	0.001 685 70
28	LYZ	Lysozyme C	P61626	4	0.000 446 00
29	NAGA	Alpha-N-acetylgalactosaminidase	P17050	3	0.000 179 00
30	MAPK14	Mitogen-activated protein kinase 14	Q16539	12	0.005 908 20
31	MIF	Macrophage migration inhibitory factor	P14174	11	0.004 547 20
32	MMP12	Macrophage metalloelastase	P39900	2	0.000 838 00
33	MMP3	Stromelysin-1	P08254	10	0.006 777 20
34	NOS1	Nitric oxide synthase, brain	P29475	10	0.015 600 90
35	NOS2	Nitric oxide synthase, inducible	P35228	19	0.019 989 60
36	NOS3	Nitric oxide synthase, endothelial	P29474	17	0.033 725 50
37	NR3C1	Glucocorticoid receptor	P04150	25	0.067 122 32
38	PAH	Phenylalanine-4-hydroxylase	P00439	11	0.011 512 30
39	PARP1	Poly[ADP-ribose] polymerase 1	P09874	11	0.005 384 30
40	PRKCD	Protein kinase C delta type	Q05655	6	0.001 222 29
41	PRNP	Major prion protein	P04156	4	0.000 527 00
42	RAC1	Ras-related C3 botulinum toxin substrate 1	P63000	3	0.000 409 00
43	RBP4	Retinol-binding protein 4	P02753	5	0.002 304 95
44	RELA	Transcription factor p65	Q04206	3	0.000 527 00
45	REN	Renin	P00797	3	0.000 235 00
46	RETN	Resistin	Q9HD89	7	0.001 496 87
47	RHO	Rhodopsin	P08100	20	0.041 283 12
48	STS	Steryl-sulfatase	P08842	10	0.003 092 04
49	TNF	Tumor necrosis factor	P01375	4	0.000 405 00
50	TTR	Transthyretin	P02766	20	0.014 016 25

No.

Gene name

Protein name

UniProt ID

Degree

Betweenness

ACE

Angiotensin-converting enzyme

P12821

0.013 999 41

ACHE

Acetylcholinesterase

P22303

0.074 162 56

ADA

Adenosine deaminase

P00813

0.014 974 62

AKT1

RAC-alpha serine/threonine-protein kinase

P31749

0.017 560 56

ALB

Serum albumin

P02768

0.008 759 52

ALDH2

Aldehyde dehydrogenase, mitochondrial

P05091

0.000 869 00

ANXA5

Annexin A5

P08758

0.001 697 63

APOA2

Apolipoprotein A-Ⅱ

P02652

0.003 092 04

AQP1

Aquaporin-1

P29972

0.002 868 61

CCNA2

Cyclin-A2

P20248

0.011 603 99

CD38

ADP-ribosyl cyclase

P28907

0.001 958 75

DDC

Aromatic-L-amino-acid decarboxylase

P20711

0.013 839 84

Prothrombin

P00734

0.032 690 05

FBP1

Fructose-1, 6-bisphosphatase 1

P09467

0.000 950 00

G6PD

Glucose-6-phosphate1-dehydrogenase

P11413

0.004 196 00

Vitamin D-binding protein

P02774

0.021 355 00

GSR

Glutathione reductase, mitochondrial

P00390

0.012 622 60

GSTM1

Glutathione S-transferase Mu 1

P09488

0.008 155 00

GSTP1

Glutathione S-transferase P

P09211

0.010 657 50

HMGCR

3-Hydroxy-3-methylglutaryl-coenzyme A reductase

P04035

0.005 811 70

HPRT1

Hypoxanthine-guanine phosphoribosyltransferase

P00492

0.000 247 00

HSD11B1

Corticosteroid 11-beta-dehydrogenase isozyme 1

P28845

0.005 933 00

HSP90AA1

Heat shock protein HSP 90-alpha

P07900

0.009 452 50

INS

Insulin

P01308

0.039 836 80

KDR

Kinase insert domain receptor

P35968

0.004 099 40

LCN2

Neutrophil gelatinase-associated lipocalin

P80188

0.001 563 40

LTA4H

Leukotriene A-4 hydrolase

P09960

0.001 685 70

LYZ

Lysozyme C

P61626

0.000 446 00

NAGA

Alpha-N-acetylgalactosaminidase

P17050

0.000 179 00

MAPK14

Mitogen-activated protein kinase 14

Q16539

0.005 908 20

MIF

Macrophage migration inhibitory factor

P14174

0.004 547 20

MMP12

Macrophage metalloelastase

P39900

0.000 838 00

MMP3

Stromelysin-1

P08254

0.006 777 20

NOS1

Nitric oxide synthase, brain

P29475

0.015 600 90

NOS2

Nitric oxide synthase, inducible

P35228

0.019 989 60

NOS3

Nitric oxide synthase, endothelial

P29474

0.033 725 50

NR3C1

Glucocorticoid receptor

P04150

0.067 122 32

PAH

Phenylalanine-4-hydroxylase

P00439

0.011 512 30

PARP1

Poly[ADP-ribose] polymerase 1

P09874

0.005 384 30

PRKCD

Protein kinase C delta type

Q05655

0.001 222 29

PRNP

Major prion protein

P04156

0.000 527 00

RAC1

Ras-related C3 botulinum toxin substrate 1

P63000

0.000 409 00

RBP4

Retinol-binding protein 4

P02753

0.002 304 95

RELA

Transcription factor p65

Q04206

0.000 527 00

REN

Renin

P00797

0.000 235 00

RETN

Resistin

Q9HD89

0.001 496 87

RHO

Rhodopsin

P08100

0.041 283 12

STS

Steryl-sulfatase

P08842

0.003 092 04

TNF

Tumor necrosis factor

P01375

0.000 405 00

TTR

Transthyretin

P02766

0.014 016 25

No.	Gene name	Protein name	UniProt ID	Degree	Betweenness
1	ACE	Angiotensin-converting enzyme	P12821	7	0.013 999 41
2	ACHE	Acetylcholinesterase	P22303	24	0.074 162 56
3	ADA	Adenosine deaminase	P00813	13	0.014 974 62
4	AKT1	RAC-alpha serine/threonine-protein kinase	P31749	8	0.017 560 56
5	ALB	Serum albumin	P02768	15	0.008 759 52
6	ALDH2	Aldehyde dehydrogenase, mitochondrial	P05091	5	0.000 869 00
7	ANXA5	Annexin A5	P08758	7	0.001 697 63
8	APOA2	Apolipoprotein A-Ⅱ	P02652	10	0.003 092 04
9	AQP1	Aquaporin-1	P29972	9	0.002 868 61
10	CCNA2	Cyclin-A2	P20248	17	0.011 603 99
11	CD38	ADP-ribosyl cyclase	P28907	7	0.001 958 75
12	DDC	Aromatic-L-amino-acid decarboxylase	P20711	9	0.013 839 84
13	F2	Prothrombin	P00734	20	0.032 690 05
14	FBP1	Fructose-1, 6-bisphosphatase 1	P09467	3	0.000 950 00
15	G6PD	Glucose-6-phosphate1-dehydrogenase	P11413	6	0.004 196 00
16	GC	Vitamin D-binding protein	P02774	13	0.021 355 00
17	GSR	Glutathione reductase, mitochondrial	P00390	14	0.012 622 60
18	GSTM1	Glutathione S-transferase Mu 1	P09488	8	0.008 155 00
19	GSTP1	Glutathione S-transferase P	P09211	13	0.010 657 50
20	HMGCR	3-Hydroxy-3-methylglutaryl-coenzyme A reductase	P04035	6	0.005 811 70
21	HPRT1	Hypoxanthine-guanine phosphoribosyltransferase	P00492	2	0.000 247 00
22	HSD11B1	Corticosteroid 11-beta-dehydrogenase isozyme 1	P28845	12	0.005 933 00
23	HSP90AA1	Heat shock protein HSP 90-alpha	P07900	15	0.009 452 50
24	INS	Insulin	P01308	21	0.039 836 80
25	KDR	Kinase insert domain receptor	P35968	10	0.004 099 40
26	LCN2	Neutrophil gelatinase-associated lipocalin	P80188	4	0.001 563 40
27	LTA4H	Leukotriene A-4 hydrolase	P09960	7	0.001 685 70
28	LYZ	Lysozyme C	P61626	4	0.000 446 00
29	NAGA	Alpha-N-acetylgalactosaminidase	P17050	3	0.000 179 00
30	MAPK14	Mitogen-activated protein kinase 14	Q16539	12	0.005 908 20
31	MIF	Macrophage migration inhibitory factor	P14174	11	0.004 547 20
32	MMP12	Macrophage metalloelastase	P39900	2	0.000 838 00
33	MMP3	Stromelysin-1	P08254	10	0.006 777 20
34	NOS1	Nitric oxide synthase, brain	P29475	10	0.015 600 90
35	NOS2	Nitric oxide synthase, inducible	P35228	19	0.019 989 60
36	NOS3	Nitric oxide synthase, endothelial	P29474	17	0.033 725 50
37	NR3C1	Glucocorticoid receptor	P04150	25	0.067 122 32
38	PAH	Phenylalanine-4-hydroxylase	P00439	11	0.011 512 30
39	PARP1	Poly[ADP-ribose] polymerase 1	P09874	11	0.005 384 30
40	PRKCD	Protein kinase C delta type	Q05655	6	0.001 222 29
41	PRNP	Major prion protein	P04156	4	0.000 527 00
42	RAC1	Ras-related C3 botulinum toxin substrate 1	P63000	3	0.000 409 00
43	RBP4	Retinol-binding protein 4	P02753	5	0.002 304 95
44	RELA	Transcription factor p65	Q04206	3	0.000 527 00
45	REN	Renin	P00797	3	0.000 235 00
46	RETN	Resistin	Q9HD89	7	0.001 496 87
47	RHO	Rhodopsin	P08100	20	0.041 283 12
48	STS	Steryl-sulfatase	P08842	10	0.003 092 04
49	TNF	Tumor necrosis factor	P01375	4	0.000 405 00
50	TTR	Transthyretin	P02766	20	0.014 016 25

No.

Gene name

Protein name

UniProt ID

Degree

Betweenness

ACE

Angiotensin-converting enzyme

P12821

0.013 999 41

ACHE

Acetylcholinesterase

P22303

0.074 162 56

ADA

Adenosine deaminase

P00813

0.014 974 62

AKT1

RAC-alpha serine/threonine-protein kinase

P31749

0.017 560 56

ALB

Serum albumin

P02768

0.008 759 52

ALDH2

Aldehyde dehydrogenase, mitochondrial

P05091

0.000 869 00

ANXA5

Annexin A5

P08758

0.001 697 63

APOA2

Apolipoprotein A-Ⅱ

P02652

0.003 092 04

AQP1

Aquaporin-1

P29972

0.002 868 61

CCNA2

Cyclin-A2

P20248

0.011 603 99

CD38

ADP-ribosyl cyclase

P28907

0.001 958 75

DDC

Aromatic-L-amino-acid decarboxylase

P20711

0.013 839 84

Prothrombin

P00734

0.032 690 05

FBP1

Fructose-1, 6-bisphosphatase 1

P09467

0.000 950 00

G6PD

Glucose-6-phosphate1-dehydrogenase

P11413

0.004 196 00

Vitamin D-binding protein

P02774

0.021 355 00

GSR

Glutathione reductase, mitochondrial

P00390

0.012 622 60

GSTM1

Glutathione S-transferase Mu 1

P09488

0.008 155 00

GSTP1

Glutathione S-transferase P

P09211

0.010 657 50

HMGCR

3-Hydroxy-3-methylglutaryl-coenzyme A reductase

P04035

0.005 811 70

HPRT1

Hypoxanthine-guanine phosphoribosyltransferase

P00492

0.000 247 00

HSD11B1

Corticosteroid 11-beta-dehydrogenase isozyme 1

P28845

0.005 933 00

HSP90AA1

Heat shock protein HSP 90-alpha

P07900

0.009 452 50

INS

Insulin

P01308

0.039 836 80

KDR

Kinase insert domain receptor

P35968

0.004 099 40

LCN2

Neutrophil gelatinase-associated lipocalin

P80188

0.001 563 40

LTA4H

Leukotriene A-4 hydrolase

P09960

0.001 685 70

LYZ

Lysozyme C

P61626

0.000 446 00

NAGA

Alpha-N-acetylgalactosaminidase

P17050

0.000 179 00

MAPK14

Mitogen-activated protein kinase 14

Q16539

0.005 908 20

MIF

Macrophage migration inhibitory factor

P14174

0.004 547 20

MMP12

Macrophage metalloelastase

P39900

0.000 838 00

MMP3

Stromelysin-1

P08254

0.006 777 20

NOS1

Nitric oxide synthase, brain

P29475

0.015 600 90

NOS2

Nitric oxide synthase, inducible

P35228

0.019 989 60

NOS3

Nitric oxide synthase, endothelial

P29474

0.033 725 50

NR3C1

Glucocorticoid receptor

P04150

0.067 122 32

PAH

Phenylalanine-4-hydroxylase

P00439

0.011 512 30

PARP1

Poly[ADP-ribose] polymerase 1

P09874

0.005 384 30

PRKCD

Protein kinase C delta type

Q05655

0.001 222 29

PRNP

Major prion protein

P04156

0.000 527 00

RAC1

Ras-related C3 botulinum toxin substrate 1

P63000

0.000 409 00

RBP4

Retinol-binding protein 4

P02753

0.002 304 95

RELA

Transcription factor p65

Q04206

0.000 527 00

REN

Renin

P00797

0.000 235 00

RETN

Resistin

Q9HD89

0.001 496 87

RHO

Rhodopsin

P08100

0.041 283 12

STS

Steryl-sulfatase

P08842

0.003 092 04

TNF

Tumor necrosis factor

P01375

0.000 405 00

TTR

Transthyretin

P02766

0.014 016 25

Target name	PDB ID	Ingredient	Docking score
ACHE	3LII	TFA1	5.426
NR3C1	3BQD	TFA1	5.299
INS	1TYL	TFA1	5.792
RHO	1A62	TFA1	6.972
TTR	1GHE	TFA1	5.793
ACHE	3LII	TFA2	6.81
NR3C1	3BQD	TFA2	6.355
INS	1TYL	TFA2	5.616
RHO	1A62	TFA2	6.702
TTR	1GHE	TFA2	6.821
ACHE	3LII	TFA4	5.337
NR3C1	3BQD	TFA4	6.773
INS	1TYL	TFA4	5.602
RHO	1A62	TFA4	5.278
TTR	1GHE	TFA4	6.178
ACHE	3LII	TFA6	5.335
NR3C1	3BQD	TFA6	8.13
INS	1TYL	TFA6	5.585
RHO	1A62	TFA6	5.272
TTR	1GHE	TFA6	6.196
ACHE	3LII	TFA7	5.374
NR3C1	3BQD	TFA7	7.038
INS	1TYL	TFA7	5.909
RHO	1A62	TFA7	5.246
TTR	1GHE	TFA7	6.171
ACHE	3LII	TFA8	5.302
NR3C1	3BQD	TFA8	7.106
INS	1TYL	TFA8	5.751
RHO	1A62	TFA8	5.28
TTR	1GHE	TFA8	6.438
ACHE	3LII	TFA9	5.174
NR3C1	3BQD	TFA9	8.11
INS	1TYL	TFA9	6.835
RHO	1A62	TFA9	6.302
TTR	1GHE	TFA9	8.172
ACHE	3LII	TFA10	6.993
NR3C1	3BQD	TFA10	6.524
INS	1TYL	TFA10	4.784
RHO	1A62	TFA10	6.79
TTR	1GHE	TFA10	6.944
ACHE	3LII	TFA11	5.429
NR3C1	3BQD	TFA11	7.086
INS	1TYL	TFA11	5.714
RHO	1A62	TFA11	5.284
TTR	1GHE	TFA11	6.237
ACHE	3LII	TFA12	5.395
NR3C1	3BQD	TFA12	7.086
INS	1TYL	TFA12	5.844
RHO	1A62	TFA12	5.231
TTR	1GHE	TFA12	6.209
ACHE	3LII	TFA14	5.363
NR3C1	3BQD	TFA14	7.075
INS	1TYL	TFA14	5.738
RHO	1A62	TFA14	5.208
TTR	1GHE	TFA14	6.251
ACHE	3LII	TFA17	6.733
NR3C1	3BQD	TFA17	7.013
INS	1TYL	TFA17	6.025
RHO	1A62	TFA17	6.552
TTR	1GHE	TFA17	6.703
ACHE	3LII	TFA18	5.271
NR3C1	3BQD	TFA18	8.234
INS	1TYL	TFA18	5.972
RHO	1A62	TFA18	5.33
TTR	1GHE	TFA18	6.21
ACHE	3LII	TFA21	5.354
NR3C1	3BQD	TFA21	8.286
INS	1TYL	TFA21	5.976
RHO	1A62	TFA21	5.349
TTR	1GHE	TFA21	6.259
ACHE	3LII	TFA23	5.438
NR3C1	3BQD	TFA23	7.086
INS	1TYL	TFA23	5.685
RHO	1A62	TFA23	5.21
TTR	1GHE	TFA23	6.129
ACHE	3LII	TFA25	5.425
NR3C1	3BQD	TFA25	8.353
INS	1TYL	TFA25	6.372
RHO	1A62	TFA25	5.378
TTR	1GHE	TFA25	6.374
ACHE	3LII	TFA28	6.699
NR3C1	3BQD	TFA28	6.678
INS	1TYL	TFA28	5.636
RHO	1A62	TFA28	6.464
TTR	1GHE	TFA28	6.778
ACHE	3LII	TFA29	6.662
NR3C1	3BQD	TFA29	6.684
INS	1TYL	TFA29	5.623
RHO	1A62	TFA29	6.471
TTR	1GHE	TFA29	6.715
ACHE	3LII	Tacrolimus	4.991
NR3C1	3BQD	Tacrolimus	7.992
INS	1TYL	Tacrolimus	7.223
RHO	1A62	Tacrolimus	6.197
TTR	1GHE	Tacrolimus	8.361

Target name

PDB ID

Ingredient

Docking score

ACHE

3LII

TFA1

5.426

NR3C1

3BQD

TFA1

5.299

INS

1TYL

TFA1

5.792

RHO

1A62

TFA1

6.972

TTR

1GHE

TFA1

5.793

ACHE

3LII

TFA2

6.81

NR3C1

3BQD

TFA2

6.355

INS

1TYL

TFA2

5.616

RHO

1A62

TFA2

6.702

TTR

1GHE

TFA2

6.821

ACHE

3LII

TFA4

5.337

NR3C1

3BQD

TFA4

6.773

INS

1TYL

TFA4

5.602

RHO

1A62

TFA4

5.278

TTR

1GHE

TFA4

6.178

ACHE

3LII

TFA6

5.335

NR3C1

3BQD

TFA6

8.13

INS

1TYL

TFA6

5.585

RHO

1A62

TFA6

5.272

TTR

1GHE

TFA6

6.196

ACHE

3LII

TFA7

5.374

NR3C1

3BQD

TFA7

7.038

INS

1TYL

TFA7

5.909

RHO

1A62

TFA7

5.246

TTR

1GHE

TFA7

6.171

ACHE

3LII

TFA8

5.302

NR3C1

3BQD

TFA8

7.106

INS

1TYL

TFA8

5.751

RHO

1A62

TFA8

5.28

TTR

1GHE

TFA8

6.438

ACHE

3LII

TFA9

5.174

NR3C1

3BQD

TFA9

8.11

INS

1TYL

TFA9

6.835

RHO

1A62

TFA9

6.302

TTR

1GHE

TFA9

8.172

ACHE

3LII

TFA10

6.993

NR3C1

3BQD

TFA10

6.524

INS

1TYL

TFA10

4.784

RHO

1A62

TFA10

6.79

TTR

1GHE

TFA10

6.944

ACHE

3LII

TFA11

5.429

NR3C1

3BQD

TFA11

7.086

INS

1TYL

TFA11

5.714

RHO

1A62

TFA11

5.284

TTR

1GHE

TFA11

6.237

ACHE

3LII

TFA12

5.395

NR3C1

3BQD

TFA12

7.086

INS

1TYL

TFA12

5.844

RHO

1A62

TFA12

5.231

TTR

1GHE

TFA12

6.209

ACHE

3LII

TFA14

5.363

NR3C1

3BQD

TFA14

7.075

INS

1TYL

TFA14

5.738

RHO

1A62

TFA14

5.208

TTR

1GHE

TFA14

6.251

ACHE

3LII

TFA17

6.733

NR3C1

3BQD

TFA17

7.013

INS

1TYL

TFA17

6.025

RHO

1A62

TFA17

6.552

TTR

1GHE

TFA17

6.703

ACHE

3LII

TFA18

5.271

NR3C1

3BQD

TFA18

8.234

INS

1TYL

TFA18

5.972

RHO

1A62

TFA18

5.33

TTR

1GHE

TFA18

6.21

ACHE

3LII

TFA21

5.354

NR3C1

3BQD

TFA21

8.286

INS

1TYL

TFA21

5.976

RHO

1A62

TFA21

5.349

TTR

1GHE

TFA21

6.259

ACHE

3LII

TFA23

5.438

NR3C1

3BQD

TFA23

7.086

INS

1TYL

TFA23

5.685

RHO

1A62

TFA23

5.21

TTR

1GHE

TFA23

6.129

ACHE

3LII

TFA25

5.425

NR3C1

3BQD

TFA25

8.353

INS

1TYL

TFA25

6.372

RHO

1A62

TFA25

5.378

TTR

1GHE

TFA25

6.374

ACHE

3LII

TFA28

6.699

NR3C1

3BQD

TFA28

6.678

INS

1TYL

TFA28

5.636

RHO

1A62

TFA28

6.464

TTR

1GHE

TFA28

6.778

ACHE

3LII

TFA29

6.662

NR3C1

3BQD

TFA29

6.684

INS

1TYL

TFA29

5.623

RHO

1A62

TFA29

6.471

TTR

1GHE

TFA29

6.715

ACHE

3LII

Tacrolimus

4.991

NR3C1

3BQD

Tacrolimus

7.992

INS

1TYL

Tacrolimus

7.223

RHO

1A62

Tacrolimus

6.197

TTR

1GHE

Tacrolimus

8.361

Target name	PDB ID	Ingredient	Docking score
ACHE	3LII	TFA1	5.426
NR3C1	3BQD	TFA1	5.299
INS	1TYL	TFA1	5.792
RHO	1A62	TFA1	6.972
TTR	1GHE	TFA1	5.793
ACHE	3LII	TFA2	6.81
NR3C1	3BQD	TFA2	6.355
INS	1TYL	TFA2	5.616
RHO	1A62	TFA2	6.702
TTR	1GHE	TFA2	6.821
ACHE	3LII	TFA4	5.337
NR3C1	3BQD	TFA4	6.773
INS	1TYL	TFA4	5.602
RHO	1A62	TFA4	5.278
TTR	1GHE	TFA4	6.178
ACHE	3LII	TFA6	5.335
NR3C1	3BQD	TFA6	8.13
INS	1TYL	TFA6	5.585
RHO	1A62	TFA6	5.272
TTR	1GHE	TFA6	6.196
ACHE	3LII	TFA7	5.374
NR3C1	3BQD	TFA7	7.038
INS	1TYL	TFA7	5.909
RHO	1A62	TFA7	5.246
TTR	1GHE	TFA7	6.171
ACHE	3LII	TFA8	5.302
NR3C1	3BQD	TFA8	7.106
INS	1TYL	TFA8	5.751
RHO	1A62	TFA8	5.28
TTR	1GHE	TFA8	6.438
ACHE	3LII	TFA9	5.174
NR3C1	3BQD	TFA9	8.11
INS	1TYL	TFA9	6.835
RHO	1A62	TFA9	6.302
TTR	1GHE	TFA9	8.172
ACHE	3LII	TFA10	6.993
NR3C1	3BQD	TFA10	6.524
INS	1TYL	TFA10	4.784
RHO	1A62	TFA10	6.79
TTR	1GHE	TFA10	6.944
ACHE	3LII	TFA11	5.429
NR3C1	3BQD	TFA11	7.086
INS	1TYL	TFA11	5.714
RHO	1A62	TFA11	5.284
TTR	1GHE	TFA11	6.237
ACHE	3LII	TFA12	5.395
NR3C1	3BQD	TFA12	7.086
INS	1TYL	TFA12	5.844
RHO	1A62	TFA12	5.231
TTR	1GHE	TFA12	6.209
ACHE	3LII	TFA14	5.363
NR3C1	3BQD	TFA14	7.075
INS	1TYL	TFA14	5.738
RHO	1A62	TFA14	5.208
TTR	1GHE	TFA14	6.251
ACHE	3LII	TFA17	6.733
NR3C1	3BQD	TFA17	7.013
INS	1TYL	TFA17	6.025
RHO	1A62	TFA17	6.552
TTR	1GHE	TFA17	6.703
ACHE	3LII	TFA18	5.271
NR3C1	3BQD	TFA18	8.234
INS	1TYL	TFA18	5.972
RHO	1A62	TFA18	5.33
TTR	1GHE	TFA18	6.21
ACHE	3LII	TFA21	5.354
NR3C1	3BQD	TFA21	8.286
INS	1TYL	TFA21	5.976
RHO	1A62	TFA21	5.349
TTR	1GHE	TFA21	6.259
ACHE	3LII	TFA23	5.438
NR3C1	3BQD	TFA23	7.086
INS	1TYL	TFA23	5.685
RHO	1A62	TFA23	5.21
TTR	1GHE	TFA23	6.129
ACHE	3LII	TFA25	5.425
NR3C1	3BQD	TFA25	8.353
INS	1TYL	TFA25	6.372
RHO	1A62	TFA25	5.378
TTR	1GHE	TFA25	6.374
ACHE	3LII	TFA28	6.699
NR3C1	3BQD	TFA28	6.678
INS	1TYL	TFA28	5.636
RHO	1A62	TFA28	6.464
TTR	1GHE	TFA28	6.778
ACHE	3LII	TFA29	6.662
NR3C1	3BQD	TFA29	6.684
INS	1TYL	TFA29	5.623
RHO	1A62	TFA29	6.471
TTR	1GHE	TFA29	6.715
ACHE	3LII	Tacrolimus	4.991
NR3C1	3BQD	Tacrolimus	7.992
INS	1TYL	Tacrolimus	7.223
RHO	1A62	Tacrolimus	6.197
TTR	1GHE	Tacrolimus	8.361

Target name

PDB ID

Ingredient

Docking score

ACHE

3LII

TFA1

5.426

NR3C1

3BQD

TFA1

5.299

INS

1TYL

TFA1

5.792

RHO

1A62

TFA1

6.972

TTR

1GHE

TFA1

5.793

ACHE

3LII

TFA2

6.81

NR3C1

3BQD

TFA2

6.355

INS

1TYL

TFA2

5.616

RHO

1A62

TFA2

6.702

TTR

1GHE

TFA2

6.821

ACHE

3LII

TFA4

5.337

NR3C1

3BQD

TFA4

6.773

INS

1TYL

TFA4

5.602

RHO

1A62

TFA4

5.278

TTR

1GHE

TFA4

6.178

ACHE

3LII

TFA6

5.335

NR3C1

3BQD

TFA6

8.13

INS

1TYL

TFA6

5.585

RHO

1A62

TFA6

5.272

TTR

1GHE

TFA6

6.196

ACHE

3LII

TFA7

5.374

NR3C1

3BQD

TFA7

7.038

INS

1TYL

TFA7

5.909

RHO

1A62

TFA7

5.246

TTR

1GHE

TFA7

6.171

ACHE

3LII

TFA8

5.302

NR3C1

3BQD

TFA8

7.106

INS

1TYL

TFA8

5.751

RHO

1A62

TFA8

5.28

TTR

1GHE

TFA8

6.438

ACHE

3LII

TFA9

5.174

NR3C1

3BQD

TFA9

8.11

INS

1TYL

TFA9

6.835

RHO

1A62

TFA9

6.302

TTR

1GHE

TFA9

8.172

ACHE

3LII

TFA10

6.993

NR3C1

3BQD

TFA10

6.524

INS

1TYL

TFA10

4.784

RHO

1A62

TFA10

6.79

TTR

1GHE

TFA10

6.944

ACHE

3LII

TFA11

5.429

NR3C1

3BQD

TFA11

7.086

INS

1TYL

TFA11

5.714

RHO

1A62

TFA11

5.284

TTR

1GHE

TFA11

6.237

ACHE

3LII

TFA12

5.395

NR3C1

3BQD

TFA12

7.086

INS

1TYL

TFA12

5.844

RHO

1A62

TFA12

5.231

TTR

1GHE

TFA12

6.209

ACHE

3LII

TFA14

5.363

NR3C1

3BQD

TFA14

7.075

INS

1TYL

TFA14

5.738

RHO

1A62

TFA14

5.208

TTR

1GHE

TFA14

6.251

ACHE

3LII

TFA17

6.733

NR3C1

3BQD

TFA17

7.013

INS

1TYL

TFA17

6.025

RHO

1A62

TFA17

6.552

TTR

1GHE

TFA17

6.703

ACHE

3LII

TFA18

5.271

NR3C1

3BQD

TFA18

8.234

INS

1TYL

TFA18

5.972

RHO

1A62

TFA18

5.33

TTR

1GHE

TFA18

6.21

ACHE

3LII

TFA21

5.354

NR3C1

3BQD

TFA21

8.286

INS

1TYL

TFA21

5.976

RHO

1A62

TFA21

5.349

TTR

1GHE

TFA21

6.259

ACHE

3LII

TFA23

5.438

NR3C1

3BQD

TFA23

7.086

INS

1TYL

TFA23

5.685

RHO

1A62

TFA23

5.21

TTR

1GHE

TFA23

6.129

ACHE

3LII

TFA25

5.425

NR3C1

3BQD

TFA25

8.353

INS

1TYL

TFA25

6.372

RHO

1A62

TFA25

5.378

TTR

1GHE

TFA25

6.374

ACHE

3LII

TFA28

6.699

NR3C1

3BQD

TFA28

6.678

INS

1TYL

TFA28

5.636

RHO

1A62

TFA28

6.464

TTR

1GHE

TFA28

6.778

ACHE

3LII

TFA29

6.662

NR3C1

3BQD

TFA29

6.684

INS

1TYL

TFA29

5.623

RHO

1A62

TFA29

6.471

TTR

1GHE

TFA29

6.715

ACHE

3LII

Tacrolimus

4.991

NR3C1

3BQD

Tacrolimus

7.992

INS

1TYL

Tacrolimus

7.223

RHO

1A62

Tacrolimus

6.197

TTR

1GHE

Tacrolimus

8.361

基于网络药理学的黄芪总黄酮治疗肾病综合征的机制研究

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张王宁 ¹^,² , 高耀 ¹^,² , 李科 ¹^,² , 钞建宾 ³ , 秦雪梅 ¹^,²^,^* , 李爱平 ¹^,²^,^*

药学学报 | 专题报道 2018,53(9): 1429-1441

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药学学报 | 专题报道 2018, 53(9): 1429-1441

基于网络药理学的黄芪总黄酮治疗肾病综合征的机制研究

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张王宁¹^,², 高耀¹^,², 李科¹^,², 钞建宾³, 秦雪梅¹^,²^,^*, 李爱平¹^,²^,^*

作者信息

1.山西大学中医药现代研究中心, 山西太原 030006

2.山西大学地产中药功效物质研究与利用山西省重点实验室, 山西太原 030006

3.山西大学大型仪器中心, 山西太原 030006

通讯作者:

* 秦雪梅, Tel:86-351-7011501, E-mail:qinxm@sxu.edu.cn;

李爱平, Tel:86-351-7018379, E-mail:aipingli@sxu.edu.cn

Exploration into the mechanism of total flavonoids of Astragali Radix in the treatment of nephrotic syndrome based on network pharmacology

Wang-ning ZHANG¹^,², Yao GAO¹^,², Ke LI¹^,², Jian-bin CHAO³, Xue-mei QIN¹^,²^,^*, Ai-ping LI¹^,²^,^*

Affiliations

1. Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, China

2. Shanxi Key Laboratory of Active Constituents Research and Utilization of TCM, Shanxi University, Taiyuan 030006, China

3. Scientific Instrument Center, Shanxi University, Taiyuan 030006, China

出版时间: 2018-09-15 doi: 10.16438/j.0513-4870.2018-0251

文章导航

摘要

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构建黄芪总黄酮活性成分-作用靶点网络和蛋白相互作用网络，对靶点涉及的功能和通路进行分析，探讨黄芪总黄酮治疗肾病综合征的作用机制。采用¹H NMR和LC-MS辨识黄芪总黄酮化学成分，检索TCMSP与TCMID数据库获取黄芪总黄酮主要活性成分，利用PharmMapper服务器、SEA、SIB、HOME-NCBI-GENE、GeneCards和OMIM数据库预测和筛选黄芪总黄酮治疗肾病综合征的作用靶点。采用Cytoscape软件构建活性成分-作用靶点网络与蛋白相互作用网络图，采用ClueGO软件对靶点进行GO富集分析及KEGG通路分析，通过BioGPS数据库对靶点所属的组织分布进行归属，并通过Systems Dock Web Site对成分与靶点进行分子对接验证。筛选得到黄芪总黄酮29个活性成分，涉及50个作用靶点。网络分析结果表明，黄芪总黄酮主要涉及炎症反应过程、氧化应激过程、凋亡与自噬等生物过程，通过调节AGE-RAGE、PI3K/Akt、VEGF、IL-17和MAPK等信号通路来发挥治疗肾病综合征的作用。本研究体现了黄芪总黄酮多成分、多靶点、多途径的作用特点，为进一步开展黄芪总黄酮治疗肾病综合征作用机制的研究提供了新思路和新方法。

关键词

黄芪总黄酮 / 肾病综合征 / 网络药理学 / 药理机制 / 分子对接

Abstract

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This study was designed to explore the mechanism of total flavonoids of Astragali Radix (TFA) in treating nephrotic syndrome through establishing the active components-targets network and protein-protein interaction (PPI) networks and analyzing the functions and pathways involved in the targets. The main active ingredients of TFA were obtained by ¹H NMR and LC-MS, TCMSP and TCMID database. PharmMapper, SEA, SIB, HOME-NCBI-GENE, GeneCards and OMIM were used to predict and screen the active components of TFA. The Cytoscape software was used to construct the active components-targets network and protein-protein interactions network. The relation between the main active ingredients and targets were validated by Systems Dock Web Site. The GO and KEGG pathways involved in the targets were analyzed by ClueGO software. The target organ distribution was assigned by the BioGPS database. The results showed that 29 active components and 50 targets of TFA were screened and predicted. The network results showed that the TFA were mainly involved in biological processes such as inflammatory reaction process, oxidative stress process, apoptosis and autophagy, and played a role in the regulation of AGE-RAGE, PI3K/Akt, VEGF, IL-17 and MAPK signaling pathways to treat the nephrotic syndrome. This study reflects the characteristics of multi-components, multi-targets and multi-pathways of TFA, which provides new ideas and clues for further research on the mechanism of anti-nephrotic syndrome effects of TFA.

Key words

total flavonoids of Astragali Radix / nephrotic syndrome / network pharmacology / pharmacological mechanism / molecular docking

引用本文

张王宁, 高耀, 李科, 钞建宾, 秦雪梅, 李爱平. 基于网络药理学的黄芪总黄酮治疗肾病综合征的机制研究. 药学学报, 2018 , 53 (9) : 1429 -1441 . DOI: 10.16438/j.0513-4870.2018-0251

Wang-ning ZHANG, Yao GAO, Ke LI, Jian-bin CHAO, Xue-mei QIN, Ai-ping LI. Exploration into the mechanism of total flavonoids of Astragali Radix in the treatment of nephrotic syndrome based on network pharmacology[J]. Acta Pharmaceutica Sinica, 2018 , 53 (9) : 1429 -1441 . DOI: 10.16438/j.0513-4870.2018-0251

正文

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肾病综合征(NS)是一种由环境因素和遗传因素相互作用而引起的慢性代谢性疾病^[1]。由各种原因引起的肾小球滤过膜通透性改变以及大量的尿蛋白产生是其主要特征和诱因, 且大量的尿蛋白会引起高血压和高脂血症, 从而促使肾小球硬化^[2]。NS的发病机制非常复杂, 主要涉及循环和代谢系统。研究表明, 肾脏炎症、细胞凋亡、氧化应激和足细胞损伤与NS的病理特征^[3-5]相关。在现有的抗肾病综合征药物中, 免疫抑制剂和糖皮质激素药物是治疗轻、中度肾病综合征的首选药物。然而, 免疫抑制疗法^[6]可引起许多严重的不良反应, 如真菌感染、各种器官衰竭(心脏、肾脏和耳朵), 以及治疗后的快速复发。每日口服糖皮质激素的要求常常使患者依从性差, 限制了糖皮质激素在NS治疗中的使用^[7]。此外, 免疫抑制剂和糖皮质激素药物在所有患者中并不普遍有效, 尽管它们是临床实践中肾病综合征的推荐药物。

黄芪总黄酮(total flavonoids of Astragali Radix, TFA)是从传统中药黄芪中分离出的黄酮类成分, 具有体内外抗炎作用、免疫作用、抑制内质网应激等生物活性。Guo等^[8]研究了黄芪总黄酮对脂多糖刺激的RAW264.7细胞中炎症因子转录水平的影响, 得出黄芪总黄酮具有抗炎免疫的调节作用。Guo和Zhang^{[9, 10]}均对黄芪总黄酮进行活性研究, 得出了黄芪总黄酮可以减少细胞凋亡, 并参与了细胞的抗氧化应激反应。本课题组前期实验得出黄芪总黄酮对肾病综合征有治疗作用。然而, 黄芪总黄酮多成分多靶点的调节作用, 使黄芪总黄酮治疗肾病综合征的作用机制仍不明确, 因此借助网络药理学的方法挖掘治疗肾病综合征的作用靶点与通路, 从系统生物学角度整体阐释黄芪总黄酮治疗肾病综合征的作用机制具有重要意义。

网络药理学是药理学中的新兴学科, 旨在以整体的方式了解药物在生物系统中的作用, 为理解药物成分与疾病靶点之间的复杂相互作用提供新的视角, 特别适合于多成分、多靶点、多途径的中药药效机制和物质基础研究。网络药理学对中药治疗疾病的作用机制研究越来越多, Wu等^[11]基于网络药理学对柴胡抗抑郁的作用机制, 得出柴胡可能通过调节PI3K/Akt、MAPK、Rap1、Ras、FexO和neurotrophin等信号通路发挥抗抑郁作用。Zhai等^[12]通过构建“成分-核心靶点-通路”网络模型, 预测二至丸主要干预胰岛素、FoxO、代谢通路与糖酵解等通路发挥保肝作用。

基于本课题组前期工作, 以多柔比星诱导的肾病大鼠为模型, 腹腔注射黄芪总黄酮后, 大鼠24 h尿蛋白、血清生化指标、组织病理切片等指标都有明显的改善, 且通过代谢组学的研究, 有68%代谢物有回调现象, 表明黄芪总黄酮对肾病综合征有确切疗效^[13]。因此, 本文以黄芪中的黄酮类化合物为研究对象, 采用网络药理学方法阐释黄芪总黄酮多成分、多靶点、多途径的作用机制, 为后续实验提供理论依据。

材料与方法

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黄芪总黄酮化学成分的确定 将黄芪药材水提取液浓缩至0.5 g·mL^-1, 将浓缩液通过预处理的AB-8大孔吸附树脂柱, 依次用20倍体积水、10倍体积10%乙醇、10倍体积35%乙醇进行洗脱, 收集35%乙醇洗脱液, 浓缩, 乙酸乙酯萃取3次, 浓缩至干, 80 ℃减压干燥24 h至恒重, 得黄芪总黄酮固体, 进而对其进行核磁与液质分析。对黄芪总黄酮的¹H NMR图谱与UHPLC-Q-Exactive-Orbittrap-HRMS图谱鉴定出的化学成分^[14]以及利用TCMSP数据库^[15] (http://lsp.nwu.edu.cn/tcmsp.php)、TCMID数据库^[16] (http://www.megabionet.org/tcmid/)整合的活性成分, 共同作为黄芪总黄酮的活性成分。因中药用药多为汤剂, 需通过吸收(absorption)、分布(distribution)、代谢(metabolism)和排泄(excretion)的过程发挥药效作用, 即ADME过程。通常, 中药有效成分的发现需要经过分离、提纯和结构鉴定等传统过程, 耗时耗力。为更有效地对中药有效成分进行研究, 计算机虚拟筛选方法应运而生, 通过模拟ADME过程筛选活性成分, 主要以脂溶性预测(AlogP)、口服利用度预测(OB%)、Caco-2渗透率预测、血脑屏障(BBB)、类药性(DL)等参数作为评价指标。其中OB和DL是用于筛选药物活性物质的重要参数, 是中药成分ADME的关键。OB指药物的有效成分或活性基被吸收到达体循环并被吸收的速度与程度; DL指药物包含一些特定的功能基团或者具有与大多数药物相同或相似的物理特征。因此利用TCMSP数据库与TCMID数据库, 筛选出同时满足OB≥30%和DL≥0.18的化学成分, 结合图谱鉴定出的化学成分共同作为黄芪总黄酮的活性成分。

黄芪总黄酮潜在作用靶点的筛选 筛选出的所有活性成分在PubChem数据库中下载其化学结构图的.sdf格式以及Smiles化学式。首先, 登录反向药效团匹配数据库“PharmMapper” (http://59.78.98.102/pharmmapper/submit_file.php), 上传黄芪总黄酮活性成分的.sdf格式文件, 然后选择Pharmacophore Models Whose Pkd≥6.0, 设置匹配的靶点数目为300, 点击submit, 即可得到每个活性成分对应得分排名前300的靶点。其次, 将活性成分对应的Smiles化学式输入到SEA (http://sea.bkslab.org/)与SIB (http://www.swisstargetprediction.ch/)数据库, 得到作用靶点。为提高作用靶点的准确度, 将这3个数据库得到的作用靶点取交集, 作为黄芪总黄酮潜在作用靶点, 即成分靶点。最后, 应用蛋白质数据库(UniProt)中UniProtKB搜索功能(http://www.uniprot.org/uniprot/), 通过输入靶点名称并限定物种为人, 将检索得到的所有靶点校正为其官方名称(official symbol)后, 获取与活性成分相关的靶点和Unitprot编号。

肾病综合征潜在作用靶点的筛选 利用在线文本挖掘服务器GeneCards (http://www.genecards.org/)、HOME-NCBI-GENE (https://www.ncbi.nlm.nih.gov/gene)、人类孟德尔遗传OMIM (http://www.omim.org/)数据库输入关键词查找分析相关的人类基因。通过输入关键词“nephrotic syndrome”得到与肾病综合征相关的作用靶点, 即疾病靶点。

靶点相互作用网络图构建与分析 将黄芪总黄酮成分靶点与肾病综合征疾病靶点取交集, 得到黄芪总黄酮治疗肾病综合征的潜在作用靶点, 即:黄芪总黄酮-靶点-肾病综合征。String Version 10.5数据库(https://string-db.org/)^[17]是一种包含已知和预测的蛋白质-蛋白质相互作用(PPI)的数据库, 收集了大量的蛋白相互作用关系, 共涉及9 643 763个蛋白, 1 380 838 440种相互作用, 包括实验验证得到的和通过生物信息学方法预测得到的数据。将作用靶点导入String数据库, 限定物种为人, 获取其相互作用关系, 结果保存成RTF格式, 保留文件中节点(node 1、node 2)和结合率评分(combined score)信息并导入到Cytoscape version 3.5.1软件绘制相互作用网路, 并对网络进行分析, 保存网络分析结果, 使用Cytoscape中的“generate style from statistics”工具将节点大小和颜色设置用于反映成分连接靶点个数(degree)的多少, 边的粗细设置用于反映combine score的大小, 获得最终的蛋白相互作用网络。

作用靶点分布网络图构建 使用BioGPS (http://biogps.org/#goto=welcome)数据库^[18], 以中位数的基因表达量为界限筛选出每个作用靶点主要分布的器官/部位; 构建作用靶点-组织分布(targets-organ, T-O图)网络图, 以得出黄芪总黄酮治疗肾病综合征主要分布的组织器官, 从而揭示其作用机制。

作用靶点富集分析网络图构建 应用ClueGO version 2.3.4软件与其插件CluePedia分析工具^[19]对黄芪总黄酮作用靶点的生物过程(biological process, BP)、分子功能(molecular function, MF)、细胞成分(cell component, CC)和The Kyoto Encyclopedia of Genes and Genomes (KEGG)通路富集分析, 以进一步揭示黄芪总黄酮作用机制。

活性成分-作用靶点网络图构建 将黄芪总黄酮的活性成分和作用靶点导入Cytoscape软件, 构建黄芪总黄酮活性成分-作用靶点网络, 预测出黄芪总黄酮治疗肾病综合征发挥主要作用的作用靶点与主要的活性成分。

活性成分-作用靶点分子对接 Systems Dock Web Site是一个基于网络药理学预测和分析的网络服务器, 可以用于说明配体如何作用于复杂的分子网络。它通过DocK-IN评分的分子对接功能评估蛋白质-配体结合潜力^[20]。采用Systems Dock Web Site Version 2.0 (http://systemsdock.unit.oist.jp)对作用靶点与活性成分进行分子对接验证。保存分子对接结果, 并对其Docking Score进行分析, 用以评价黄芪总黄酮活性成分与靶点之间的结合活性, 并对阳性药他克莫司(tacrolimus)与靶点进行对接分析。

通路图绘制 利用DAVID Bioinformatics Resources 6.8数据库^[21] (https://david.ncifcrf.gov/)输入由ClueGO软件得出的前10条通路, 进行整合绘制最终的通路图。

结果

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1 黄芪总黄酮的化学成分

由¹H NMR图谱与LC-MS图谱鉴定出19个黄酮类化学成分, 检索TCMSP数据库与TDMID数据库获得黄芪黄酮类化学成分12个, 共得到黄酮类化合物29个, 详见表 1。

2 作用靶点预测

将PharmMapper、SEA和SIA数据库得到的所有靶点, 删除重复并去除假阳性, 整合得到黄芪总黄酮作用靶点441个。由GeneCards、HOME-NCBI- GENE与OMIM数据库检索整合得到的肾病综合征靶点共745个, 黄芪总黄酮作用靶点与肾病综合征作用靶点取交集共得潜在作用靶点50个, 其具体靶点名称、Uniprot ID以及靶点的degree、betweenness见表 2。

3 网络图分析

3.1 作用靶点相互作用网络构建与分析

由String数据库得到靶点相互作用网络图(图 1), 其中“边” (edge)代表作用靶点之间的关联, 边的粗细用combine score表示, 边越粗, combine score值越大, 代表其结合度越大。节点(node)代表作用靶点, “degree”值代表其作用强度, 且degree值越大, 节点越大, 颜色由蓝变红对应的degree值越大。图中共48个节点, 231条边, 平均节点度为9.8, 平均局部聚类系数为0.652。如靶点丝裂原活化蛋白激酶14 (MAPK14)与激酶插入区域受体(KDR), 靶点MAPK14与RAC丝氨酸/苏氨酸蛋白激酶(Akt1), 靶点3-羟基-3-甲基戊二酰辅酶A还原酶(HMGCR)和内皮一氧化氮合酶(NOS3)相连接的边较粗, 代表其结合度较大; 同时, 靶点血清白蛋白(ALB)、胰岛素(INS)、Akt1、肿瘤坏死因子(TNF)和MAPK14等degree值较大, 预测其在体内治疗肾病综合征发挥主要作用。其中ALB主要作为载体蛋白, 对细胞外液渗透压的稳定起着重要作用^[22];若人体尿液中存在血清白蛋白, 表明肾脏疾病的存在。INS是一种肽类激素, 可以促进代谢碳水化合物、脂肪和蛋白质的吸收, 特别是从血液进入肝脏、脂肪与骨骼肌细胞的葡萄糖。最新研究表明^[23]血脂异常引起炎症、氧化应激反应, 进而引起胆固醇从血循环向肾脏组织分布, 造成肾脏损害。Akt1属于丝氨酸/苏氨酸激酶Akt家族, 可以抑制细胞凋亡^[24]。TNF是一类含有TNF同源结构域并形成三聚体的Ⅱ型跨膜蛋白超家族, 可以通过细胞外蛋白水解和细胞因子的功能从细胞膜中释放, 主要调节免疫反应与炎症反应^[25]。MAPK14是一类丝裂原活化蛋白激酶, 参与细胞分化、凋亡和自噬^[26]。可以看出这些靶点主要涉及细胞自噬、凋亡和氧化应激反应等。

3.2 作用靶点与组织分布网络构建与分析

使用Cytoscape软件构建黄芪总黄酮潜在作用靶点-组织分布的网络图, 如图 2如示, 图中共有92个节点, 226条边, 其中蓝色椭圆形节点代表潜在作用靶点, 红色三角形节点代表这些潜在作用靶点分布的器官/组织; 边代表靶点与器官的相互作用。由图可以看出, 15个基因在淋巴细胞(blymphoblasts)高表达, 14个基因主要分布在脂肪细胞(adipocyte), 有较多基因存在一些抗原蛋白上, 例如CD14、CD19、CD33、CD34、CD56和CD71。其中CD34在趋化因子依赖性的嗜酸性粒细胞和树突状细胞中迁移^[27]; CD19表面免疫球蛋白(Sig)相关分子可以促进信号转导, 在B细胞上, 抗免疫球蛋白抗体可以模拟外源性抗原, 增强免疫作用^[28]。

黄芪总黄酮治疗肾病综合征的作用靶点50个, 其中与炎症反应相关的靶点有F2、MMP3和TNF等^{[29, 30]};与氧化还原/应激反应有关的靶点有ADA、Akt1、GSTP1、NOS1、NOS2和NOS3等^{[31, 32]};与肾病直接相关报道的靶点有ALB、ACE、MAPK14、NOS1、NOS2、NOS3、RAC1和REN等^{[33, 34]};与细胞凋亡有关的靶点有HSP90AA等^[35]。因此, 由靶点分布状态与其自身特性推测黄芪总黄酮发挥药效主要通过提高体内免疫反应, 抑制氧化应激反应与细胞凋亡反应。

3.3 GO分类富集分析与KEGG富集分析

ClueGO数据库将GO数据库与Cytoscape进行连接, 是Cytoscape可视化分析软件的一个重要插件。ClueGO分析技术能够使来源于不同数据库中的靶点产物功能使用相同的描述符, 进而从生物过程、分子功能、细胞成分3个水平对靶点进行分类分析, 以及KEGG通路富集分析, 预测黄芪总黄酮治疗肾病综合征的作用机制。

生物过程如图 3, 可以看出这些靶点主要涉及活性氧代谢过程(reactive oxygen species metabolic process)、炎症反应(inflammatory response)、细胞对氧化应激的反应(cellular response to oxidative stress)和一氧化氮的生物合成过程(nitricoxide biosynthetic process)等生物过程。有研究^[36]指出氧化ATP代谢过程中的K_ATP通道结构和功能的改变与肾功能的改变密切相关, 而晚期氧化蛋白产物可以诱导细胞凋亡、肾小管上皮损伤和肾脏系膜细胞增生及分化。Zhu^[37]研究得出黄芪能够调节肾脏疾病小鼠白细胞和单核细胞的数量, 从而抑制炎症反应发挥肾脏保护作用。提示炎症反应、氧化应激以及一氧化氮合成等生物过程可能与肾病综合征的发病机制密切相关。

分子功能如图 4, 其靶点主要涉及蛋白体的活动(protein homodimerization activity)、蛋白激酶结合(protein kinase binding)、NADP结合(NADP binding)与一氧化氮合酶活性(nitric-oxide synthase activity)分子功能, 上述分子功能关联的基因较多, 且具有显著性。其中一氧化氮合酶催化左旋精氨酸可以产生一氧化氮(NO), 而NO具有强烈的扩血管作用, 能降低平均动脉血压, 调节全身各血管的静息张力, 也是肾血流动力学调节的重要因子^[38]; Zhou等^[39]对一氧化氮及其合酶研究, 推测在肾病综合征后期可以通过上调iNOS、cNOS和nNOS的表达, 升高NO含量, 扩张肾脏血管, 减少蛋白尿的排泄, 改善肾脏损伤程度。由此可以推测, 肾小球高灌注和高滤过等血流动力学的异常是通过NO合酶等分子诱导导致肾病综合征。

细胞成分见图 5, 其靶点主要涉及内质网(endoplasmic reticulum)、膜的整体成分(integral component of membrane)、核(nucleus)与核浆(nucleoplasm)分子功能关联的基因。越来越多的研究^[40-42]表明, 足细胞与神经元具有相似性, 在神经元细胞中, 敲低基质相互作用分子1 (STIM1)的表达可减轻细胞内钙超载, 保护线粒体膜电位, 减轻内质网应激和线粒体功能障碍, 抑制氧化应激损伤和细胞凋亡, 从而减轻多柔比星诱导的足细胞损伤^[43]。

KEGG通路富集分析(图 6)可以得出, 这些作用靶点主要与AGE-RAGE、IL-17、MAPK、HIF-1和PI3K/Akt信号通路等通路相关。表明黄芪总黄酮主要活性成分的作用靶点分布于不同的代谢通路, 多成分、多靶点相互调节是治疗肾病综合征的可能作用机制。

3.4 活性成分-作用靶点网络图构建

使用Cytoscape软件构建黄芪总黄酮成分-作用靶点的网络图, 如图 7如示, 图中共有79个节点, 504条边, 其中蓝紫色节点代表黄芪总黄酮的50个作用靶点, 蓝色越深代表其关联的活性成分越多, 可能发挥的作用越大; 黄色节点代表黄芪总黄酮的活性成分; 每条边代表活性成分与靶点间的相互作用。分析结果显示, 靶点糖皮质激素受体(NR3C1)、乙酸胆碱酯酶(ACHE)、INS、甲状腺素运载蛋白(TTR)和视紫红质(RHO)等与化学成分的关联度较大。其中NR3C1与25个化学成分相关联; ACHE与24个活性成分相关联; INS、RHO、TTR、F2分别与21、20、20、20个活性成分相关联。ACHE作为一种水解酶, Baldissera等^[44]研究得出乙酰胆碱酶活性降低, 可以防止感染引起的炎症损伤。NR3C1作为糖皮质激素受体, 调节控制发育、新陈代谢及免疫反应, 有研究得出NR3C1与肾脏疾病密切相关^[45]。TTR作为转运蛋白, Li等^[46]根据基因芯片技术、质谱分析以及免疫印迹实验, 得出过度的TTR能抑制细胞凋亡, 预测TTR是导致急性肾损伤的主要原因。RHO是一种感光受体蛋白, 有研究^[47]表明Rho相关蛋白RhoA/ROCK, 对足细胞的肌动蛋白纤维具有保护作用。

4 分子对接

上述相互作用网络中degree表示某个靶点具有相互作用的靶点的数目。一般而言, 在一个网络中, 只有少数的节点具有很高的degree, 这些节点为“中枢节点”, 在整个网络中占据重要地位。也就是说, 在蛋白相互作用网络中筛选出的degree排名靠前的靶蛋白在黄芪总黄酮治疗肾病综合征的过程中发挥着重要的作用。对成分-靶点网络图中degree数值排名前5位的重要靶点进行分子对接验证。将排名前5的靶点ACHE、NR3C1、INS、RHO、TTR的PDB ID导入Systems Dock WebSite分子对接软件并与黄芪总黄酮的29个成分进行对接, 对接结果详见表 3 (得分大于4.25)。分子对接结果显示, docking score值大于7.0的有13个(10%), 介于7.0~5.0之间的有76个(58.5%), 介于5.0~4.25之间的有9个(7.0%), 小于4.25的有32个(24.5%)。一般认为docking score值在4.25以上时表示分子与靶点之间有一定的结合活性, 大于5.0表明分子与靶点有较好的结合活性, 大于7.0则说明具有强烈的结合活性。分子对接结果表明, 黄芪总黄酮18个活性成分与重要靶点的结合活性较好, 且阳性药他克莫司与靶点的结合有很高的评分, 进一步证明了靶点ACHE、NR3C1、INS、RHO和TTR的重要性。

5 靶点通路分析图

利用KEGG Mapper工具获取黄芪总黄酮治疗肾病综合征作用的通路图, 将KEGG得出的前10条信号通路整合绘制最终的通路图(图 8)。图中通路靶点标记为浅绿色, 黄芪总黄酮治疗肾病综合征的靶点标记为深蓝色。图中显示出AGE-RAGE、MAPK、VEGF、IL-17和PI3K/Akt信号通路等, 涉及12个黄芪总黄酮治疗肾病综合征的靶点(占黄芪总黄酮治疗肾病综合征靶点的24%)。提示黄芪总黄酮治疗肾病综合征的靶点主要分散于这几条通路中, 通过调节其中的几个环节发挥作用, 绝大多数靶点在多条通路中发挥作用, 如MAPK14、Akt1等。

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黄芪具有利水消肿的作用, 以其为主要药物的复方在肾病综合征的治疗中占了绝大比例。因此, 对黄芪总黄酮治疗肾病综合征的研究具有重要意义, 黄芪总黄酮主要活性成分的作用靶点分布于不同的代谢通路, 多成分、多靶点相互调节是治疗肾病综合征的可能作用机制。

富集分析得出黄芪总黄酮主要涉及炎症反应、氧化应激以及一氧化氮合成的生物过程; 通过减轻内质网应激, 抑制氧化应激损伤和细胞凋亡, 可以减轻多柔比星诱导的足细胞损伤; 肾小球高灌注和高滤过等血流动力学异常也可诱导肾病综合征的发生。活性成分-组织分布图预测了黄芪总黄酮可能通过提高体内免疫反应, 抑制氧化应激与细胞凋亡反应发挥药效。

从通路图中可以看出, PI3K与Akt/PKB蛋白连接着AGE-RAGE信号通路、PI3K/Akt信号通路、VEGF信号通路以及insulin resistance信号通路, 预测黄芪总黄酮主要通过PI3K、Akt相关蛋白发挥药效作用。有研究^[48]表明AGE与RAGE蛋白结合可以激活PI3K-Akt信号通路, PI3K/Akt信号通路为细胞内重要信号传导通路之一, 能够促进细胞代谢、增殖、存活以及生长。Zhong等^[49]研究抗纤灵方对PI3K/ Akt/mTOR信号通路的影响, 预测抗纤灵方能够降低尿蛋白水平, 延缓肾纤维化的机制可能与抑制PI3K/ Akt/mTOR信号通路, 进而发挥肾保护作用相关。Shen^[50]研究得出益气祛风通络通过降低p-PI3K、p-Akt、NF-κB、MCP-1蛋白及mRNA表达水平来调控糖尿病肾病大鼠PI3K/Akt/NF-κB信号通路, 减轻肾脏损伤。同样, MAPKs蛋白连接了IL-17信号通路与MAPK信号通路。IL-17生物学效应是促进炎性反应, IL-17A产生的主要途径是肾脏Th17细胞上的趋化因子受体CCR6与CCL20反应。Li^[51]研究发现, IL-17可能通过MAPK信号通路对小鼠肾足细胞炎症因子进行调控, IL-17促进多柔比星肾病小鼠的炎症过程, 而且它还能促使Th1细胞分化降低, 大量的IL-17可导致多柔比星肾病小鼠严重的肾功能损害。Tong等^[52]对p38MAPK在EVE小鼠免疫致炎机制方面进行综述, 阐述了p38MAPK在多种适应性和固有免疫细胞等多种细胞中参与免疫炎性损伤。Nan等^[53]以筋骨草总黄酮(TFA)含药血清干预LPS诱导的肾小球系膜细胞, 结果显示, TFA含药血清能够抑制肾小球系膜细胞增殖, 下调炎症因子IL-1β、TNF-α等的表达, 其分子机制是通过抗氧化以及调控p38MAPK/NF-κB信号通路发挥肾保护作用, 进而改善肾组织功能。预测黄芪总黄酮发挥药效主要与PI3K、Akt/PKB、MAPKs蛋白相关。

综上所述, 网络药理结果显示黄芪总黄酮中29个活性成分作用于50个靶点, 涉及多种生物过程、分子功能和细胞成分, 体现了黄芪总黄酮多成分、多靶点、多途径的作用特点, 上述结果与文献报道基本一致。本文通过蛋白相互作用网络预测了黄芪总黄酮治疗肾病综合征的5个重要靶蛋白, 并对其进行了分子对接验证, 分子对接结果显示18个成分与重要靶点之间存在较好的结合活性, 从某种程度上验证了PharmMapper预测靶点的可靠性。此外, 活性成分-组织分布图预测了黄芪总黄酮可能通过提高体内免疫反应, 抑制氧化应激与细胞凋亡反应发挥药效。活性成分-靶点网络图显示了黄芪总黄酮多成分、多靶点治疗肾病综合征的作用特点。靶点相互作用网络结果显示, 黄芪总黄酮靶点间存在着相互关系, 是一个复杂交互的网络而并非单独起作用。通路图表明了AGE-RAGE、IL-17、MAPK、HIF-1和PI3K/Akt信号通路具有枢纽作用, 为深入阐明黄芪总黄酮治疗肾病综合征的作用机制提供科学依据。

基金

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国家自然科学基金资助项目(31570346)

参考文献

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文献

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参考文献引证文献

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2018年第53卷第9期

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文章信息

doi: 10.16438/j.0513-4870.2018-0251

接收时间：2018-03-23
首发时间：2026-01-15
出版时间：2018-09-15

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作者

出版历史

收稿日期：2018-03-23
修回日期：2018-05-14

基金

国家自然科学基金资助项目(31570346)

作者信息

1.山西大学中医药现代研究中心, 山西太原 030006

2.山西大学地产中药功效物质研究与利用山西省重点实验室, 山西太原 030006

3.山西大学大型仪器中心, 山西太原 030006

通讯作者:

* 秦雪梅, Tel:86-351-7011501, E-mail:qinxm@sxu.edu.cn;

李爱平, Tel:86-351-7018379, E-mail:aipingli@sxu.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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TxT

Number	Composition	Degree	Betweeness	OB/%	DL
TFA1^*	Calycosin-7-O-β-D-glycoside	20	0.030 817 68	-	-
TFA2^*	Apigenin-hex	21	0.033 418 38	-	-
TFA3^*	7, 2'-Dihydroxy-3', 4'-dimethoxy-isoflavan-7, 2'-di-O-β-D-glucoside	24	0.037 978 17	-	-
TFA4^*	Calycosin	19	0.016 360 85	47.75	0.24
TFA5^*	Pratensein-7-O-β-D-glucoside	28	0.056 452 29	-	-
TFA6^*	10-Hydroxy-9-methoxypterocarpan-3-O-β-D-glucoside	19	0.027 192 82	-	-
TFA7^*	6''-O-Acetyl calycosin-7-O-β-D-glycoside	20	0.023 329 57	-	-
TFA8^*	Glycyroside	22	0.030 656 15	37.25	0.79
TFA9^*	Ononin	20	0.035 375 44	11.52	0.78
TFA10^*	3-Hydroxy-9, 10-dimethoxypterocarpan-3-O-β-D-glucoside	21	0.022 477 57	-	-
TFA11^*#	7, 2'-Dihydroxy-3', 4'-dimethoxy-isoflavan-7-O-β-D-glucoside	16	0.015 809 63	16.16	0.86
TFA12^*#	Calycosin	26	0.051 131 86	47.75	0.24
TFA13^*	Dihydroxy-dimethoxyisoflavone	19	0.016 586 87	-	-
TFA14^*	6''-O-Acetyl ononin	25	0.036 401 27	-	-
TFA15^*	Dihydroxy-trimethoxy dihydroisoflavone	30	0.061 953 26	-	-
TFA16^*	3-Hydroxy-9, 10-dimethoxypterocarpan	21	0.026 405 55	-	-
TFA17^*	7, 2'-Dihydroxy-3', 4'-dimethoxy-isoflavan	23	0.032 532 35	-	-
TFA18^*	Formononetin	18	0.022 347 14	69.67	0.21
TFA19^*	7-Hydroxy-6, 4'-dimethoxyisoflavan	23	0.038 222 03	-	-
TFA20^#	(3R)-3-(2-Hydroxy-3, 4-dimethoxyphenyl)chroman-7-ol	14	0.040 249 27	67.67	0.26
TFA21^#	5'-Hydroxyiso-muronulatol-2', 5'-di-O-glucoside	11	0.036 514 41	41.72	0.69
TFA22^#	7-O-Methylisomucronulatol	12	0.036 690 85	74.69	0.3
TFA23^#	9, 10-Dimethoxypterocarpan-3-O-β-D-glucoside	8	0.011 433 53	36.74	0.92
TFA24^#	Isoflavanone	12	0.045 879 49	109.99	0.3
TFA25^#	Isomucronulatol-7, 2'-di-O-glucosiole	7	0.010 033 14	49.28	0.62
TFA26^#	Isorhamnetin	6	0.006 536 52	49.6	0.31
TFA27^#	Jaranol	7	0.011 916 39	50.83	0.29
TFA28^#	Kaempferol	5	0.004 295 97	41.88	0.24
TFA29^#	Quercetin	7	0.015 167 40	47.75	0.24

Number

Composition

Degree

Betweeness

OB/%

TFA1^*

Calycosin-7-O-β-D-glycoside

0.030 817 68

TFA2^*

Apigenin-hex

0.033 418 38

TFA3^*

7, 2'-Dihydroxy-3', 4'-dimethoxy-isoflavan-7, 2'-di-O-β-D-glucoside

0.037 978 17

TFA4^*

Calycosin

0.016 360 85

47.75

0.24

TFA5^*

Pratensein-7-O-β-D-glucoside

0.056 452 29

TFA6^*

10-Hydroxy-9-methoxypterocarpan-3-O-β-D-glucoside

0.027 192 82

TFA7^*

6''-O-Acetyl calycosin-7-O-β-D-glycoside

0.023 329 57

TFA8^*

Glycyroside

0.030 656 15

37.25

0.79

TFA9^*

Ononin

0.035 375 44

11.52

0.78

TFA10^*

3-Hydroxy-9, 10-dimethoxypterocarpan-3-O-β-D-glucoside

0.022 477 57

TFA11^*#

7, 2'-Dihydroxy-3', 4'-dimethoxy-isoflavan-7-O-β-D-glucoside

0.015 809 63

16.16

0.86

TFA12^*#

Calycosin

0.051 131 86

47.75

0.24

TFA13^*

Dihydroxy-dimethoxyisoflavone

0.016 586 87

TFA14^*

6''-O-Acetyl ononin

0.036 401 27

TFA15^*

Dihydroxy-trimethoxy dihydroisoflavone

0.061 953 26

TFA16^*

3-Hydroxy-9, 10-dimethoxypterocarpan

0.026 405 55

TFA17^*

7, 2'-Dihydroxy-3', 4'-dimethoxy-isoflavan

0.032 532 35

TFA18^*

Formononetin

0.022 347 14

69.67

0.21

TFA19^*

7-Hydroxy-6, 4'-dimethoxyisoflavan

0.038 222 03

TFA20^#

(3R)-3-(2-Hydroxy-3, 4-dimethoxyphenyl)chroman-7-ol

0.040 249 27

67.67

0.26

TFA21^#

5'-Hydroxyiso-muronulatol-2', 5'-di-O-glucoside

0.036 514 41

41.72

0.69

TFA22^#

7-O-Methylisomucronulatol

0.036 690 85

74.69

0.3

TFA23^#

9, 10-Dimethoxypterocarpan-3-O-β-D-glucoside

0.011 433 53

36.74

0.92

TFA24^#

Isoflavanone

0.045 879 49

109.99

0.3

TFA25^#

Isomucronulatol-7, 2'-di-O-glucosiole

0.010 033 14

49.28

0.62

TFA26^#

Isorhamnetin

0.006 536 52

49.6

0.31

TFA27^#

Jaranol

0.011 916 39

50.83

0.29

TFA28^#

Kaempferol

0.004 295 97

41.88

0.24

TFA29^#

Quercetin

0.015 167 40

47.75

0.24

No.	Gene name	Protein name	UniProt ID	Degree	Betweenness
1	ACE	Angiotensin-converting enzyme	P12821	7	0.013 999 41
2	ACHE	Acetylcholinesterase	P22303	24	0.074 162 56
3	ADA	Adenosine deaminase	P00813	13	0.014 974 62
4	AKT1	RAC-alpha serine/threonine-protein kinase	P31749	8	0.017 560 56
5	ALB	Serum albumin	P02768	15	0.008 759 52
6	ALDH2	Aldehyde dehydrogenase, mitochondrial	P05091	5	0.000 869 00
7	ANXA5	Annexin A5	P08758	7	0.001 697 63
8	APOA2	Apolipoprotein A-Ⅱ	P02652	10	0.003 092 04
9	AQP1	Aquaporin-1	P29972	9	0.002 868 61
10	CCNA2	Cyclin-A2	P20248	17	0.011 603 99
11	CD38	ADP-ribosyl cyclase	P28907	7	0.001 958 75
12	DDC	Aromatic-L-amino-acid decarboxylase	P20711	9	0.013 839 84
13	F2	Prothrombin	P00734	20	0.032 690 05
14	FBP1	Fructose-1, 6-bisphosphatase 1	P09467	3	0.000 950 00
15	G6PD	Glucose-6-phosphate1-dehydrogenase	P11413	6	0.004 196 00
16	GC	Vitamin D-binding protein	P02774	13	0.021 355 00
17	GSR	Glutathione reductase, mitochondrial	P00390	14	0.012 622 60
18	GSTM1	Glutathione S-transferase Mu 1	P09488	8	0.008 155 00
19	GSTP1	Glutathione S-transferase P	P09211	13	0.010 657 50
20	HMGCR	3-Hydroxy-3-methylglutaryl-coenzyme A reductase	P04035	6	0.005 811 70
21	HPRT1	Hypoxanthine-guanine phosphoribosyltransferase	P00492	2	0.000 247 00
22	HSD11B1	Corticosteroid 11-beta-dehydrogenase isozyme 1	P28845	12	0.005 933 00
23	HSP90AA1	Heat shock protein HSP 90-alpha	P07900	15	0.009 452 50
24	INS	Insulin	P01308	21	0.039 836 80
25	KDR	Kinase insert domain receptor	P35968	10	0.004 099 40
26	LCN2	Neutrophil gelatinase-associated lipocalin	P80188	4	0.001 563 40
27	LTA4H	Leukotriene A-4 hydrolase	P09960	7	0.001 685 70
28	LYZ	Lysozyme C	P61626	4	0.000 446 00
29	NAGA	Alpha-N-acetylgalactosaminidase	P17050	3	0.000 179 00
30	MAPK14	Mitogen-activated protein kinase 14	Q16539	12	0.005 908 20
31	MIF	Macrophage migration inhibitory factor	P14174	11	0.004 547 20
32	MMP12	Macrophage metalloelastase	P39900	2	0.000 838 00
33	MMP3	Stromelysin-1	P08254	10	0.006 777 20
34	NOS1	Nitric oxide synthase, brain	P29475	10	0.015 600 90
35	NOS2	Nitric oxide synthase, inducible	P35228	19	0.019 989 60
36	NOS3	Nitric oxide synthase, endothelial	P29474	17	0.033 725 50
37	NR3C1	Glucocorticoid receptor	P04150	25	0.067 122 32
38	PAH	Phenylalanine-4-hydroxylase	P00439	11	0.011 512 30
39	PARP1	Poly[ADP-ribose] polymerase 1	P09874	11	0.005 384 30
40	PRKCD	Protein kinase C delta type	Q05655	6	0.001 222 29
41	PRNP	Major prion protein	P04156	4	0.000 527 00
42	RAC1	Ras-related C3 botulinum toxin substrate 1	P63000	3	0.000 409 00
43	RBP4	Retinol-binding protein 4	P02753	5	0.002 304 95
44	RELA	Transcription factor p65	Q04206	3	0.000 527 00
45	REN	Renin	P00797	3	0.000 235 00
46	RETN	Resistin	Q9HD89	7	0.001 496 87
47	RHO	Rhodopsin	P08100	20	0.041 283 12
48	STS	Steryl-sulfatase	P08842	10	0.003 092 04
49	TNF	Tumor necrosis factor	P01375	4	0.000 405 00
50	TTR	Transthyretin	P02766	20	0.014 016 25

No.

Gene name

Protein name

UniProt ID

Degree

Betweenness

ACE

Angiotensin-converting enzyme

P12821

0.013 999 41

ACHE

Acetylcholinesterase

P22303

0.074 162 56

ADA

Adenosine deaminase

P00813

0.014 974 62

AKT1

RAC-alpha serine/threonine-protein kinase

P31749

0.017 560 56

ALB

Serum albumin

P02768

0.008 759 52

ALDH2

Aldehyde dehydrogenase, mitochondrial

P05091

0.000 869 00

ANXA5

Annexin A5

P08758

0.001 697 63

APOA2

Apolipoprotein A-Ⅱ

P02652

0.003 092 04

AQP1

Aquaporin-1

P29972

0.002 868 61

CCNA2

Cyclin-A2

P20248

0.011 603 99

CD38

ADP-ribosyl cyclase

P28907

0.001 958 75

DDC

Aromatic-L-amino-acid decarboxylase

P20711

0.013 839 84

Prothrombin

P00734

0.032 690 05

FBP1

Fructose-1, 6-bisphosphatase 1

P09467

0.000 950 00

G6PD

Glucose-6-phosphate1-dehydrogenase

P11413

0.004 196 00

Vitamin D-binding protein

P02774

0.021 355 00

GSR

Glutathione reductase, mitochondrial

P00390

0.012 622 60

GSTM1

Glutathione S-transferase Mu 1

P09488

0.008 155 00

GSTP1

Glutathione S-transferase P

P09211

0.010 657 50

HMGCR

3-Hydroxy-3-methylglutaryl-coenzyme A reductase

P04035

0.005 811 70

HPRT1

Hypoxanthine-guanine phosphoribosyltransferase

P00492

0.000 247 00

HSD11B1

Corticosteroid 11-beta-dehydrogenase isozyme 1

P28845

0.005 933 00

HSP90AA1

Heat shock protein HSP 90-alpha

P07900

0.009 452 50

INS

Insulin

P01308

0.039 836 80

KDR

Kinase insert domain receptor

P35968

0.004 099 40

LCN2

Neutrophil gelatinase-associated lipocalin

P80188

0.001 563 40

LTA4H

Leukotriene A-4 hydrolase

P09960

0.001 685 70

LYZ

Lysozyme C

P61626

0.000 446 00

NAGA

Alpha-N-acetylgalactosaminidase

P17050

0.000 179 00

MAPK14

Mitogen-activated protein kinase 14

Q16539

0.005 908 20

MIF

Macrophage migration inhibitory factor

P14174

0.004 547 20

MMP12

Macrophage metalloelastase

P39900

0.000 838 00

MMP3

Stromelysin-1

P08254

0.006 777 20

NOS1

Nitric oxide synthase, brain

P29475

0.015 600 90

NOS2

Nitric oxide synthase, inducible

P35228

0.019 989 60

NOS3

Nitric oxide synthase, endothelial

P29474

0.033 725 50

NR3C1

Glucocorticoid receptor

P04150

0.067 122 32

PAH

Phenylalanine-4-hydroxylase

P00439

0.011 512 30

PARP1

Poly[ADP-ribose] polymerase 1

P09874

0.005 384 30

PRKCD

Protein kinase C delta type

Q05655

0.001 222 29

PRNP

Major prion protein

P04156

0.000 527 00

RAC1

Ras-related C3 botulinum toxin substrate 1

P63000

0.000 409 00

RBP4

Retinol-binding protein 4

P02753

0.002 304 95

RELA

Transcription factor p65

Q04206

0.000 527 00

REN

Renin

P00797

0.000 235 00

RETN

Resistin

Q9HD89

0.001 496 87

RHO

Rhodopsin

P08100

0.041 283 12

STS

Steryl-sulfatase

P08842

0.003 092 04

TNF

Tumor necrosis factor

P01375

0.000 405 00

TTR

Transthyretin

P02766

0.014 016 25

Target name	PDB ID	Ingredient	Docking score
ACHE	3LII	TFA1	5.426
NR3C1	3BQD	TFA1	5.299
INS	1TYL	TFA1	5.792
RHO	1A62	TFA1	6.972
TTR	1GHE	TFA1	5.793
ACHE	3LII	TFA2	6.81
NR3C1	3BQD	TFA2	6.355
INS	1TYL	TFA2	5.616
RHO	1A62	TFA2	6.702
TTR	1GHE	TFA2	6.821
ACHE	3LII	TFA4	5.337
NR3C1	3BQD	TFA4	6.773
INS	1TYL	TFA4	5.602
RHO	1A62	TFA4	5.278
TTR	1GHE	TFA4	6.178
ACHE	3LII	TFA6	5.335
NR3C1	3BQD	TFA6	8.13
INS	1TYL	TFA6	5.585
RHO	1A62	TFA6	5.272
TTR	1GHE	TFA6	6.196
ACHE	3LII	TFA7	5.374
NR3C1	3BQD	TFA7	7.038
INS	1TYL	TFA7	5.909
RHO	1A62	TFA7	5.246
TTR	1GHE	TFA7	6.171
ACHE	3LII	TFA8	5.302
NR3C1	3BQD	TFA8	7.106
INS	1TYL	TFA8	5.751
RHO	1A62	TFA8	5.28
TTR	1GHE	TFA8	6.438
ACHE	3LII	TFA9	5.174
NR3C1	3BQD	TFA9	8.11
INS	1TYL	TFA9	6.835
RHO	1A62	TFA9	6.302
TTR	1GHE	TFA9	8.172
ACHE	3LII	TFA10	6.993
NR3C1	3BQD	TFA10	6.524
INS	1TYL	TFA10	4.784
RHO	1A62	TFA10	6.79
TTR	1GHE	TFA10	6.944
ACHE	3LII	TFA11	5.429
NR3C1	3BQD	TFA11	7.086
INS	1TYL	TFA11	5.714
RHO	1A62	TFA11	5.284
TTR	1GHE	TFA11	6.237
ACHE	3LII	TFA12	5.395
NR3C1	3BQD	TFA12	7.086
INS	1TYL	TFA12	5.844
RHO	1A62	TFA12	5.231
TTR	1GHE	TFA12	6.209
ACHE	3LII	TFA14	5.363
NR3C1	3BQD	TFA14	7.075
INS	1TYL	TFA14	5.738
RHO	1A62	TFA14	5.208
TTR	1GHE	TFA14	6.251
ACHE	3LII	TFA17	6.733
NR3C1	3BQD	TFA17	7.013
INS	1TYL	TFA17	6.025
RHO	1A62	TFA17	6.552
TTR	1GHE	TFA17	6.703
ACHE	3LII	TFA18	5.271
NR3C1	3BQD	TFA18	8.234
INS	1TYL	TFA18	5.972
RHO	1A62	TFA18	5.33
TTR	1GHE	TFA18	6.21
ACHE	3LII	TFA21	5.354
NR3C1	3BQD	TFA21	8.286
INS	1TYL	TFA21	5.976
RHO	1A62	TFA21	5.349
TTR	1GHE	TFA21	6.259
ACHE	3LII	TFA23	5.438
NR3C1	3BQD	TFA23	7.086
INS	1TYL	TFA23	5.685
RHO	1A62	TFA23	5.21
TTR	1GHE	TFA23	6.129
ACHE	3LII	TFA25	5.425
NR3C1	3BQD	TFA25	8.353
INS	1TYL	TFA25	6.372
RHO	1A62	TFA25	5.378
TTR	1GHE	TFA25	6.374
ACHE	3LII	TFA28	6.699
NR3C1	3BQD	TFA28	6.678
INS	1TYL	TFA28	5.636
RHO	1A62	TFA28	6.464
TTR	1GHE	TFA28	6.778
ACHE	3LII	TFA29	6.662
NR3C1	3BQD	TFA29	6.684
INS	1TYL	TFA29	5.623
RHO	1A62	TFA29	6.471
TTR	1GHE	TFA29	6.715
ACHE	3LII	Tacrolimus	4.991
NR3C1	3BQD	Tacrolimus	7.992
INS	1TYL	Tacrolimus	7.223
RHO	1A62	Tacrolimus	6.197
TTR	1GHE	Tacrolimus	8.361

Target name

PDB ID

Ingredient

Docking score

ACHE

3LII

TFA1

5.426

NR3C1

3BQD

TFA1

5.299

INS

1TYL

TFA1

5.792

RHO

1A62

TFA1

6.972

TTR

1GHE

TFA1

5.793

ACHE

3LII

TFA2

6.81

NR3C1

3BQD

TFA2

6.355

INS

1TYL

TFA2

5.616

RHO

1A62

TFA2

6.702

TTR

1GHE

TFA2

6.821

ACHE

3LII

TFA4

5.337

NR3C1

3BQD

TFA4

6.773

INS

1TYL

TFA4

5.602

RHO

1A62

TFA4

5.278

TTR

1GHE

TFA4

6.178

ACHE

3LII

TFA6

5.335

NR3C1

3BQD

TFA6

8.13

INS

1TYL

TFA6

5.585

RHO

1A62

TFA6

5.272

TTR

1GHE

TFA6

6.196

ACHE

3LII

TFA7

5.374

NR3C1

3BQD

TFA7

7.038

INS

1TYL

TFA7

5.909

RHO

1A62

TFA7

5.246

TTR

1GHE

TFA7

6.171

ACHE

3LII

TFA8

5.302

NR3C1

3BQD

TFA8

7.106

INS

1TYL

TFA8

5.751

RHO

1A62

TFA8

5.28

TTR

1GHE

TFA8

6.438

ACHE

3LII

TFA9

5.174

NR3C1

3BQD

TFA9

8.11

INS

1TYL

TFA9

6.835

RHO

1A62

TFA9

6.302

TTR

1GHE

TFA9

8.172

ACHE

3LII

TFA10

6.993

NR3C1

3BQD

TFA10

6.524

INS

1TYL

TFA10

4.784

RHO

1A62

TFA10

6.79

TTR

1GHE

TFA10

6.944

ACHE

3LII

TFA11

5.429

NR3C1

3BQD

TFA11

7.086

INS

1TYL

TFA11

5.714

RHO

1A62

TFA11

5.284

TTR

1GHE

TFA11

6.237

ACHE

3LII

TFA12

5.395

NR3C1

3BQD

TFA12

7.086

INS

1TYL

TFA12

5.844

RHO

1A62

TFA12

5.231

TTR

1GHE

TFA12

6.209

ACHE

3LII

TFA14

5.363

NR3C1

3BQD

TFA14

7.075

INS

1TYL

TFA14

5.738

RHO

1A62

TFA14

5.208

TTR

1GHE

TFA14

6.251

ACHE

3LII

TFA17

6.733

NR3C1

3BQD

TFA17

7.013

INS

1TYL

TFA17

6.025

RHO

1A62

TFA17

6.552

TTR

1GHE

TFA17

6.703

ACHE

3LII

TFA18

5.271

NR3C1

3BQD

TFA18

8.234

INS

1TYL

TFA18

5.972

RHO

1A62

TFA18

5.33

TTR

1GHE

TFA18

6.21

ACHE

3LII

TFA21

5.354

NR3C1

3BQD

TFA21

8.286

INS

1TYL

TFA21

5.976

RHO

1A62

TFA21

5.349

TTR

1GHE

TFA21

6.259

ACHE

3LII

TFA23

5.438

NR3C1

3BQD

TFA23

7.086

INS

1TYL

TFA23

5.685

RHO

1A62

TFA23

5.21

TTR

1GHE

TFA23

6.129

ACHE

3LII

TFA25

5.425

NR3C1

3BQD

TFA25

8.353

INS

1TYL

TFA25

6.372

RHO

1A62

TFA25

5.378

TTR

1GHE

TFA25

6.374

ACHE

3LII

TFA28

6.699

NR3C1

3BQD

TFA28

6.678

INS

1TYL

TFA28

5.636

RHO

1A62

TFA28

6.464

TTR

1GHE

TFA28

6.778

ACHE

3LII

TFA29

6.662

NR3C1

3BQD

TFA29

6.684

INS

1TYL

TFA29

5.623

RHO

1A62

TFA29

6.471

TTR

1GHE

TFA29

6.715

ACHE

3LII

Tacrolimus

4.991

NR3C1

3BQD

Tacrolimus

7.992

INS

1TYL

Tacrolimus

7.223

RHO

1A62

Tacrolimus

6.197

TTR

1GHE

Tacrolimus

8.361