药学学报

ID	Compound	Molecular weight	Formular	Source
GL1	Beta-D-arabinopyranose	150.05	C₅H₁₀O₅	GL
GL2	Vanillic acid 4-β-D-glucoside	330.09	C₁₄H₁₈O₉	GL
GL3	2, 3, 4, 9-Tetrahydro-1H-pyrido[3, 4-b]indole-3-carboxylic acid	216.09	C₁₂H₁₂N₂O₂	GL
GL4	Rutin	610.15	C₂₇H₃₀O₁₆	GL
GL5	Kaempferol-3-O-β-rutinoside	594.16	C₂₇H₃₀O₁₅	GL
GL6	Quercitrin	448.10	C₂₁H₂₀O₁₁	GL
GL7	Quercetin	302.04	C₁₅H₁₀O₇	GL
GL8	Quercetin-3-O-α-D-riboside	434.08	C₂₀H₁₈O₁₁	GL
GL9	Kaempferol-3-D-glucoside-7-O-rhamnoside	578.16	C₂₇H₃₀O₁₄	GL
GL10	Apigenin-7-O-β-D-glucoside	432.11	C₂₁H₂₀O₁₀	GL
GL11	Chrysoeriol-7-O-β-D-glucoside	462.12	C₂₂H₂₂O₁₁	GL
GL12	Bryoamaride	678.36	C₃₆H₅₄O₁₂	GL
GL13	25-O-Acetylbryoamaride	720.37	C₃₈H₅₆O₁₃	GL
GL14	Cucurbitacin D	516.31	C₃₀H₄₄O₇	GL
GL15	Tianshic acid	330.24	C₁₈H₃₄O₅	GL
GL16	Cucurbitacin B	558.32	C₃₂H₄₆O₈	GL
GL17	Isocucurbitacin B	558.32	C₃₂H₄₆O₈	GL
GL18	Pentadecanoic acid	242.22	C₁₅H₃₀O₂	GL
GL19	Punicic acid	278.22	C₁₈H₃₀O₂	GL
GL20	Apigenin	270.24	C₁₅H₁₀O₅	GL
GL21	Chrysoeriol	300.26	C₁₆H₁₂O₆	GL
GL22	Kaempferol	286.24	C₁₅H₁₀O₆	GL
GL23	Mandenol	308.56	C₂₀H₃₆O₂	GL
GL24	Diosmetin	300.28	C₁₆H₁₂O₆	GL
GL25	Spinasterol	412.77	C₂₉H₄₈O	GL
GL26	Hydroxygenkwanin	300.26	C₁₆H₁₂O₆	GL
GL27	Schottenol	414.79	C₂₉H₅₀O	GL
GL28	10α-Cucurbita-5, 24-diene-3β-ol	426.80	C₃₀H₅₀O	GL
GL29	7-Oxo-dihydrokaro-unidiol	456.78	C₃₀H₄₈O₃	GL
GL30	Karounidiol 3-O-benzoate	544.89	C₃₇H₅₂O₃	GL
GL31	Linolenic acid ethyl ester	306.54	C₂₀H₃₄O₂	GL
GL32	Vitamin-e	490.69	C₂₄H₃₄N₄O₅S	GL
GL33	5-Dehydrokarounidiol	438.76	C₃₀H₄₆O₂	GL
XB1	DiAllS2	146.02	C₆H₁₀S₂	XB
XB2	(1S, 3S)-2, 3, 4, 9-Tetrahydro-1-methyl-1H-pyrido[3, 4-b] indole-3-carboxylic acid	230.11	C₁₃H₁₄N₂O₂	XB
XB3	Chinenoside V	916.47	C₄₅H₇₂O₁₉	XB
XB4	26-[(β-D-Glucopyranosyl)oxy]-2β, 22-dihydroxy-5β-furostan-25(27)-en-3β-yl-O-β-D-glucopyranosyl-(1→2)-β-D-galactopyranoside	934.48	C₄₅H₇₂O₂₀	XB
XB5	Macrostemonoside J	936.49	C₄₅H₇₆O₂₀	XB
XB6	Macrostemonoside I	932.46	C₄₅H₇₂O₂₀	XB
XB7	Macrostemonoside G	934.48	C₄₅H₇₄O₂₀	XB
XB8	Macrostemonoside P	936.49	C₄₅H₇₆O₂₀	XB
XB9	25R-Macrostemonoside P	936.49	C₄₅H₇₆O₂₀	XB
XB10	Macrostemonoside O	918.48	C₄₅H₇₄O₁₉	XB
XB11	Timosaponin BII	920.50	C₁₃H₁₄N₂O₂	XB
XB12	25R-Timosaponin BII	920.50	C₁₃H₁₄N₂O₂	XB
XB13	Macrostemonoside F	902.49	C₄₅H₇₄O₁₈	XB
XB14	Timosaponin C	902.49	C₄₅H₇₄O₁₈	XB
XB15	Macrostemonoside S	754. 41	C₃₉H₆₂O₁₄	XB
XB16	Timosaponin A Ⅲ	740.44	C₃₉H₆₄O₁₃	XB
XB17	Macrostemonoside A	1 064.54	C₅₁H₈₄O₂₃	XB
XB18	Macrostemonoside D	1 106.55	C₅₃H₈₆O₂₄	XB
XB19	Sitogluside	576.44	C₃₅H₆₀O₆	XB
XB20	Macrostemonoside B	1 245.35	C₅₇H₉₆O₂₉	XB
XB21	25S-Macrostemonoside B	1 245.35	C₅₇H₉₆O₂₉	XB
XB22	Sitosteryl acetate	456.83	C₃₁H₅₂O₂	XB
XB23	Hesperetin	302.30	C₁₆H₁₄O₆	XB
XB24	Beta-sitosterol	414.79	C₂₉H₅₀O	XB
XB25	Naringenin	272.27	C₁₅H₁₂O₅	XB
XB26	Macrostemonoside e_qt	416.71	C₂₇H₄₄O₃	XB
XB27	Prostaglandin A1	336.52	C2₀H₃₂O₄	XB
XB28	Prostaglandin B1	336.52	C₂₀H₃₂O₄	XB
XB29	n-Coumaroyltyramine	283.35	C₁₇H₁₇NO₃	XB
XB30	(Z)-3-(4-Hydroxy-3-methoxy-phenyl)-N-[2-(4-hydroxyphenyl)ethyl]acrylamide	313.38	C₁₈H₁₉NO₄	XB
XB31	Coumaroyltyramine	283.35	C₁₇H₁₇NO₃	XB
GX1	Adenosine	267.10	C₉H₁₃O₄N₅	GL/XB
GX2	Guanosine	283.09	C₅H₅N₅O	GL/XB
GX3	L-Phenylalanine	165.08	C₉H₁₁NO₂	GL/XB
GX4	DL-Tryptophan	204.09	C₁₁H₁₂N₂O₂	GL/XB
GX5	Linolenic acid	278.22	C₁₈H₃₀O₂	GL/XB

ID	Compound	Molecular weight	Formular	Source
GL1	Beta-D-arabinopyranose	150.05	C₅H₁₀O₅	GL
GL2	Vanillic acid 4-β-D-glucoside	330.09	C₁₄H₁₈O₉	GL
GL3	2, 3, 4, 9-Tetrahydro-1H-pyrido[3, 4-b]indole-3-carboxylic acid	216.09	C₁₂H₁₂N₂O₂	GL
GL4	Rutin	610.15	C₂₇H₃₀O₁₆	GL
GL5	Kaempferol-3-O-β-rutinoside	594.16	C₂₇H₃₀O₁₅	GL
GL6	Quercitrin	448.10	C₂₁H₂₀O₁₁	GL
GL7	Quercetin	302.04	C₁₅H₁₀O₇	GL
GL8	Quercetin-3-O-α-D-riboside	434.08	C₂₀H₁₈O₁₁	GL
GL9	Kaempferol-3-D-glucoside-7-O-rhamnoside	578.16	C₂₇H₃₀O₁₄	GL
GL10	Apigenin-7-O-β-D-glucoside	432.11	C₂₁H₂₀O₁₀	GL
GL11	Chrysoeriol-7-O-β-D-glucoside	462.12	C₂₂H₂₂O₁₁	GL
GL12	Bryoamaride	678.36	C₃₆H₅₄O₁₂	GL
GL13	25-O-Acetylbryoamaride	720.37	C₃₈H₅₆O₁₃	GL
GL14	Cucurbitacin D	516.31	C₃₀H₄₄O₇	GL
GL15	Tianshic acid	330.24	C₁₈H₃₄O₅	GL
GL16	Cucurbitacin B	558.32	C₃₂H₄₆O₈	GL
GL17	Isocucurbitacin B	558.32	C₃₂H₄₆O₈	GL
GL18	Pentadecanoic acid	242.22	C₁₅H₃₀O₂	GL
GL19	Punicic acid	278.22	C₁₈H₃₀O₂	GL
GL20	Apigenin	270.24	C₁₅H₁₀O₅	GL
GL21	Chrysoeriol	300.26	C₁₆H₁₂O₆	GL
GL22	Kaempferol	286.24	C₁₅H₁₀O₆	GL
GL23	Mandenol	308.56	C₂₀H₃₆O₂	GL
GL24	Diosmetin	300.28	C₁₆H₁₂O₆	GL
GL25	Spinasterol	412.77	C₂₉H₄₈O	GL
GL26	Hydroxygenkwanin	300.26	C₁₆H₁₂O₆	GL
GL27	Schottenol	414.79	C₂₉H₅₀O	GL
GL28	10α-Cucurbita-5, 24-diene-3β-ol	426.80	C₃₀H₅₀O	GL
GL29	7-Oxo-dihydrokaro-unidiol	456.78	C₃₀H₄₈O₃	GL
GL30	Karounidiol 3-O-benzoate	544.89	C₃₇H₅₂O₃	GL
GL31	Linolenic acid ethyl ester	306.54	C₂₀H₃₄O₂	GL
GL32	Vitamin-e	490.69	C₂₄H₃₄N₄O₅S	GL
GL33	5-Dehydrokarounidiol	438.76	C₃₀H₄₆O₂	GL
XB1	DiAllS2	146.02	C₆H₁₀S₂	XB
XB2	(1S, 3S)-2, 3, 4, 9-Tetrahydro-1-methyl-1H-pyrido[3, 4-b] indole-3-carboxylic acid	230.11	C₁₃H₁₄N₂O₂	XB
XB3	Chinenoside V	916.47	C₄₅H₇₂O₁₉	XB
XB4	26-[(β-D-Glucopyranosyl)oxy]-2β, 22-dihydroxy-5β-furostan-25(27)-en-3β-yl-O-β-D-glucopyranosyl-(1→2)-β-D-galactopyranoside	934.48	C₄₅H₇₂O₂₀	XB
XB5	Macrostemonoside J	936.49	C₄₅H₇₆O₂₀	XB
XB6	Macrostemonoside I	932.46	C₄₅H₇₂O₂₀	XB
XB7	Macrostemonoside G	934.48	C₄₅H₇₄O₂₀	XB
XB8	Macrostemonoside P	936.49	C₄₅H₇₆O₂₀	XB
XB9	25R-Macrostemonoside P	936.49	C₄₅H₇₆O₂₀	XB
XB10	Macrostemonoside O	918.48	C₄₅H₇₄O₁₉	XB
XB11	Timosaponin BII	920.50	C₁₃H₁₄N₂O₂	XB
XB12	25R-Timosaponin BII	920.50	C₁₃H₁₄N₂O₂	XB
XB13	Macrostemonoside F	902.49	C₄₅H₇₄O₁₈	XB
XB14	Timosaponin C	902.49	C₄₅H₇₄O₁₈	XB
XB15	Macrostemonoside S	754. 41	C₃₉H₆₂O₁₄	XB
XB16	Timosaponin A Ⅲ	740.44	C₃₉H₆₄O₁₃	XB
XB17	Macrostemonoside A	1 064.54	C₅₁H₈₄O₂₃	XB
XB18	Macrostemonoside D	1 106.55	C₅₃H₈₆O₂₄	XB
XB19	Sitogluside	576.44	C₃₅H₆₀O₆	XB
XB20	Macrostemonoside B	1 245.35	C₅₇H₉₆O₂₉	XB
XB21	25S-Macrostemonoside B	1 245.35	C₅₇H₉₆O₂₉	XB
XB22	Sitosteryl acetate	456.83	C₃₁H₅₂O₂	XB
XB23	Hesperetin	302.30	C₁₆H₁₄O₆	XB
XB24	Beta-sitosterol	414.79	C₂₉H₅₀O	XB
XB25	Naringenin	272.27	C₁₅H₁₂O₅	XB
XB26	Macrostemonoside e_qt	416.71	C₂₇H₄₄O₃	XB
XB27	Prostaglandin A1	336.52	C2₀H₃₂O₄	XB
XB28	Prostaglandin B1	336.52	C₂₀H₃₂O₄	XB
XB29	n-Coumaroyltyramine	283.35	C₁₇H₁₇NO₃	XB
XB30	(Z)-3-(4-Hydroxy-3-methoxy-phenyl)-N-[2-(4-hydroxyphenyl)ethyl]acrylamide	313.38	C₁₈H₁₉NO₄	XB
XB31	Coumaroyltyramine	283.35	C₁₇H₁₇NO₃	XB
GX1	Adenosine	267.10	C₉H₁₃O₄N₅	GL/XB
GX2	Guanosine	283.09	C₅H₅N₅O	GL/XB
GX3	L-Phenylalanine	165.08	C₉H₁₁NO₂	GL/XB
GX4	DL-Tryptophan	204.09	C₁₁H₁₂N₂O₂	GL/XB
GX5	Linolenic acid	278.22	C₁₈H₃₀O₂	GL/XB

Compound name	Gene target	PDB ID	Estimated ΔG/kcal·mol^-1
Apigenin	Akt1	7NH5	-8.8
TNF	6Q01	-6.1
IL6	4CNI	-4.5
VEGFA	3QTK	-6.1
Tp53	4CZ7	-7.5
Cucurbitacin D	Akt1	7NH5	-10.8
TNF	6Q01	-6.1
IL6	4CNI	-5.1
VEGFA	3QTK	-7.2
Tp53	4CZ7	-
Linolenic acid	Akt1	7NH5	-5.7
TNF	6Q01	-3.6
IL6	4CNI	-2.8
VEGFA	3QTK	-4.2
Tp53	4CZ7	-5.7
Kaempferol	Akt1	7NH5	-8.7
TNF	6Q01	-5.9
IL6	4CNI	-4.4
VEGFA	3QTK	-5.8
Tp53	4CZ7	-6.7
Quercetin	Akt1	7NH5	-9.3
TNF	6Q01	-6.4
IL6	4CNI	-4.4
VEGFA	3QTK	-6
Tp53	4CZ7	-7.5
Naringenin	Akt1	7NH5	-8.7
TNF	6Q01	-6.1
IL6	4CNI	-4.5
VEGFA	3QTK	-6.3
Tp53	4CZ7	-7.4

Compound name	Gene target	PDB ID	Estimated ΔG/kcal·mol^-1
Apigenin	Akt1	7NH5	-8.8
TNF	6Q01	-6.1
IL6	4CNI	-4.5
VEGFA	3QTK	-6.1
Tp53	4CZ7	-7.5
Cucurbitacin D	Akt1	7NH5	-10.8
TNF	6Q01	-6.1
IL6	4CNI	-5.1
VEGFA	3QTK	-7.2
Tp53	4CZ7	-
Linolenic acid	Akt1	7NH5	-5.7
TNF	6Q01	-3.6
IL6	4CNI	-2.8
VEGFA	3QTK	-4.2
Tp53	4CZ7	-5.7
Kaempferol	Akt1	7NH5	-8.7
TNF	6Q01	-5.9
IL6	4CNI	-4.4
VEGFA	3QTK	-5.8
Tp53	4CZ7	-6.7
Quercetin	Akt1	7NH5	-9.3
TNF	6Q01	-6.4
IL6	4CNI	-4.4
VEGFA	3QTK	-6
Tp53	4CZ7	-7.5
Naringenin	Akt1	7NH5	-8.7
TNF	6Q01	-6.1
IL6	4CNI	-4.5
VEGFA	3QTK	-6.3
Tp53	4CZ7	-7.4

Group	Mental state and weight	Dietary quantity	Hair state	Feces state	Tongue coating	Skin state	Total score
Control	0	0	0	0	0	0	0
Model	2.60 ± 0.28^**	2.26 ± 0.41^**	1.65 ± 0.21^**	1.88 ± 0.58^**	2.40 ± 0.36^**	2.45 ± 0.31^**	13.24 ± 1.78^**
GX-L	1.87 ± 0.30^#	1.64 ± 0.36^#	1.17 ± 0.21^##	1.20 ± 0.35^#	1.70 ± 0.22^##	1.70 ± 0.26^##	9.28 ± 1.41^##
GX-M	1.77 ± 0.65^#	1.35 ± 0.25^##	0.72 ± 0.13^##	1.15 ± 0.29^#	1.55 ± 0.36^##	1.53 ± 0.34^##	8.06 ± 1.62^##
GX-H	1.05 ± 0.39^##	1.01 ± 0.39^##	0.65 ± 0.18^##	1.25 ± 0.19^#	1.77 ± 0.33^##	1.42 ± 0.26^##	6.74 ± 1.24^##
Danlou tablet	1.18 ± 0.40^##	1.02 ± 0.30^##	0.62 ± 0.22^##	1.07 ± 0.27^##	1.30 ± 0.35^##	1.35 ± 0.26^##	5.19 ± 0.89^##

Group	Mental state and weight	Dietary quantity	Hair state	Feces state	Tongue coating	Skin state	Total score
Control	0	0	0	0	0	0	0
Model	2.60 ± 0.28^**	2.26 ± 0.41^**	1.65 ± 0.21^**	1.88 ± 0.58^**	2.40 ± 0.36^**	2.45 ± 0.31^**	13.24 ± 1.78^**
GX-L	1.87 ± 0.30^#	1.64 ± 0.36^#	1.17 ± 0.21^##	1.20 ± 0.35^#	1.70 ± 0.22^##	1.70 ± 0.26^##	9.28 ± 1.41^##
GX-M	1.77 ± 0.65^#	1.35 ± 0.25^##	0.72 ± 0.13^##	1.15 ± 0.29^#	1.55 ± 0.36^##	1.53 ± 0.34^##	8.06 ± 1.62^##
GX-H	1.05 ± 0.39^##	1.01 ± 0.39^##	0.65 ± 0.18^##	1.25 ± 0.19^#	1.77 ± 0.33^##	1.42 ± 0.26^##	6.74 ± 1.24^##
Danlou tablet	1.18 ± 0.40^##	1.02 ± 0.30^##	0.62 ± 0.22^##	1.07 ± 0.27^##	1.30 ± 0.35^##	1.35 ± 0.26^##	5.19 ± 0.89^##

Group	ET-1/pg·mL^-1	NO/μmol·L^-1	eNOS/pg·mL^-1
Control	18.86 ± 1.91	16.57 ± 2.85	15.74 ± 1.31
Model	34.11 ± 2.39^**	2.66 ± 0.83^**	8.49 ± 0.63^**
GX-L	29.85 ± 2.44^##	6.36 ± 0.80^#	10.13 ± 0.51^#
GX-M	26.29 ± 1.00^##	8.15 ± 1.60^##	11.69 ± 0.45^##
GX-H	24.27 ± 1.47^##	11.89 ± 2.05^##	13.46 ± 1.28^##
Danlou tablet	22.85 ± 1.04^##	13.15 ± 1.86^##	14.47 ± 0.90^##

Group	ET-1/pg·mL^-1	NO/μmol·L^-1	eNOS/pg·mL^-1
Control	18.86 ± 1.91	16.57 ± 2.85	15.74 ± 1.31
Model	34.11 ± 2.39^**	2.66 ± 0.83^**	8.49 ± 0.63^**
GX-L	29.85 ± 2.44^##	6.36 ± 0.80^#	10.13 ± 0.51^#
GX-M	26.29 ± 1.00^##	8.15 ± 1.60^##	11.69 ± 0.45^##
GX-H	24.27 ± 1.47^##	11.89 ± 2.05^##	13.46 ± 1.28^##
Danlou tablet	22.85 ± 1.04^##	13.15 ± 1.86^##	14.47 ± 0.90^##

基于网络药理学和实验验证探究经典药对“瓜蒌-薤白”治疗痰瘀互结心血管疾病的作用机制

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张博 , 梁玉宁 , 鲍友利 , 朱利 , 孙鑫 , 吴鸿飞 ^*

药学学报 | 专题报道: 基于整合药理学的中医药现代化研究 2023,58(6): 1452-1463

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药学学报 |专题报道: 基于整合药理学的中医药现代化研究 2023 , 58 (6) : 1452 -1463

基于网络药理学和实验验证探究经典药对“瓜蒌-薤白”治疗痰瘀互结心血管疾病的作用机制

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张博, 梁玉宁, 鲍友利, 朱利, 孙鑫, 吴鸿飞^*

作者信息

安徽中医药大学药学院, 中药研究与开发安徽省重点实验室, 安徽合肥 230012

通讯作者:

*吴鸿飞, Tel: 86-551-68129184, E-mail: wuhongfei@ahtcm.edu.cn

The mechanism of "Trichosanthis Fructus-Allii Macrostemonis Bulbus" on phlegm and blood stasis syndrome-related cardiovascular diseases based on network pharmacology and experimental verification

Bo ZHANG, Yu-ning LIANG, You-li BAO, Li ZHU, Xin SUN, Hong-fei WU^*

Affiliations

Anhui Province Key Laboratory of Research and Development of Chinese Medicine, Department of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China

出版时间: 2023-06-12 doi: 10.16438/j.0513-4870.2023-0086

文章导航

摘要

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“瓜蒌-薤白”药对(GX) 应用历史悠久, 为历代医家长期遣方用药的经验总结, 但其治疗痰瘀互结心血管疾病的作用机制尚未完全阐明。本研究采用网络药理学分析与动物实验验证相整合的研究策略, 探究经典药对GX治疗痰瘀互结心血管疾病的分子作用机制。动物实验过程均遵循安徽中医药大学实验动物伦理委员会的规定(批准号: AHUCM-rats-2021070)。基于前期HPLC-Q-TOF-MS分析结合数据库, 获取69个GX药对的化学成分及163个GX治疗痰瘀互结心血管疾病的靶点, 筛选出丝氨酸/苏氨酸蛋白激酶1 (Akt1)、肿瘤坏死因子(TNF)、白介素6 (IL6)、血管内皮生长因子A (VEGFA)、细胞肿瘤抗原p53 (Tp53) 等关键靶点, 富集分析表明GX治疗痰瘀互结心血管疾病的靶点主要参与PI3K/Akt信号通路、鞘脂代谢、血小板激活、缺氧诱导因子-1 (HIF-1)、ras相关蛋白1 (rap1) 等信号通路, 分子对接分析显示芹菜素、葫芦素D、亚麻酸、山柰酚等6个关键化学成分与Akt1、TNF、IL6、VEGFA和Tp53均具有潜在的结合能力。在动物实验验证中, 与痰瘀互结证大鼠模型相比, GX能显著降低模型大鼠的痰瘀互结证候积分, 改善血液流变学、血脂及血管内皮结构紊乱, 显著降低血清内皮素-1 (ET-1) 水平, 升高血清一氧化氮(NO) 和一氧化氮合成酶(eNOS) 水平, 恢复主动脉血管内皮功能; 并能显著减少主动脉中细胞间黏附分子-1 (ICAM-1) 及血管细胞黏附分子-1 (VCAM-1) 表达, 改善主动脉血管内皮损伤; Western blot实验显示GX显著降低主动脉磷脂酰肌醇3-激酶(PI3K) 及Akt蛋白磷酸化水平。本研究揭示了GX治疗痰瘀互结心血管疾病的多成分、多靶点、多通路的作用特征, 并阐明GX逆转痰瘀互结大鼠模型病理变化, 改善血管内皮功能及炎性损伤, 可能与其抑制PI3K/Akt信号通路有关。

关键词

瓜蒌-薤白 / 痰瘀互结证 / 心血管疾病 / 网络药理学 / 分子对接 / 靶点 / 通路 / 磷酸化水平

Abstract

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This study aimed to investigate the mechanism of "Trichosanthis Fructus-Allii Macrostemonis Bulbus" (GX) on phlegm and blood stasis syndrome (PBSS) rats combining the methods of network pharmacology and experimental verification. Animal experiment ethical requirements were approved by the Ethical Committee Experimental Animal Center of Anhui University of Chinese Medicine (grant number: AHUCM-rats-2021070). Based on the HPLC-Q-TOF-MS analysis and database, 69 chemical constituents of GX and 163 targets of GX for the treatment of phlegm and blood stasis-related cardiovascular diseases were obtained. Then, key targets such as serine/threonine kinase 1 (Akt1), tumor necrosis factor (TNF), interleukin 6 (IL6), vascular endothelial growth factor A (VEGFA), cellular tumor antigen p53 (Tp53) were screened. Pathway analysis showed that the targets of GX in the treatment of phlegm and blood stasis-relate cardiovascular diseases were mainly involved in PI3K/Akt signaling pathway, sphingolipid metabolism, platelet activation, hypoxia inducible factor-1 (HIF-1), ras-proximate-1 (rap1) and other signaling pathways. In addition, molecular docking analysis showed that apigenin, cucurbitacin D, linolenic acid and kaempferol and other key components had potential binding ability with Akt1, TNF, IL6, VEGFA and Tp53. In the animal experiments, compared to the phlegm and blood stasis syndrome group, GX could significantly improve the traditional Chinese medicine syndrome score, blood lipid, vascular endothelial structure disorders and reduce serum endothelin-1 (ET-1) level, increase serum nitric oxide (NO) and endothelial nitric oxide synthase (eNOS) levels, which could restore aortic endothelial function. In addition, the expression of intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in aorta could be significantly reduced, which could improve the vascular endothelial injury of aorta. Western blot revealed that GX could significantly decrease the phosphorylation levels of phosphoinositide 3-kinase (PI3K) and Akt in aorta. This study revealed the mechanism of GX in treatment of phlegm and blood stasis-relate cardiovascular diseases is consistent with the characteristics of multiple ingredients, multiple targets and multiple pathways. In addition, this study also clarified that the reversal of pathological of phlegm and blood stasis syndrome rats may be related to GX inhibiting PI3K/Akt signaling pathway, which could improve vascular inflammation and vascular endothelial function injury.

Key words

Trichosanthis Fructus-Allii Macrostemonis Bulbus / phlegam and blood stasis syndrome / cardiovascular disease / network pharmacology / molecular docking / target / pathway / phosphorylation level

引用本文

张博, 梁玉宁, 鲍友利, 朱利, 孙鑫, 吴鸿飞. 基于网络药理学和实验验证探究经典药对“瓜蒌-薤白”治疗痰瘀互结心血管疾病的作用机制. 药学学报, 2023 , 58 (6) : 1452 -1463 . DOI: 10.16438/j.0513-4870.2023-0086

Bo ZHANG, Yu-ning LIANG, You-li BAO, Li ZHU, Xin SUN, Hong-fei WU. The mechanism of "Trichosanthis Fructus-Allii Macrostemonis Bulbus" on phlegm and blood stasis syndrome-related cardiovascular diseases based on network pharmacology and experimental verification[J]. Acta Pharmaceutica Sinica, 2023 , 58 (6) : 1452 -1463 . DOI: 10.16438/j.0513-4870.2023-0086

正文

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痰瘀是诸多慢性疑难疾病的基本病机^[1], 与动脉粥样硬化、冠心病、高脂血症等心血管疾病密切相关, 亦为心血管疾病诊治的关键环节。

中医理论认为, “痰”为“痰浊”, 即体内水湿津液代谢障碍, 停聚而成的较稠浊的病理产物和致病因素; “瘀”为“血瘀”, 即血液循环迟缓, 流行不畅, 甚则血液停滞的病理状态。现代医学研究表明, “痰”与脂代谢紊乱具有高度相关性, “瘀”与微循环障碍有关, 具有血流变学异常、血脂异常、血管内皮损伤等病理改变^[2], 为众多心血管疾病的病理基础。近代医家从痰瘀论治心血管疾病, 临床疗效显著, 成果丰富, “痰瘀互结证”已经成为中医理论研究与临床关注的重点与热点^[3]。

“瓜蒌-薤白”药对(GX) 始载于《金匮要略》的瓜蒌薤白白酒汤、瓜蒌薤白半夏汤、枳实薤白桂枝汤等经典方剂中。有学者统计含此药对的典型医案120例, 涉及临证处方120首, 广泛用于痰瘀互结心血管疾病的临床治疗^[4]。前期课题组利用HPLC-Q-TOF-MS解析出GX的43个化学成分^[5], 发现GX可显著纠正高脂血症大鼠及动脉粥样硬化小鼠体内脂质代谢紊乱^[6-8], 改善主动脉血管内皮炎性损伤^[9], 抑制高脂血症及动脉粥样硬化的发生发展。然而, 既往研究多聚焦于具体疾病, 经典药对治疗痰瘀互结心血管疾病的作用机制尚不明确, 缺乏从证候的角度揭示药对治疗疾病的科学内涵。

网络药理学基于药物成分及作用靶标, 从系统生物学角度分析药物与疾病靶蛋白的相互作用, 整体观揭示中药治疗疾病的作用及机制^[10]。鉴于GX类方剂在临床治疗痰瘀互结心血管疾病的重要作用, 本研究以GX这一小复方为出发点, 以“痰瘀互结证”心血管疾病及中医证候收集疾病靶点, 利用现代科学技术揭示“痰瘀互结证”的科学内涵, 并解析GX治疗痰瘀互结心血管疾病的作用及机制, 为GX类方剂治疗心血管疾病提供理论依据。

材料与方法

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药物与试剂 瓜蒌(GL, 180601)、薤白(XB, 1903129) 均购于北京同仁堂合肥药店, 经安徽中医药大学刘先华高级实验师鉴定, 符合2020年版《中国药典》要求。参考本课题组前期研究方法^[8], 称取瓜蒌皮-薤白(2∶1), 按比例混合, 充分粉碎, 用50%乙醇(药材5倍量) 充分浸泡1 h, 80 ℃回流提取2次, 每次2 h。过滤提取物, 合并滤液, 减压浓缩, 制备质量浓度为1 g·mL^-1 (相当于原药材) 的GX溶液。丹蒌片(吉林康乃尔药业有限公司, Z20050244), 研碎后溶于0.5%羧甲基纤维素钠制成混悬液^[11]; 高脂饲料(江苏协同生物工程有限责任公司, 20210712); 胆固醇(TC) 生物测定试剂盒(XL-2038)、总甘油三酯(TG) 测定试剂盒(XL-2037)、低密度脂蛋白(LDL-C) 测定试剂盒(XL-8469)、高密度脂蛋白(HDL-C) 测定试剂盒(XL-3159) 及一氧化氮(NO) 测定试剂盒(20214532) 均购于南京建成生物科技有限公司; 兔抗细胞间黏附分子-1 (ICAM-1) 抗体(bs-4617R) 及血管细胞黏附分子-1 (VCAM-1) 抗体(bs-6562R) 均购于美国Bioss公司; 内皮素-1 (ET-1) ELISA试剂盒(ml025101)、一氧化氮合成酶(eNOS) ELISA试剂盒(ml025093) 均购于上海酶联生物科技有限公司; 苏木素染液(安徽欣乐技术有限公司, 批号09232110); PI3K一抗抗体、Akt一抗抗体(成都正能生物技术有限责任公司, 13256-1-AP、R25721); p-PI3K一抗抗体(美国Abcam公司, ab207484); p-Akt一抗抗体(合肥泽木生物科技有限公司, AF0016)。

实验动物 SPF级SD雄性大鼠36只, 体质量(200 ± 20) g, 购于江苏省东方养殖有限公司, 许可证号SCXK (苏) 2017-0003。所有实验均获安徽中医药大学动物伦理委员会批准, 编号AHUCM-rats-2021070。

主要仪器 SA-5000型全自动血液流变仪(北京赛科希德有限公司); YB-7F型生物组织包埋机(湖北亚光有限公司); RM2135型封闭式切片机(德国LEICA公司); ReadMax 1500型全波长酶标仪(美国Thermo Scientific公司); D-37520型低温高速冷冻离心机(德国Eppendorf股份公司); JEM-1230型透射电子显微镜(日本Hitachi Limited公司); AI600型超灵敏多功能成像仪(美国General Electric公司)。

潜在活性成分收集 结合前期HPLC-Q-TOF-MS分析结果^[5]及文献检索收集药对化学成分, 并以口服生物利用度(oral bioavailability, OB) ≥ 30%、类药性(drug likeness, DL) ≥ 0.18为条件经TCMSP数据库筛选成分信息, 共鉴定收集GX中69个化学成分。以此69个化学成分为研究对象, 通过PubChem (https://pubchem.ncbi.nlm.nih.gov/) 平台, 绘制化学结构。

靶点的预测与筛选 将GX中69个化学成分变换格式导入SwissTargetPrediction数据库 ( http://www.swis-stargetprediction.ch/ ) 及SEA数据库 ( https://sea.bkslab.org/ ) 进行靶点预测^{[12, 13]}, 得到化学成分作用靶点。然后, 将靶点信息输入UniProt数据库(https://www.uniprot.org/) 规范靶点名称。在TTD ( http://db.idrblab.net/ttd/ ) 数据库中检索关键词“cardiovascular diseases”、“atherosclerosis”、“coronary heart disease”、“hyperlipidemia”、“thrombus”、“inflammation”、“pain”、“insulin resistance”为关键词^[14], 汇总整理痰瘀互结心血管疾病相关病理及疾病靶点, 并与化学成分作用靶点整合取交集, 获得GX治疗痰瘀互结心血管疾病的潜在靶点。

蛋白互作(PPI) 网络的构建 痰瘀互结心血管的发病分子机制复杂, 与疾病相关的靶点往往存在直接的物理相互作用或间接的功能关联, 从而影响痰瘀互结相关疾病的发生发展。为了更好地分析靶点间的相互作用, 将潜在作用靶点导入STRING (https://cn.string-db.org/) 数据库, 物种选择“Human”。保存结果并导入Cytoscape 3.8.0软件构建PPI网络, 对其网络进行分析, 并将节点(node) 大小和颜色设置用于反映度值(degree) 的大小。

KEGG通路分析 将潜在作用靶点导入DAVID 6.8数据库(https://david.ncifcrf.gov/), 物种选择“Human”, 进行KEGG通路分析(P < 0.05), 分析潜在靶点聚类于痰瘀互结心血管疾病相关的信号通路^[15]。

“成分-靶点-通路”网络构建 将GX中化学成分、治疗痰瘀互结心血管疾病的潜在靶点、作用通路分析结果导入Cytoscape 3.8.0软件, 构建“成分-靶点-通路”网络图。

分子对接虚拟计算 将GX核心成分与核心靶点进行分子对接。利用ChemBio3DUltra14.0将所得活性成分的mol2格式文件转化为3D结构。利用PDB (https://www.rcsb.org/) 数据库获取核心靶点基因的PDB格式文件, 利用PyMOL2.4.1软件对蛋白质进行去水、加氢操作, 再通过AutoDockVin1.1.2软件进行药物活性成分与核心靶点基因进行分子对接^[16]。

痰瘀互结大鼠模型建立与药效学实验 取SD大鼠36只, 随机分组, 每组6只, 适应性饲养1周后, 设立空白组、模型组、GX低剂量组(GX-L)、GX中剂量组(GX-M)、GX高剂量组(GX-H)、丹蒌片组。按照文献^[17]方法, 除空白组外, 其余各组喂养高脂饲料, 并于每日9:00将大鼠浸入浴温0~4 ℃的冰水中, 浸泡至大鼠全身僵直后取出(约20 min)。从造模第15天开始, 皮下注射盐酸肾上腺素, 每天1次, 给药剂量为0.8 g·kg^-1 (0.8 mL·kg^-1), 持续造模共30天。依据文献^[17-19]动物造模方法, 采用观察症状体征与检测病理学指标相结合, 以痰瘀互结证候积分显著增加、血液流变学及血脂指标异常、血管内皮结构紊乱, 为痰瘀互结大鼠模型建立成功的判断标准。

痰瘀互结大鼠模型建立成功后, 空白组、模型组大鼠灌胃生理盐水, GX-L (2 g·kg^-1·d^-1)、GX-M (4 g·kg^-1·d^-1)、GX-H (8 g·kg^-1·d^-1) 组大鼠分别灌胃相应浓度GX提取液, 丹蒌片组(0.4 g·kg^-1·d^-1) 组大鼠灌胃相应浓度的丹蒌片混悬液。所有大鼠均在同一环境同时间内进行操作, 灌胃给药2周, 给药体积为10 mL·kg^-1。

中医证候评分量表评价痰瘀互结大鼠模型 参照文献^[18]制订中医证候评分量表, 对痰瘀互结大鼠进行中医证候评分, 从精神体质量、饮食饮水、毛发的色泽与脱落情况、粪便、舌象、皮肤瘀斑瘀点情况等6个方面的表征进行评估, 评分等级分为0~3分。证候的轻重程度与分值的高低呈正相关, 分值越高痰瘀互结证候越显著。

血液流变学及血脂的检测 大鼠麻醉后, 腹主动脉采集取血, 全自动血液流变分析仪测定1、100、200 s^-1切边率下的全血黏度和红细胞聚集指数。剩余全血于4 ℃条件下, 2 500 r·min^-1离心20 min, 取上清液测定TC、TG、LDL-C、HDL-C水平。

ELISA法测定血清NO、ET-1及eNOS含量 取大鼠全血于4 ℃条件下, 2 500 r·min^-1离心20 min, 选取上清液后按照试剂盒说明书分别测定ET-1、NO及eNOS水平。

大鼠主动脉病理形态及黏附因子表达的检测 主动脉组织用4%甲醛磷酸盐缓冲液处理过夜, 脱水石蜡包埋, 苏木素-伊红染色(HE) 染色, 光学显微下观察主动脉组织形态学变化, 并利用Image J图像分析系统对主动脉中膜厚度进行统计分析。免疫组化检测ICAM-1、VCAM-1表达, 光学显微镜下观察并拍照, 光学显微镜下可见棕黄色点状或纤维状染色集中在细胞膜、细胞浆或细胞间, 则为阳性表达, 阴性表达则无棕黄色染色, 并利用Image Pro Plus 6.0图像分析系统对ICAM-1及VCAM-1进行统计分析。

Western blot法靶点表达验证 取主动脉组织适量, RIPA裂解液提取总蛋白, 加入上样缓冲液, 100 ℃煮沸10 min, -20 ℃储存。取适量蛋白样品经SDS-PAGE凝胶电泳, 200 mA湿法转膜, 5%脱脂奶粉37 ℃封闭, TBST漂洗, 加入一抗4 ℃孵育; TBST漂洗, 加入二抗, 室温孵育, TBST漂洗, ECL化学发光试剂显色, 超灵敏多功能成像仪检测, 图像分析软件Image-Pro Plus 6.0进行灰度分析。

统计学分析 实验数据以x ± s表示, 结果采用GraphPad Prism 8.0软件进行数据分析, 多组间数据比较采用单因素方差分析(one-way ANOVA), 组间两两比较采用LSD法, P < 0.05表明差异具有统计学意义。

结果

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1 靶点的预测与筛选

将69个GX化学成分导入SwissTargetPrediction及SEA数据库进行靶点预测, 通过整合得到815个靶点。检索TTD数据平台, 得到与痰瘀互结心血管疾病靶基因362个。Venn软件作图取交集, 得到163个GX治疗痰瘀互结心血管疾病的潜在靶点(表 1)。

2 蛋白互作(PPI) 网络的构建

潜在靶点的蛋白质相互作用PPI网络中共有161个节点(靶点蛋白)、1 878条边(蛋白相互作用) (图 1)。节点大小和颜色表示该节点度值的大小, 节点越大、红色越深, 对应的度值越大, 表明在所预测的疾病相关靶点中, 能与该靶点产生有效互相作用的靶点越多。其中, 丝氨酸/苏氨酸蛋白激酶1 (Akt1, 95)、肿瘤坏死因子(TNF, 89)、白介素6 (IL6, 84)、血管内皮生长因子A (VEGFA, 76)、细胞肿瘤抗原p53 (Tp53, 72) 度值较大, 可能为痰瘀互结心血管疾病的关键靶点。

3 KEGG通路富集分析

通过DAVID 6.8数据平台对GX治疗痰瘀互结心血管疾病的潜在靶点进行KEGG通路富集分析(P < 0.05) 并绘制柱状图(图 2)。KEGG分析主要涉及炎症通路、脂质代谢通路、凋亡通路和疾病相关通路等。炎症相关通路主要包括PI3K/Akt信号通路(PI3K/Akt signaling pathway)、HIF-1信号通路(HIF-1 signaling pathway); 脂质代谢相关通路主要包括鞘脂信号通路(sphingolipid signaling pathway)、脂肪细胞中脂肪分解的调节(regulation of lipolysis in adipocytes); 凋亡相关通路主要包括rap1信号通路(rap1 signaling pathway); 血小板形成相关通路包括血小板激活(platelet activation); 疾病通路主要包括癌症通路(pathways in cancer)、非小细胞肺癌(non-small cell lung cancer) 等通路。

4 “成分-靶点-通路”网络构建

采用Cytoscape 3.8.0软件构建网络时, 筛选PPI蛋白互作度值排名靠前的30个靶点参与“成分-靶点-通路”网络构建, 见图 3。该网络有93个节点和401条边。度值越大, 代表与该节点相连的其他节点越多, 证明该节点在网络中的贡献率较大。芹菜素(apigenin, 11)、葫芦素D (cucurbitacin D, 9)、亚麻酸(linolenic acid, 9)、山柰酚(kaempferol, 8)、柚皮素(naringenin, 8)、槲皮素(quercetin, 6) 等成分度值较大, 均与多个靶点连接, 可能是GX的核心化学成分。度值较大的靶点包括血管内皮生长因子A (VEGFA, 24)、丝氨酸/苏氨酸蛋白激酶1 (Akt1, 23)、丝裂原活化蛋白激酶1 (MAPK1, 22) 等。对应度值较大的通路包括PI3K/Akt信号通路(PI3K/Akt signaling pathway, 17)、HIF-1信号通路(HIF-1 signaling pathway, 12)、rap1信号通路(rap1 signaling pathway, 10)、血小板活化(platelet activation, 9) 和鞘脂信号通路(sphingolipid signaling pathway, 9) 等。

5 分子对接虚拟计算结果

将PPI网络中排名靠前的靶点, 分别与GX核心成分进行分子对接验证, 结果见表 2。根据痰瘀互结心血管疾病特点, 靶点蛋白选取时, 分别选取了影响炎症、细胞凋亡和脂质代谢3个方面的靶蛋白, 参与分子对接。分子对接结合能越小, 表明其结合性越好。结果显示, 芹菜素、葫芦素D、亚麻酸、山柰酚、柚皮素、槲皮素与Akt1、TNF、IL6、VEGFA和Tp53靶蛋白的平均结合性能绝大部分小于-1.2 kcal·mol^-1。以上结果表明, GX核心成分能较好地与痰瘀互结心血管疾病相关靶点对接, 潜在生物活性高。

6 药效学实验及Western blot法验证关键靶点蛋白表达

6.1 GX改善痰瘀互结证大鼠中医证候症状

高脂饮食喂养、冰水浸浴及皮下注射盐酸肾上腺素, 建立痰瘀互结大鼠模型。与空白组相比, 模型组大鼠痰瘀互结证候积分显著升高, 出现体胖腹大、不思饮食、皮肤瘀斑瘀点、舌色紫暗、大便黏腻不成形、小便黄等痰瘀互结证候的特征性表现。与模型组相比, GX及丹蒌片干预给药可显著降低大鼠中医证候积分(表 3), GX各剂量组及丹蒌片组大鼠精神状态良好, 摄食量、饮水量呈上升趋势, 无嗜睡、纳呆、瘀斑瘀点, 毛发较光亮, 大便转干; 表明GX显著改善痰瘀互结证大鼠的中医证候症状。

6.2 GX改善痰瘀互结证大鼠血液流变学及血脂水平紊乱

与空白组相比, 模型组大鼠全血(低切、中切、高切) 黏度及红细胞聚集指数均显著升高; 模型组大鼠血液流变学发生异常改变, 符合痰瘀互结证病理变化; 与模型组相比, GX各剂量组及丹蒌片组大鼠全血(低切、中切、高切) 黏度及红细胞聚集指数均显著降低(图 4)。

与空白组比较, 模型组大鼠血清中TC、TG及LDL-C的水平均显著升高, HDL-C水平显著降低; 模型组大鼠血脂发生异常改变, 符合痰瘀互结证病理变化; 与模型组相比, GX各剂量组及丹蒌片组大鼠血清中TC、TG、LDL-C水平显著降低, HDL-C水平显著升高且呈剂量依赖性(图 5)。

6.3 GX改善痰瘀互结证大鼠血管内皮结构异常

与空白组相比, 模型组大鼠主动脉内膜内皮细胞排列不齐, 内皮细胞有脱落, 中膜增厚; 与模型组相比, GX各剂量组及丹蒌片组大鼠的主动脉组织形态均明显改善, 主动脉中膜厚度显著性降低(图 6)。

与空白组相比, 模型组大鼠血清中NO、eNOS水平显著降低, ET-1水平显著升高; 与模型组相比, GX各剂量组及丹蒌片组大鼠血清中NO和eNOS水平均显著升高, ET-1水平均显著降低, 且呈剂量依赖性(表 4)。

与空白组相比, 模型组大鼠主动脉组织中ICAM-1、VCAM-1的阳性表达均显著升高; 与模型组相比, GX各剂量组及丹蒌片组大鼠主动脉组织中ICAM-1、VCAM-1的阳性表达均显著降低(图 7、8)。

综上结果表明, GX可显著改善痰瘀互结证大鼠血液“浓”、“黏”、“聚”的特点, 改善血管内皮结构紊乱及血管内皮功能, 抑制血管炎性反应, 逆转痰瘀互结证大鼠特征病理性变化。

6.4 Western blot法验证GX调控PI3K/Akt蛋白表达

血管炎症及血管内皮功能损伤是痰瘀互结心血管疾病的重要临床表现之一。在炎症和内皮损伤的进程中, PI3K/Akt通路的表达发挥了关键作用^[20]。根据网络预测结果, 关键靶点Akt1、IL6、VEGFA、Tp53均富集在PI3K/Akt信号通路, 参与PI3K/Akt信号通路的调控。因此, 本实验以PI3K、p-PI3K、Akt及p-Akt蛋白表达, 对网络药理学预测结果进行验证。

与空白组相比, 模型组大鼠主动脉组织中p-PI3K及p-Akt蛋白的表达均明显升高; 与模型组相比, GX各剂量及丹蒌片组大鼠主动脉中p-PI3K及p-Akt蛋白的表达明显降低(图 9)。以上结果表明, GX各剂量组可不同程度降低痰瘀互结大鼠主动脉组织中p-PI3K及p-Akt表达。

讨论

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痰瘀互结证是中医常见证型, 与动脉粥样硬化、冠心病、高脂血症等心血管疾病密切相关^[21], 成为中医理论与临床研究的热点。中医临床认为, 痰瘀互结证患者可同时出现痰证、血瘀证的表现。痰证多见形体肥胖、纳呆、胸闷胸痛、眩晕、痰多、头身困重、嗜睡懒动、口干不欲饮水、大便黏腻不成形, 舌苔白腻或黄腻, 脉滑; 血瘀证多见刺痛、痛有定处, 脉络淤血(诸如口唇、齿龈、爪甲紫黯, 肤表赤缕, 或腹部青筋外露), 皮下瘀斑, 癥积, 舌质紫黯或有瘀点瘀斑, 脉细涩或沉弦等^{[22, 23]}, 根据上述表现可判断为痰瘀互结证。

现代医学研究表明, 痰瘀互结证具有某些实验室指标的特征性改变, 痰证型冠心病患者更易出现脂肪代谢紊乱, 血脂及血液黏度水平异常升高; 血瘀型冠心病患者更易出现脂肪代谢紊乱, 严重的血管细胞膜损伤等^[24]。研究表明, 痰瘀互结模型大鼠血浆总胆固醇(CHO)、TG、LDL-C含量均显著升高, HDL-C含量显著降低^[25]。利用冰水浴联合盐酸肾上腺素注射大鼠研究可升高血浆黏度, 导致血液易凝聚等血液流变性改变, 并伴随严重的血管内皮损伤, 为血瘀证重要的病理基础^[26]。本实验基于文献方法建立的痰瘀互结大鼠模型, 与中医证候表现及现代药理学指标相一致。本研究表明, GX显著改善痰瘀互结证的中医证候症状, 改善大鼠血液“浓”“黏”“聚”的特点, 改善痰瘀互结大鼠血管内皮功能, 抑制血管炎性反应, 逆转痰瘀互结大鼠特征病理性变化。

GX药对主要由瓜蒌、薤白两味中药组成, “瓜蒌-薤白”类方可有效防治痰瘀互结型心血管疾病^{[27, 28]}, 但其治疗痰瘀互结心血管疾病的作用机制尚未完全阐明。本研究利用网络药理学方法预测了GX药对治疗痰瘀互结心血管疾病的关键靶点、核心成分及相关通路。PPI网络显示, 靶点之间存在着多种关联, 连接度值越高, 靶点的潜在治疗作用越大。Akt1、TNF、IL6、VEGFA和Tp53排名靠前, 可能是GX治疗痰瘀互结心血管疾病的核心靶点。Akt1参与多种生物学过程, 包括代谢、增殖、血管生成等, 是PI3K/Akt信号通路中的核心因子^[29]。TNF是健康机体和疾病条件下哺乳动物免疫反应的关键中介和调节因子, 可导致血管炎症、血脂异常及胰岛素抵抗, 在早期动脉粥样硬化等心血管疾病有明显升高趋势^[30]。IL6属于白细胞介素家族, 在传递信息及炎症反应中起重要作用^[31]。VEGFA是VEGF家族的一员, 可促进内皮细胞生长, 伴随着较高的血管通透性, 与梗死区微血管密度增加呈正相关^[32]。Tp53在细胞生长中起着关键调控作用, 参与细胞生长、凋亡等生理功能, 可通过调节甲羟戊酸途径, 进而影响高脂血症的发展^[33]。课题组前期研究表明, GX可通过降低大鼠血清中TNF-α及IL6等炎性因子的表达, 抑制血管炎症反应^[8]。本实验结果亦表明, GX治疗痰瘀互结证心血管疾病所涉及的核心靶点主要在炎症反应、脂质代谢、细胞增殖分化和凋亡中发挥重要作用。靶点与靶点之间联系密切, 也体现了GX具有多靶点多协同治疗疾病的优势。

“成分-靶点-通路”网络显示, GX治疗痰瘀互结心血管疾病的核心成分可能为芹菜素、葫芦素D、亚麻酸、山柰酚、柚皮素、槲皮素等活性成分。有研究表明芹菜素可通过抑制NF-κB活化及其下游细胞因子ICAM-1的表达, 减轻血管内皮炎症, 改善内皮功能, 发挥治疗心血管疾病的作用^[34]。葫芦素具有较强的抗炎活性, 通过降低TNF-α等炎性因子的释放, 降低血管炎性反应^[35]。亚麻酸为人体必需脂肪酸, 具有抗动脉粥样硬化、抗血栓形成、降低心血管疾病风险等药理作用。研究表明, 亚麻酸可以通过抑制PI3K/Akt信号通路, 改善高脂饮食大鼠主动脉血管的血栓形成^[36]。山柰酚通过减少TNF-α、IL6等炎性因子, 抑制血管黏附因子ICAM-1及VCAM-1表达, 改善血管内皮炎症损伤^[37]; 其还可通过调节家兔体内血脂紊乱, 减少主动脉粥样硬化斑块面积, 发挥抗动脉粥样硬化的作用^[38]。柚皮素可调节小鼠体内TC和TG水平, 改善血脂代谢紊乱, 降低血液黏度, 抑制动脉粥样硬化发生发展^[39]。槲皮素降低主动脉血管壁细胞的NF-κB转录活性, 显著改善冠心病患者的临床症状^[40]; 柚皮素及槲皮素可降低黏附分子水平及炎症标志物, 保护内皮细胞功能, 治疗心血管疾病^[41]。

KEGG信号通路富集分析发现, PI3K/Akt信号通路、HIF-1信号通路、鞘脂代谢信号通路等是调控痰瘀互结心血管疾病的重要通路。PI3K/Akt信号通路可调节心肌细胞凋亡、血管内皮再生、物质代谢和炎症反应, 在冠心病的发生发展中起着重要作用^{[42, 43]}。HIF-1信号通路上调与血管系统相关蛋白基因的表达, 与心血管疾病的发生与发展密切相关^[44]。鞘脂代谢信号通路可保护心脏免受脂质堆积, 降低动脉粥样硬化等心血管疾病的发生率^[45], 其相关代谢物参与人冠状动脉平滑肌细胞炎症反应, 在炎症信号中起着至关重要的作用^[46]。可见, 上述信号通路参与炎症、脂质合成和内皮功能障碍等病理环节, 调控痰瘀互结心血管疾病的发生发展。结合动物实验验证, 本研究发现GX降低痰瘀互结模型大鼠主动脉内p-PI3K、p-Akt蛋白的表达, 与预测结果一致; 表明GX改善痰瘀互结模型大鼠血管炎症及内皮功能损伤, 与其调控PI3K/Akt信号通路密切相关。本研究以GX这一小复方为出发点, 利用现代科学技术解析GX治疗痰瘀互结心血管疾病的作用机制, 为GX类方剂治疗心血管疾病提供理论依据。

作者贡献: 本文设计思路由吴鸿飞教授提供; 张博和梁玉宁具体参与靶点筛选、通路富集、网络构建及分子对接工作; 张博、鲍友利、朱利和孙鑫负责GX药效实验及Western blot蛋白表达实验。

利益冲突: 本文不存在利益冲突。

基金

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国家自然科学基金资助项目(82274137)
国家自然科学基金资助项目(81873038)
安徽省自然科学基金资助项目(2208085MH275)
安徽省高校杰出青年科研项目(2022AH020041)
安徽高校自然科学研究项目(KJ2021A0592)

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2023年第58卷第6期

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doi: 10.16438/j.0513-4870.2023-0086

接收时间：2023-01-31
首发时间：2025-11-21
出版时间：2023-06-12

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收稿日期：2023-01-31
修回日期：2023-03-09

基金

国家自然科学基金资助项目(82274137)

国家自然科学基金资助项目(81873038)

安徽省自然科学基金资助项目(2208085MH275)

安徽省高校杰出青年科研项目(2022AH020041)

安徽高校自然科学研究项目(KJ2021A0592)

作者信息

安徽中医药大学药学院, 中药研究与开发安徽省重点实验室, 安徽合肥 230012

通讯作者:

*吴鸿飞, Tel: 86-551-68129184, E-mail: wuhongfei@ahtcm.edu.cn

参考文献

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https://castjournals.cast.org.cn/joweb/yxxb/CN/10.16438/j.0513-4870.2023-0086

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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

ID	Compound	Molecular weight	Formular	Source
GL1	Beta-D-arabinopyranose	150.05	C₅H₁₀O₅	GL
GL2	Vanillic acid 4-β-D-glucoside	330.09	C₁₄H₁₈O₉	GL
GL3	2, 3, 4, 9-Tetrahydro-1H-pyrido[3, 4-b]indole-3-carboxylic acid	216.09	C₁₂H₁₂N₂O₂	GL
GL4	Rutin	610.15	C₂₇H₃₀O₁₆	GL
GL5	Kaempferol-3-O-β-rutinoside	594.16	C₂₇H₃₀O₁₅	GL
GL6	Quercitrin	448.10	C₂₁H₂₀O₁₁	GL
GL7	Quercetin	302.04	C₁₅H₁₀O₇	GL
GL8	Quercetin-3-O-α-D-riboside	434.08	C₂₀H₁₈O₁₁	GL
GL9	Kaempferol-3-D-glucoside-7-O-rhamnoside	578.16	C₂₇H₃₀O₁₄	GL
GL10	Apigenin-7-O-β-D-glucoside	432.11	C₂₁H₂₀O₁₀	GL
GL11	Chrysoeriol-7-O-β-D-glucoside	462.12	C₂₂H₂₂O₁₁	GL
GL12	Bryoamaride	678.36	C₃₆H₅₄O₁₂	GL
GL13	25-O-Acetylbryoamaride	720.37	C₃₈H₅₆O₁₃	GL
GL14	Cucurbitacin D	516.31	C₃₀H₄₄O₇	GL
GL15	Tianshic acid	330.24	C₁₈H₃₄O₅	GL
GL16	Cucurbitacin B	558.32	C₃₂H₄₆O₈	GL
GL17	Isocucurbitacin B	558.32	C₃₂H₄₆O₈	GL
GL18	Pentadecanoic acid	242.22	C₁₅H₃₀O₂	GL
GL19	Punicic acid	278.22	C₁₈H₃₀O₂	GL
GL20	Apigenin	270.24	C₁₅H₁₀O₅	GL
GL21	Chrysoeriol	300.26	C₁₆H₁₂O₆	GL
GL22	Kaempferol	286.24	C₁₅H₁₀O₆	GL
GL23	Mandenol	308.56	C₂₀H₃₆O₂	GL
GL24	Diosmetin	300.28	C₁₆H₁₂O₆	GL
GL25	Spinasterol	412.77	C₂₉H₄₈O	GL
GL26	Hydroxygenkwanin	300.26	C₁₆H₁₂O₆	GL
GL27	Schottenol	414.79	C₂₉H₅₀O	GL
GL28	10α-Cucurbita-5, 24-diene-3β-ol	426.80	C₃₀H₅₀O	GL
GL29	7-Oxo-dihydrokaro-unidiol	456.78	C₃₀H₄₈O₃	GL
GL30	Karounidiol 3-O-benzoate	544.89	C₃₇H₅₂O₃	GL
GL31	Linolenic acid ethyl ester	306.54	C₂₀H₃₄O₂	GL
GL32	Vitamin-e	490.69	C₂₄H₃₄N₄O₅S	GL
GL33	5-Dehydrokarounidiol	438.76	C₃₀H₄₆O₂	GL
XB1	DiAllS2	146.02	C₆H₁₀S₂	XB
XB2	(1S, 3S)-2, 3, 4, 9-Tetrahydro-1-methyl-1H-pyrido[3, 4-b] indole-3-carboxylic acid	230.11	C₁₃H₁₄N₂O₂	XB
XB3	Chinenoside V	916.47	C₄₅H₇₂O₁₉	XB
XB4	26-[(β-D-Glucopyranosyl)oxy]-2β, 22-dihydroxy-5β-furostan-25(27)-en-3β-yl-O-β-D-glucopyranosyl-(1→2)-β-D-galactopyranoside	934.48	C₄₅H₇₂O₂₀	XB
XB5	Macrostemonoside J	936.49	C₄₅H₇₆O₂₀	XB
XB6	Macrostemonoside I	932.46	C₄₅H₇₂O₂₀	XB
XB7	Macrostemonoside G	934.48	C₄₅H₇₄O₂₀	XB
XB8	Macrostemonoside P	936.49	C₄₅H₇₆O₂₀	XB
XB9	25R-Macrostemonoside P	936.49	C₄₅H₇₆O₂₀	XB
XB10	Macrostemonoside O	918.48	C₄₅H₇₄O₁₉	XB
XB11	Timosaponin BII	920.50	C₁₃H₁₄N₂O₂	XB
XB12	25R-Timosaponin BII	920.50	C₁₃H₁₄N₂O₂	XB
XB13	Macrostemonoside F	902.49	C₄₅H₇₄O₁₈	XB
XB14	Timosaponin C	902.49	C₄₅H₇₄O₁₈	XB
XB15	Macrostemonoside S	754. 41	C₃₉H₆₂O₁₄	XB
XB16	Timosaponin A Ⅲ	740.44	C₃₉H₆₄O₁₃	XB
XB17	Macrostemonoside A	1 064.54	C₅₁H₈₄O₂₃	XB
XB18	Macrostemonoside D	1 106.55	C₅₃H₈₆O₂₄	XB
XB19	Sitogluside	576.44	C₃₅H₆₀O₆	XB
XB20	Macrostemonoside B	1 245.35	C₅₇H₉₆O₂₉	XB
XB21	25S-Macrostemonoside B	1 245.35	C₅₇H₉₆O₂₉	XB
XB22	Sitosteryl acetate	456.83	C₃₁H₅₂O₂	XB
XB23	Hesperetin	302.30	C₁₆H₁₄O₆	XB
XB24	Beta-sitosterol	414.79	C₂₉H₅₀O	XB
XB25	Naringenin	272.27	C₁₅H₁₂O₅	XB
XB26	Macrostemonoside e_qt	416.71	C₂₇H₄₄O₃	XB
XB27	Prostaglandin A1	336.52	C2₀H₃₂O₄	XB
XB28	Prostaglandin B1	336.52	C₂₀H₃₂O₄	XB
XB29	n-Coumaroyltyramine	283.35	C₁₇H₁₇NO₃	XB
XB30	(Z)-3-(4-Hydroxy-3-methoxy-phenyl)-N-[2-(4-hydroxyphenyl)ethyl]acrylamide	313.38	C₁₈H₁₉NO₄	XB
XB31	Coumaroyltyramine	283.35	C₁₇H₁₇NO₃	XB
GX1	Adenosine	267.10	C₉H₁₃O₄N₅	GL/XB
GX2	Guanosine	283.09	C₅H₅N₅O	GL/XB
GX3	L-Phenylalanine	165.08	C₉H₁₁NO₂	GL/XB
GX4	DL-Tryptophan	204.09	C₁₁H₁₂N₂O₂	GL/XB
GX5	Linolenic acid	278.22	C₁₈H₃₀O₂	GL/XB

Compound

Molecular weight

Formular

Source

GL1

Beta-D-arabinopyranose

150.05

C₅H₁₀O₅

GL2

Vanillic acid 4-β-D-glucoside

330.09

C₁₄H₁₈O₉

GL3

2, 3, 4, 9-Tetrahydro-1H-pyrido[3, 4-b]indole-3-carboxylic acid

216.09

C₁₂H₁₂N₂O₂

GL4

Rutin

610.15

C₂₇H₃₀O₁₆

GL5

Kaempferol-3-O-β-rutinoside

594.16

C₂₇H₃₀O₁₅

GL6

Quercitrin

448.10

C₂₁H₂₀O₁₁

GL7

Quercetin

302.04

C₁₅H₁₀O₇

GL8

Quercetin-3-O-α-D-riboside

434.08

C₂₀H₁₈O₁₁

GL9

Kaempferol-3-D-glucoside-7-O-rhamnoside

578.16

C₂₇H₃₀O₁₄

GL10

Apigenin-7-O-β-D-glucoside

432.11

C₂₁H₂₀O₁₀

GL11

Chrysoeriol-7-O-β-D-glucoside

462.12

C₂₂H₂₂O₁₁

GL12

Bryoamaride

678.36

C₃₆H₅₄O₁₂

GL13

25-O-Acetylbryoamaride

720.37

C₃₈H₅₆O₁₃

GL14

Cucurbitacin D

516.31

C₃₀H₄₄O₇

GL15

Tianshic acid

330.24

C₁₈H₃₄O₅

GL16

Cucurbitacin B

558.32

C₃₂H₄₆O₈

GL17

Isocucurbitacin B

558.32

C₃₂H₄₆O₈

GL18

Pentadecanoic acid

242.22

C₁₅H₃₀O₂

GL19

Punicic acid

278.22

C₁₈H₃₀O₂

GL20

Apigenin

270.24

C₁₅H₁₀O₅

GL21

Chrysoeriol

300.26

C₁₆H₁₂O₆

GL22

Kaempferol

286.24

C₁₅H₁₀O₆

GL23

Mandenol

308.56

C₂₀H₃₆O₂

GL24

Diosmetin

300.28

C₁₆H₁₂O₆

GL25

Spinasterol

412.77

C₂₉H₄₈O

GL26

Hydroxygenkwanin

300.26

C₁₆H₁₂O₆

GL27

Schottenol

414.79

C₂₉H₅₀O

GL28

10α-Cucurbita-5, 24-diene-3β-ol

426.80

C₃₀H₅₀O

GL29

7-Oxo-dihydrokaro-unidiol

456.78

C₃₀H₄₈O₃

GL30

Karounidiol 3-O-benzoate

544.89

C₃₇H₅₂O₃

GL31

Linolenic acid ethyl ester

306.54

C₂₀H₃₄O₂

GL32

Vitamin-e

490.69

C₂₄H₃₄N₄O₅S

GL33

5-Dehydrokarounidiol

438.76

C₃₀H₄₆O₂

XB1

DiAllS2

146.02

C₆H₁₀S₂

XB2

(1S, 3S)-2, 3, 4, 9-Tetrahydro-1-methyl-1H-pyrido[3, 4-b] indole-3-carboxylic acid

230.11

C₁₃H₁₄N₂O₂

XB3

Chinenoside V

916.47

C₄₅H₇₂O₁₉

XB4

26-[(β-D-Glucopyranosyl)oxy]-2β, 22-dihydroxy-5β-furostan-25(27)-en-3β-yl-O-β-D-glucopyranosyl-(1→2)-β-D-galactopyranoside

934.48

C₄₅H₇₂O₂₀

XB5

Macrostemonoside J

936.49

C₄₅H₇₆O₂₀

XB6

Macrostemonoside I

932.46

C₄₅H₇₂O₂₀

XB7

Macrostemonoside G

934.48

C₄₅H₇₄O₂₀

XB8

Macrostemonoside P

936.49

C₄₅H₇₆O₂₀

XB9

25R-Macrostemonoside P

936.49

C₄₅H₇₆O₂₀

XB10

Macrostemonoside O

918.48

C₄₅H₇₄O₁₉

XB11

Timosaponin BII

920.50

C₁₃H₁₄N₂O₂

XB12

25R-Timosaponin BII

920.50

C₁₃H₁₄N₂O₂

XB13

Macrostemonoside F

902.49

C₄₅H₇₄O₁₈

XB14

Timosaponin C

902.49

C₄₅H₇₄O₁₈

XB15

Macrostemonoside S

754. 41

C₃₉H₆₂O₁₄

XB16

Timosaponin A Ⅲ

740.44

C₃₉H₆₄O₁₃

XB17

Macrostemonoside A

1 064.54

C₅₁H₈₄O₂₃

XB18

Macrostemonoside D

1 106.55

C₅₃H₈₆O₂₄

XB19

Sitogluside

576.44

C₃₅H₆₀O₆

XB20

Macrostemonoside B

1 245.35

C₅₇H₉₆O₂₉

XB21

25S-Macrostemonoside B

1 245.35

C₅₇H₉₆O₂₉

XB22

Sitosteryl acetate

456.83

C₃₁H₅₂O₂

XB23

Hesperetin

302.30

C₁₆H₁₄O₆

XB24

Beta-sitosterol

414.79

C₂₉H₅₀O

XB25

Naringenin

272.27

C₁₅H₁₂O₅

XB26

Macrostemonoside e_qt

416.71

C₂₇H₄₄O₃

XB27

Prostaglandin A1

336.52

C2₀H₃₂O₄

XB28

Prostaglandin B1

336.52

C₂₀H₃₂O₄

XB29

n-Coumaroyltyramine

283.35

C₁₇H₁₇NO₃

XB30

(Z)-3-(4-Hydroxy-3-methoxy-phenyl)-N-[2-(4-hydroxyphenyl)ethyl]acrylamide

313.38

C₁₈H₁₉NO₄

XB31

Coumaroyltyramine

283.35

C₁₇H₁₇NO₃

GX1

Adenosine

267.10

C₉H₁₃O₄N₅

GL/XB

GX2

Guanosine

283.09

C₅H₅N₅O

GL/XB

GX3

L-Phenylalanine

165.08

C₉H₁₁NO₂

GL/XB

GX4

DL-Tryptophan

204.09

C₁₁H₁₂N₂O₂

GL/XB

GX5

Linolenic acid

278.22

C₁₈H₃₀O₂

GL/XB

Compound name	Gene target	PDB ID	Estimated ΔG/kcal·mol^-1
Apigenin	Akt1	7NH5	-8.8
TNF	6Q01	-6.1
IL6	4CNI	-4.5
VEGFA	3QTK	-6.1
Tp53	4CZ7	-7.5
Cucurbitacin D	Akt1	7NH5	-10.8
TNF	6Q01	-6.1
IL6	4CNI	-5.1
VEGFA	3QTK	-7.2
Tp53	4CZ7	-
Linolenic acid	Akt1	7NH5	-5.7
TNF	6Q01	-3.6
IL6	4CNI	-2.8
VEGFA	3QTK	-4.2
Tp53	4CZ7	-5.7
Kaempferol	Akt1	7NH5	-8.7
TNF	6Q01	-5.9
IL6	4CNI	-4.4
VEGFA	3QTK	-5.8
Tp53	4CZ7	-6.7
Quercetin	Akt1	7NH5	-9.3
TNF	6Q01	-6.4
IL6	4CNI	-4.4
VEGFA	3QTK	-6
Tp53	4CZ7	-7.5
Naringenin	Akt1	7NH5	-8.7
TNF	6Q01	-6.1
IL6	4CNI	-4.5
VEGFA	3QTK	-6.3
Tp53	4CZ7	-7.4

Compound name

Gene target

PDB ID

Estimated
ΔG/kcal·mol^-1

Apigenin

Akt1

7NH5

-8.8

TNF

6Q01

-6.1

IL6

4CNI

-4.5

VEGFA

3QTK

-6.1

Tp53

4CZ7

-7.5

Cucurbitacin D

Akt1

7NH5

-10.8

TNF

6Q01

-6.1

IL6

4CNI

-5.1

VEGFA

3QTK

-7.2

Tp53

4CZ7

Linolenic acid

Akt1

7NH5

-5.7

TNF

6Q01

-3.6

IL6

4CNI

-2.8

VEGFA

3QTK

-4.2

Tp53

4CZ7

-5.7

Kaempferol

Akt1

7NH5

-8.7

TNF

6Q01

-5.9

IL6

4CNI

-4.4

VEGFA

3QTK

-5.8

Tp53

4CZ7

-6.7

Quercetin

Akt1

7NH5

-9.3

TNF

6Q01

-6.4

IL6

4CNI

-4.4

VEGFA

3QTK

-6

Tp53

4CZ7

-7.5

Naringenin

Akt1

7NH5

-8.7

TNF

6Q01

-6.1

IL6

4CNI

-4.5

VEGFA

3QTK

-6.3

Tp53

4CZ7

-7.4

Group	Mental state and weight	Dietary quantity	Hair state	Feces state	Tongue coating	Skin state	Total score
Control	0	0	0	0	0	0	0
Model	2.60 ± 0.28^**	2.26 ± 0.41^**	1.65 ± 0.21^**	1.88 ± 0.58^**	2.40 ± 0.36^**	2.45 ± 0.31^**	13.24 ± 1.78^**
GX-L	1.87 ± 0.30^#	1.64 ± 0.36^#	1.17 ± 0.21^##	1.20 ± 0.35^#	1.70 ± 0.22^##	1.70 ± 0.26^##	9.28 ± 1.41^##
GX-M	1.77 ± 0.65^#	1.35 ± 0.25^##	0.72 ± 0.13^##	1.15 ± 0.29^#	1.55 ± 0.36^##	1.53 ± 0.34^##	8.06 ± 1.62^##
GX-H	1.05 ± 0.39^##	1.01 ± 0.39^##	0.65 ± 0.18^##	1.25 ± 0.19^#	1.77 ± 0.33^##	1.42 ± 0.26^##	6.74 ± 1.24^##
Danlou tablet	1.18 ± 0.40^##	1.02 ± 0.30^##	0.62 ± 0.22^##	1.07 ± 0.27^##	1.30 ± 0.35^##	1.35 ± 0.26^##	5.19 ± 0.89^##

Group

Mental state and weight

Dietary quantity

Hair state

Feces state

Tongue coating

Skin state

Total score

Control

Model

2.60 ± 0.28^**

2.26 ± 0.41^**

1.65 ± 0.21^**

1.88 ± 0.58^**

2.40 ± 0.36^**

2.45 ± 0.31^**

13.24 ± 1.78^**

GX-L

1.87 ± 0.30^#

1.64 ± 0.36^#

1.17 ± 0.21^##

1.20 ± 0.35^#

1.70 ± 0.22^##

1.70 ± 0.26^##

9.28 ± 1.41^##

GX-M

1.77 ± 0.65^#

1.35 ± 0.25^##

0.72 ± 0.13^##

1.15 ± 0.29^#

1.55 ± 0.36^##

1.53 ± 0.34^##

8.06 ± 1.62^##

GX-H

1.05 ± 0.39^##

1.01 ± 0.39^##

0.65 ± 0.18^##

1.25 ± 0.19^#

1.77 ± 0.33^##

1.42 ± 0.26^##

6.74 ± 1.24^##

Danlou tablet

1.18 ± 0.40^##

1.02 ± 0.30^##

0.62 ± 0.22^##

1.07 ± 0.27^##

1.30 ± 0.35^##

1.35 ± 0.26^##

5.19 ± 0.89^##

Group	ET-1/pg·mL^-1	NO/μmol·L^-1	eNOS/pg·mL^-1
Control	18.86 ± 1.91	16.57 ± 2.85	15.74 ± 1.31
Model	34.11 ± 2.39^**	2.66 ± 0.83^**	8.49 ± 0.63^**
GX-L	29.85 ± 2.44^##	6.36 ± 0.80^#	10.13 ± 0.51^#
GX-M	26.29 ± 1.00^##	8.15 ± 1.60^##	11.69 ± 0.45^##
GX-H	24.27 ± 1.47^##	11.89 ± 2.05^##	13.46 ± 1.28^##
Danlou tablet	22.85 ± 1.04^##	13.15 ± 1.86^##	14.47 ± 0.90^##

Group

ET-1/pg·mL^-1

NO/μmol·L^-1

eNOS/pg·mL^-1

Control

18.86 ± 1.91

16.57 ± 2.85

15.74 ± 1.31

Model

34.11 ± 2.39^**

2.66 ± 0.83^**

8.49 ± 0.63^**

GX-L

29.85 ± 2.44^##

6.36 ± 0.80^#

10.13 ± 0.51^#

GX-M

26.29 ± 1.00^##

8.15 ± 1.60^##

11.69 ± 0.45^##

GX-H

24.27 ± 1.47^##

11.89 ± 2.05^##

13.46 ± 1.28^##

Danlou tablet

22.85 ± 1.04^##

13.15 ± 1.86^##

14.47 ± 0.90^##