Hypolipidemic effect and mechanism of Hedan tablet (荷丹片) based on network pharmacology

doi:10.19852/j.cnki.jtcm.2025.02.015

Journal of Traditional Chinese Medicine ›› 2025, Vol. 45 ›› Issue (2): 408-421.DOI: 10.19852/j.cnki.jtcm.2025.02.015

• Original articles • Previous Articles Next Articles

Hypolipidemic effect and mechanism of Hedan tablet (荷丹片) based on network pharmacology

HU Huiming¹, WENG Jiajun², TANG Fangrui³, WANG Yaqi³, FAN Shengxian³, WANG Xuecheng³, CUI Can⁴, SHAO Feng³(), ZHU Yanchen⁵()

1 College of pharmacy, Nanchang Medical College & Key Laboratory of Pharmacodynamics and Safety Evaluation, Health Commission of Jiangxi Province & Key Laboratory of Pharmacodynamics and Quality Evaluation on anti-Inflammatory Chinese Herbs, Jiangxi Administration of Traditional Chinese Medicine, Nanchang 330052, China
2 Peking University Traditional Chinese Medicine Clinical Medical School (Xiyuan), Beijing 100191, China
3 Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, Jiangxi University of Chinese Medicine, Nanchang 330004, China
4 College of pharmacy, Nanchang Medical College, Nanchang, Jiangxi 330052, China
5 College of Computer Science, Jiangxi University of Chinese Medicine, Nanchang 330004, China

Received:2023-12-22 Accepted:2024-05-24 Online:2025-04-15 Published:2025-03-10
Contact: SHAO Feng, Key Laboratory of Modern Preparation of Traditional Chinese Medicine, Ministry of Education, Jiangxi University of Chinese Medicine, Nanchang 330004, China. shaofeng0729@163.com; ZHU Yanchen, College of Computer Science, Jiangxi University of Chinese Medicine, Nanchang 330004, China. 20030761@jxutcm.edu.cn, Telephone: +86-791-87118658
Supported by:
National Natural Science Foundation of China: Effects of Hawthorn Leaves Flavonoids on Atherosclerosis Unstable Plaques based on the Mechanism of Liver-gut axis Liver X Receptor (LXR-a)-mediated Iron and Lipid Metabolism Disorders(82260794);Natural Science Foundation of Jiangxi Province: based on Secreted Phospholipase A2 Type ⅡA (sPLA2-ⅡA) Regulating Lipid Mediated Foam Cell Formation to Explore the Effect and Molecular Mechanism of Hawthorn Leaf Flavonoids on Anti-atherosclerosis(20212BAB206013);Key R&D Program of Jiangxi Province: Research on the Quality Enhancement and Industrialization Technology Improvement of the Lipid-Lowering Traditional Chinese Medicine "Hedan Tablet"(20201BBG71005);Science and Technology Project of Jiangxi Provincial Department of Education: based on the "Phlegm-Stasis" Theory to Explore the Effects and Molecular Mechanisms of Hawthorn Leaves Flavonoids on Improving Iron and Lipid Metabolism Disorders in Atherosclerosis(GJJ2203502)

1. .pdf(802KB)

Abstract

Abstract:

OBJECTIVE: To examine Hedan tablet (HDT, 荷丹片)'s potential mechanisms in hyperlipidemic rats induced by a high-fat diet (HFD), as well as its regulatory effects and primary active constituents.

METHODS: By using ultra-performance liquid chromatography (UPLC)-quadrupole-time-of-flight (QTOF)-tandem mass spectrometry (MS/MS), the components of HDT that can enter the circulatory system were found, aiming to investigate its active constituents with pharmacological effects. Based on network pharmacology approaches, the relevant HDT targets in the therapy of hyperlipidemia were anticipated. The possible mechanism of HDT for hyperlipidemia treatment was verified by in-vivo experiments, and the main active components of HDT for hyperlipidemia treatment were analyzed via in-vitro experiments.

RESULTS: UPLC-QTOF-MS/MS identified 30 components of HDT entering the circulatory system, primarily consisting of flavonoids, diterpenoids and alkaloids. The results of a network pharmacology study revealed that 30 active components mostly target 74 genes associated with hyperlipidemia. The primary active ingredients may include quercetin, kaempferol, and epicatechin, and the main gene targets may be tumor necrosis factor (TNF), interleukin-6 (IL-6), interleukin 1 beta (IL-1β), etc. The results of animal experiments demonstrated that HDT can significantly regulate the blood lipid level in rats with HFD, improve the degree of inflammatory infiltration in rat liver cells, lower TNF-α, C-reactive protein (CRP), IL-6, matrix metalloproteinase 9 (MMP9) and malondialdehyde (MDA) levels while raising total superoxide dismutase (T-SOD) level. Meanwhile, HDT can considerably lower the expression of sterol regulatory element-binding transcription factor 2 (SREBF2), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), and MMP9 while significantly increasing the expression of peroxisome proliferator-activated receptor alpha (PPAR-α) and PPAR-γ. In vitro study confirmed that quercetin and kaempferol could reduce the levels of IL-6, IL1B, MMP9 and HMGCR in the high-fat model of hepatoma G2 cells.

CONCLUSIONS: The mechanism by which HDT treats hyperlipidemia involves modification of the lipid metabolism targets such as downregulating SREBF2, HMGCR and MMP9, and upregulating PPAR-α and PPAR-γ, as well as anti-inflammatory and antioxidant actions. This study provides a pharmacological and biological rationale for the use of HDT in clinical hyperlipidemia management.

Key words: hyperlipidemia, mechanism, network pharmacology, ultra-performance liquid chromatography-quadrupole-time-of-flight-tandem mass spectrometry, Hedan tablet

HU Huiming, WENG Jiajun, TANG Fangrui, WANG Yaqi, FAN Shengxian, WANG Xuecheng, CUI Can, SHAO Feng, ZHU Yanchen. Hypolipidemic effect and mechanism of Hedan tablet (荷丹片) based on network pharmacology[J]. Journal of Traditional Chinese Medicine, 2025, 45(2): 408-421.

Figures/Tables 6

Table 1 Identification of chemical constituents of Hedan tablet by UPLC-QTOF-MS/MS

No.	Compound	Formula	Retein time	Theoretical value	Experimental value m/z	Error ppm	MS²	Reference	Source
1	Adenine	C₅H₅N₅	1.79	136.06177	136.06143	－2.5	119.0350, 94.0376	28	Heye (Folium Nelumbinis)
2	Guanine	C₅H₅N₅O	1.83	152.05669	152.05673	0.3	135.0286, 110.0327	28	Heye (Folium Nelumbinis)
3	Isopsoralen	C₁₁H₆O₃	12.18	187.03897	187.03886	－0.6	159.0439, 143.0491	29	Buguzhi (Fructus Psoraleae)
4	Psoralenoside	C₁₇H₁₈O₉	12.25	367.10236	367.10221	－0.4	187.0389	30	Buguzhi (Fructus Psoraleae)
5	Coclaurine	C₁₇H₁₉NO₃	12.87	286.14377	286.14287	－3.1	286.1425, 269.1165, 237.0901, 209.0952, 178.0849, 175.0749	30	Heye (Folium Nelumbinis)
6	Rutin	C₂₇H₃₀O₁₆	13.55	611.16066	611.15805	－4.3	465.1006, 303.0494, 137.0238	31	Shanzha (Fructus Crataegus Pinnatifidae)
7	Quercetin	C₁₅H₁₀O₇	13.89	303.04993	303.04961	－1.1	165.0197, 153.0195, 137.0224	32	Heye (Folium Nelumbinis)
8	kaempferol	C₁₅H₁₀O₆	14.73	287.05501	287.05371	－4.6	153.0199, 135.0243	32	Heye (Folium Nelumbinis)
9	N-Nornuciferine	C₁₈H₁₉NO₂	15.01	282.14886	282.14788	－3.5	265.1200, 250.0971, 235.0728, 207.0791	30	Heye (Folium Nelumbinis)
10	Nuciferine	C₁₉H₂₁NO₂	15.18	296.16451	296.16436	－0.5	296.1629, 250.0969, 234.1044, 219.0782, 207.0788, 191.0852, 179.0848	30	Heye (Folium Nelumbinis)
11	Liriodenine	C₁₇H₉NO₃	16.21	276.06552	276.06481	－2.6	248.0691	33	Heye (Folium Nelumbinis)
12	Eupafolin	C₁₆H₁₂O₇	16.68	317.06558	317.06443	－3.6	243.0658, 183.0431	28	Heye (Folium Nelumbinis)
13	Tanshindiol B	C₁₈H₁₆O₅	16.82	313.10705	313.10674	－1	295.0967, 267.0995	34	Danshen (Radix Salviae Miltiorrhizae)
14	Jaceosidin	C₁₇H₁₄O₇	17.83	331.08123	331.08007	－3.5	316.0606, 167.0348	28	Heye (Folium Nelumbinis)
15	Psoralen	C₁₁H₆O₃	18.71	187.03897	187.03886	－0.6	143.0491, 115.0541, 159.0439, 131.0491, 103.0541	35	Buguzhi (Fructus Psoraleae)
16	Tanshinone IIB	C₁₉H₁₈O₄	22.66	311.12779	311.1263	－4.8	293.1187, 275.1073, 267.1385, 252.1135, 237.1281, 223.0756	36	Danshen (Radix Salviae Miltiorrhizae)
17	Neobavaisoflavone	C₂₀H₁₈O₄	23.02	323.12779	323.12715	－2	267.0651, 239.0695	30	Buguzhi (Fructus Psoraleae)
18	Tanshinaldehyde	C₁₉H₁₆O₄	23.52	309.11214	309.11193	－0.7	281.1178, 263.1034, 235.0749	30	Danshen (Radix Salviae Miltiorrhizae)
19	Corylifolinin	C₂₀H₂₀O₄	23.55	325.14344	325.14223	－3.7	269.0810, 205.0861	37	Buguzhi (Fructus Psoraleae)
20	15, 16-Dihydrotanshinone I	C₁₈H₁₄O₃	25.15	279.10157	279.10083	－2.6	279.0994, 261.0890, 251.1046, 233.0951, 205.0995	30	Danshen (Radix Salviae Miltiorrhizae)
21	Asiatic acid	C₃₀H₄₈O₅	25.57	489.35745	489.3555	-4	401.3341, 107.0843	28	Heye (Folium Nelumbinis)
22	Danshenxinkun B	C₁₈H₁₆O₃	25.7	281.11722	281.11662	-2.1	263.1064, 235.1116, 207.1163	30	Danshen (Radix Salviae Miltiorrhizae)
23	Methyl tanshinonate	C₂₀H₁₈O₅	26.26	339.1227	339.12102	-5	279.1003, 261.0907, 233.0962, 205.1013, 190.0786	30	Danshen (Radix Salviae Miltiorrhizae)
24	Cryptotanshinone	C₁₉H₂₀O₃	27.29	297.14852	297.14846	-0.2	297.1480, 251.1417	38	Danshen (Radix Salviae Miltiorrhizae)
25	TanshinoneⅠ	C₁₈H₁₂O₃	27.71	277.08592	277.08492	-3.6	277.0839, 262.0605, 249.0892, 234.0659, 203.0843, 193.1002, 178.0768	30	Danshen (Radix Salviae Miltiorrhizae)
26	Aristolone	C₁₅H₂₂O	28.34	219.17434	219.17424	-0.5	203.1438, 177.1451, 121.0674,	28	Heye (Folium Nelumbinis)
27	1,2-Dihydrotanshinone I	C₁₈H₁₄O₃	28.47	279.10157	279.10083	-4.4	279.0994, 261.0890, 233.0951, 218.0712, 205.0994, 190.0763	28	Danshen (Radix Salviae Miltiorrhizae)
28	Tanshinone II A	C₁₉H₁₈O₃	29.463	295.13287	295.13156	-4.4	277.1221, 262.0988, 249.1271, 234.1032, 220.0855, 206.1080, 191.0855, 179.0861, 165.0698	39	Danshen (Radix Salviae Miltiorrhizae)
29	Miltirone	C₁₉H₂₂O₂	29.85	283.16926	283.16871	-1.9	265.1580, 241.1216, 237.1628, 223.1110	40	Danshen (Radix Salviae Miltiorrhizae)
30	Ursolic acid	C₃₀H₄₈O₃	31.22	457.36762	457.36722	-0.9	248.5500, 204.5100, 191.1815	41	Shanzha (Fructus Crataegus Pinnatifidae)

Table 1 Identification of chemical constituents of Hedan tablet by UPLC-QTOF-MS/MS

No.	Compound	Formula	Retein time	Theoretical value	Experimental value m/z	Error ppm	MS²	Reference	Source
1	Adenine	C₅H₅N₅	1.79	136.06177	136.06143	－2.5	119.0350, 94.0376	28	Heye (Folium Nelumbinis)
2	Guanine	C₅H₅N₅O	1.83	152.05669	152.05673	0.3	135.0286, 110.0327	28	Heye (Folium Nelumbinis)
3	Isopsoralen	C₁₁H₆O₃	12.18	187.03897	187.03886	－0.6	159.0439, 143.0491	29	Buguzhi (Fructus Psoraleae)
4	Psoralenoside	C₁₇H₁₈O₉	12.25	367.10236	367.10221	－0.4	187.0389	30	Buguzhi (Fructus Psoraleae)
5	Coclaurine	C₁₇H₁₉NO₃	12.87	286.14377	286.14287	－3.1	286.1425, 269.1165, 237.0901, 209.0952, 178.0849, 175.0749	30	Heye (Folium Nelumbinis)
6	Rutin	C₂₇H₃₀O₁₆	13.55	611.16066	611.15805	－4.3	465.1006, 303.0494, 137.0238	31	Shanzha (Fructus Crataegus Pinnatifidae)
7	Quercetin	C₁₅H₁₀O₇	13.89	303.04993	303.04961	－1.1	165.0197, 153.0195, 137.0224	32	Heye (Folium Nelumbinis)
8	kaempferol	C₁₅H₁₀O₆	14.73	287.05501	287.05371	－4.6	153.0199, 135.0243	32	Heye (Folium Nelumbinis)
9	N-Nornuciferine	C₁₈H₁₉NO₂	15.01	282.14886	282.14788	－3.5	265.1200, 250.0971, 235.0728, 207.0791	30	Heye (Folium Nelumbinis)
10	Nuciferine	C₁₉H₂₁NO₂	15.18	296.16451	296.16436	－0.5	296.1629, 250.0969, 234.1044, 219.0782, 207.0788, 191.0852, 179.0848	30	Heye (Folium Nelumbinis)
11	Liriodenine	C₁₇H₉NO₃	16.21	276.06552	276.06481	－2.6	248.0691	33	Heye (Folium Nelumbinis)
12	Eupafolin	C₁₆H₁₂O₇	16.68	317.06558	317.06443	－3.6	243.0658, 183.0431	28	Heye (Folium Nelumbinis)
13	Tanshindiol B	C₁₈H₁₆O₅	16.82	313.10705	313.10674	－1	295.0967, 267.0995	34	Danshen (Radix Salviae Miltiorrhizae)
14	Jaceosidin	C₁₇H₁₄O₇	17.83	331.08123	331.08007	－3.5	316.0606, 167.0348	28	Heye (Folium Nelumbinis)
15	Psoralen	C₁₁H₆O₃	18.71	187.03897	187.03886	－0.6	143.0491, 115.0541, 159.0439, 131.0491, 103.0541	35	Buguzhi (Fructus Psoraleae)
16	Tanshinone IIB	C₁₉H₁₈O₄	22.66	311.12779	311.1263	－4.8	293.1187, 275.1073, 267.1385, 252.1135, 237.1281, 223.0756	36	Danshen (Radix Salviae Miltiorrhizae)
17	Neobavaisoflavone	C₂₀H₁₈O₄	23.02	323.12779	323.12715	－2	267.0651, 239.0695	30	Buguzhi (Fructus Psoraleae)
18	Tanshinaldehyde	C₁₉H₁₆O₄	23.52	309.11214	309.11193	－0.7	281.1178, 263.1034, 235.0749	30	Danshen (Radix Salviae Miltiorrhizae)
19	Corylifolinin	C₂₀H₂₀O₄	23.55	325.14344	325.14223	－3.7	269.0810, 205.0861	37	Buguzhi (Fructus Psoraleae)
20	15, 16-Dihydrotanshinone I	C₁₈H₁₄O₃	25.15	279.10157	279.10083	－2.6	279.0994, 261.0890, 251.1046, 233.0951, 205.0995	30	Danshen (Radix Salviae Miltiorrhizae)
21	Asiatic acid	C₃₀H₄₈O₅	25.57	489.35745	489.3555	-4	401.3341, 107.0843	28	Heye (Folium Nelumbinis)
22	Danshenxinkun B	C₁₈H₁₆O₃	25.7	281.11722	281.11662	-2.1	263.1064, 235.1116, 207.1163	30	Danshen (Radix Salviae Miltiorrhizae)
23	Methyl tanshinonate	C₂₀H₁₈O₅	26.26	339.1227	339.12102	-5	279.1003, 261.0907, 233.0962, 205.1013, 190.0786	30	Danshen (Radix Salviae Miltiorrhizae)
24	Cryptotanshinone	C₁₉H₂₀O₃	27.29	297.14852	297.14846	-0.2	297.1480, 251.1417	38	Danshen (Radix Salviae Miltiorrhizae)
25	TanshinoneⅠ	C₁₈H₁₂O₃	27.71	277.08592	277.08492	-3.6	277.0839, 262.0605, 249.0892, 234.0659, 203.0843, 193.1002, 178.0768	30	Danshen (Radix Salviae Miltiorrhizae)
26	Aristolone	C₁₅H₂₂O	28.34	219.17434	219.17424	-0.5	203.1438, 177.1451, 121.0674,	28	Heye (Folium Nelumbinis)
27	1,2-Dihydrotanshinone I	C₁₈H₁₄O₃	28.47	279.10157	279.10083	-4.4	279.0994, 261.0890, 233.0951, 218.0712, 205.0994, 190.0763	28	Danshen (Radix Salviae Miltiorrhizae)
28	Tanshinone II A	C₁₉H₁₈O₃	29.463	295.13287	295.13156	-4.4	277.1221, 262.0988, 249.1271, 234.1032, 220.0855, 206.1080, 191.0855, 179.0861, 165.0698	39	Danshen (Radix Salviae Miltiorrhizae)
29	Miltirone	C₁₉H₂₂O₂	29.85	283.16926	283.16871	-1.9	265.1580, 241.1216, 237.1628, 223.1110	40	Danshen (Radix Salviae Miltiorrhizae)
30	Ursolic acid	C₃₀H₄₈O₃	31.22	457.36762	457.36722	-0.9	248.5500, 204.5100, 191.1815	41	Shanzha (Fructus Crataegus Pinnatifidae)

Table 2 Information of 18 active compounds in Hedan tablet

No.	ID	Ingredients	Herbs	No.	ID	Ingredients	Herbs
1	A	Kaempferol	Heye (Folium Nelumbinis), Shanzha (Fructus Crataegus Pinnatifidae), Fanxieye (Folium Sennae)	10	DS2	Cryptotanshinone	Danshen (Radix Salviae Miltiorrhizae)
2	B	Quercetin	Heye (Folium Nelumbinis), Shanzha (Fructus Crataegus Pinnatifidae)	11	DS3	Tanshinone I	Danshen (Radix Salviae Miltiorrhizae)
3	C	Rutin	Heye (Folium Nelumbinis), Shanzha (Fructus Crataegus Pinnatifidae), Fanxieye (Folium Sennae), Danshen (Radix Salviae Miltiorrhizae)	12	DS4	Tanshinone IIA	Danshen (Radix Salviae Miltiorrhizae)
4	D	Ursolic acid	Shanzha (Fructus Crataegus Pinnatifidae), Danshen (Radix Salviae Miltiorrhizae)	13	DS5	Tanshinone IIB	Danshen (Radix Salviae Miltiorrhizae)
5	BGZ1	Corylifolinin	Buguzhi (Fructus Psoraleae)	14	HY1	Adenine	Heye (Folium Nelumbinis)
6	BGZ2	Isopsoralen	Buguzhi (Fructus Psoraleae)	15	HY2	Asiatic acid	Heye (Folium Nelumbinis)
7	BGZ3	Neobavaisoflavone	Buguzhi (Fructus Psoraleae)	16	HY3	Coclaurine	Heye (Folium Nelumbinis)
8	BGZ4	Psoralen	Buguzhi (Fructus Psoraleae)	17	HY4	Eupafolin	Heye (Folium Nelumbinis)
9	DS1	15,16-Dihydrotanshinone I	Danshen (Radix Salviae Miltiorrhizae)	18	HY5	Guanine	Heye (Folium Nelumbinis)

Figure 1 “TCMs - active ingredient- target" network diagram Blue diamonds represent herbs, yellow circles represent active ingredients of drugs, and red hexagons represent "herbs-disease" co-targets. The larger the pattern and the darker the color represents the greater the degree, meaning the more critical the node; DS: Danshen (Radix Salviae Miltiorrhizae); SZ: Shanzha (Fructus Crataegus Pinnatifidae); BGZ: Buguzhi (Fructus Psoraleae); FXY: Fanxieye (Folium Sennae); HY: Heye (Folium Nelumbinis); A: Kaempferol; B: Quercetin; C: Rutin; D: Ursolic acid; BGZ1: Corylifolinin; BGZ2: Isopsoralen; BGZ3: Neobavaisoflavone; BGZ4: Psoralen; DS1: 15,16-Dihydrotanshinone I; DS2: Cryptotanshinone; DS3: Tanshinone I; DS4: Tanshinone ⅡA; DS5: Tanshinone ⅡB; HY1: Adenine; HY2: Asiatic acid; HY3: Coclaurine; HY4: Eupafolin; HY5: Guanine; SELP: p-selectin; TXNIP: thioredoxin-interacting protein; NPC1L1: Niemann-Pick C1-like 1; PIK3C2A: phosphatidylinositol-4-phosphate 3-kinase C2 domain containing subunit alpha; NR1H3: nuclear receptor subfamily 1 group H member 3 (LXRα); PDX1: pancreatic and duodenal homeobox 1; APOA1: apolipoprotein A-I; SHBG: sex hormone-binding globulin; SREBF2: sterol regulatory element-binding transcription factor 2; PON2: paraoxonase 2; PHKA2: phosphorylase kinase regulatory subunit alpha 2; APOB: apolipoprotein B; LCAT: lecithin-cholesterol acyltransferase; CAV1: caveolin-1; CYBA: cytochrome b-245 light chain; AKT2: RAC-beta serine/threonine-protein kinase; INS: insulin; ABCG5: ATP-binding cassette subfamily G member 5; ITGB3: integrin beta-3; INSR: insulin receptor; LDLR: low-density lipoprotein receptor; ADIPOQ: adiponectin; FASN: fatty acid synthase; UCP1: uncoupling protein 1; SERPINE1: serpin family E member 1 (plasminogen activator inhibitor-1); CPT1A: carnitine palmitoyltransferase 1A; PYGL: glycogen phosphorylase, liver form; SREBF1: sterol regulatory element-binding transcription factor 1; SELE: e-selectin; CRP: C-reactive protein; MTTP: microsomal triglyceride transfer protein; APOE: apolipoprotein E; ACE: angiotensin-converting enzyme; LEPR: leptin receptor; PON1: paraoxonase 1; ESR1: estrogen receptor 1; CDKN2A: cyclin-dependent kinase inhibitor 2A; ABCA1: ATP-binding cassette subfamily A member 1; EGF: epidermal growth factor; LRP1: low-density lipoprotein receptor-related protein 1; F3: coagulation factor Ⅲ (tissue factor); ALB: albumin; VCAM1: vascular cell adhesion molecule 1; SLC2A4: solute carrier family 2 member 4 (glucose transporter 4); PLAT: plasminogen activator, tissue type; IL-18: interleukin-18; PPARA: peroxisome proliferator-activated receptor alpha; IRS1: insulin receptor substrate 1; IGF1: insulin-like growth factor 1; CCL5: C-C motif chemokine ligand 5; OLR1: oxidized low-density lipoprotein receptor 1; MPO: myeloperoxidase; F2: coagulation factor Ⅱ (thrombin); LEPR: leptin receptor; ICAM1: intercellular adhesion molecule 1; CD36: CD36 molecule; NR3C1: nuclear receptor subfamily 3 group C member 1 (glucocorticoid receptor); CCL2: C-C motif chemokine ligand 2; HMGCR: 3-hydroxy-3-methylglutaryl-CoA reductase; SOD1: superoxide dismutase 1; AGT: angiotensinogen; CAT: catalase; EDN1: endothelin 1; GPT: glutamate pyruvate transaminase; CXCL8: C-X-C motif chemokine ligand 8 (interleukin-8); PPARG: peroxisome proliferator-activated receptor gamma; VEGFA: vascular endothelial growth factor A; NOS3: nitric oxide synthase 3; MMP9: matrix metallopeptidase 9; FOS: fos proto-oncogene, AP-1 transcription factor subunit; CYP3A4: cytochrome P450 3A4; IL1B: interleukin-1 beta; IL6: interleukin-6; TNF: tumor necrosis factor.

Figure 2 Effect of QR and KM on the mRNA expression of key factors in HepG2 cells A: the expression of HMGCR mRNA in each group of cells by QR; B: the expression of IL1B mRNA in each group of cells by QR; C: the expression of IL-6 mRNA in each group of cells by QR; D: the expression of MMP9 mRNA in each group of cells by QR; E: the expression of HMGCR mRNA in each group of cells by KM; F: the expression of IL-1β mRNA in each group of cells by KM; G: the expression of IL-6 mRNA in each group of cells by KM; H: the expression of MMP9 mRNA in each group of cells by KM. Nor: Normal control group, Mod: Model control group, QR-L: 5μmol/L of quercetin, QR-M: 10 μmol/L of quercetin, QR-H: 20 μmol/L of quercetin, KM-L: 5 μmol/L of kaempferol, KM-M: 10 μmol/L of kaempferol, KM-H: 20 μmol/L of kaempferol. HMGCR: 3-hydroxy-3-methylglutaryl-CoA reductase; QR: quercetin; IL-1β: interleukin 1 beta; IL-6: interleukin-6; MMP9: matrix metalloproteinase 9; KM: kaempferol; QR-L: quercetin low dose group; QR-M: quercetin medium dose group; QR-H: quercetin high dose group; KM-L: kaempferol low dose group; KM-M: kaempferol medium dose group; KM-H: kaempferol high dose group. These data are presented as the mean ± standard deviation (n = 3); t-test, compared with Mod, aP < 0.001, bP < 0.05, cP < 0.01.

Figure 3 Results of in vivo experiments A: the levels of serum TC in rats; B: the levels of serum LDL-C in rats; C: the levels of serum HDL-C in rats; D: the levels of plasma CRP in rats; E: the levels of plasma IL-6 in rats; F: the levels of plasma TNF-α in rats; G: the levels of plasma MMP9 in rats; H: the levels of plasma MDA in rats; I: the levels of plasma T-SOD in rats. Nor: the normal control group, Mod: the high-fat diet model group, HDT-L: low-dose group of Hedan tablet (0.22 g/kg), HDT-M: medium-dose group of Hedan tablet (0.44 g/kg), HDT-H: high-dose group of Hedan tablet (0.88 g/kg), AVT: atorvastatin (7 mg/kg). TC: serum total cholesterol; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol; CRP: C-reactive protein; IL-6: interleukin-6; TNF-α: tumor necrosis factor-alpha; MMP9: matrix metalloproteinase 9; MDA: malondialdehyde; T-SOD: total superoxide dismutase. These data are presented as the mean ± standard deviation (n = 10); t-test, compared with Mod, aP < 0.001, bP < 0.05, cP < 0.01.

Figure 4 Effects of HDT on expression of proteins for the potential drug targets A: representative photographs of proteins by Western blotting; B: the expression levels of SREBF2; C: the expression levels of HMGCR; D: the expression levels of MMP9; E: the expression levels of PPAR-γ; F: the expression levels of PPAR-α. Nor: the normal control group, Mod: the high-fat diet model group, HDT-L: low-dose group of Hedan tablet (0.22 g/kg), HDT-M: medium-dose group of Hedan tablet (0.44 g/kg), HDT-H: high-dose group of Hedan tablet (0.88 g/kg), AVT: atorvastatin (7 mg/kg) SREBF2: sterol regulatory element-binding transcription factor 2; HMGCR: 3-hydroxy-3-methylglutaryl-CoA reductase; MMP9: matrix metalloproteinase 9; PPAR-γ: peroxisome proliferator-activated receptor gamma. These data are presented as the mean ± standard deviation (n = 3); t-test, compared with Mod, aP < 0.01, bP < 0.05.

References 68.

1.	Newton SL, Hoffmann AP, Yu Z, Haidermota S, Natarajan P, Honigberg MC. Management of severe and moderate hyper-cholesterolemia in young women and men. JAMA Cardiol 2022; 7: 227-30.
2.	Hegele RA. Apolipoprotein C-Ⅲ inhibition to lower triglycerides: one ring to rule them all? Eur Heart J 2022; 43: 1413-5.
3.	Ward NC, Chan DC, Watts GF. A tale of two new targets for hypertriglyceridaemia: which choice of therapy? Bio Drugs 2022; 36: 121-35.
4.	Stone NJ. Treating severe hypercholesterolemia-If not now, when? JAMA Cardiol 2022; 7: 128-9.
5.	Mortensen MB, Falk E. Primary prevention with statins in the elderly. J Am Coll Cardiol 2018; 71: 85-94. DOI PMID
6.	Thompson W, Jarbol DE, Nielsen JB, Haastrup P, Pottegard A. Statin use and discontinuation in Danes age 70 and older: a nationwide drug utilisation study. Age Ageing 2021; 50: 554-8. DOI PMID
7.	Yourman LC, Cenzer IS, Boscardin WJ, et al. Evaluation of time to benefit of statins for the primary prevention of cardiovascular events in adults aged 50 to 75 years. JAMA Intern Med 2021; 181.
8.	Zhang HY, Tian JX, Lian FM, et al. Therapeutic mechanisms of Traditional Chinese Medicine to improve metabolic diseases via the gut microbiota. Biomed Pharmacother 2021; 133: 110857.
9.	Zhang Y, Kishi H, Kobayashi S. Add-on therapy with Traditional Chinese Medicine: an efficacious approach for lipid metabolism disorders. Pharmacol Res 2018; 134: 200-11. DOI PMID
10.	Luo H, Chen H, Liu C, et al. The key issues and development strategy of Chinese classical formulas pharmaceutical preparations. Chin Med 2021; 16: 1-14.
11.	He J, Feng X, Wang K, Liu C, Qiu F. Discovery and identification of quality markers of Chinese medicine based on pharmacokinetic analysis. Phytomedicine 2018; 44: 182-6. DOI PMID
12.	Liu LY, Zhou L, Liu XZ, Zou DJ. Effect of Hedan tablets on body weight and insulin resistance in patients with metabolic syndrome. Obes Facts 2022; 15: 180-5.
13.	Xu RX, Wu NQ, Li S, et al. Effects of Hedan tablet on lipid profile, proprotein convertase subtilisin/kexin type 9 and high-density lipoprotein subfractions in patients with hyperlipidemia: a primary study. Chin J Integr Med 2016; 22: 660-5.
14.	Jin H, Zhu Y, Wang XD, et al. BDNF corrects NLRP3 inflammasome-induced pyroptosis and glucose metabolism reprogramming through KLF2/HK1 pathway in vascular endothelial cells. Cell Signal 2021; 78: 109843.
15.	Wang X, Wang ZY, Zheng JH, Li S. TCM network pharmacology: a new trend towards combining computational, experimental and clinical approaches. Chin J Nat Med 2021; 19: 1-11.
16.	Nogales C, Mamdouh ZM, List M, Kiel C, Casas AI, Schmidt H. Network pharmacology: curing causal mechanisms instead of treating symptoms. Trends Pharmacol Sci 2022; 43: 136-50.
17.	Kim S, Chen J, Cheng T, et al. PubChem in 2021: new data content and improved web interfaces. Nucleic Acids Res 2021; 49: D1388-95. DOI PMID
18.	Davis AP, Grondin CJ, Johnson RJ, et al. Comparative toxicogenomics database (CTD):update 2021. Nucleic Acids Res 2021; 49: D1138-43.
19.	UniProt C. UniProt: the universal protein knowledgebase in 2021. Nucleic Acids Res 2021; 49: D480-9. DOI PMID
20.	Fishilevich S, Zimmerman S, Kohn A, et al. Genic insights from integrated human proteomics in GeneCards. Database (Oxford) 2016; 2016: 1-17.
21.	Chen T, Zhang H, Liu Y, Liu YX, Huang L. EVenn: easy to create repeatable and editable Venn diagrams and Venn networks online. J Genet Genomics 2021; 48: 863-6. DOI PMID
22.	Mousavian Z, Khodabandeh M, Sharifi-Zarchi A, Nadafian A, Mahmoudi A. StrongestPath: a Cytoscape application for protein-protein interaction analysis. BMC Bioinformatics 2021; 22: 352. DOI PMID
23.	Zhou Y, Zhou B, Pache L, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun 2019; 10: 1523. DOI PMID
24.	Liang N, Li YM, He Z, et al. Rutin and Quercetin decrease cholesterol in HepG 2 Cells but not plasma cholesterol in hamsters by oral administration. Molecules 2021; 26: 3766.
25.	Tie F, Ding J, Hu N, Dong Q, Chen Z, Wang H. Kaempferol and Kaempferide attenuate oleic acid-induced lipid accumulation and oxidative stress in HepG2 cells. Int J Mol Sci 2021; 22: 1-17.
26.	Yang D, Hu C, Deng X, et al. Therapeuticeffect of Chitooligosaccharide tablets on lipids in high-fat diets induced hyperlipidemic rats. Molecules 2019; 24: 1-16.
27.	Tao SY, Zhao FJ, Yang MJ, et al. Therapeutic efects of Hedan tablet on rats with nonalcoholic steatohepatiti. Chin J Integr Trad West Med Liver Dis 2013; 23: 39-41.
28.	Sui ZY, Hou PY. Rapid identification the components of Nelumbinis Folium based on UHPLC-Q-Orbitrap platform. Zhong Guo Yao Xue Za Zhi 2019; 54: 813-8.
29.	Diao YP. Chemical composition of Compound Ziling capsule by UPLC-ESI-QTOF-MS-MS. Zhong Guo Shi Yan Fang Ji Xue Za Zhi 2011; 17: 64-8.
30.	Liu C. Methodology study of quality control and chemical components in Chinese medicinal herb Hedan tables. Shanghai: The Second Military Medical University, 2010: 11-20.
31.	Xiao GL, Jiang JY, Xu AL, Li YX, Bi XL. Analysis of chemical constituents in Bushao Tiaozhi capsules by UPLC-Q-TOF-MS. Zhong Guo Shi Yan Fang Ji Xue Za Zhi 2020; 26: 190-9.
32.	Huang HY, Kang JL, Yu YH, et al. Identification of chemical constituents of Bufei Yishen formula by UPLC-Q-Orbitrap MS. Fen Xi Ce Shi Xue Bao 2019; 38: 1-13.
33.	Dantas E, Monteiro J, de Medeiros L, et al. Dereplication of Aporphine Alkaloids by UHPLC-HR-ESI-MS/MS and NMR from Duguetia lanceolata St.-Hil (Annonaceae) and antiparasitic activity evaluation. J Braz Chem Soc 2020; 31: 1908-16.
34.	Chen JH, Zhang YX, Liu MH, et al. Chemical profiling of Danshen water extract by UPLC-Q-TOF-MS /MS. Guangdong Yao Ke Da Xue Xue Bao 2020; 36: 1-9.
35.	Ren XL, Huo JH, Sun GD, Wei WF, Wang WM. Analysis of chemical components as Coumarin in Saposhnikovia divaricata by UPLC-Q-TOF-MS. Zhong Guo Yao Fang 2019; 30: 349-54.
36.	Liu LW, Zhou L, Sun Z, et al. Main chemical constituents research of Qishen Yiqi dropping pills based on UHPLC-Q-Orbitrap HRMS. Zhong Cao Yao 2018; 49: 5761-71.
37.	Guan XY, Li HF, Yang WZ, et al. HPLC-DAD-MS(n) analysis and HPLC quantitation of chemical constituents in Xian-ling-gu-bao capsules. J Pharm Biomed Anal 2011; 55: 923-33.
38.	Liu AH, Lin YH, Yang M, et al. Development of the fingerprints for the quality of the roots of Salvia miltiorrhiza and its related preparations by HPLC-DAD and LC-MS(n). J Chromatogr B Analyt Technol Biomed Life Sci 2007; 846: 32-41.
39.	Zheng L, Fang L, Cong H, et al. Identification of chemical constituents and rat metabolites of Kangxianling granule by HPLC-Q-TOF-MS/MS. Biomed Chromatogr 2015; 29: 1750-8. DOI PMID
40.	Ma Z, Zhang M, Song Z. Characterization of tanshinones with quinone reductase induction activity from Radix Salvia miltiorrhiza by liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom 2009; 23: 2857-66.
41.	Tundis R, Deguin B, Menichini F, François T. Iridoids from Putoria calabrica. Biochem Syst Ecol 2002; 30: 689-91.
42.	Matsumura T, Sankai T, Yamagishi K, et al. Impact of major cardiovascular risk factors on the incidence of cardiovascular disease among overweight and non-overweight individuals: the circulatory risk in communities study (CIRCS). J Atheroscler Thromb 2022; 29: 422-37.
43.	Gaspar JC, Okine BN, Llorente-Berzal A, Roche M, Finn DP. Pharmacological blockade of PPAR isoforms increases conditioned fear responding in the presence of nociceptive tone. Molecules 2020; 25: 1007-21.
44.	Hernandez-Anzaldo S, Brglez V, Hemmeryckx B, et al. Novel role for matrix metalloproteinase 9 in modulation of cholesterol metabolism. J Am Heart Assoc 2016; 5: 1-16.
45.	Feingold KR, Grunfeld C. Role of cytokines in inducing hyperlipidemia. Diabetes 1992; 41: 97-101.
46.	Masenga SK, Kabwe LS, Chakulya M, Kirabo A. Mechanisms of oxidative stress in metabolic syndrome. Int J Mol Sci 2023; 24: 7898.
47.	Bassiouni W, Ali MAM, Schulz R. Multifunctional intracellular matrix metalloproteinases: implications in disease. FEBS J 2021; 288: 7162-82. DOI PMID
48.	Wells JM, Gaggar A, Blalock JE. MMP generated matrikines. Matrix Biol 2015; 44: 122-9.
49.	Kim IS, Yang WS, Kim CH. Physiological properties, functions, and trends in the matrix metalloproteinase inhibitors in inflammation-mediated human diseases. Curr Med Chem 2023; 30: 2075-112.
50.	Botta M, Audano M, Sahebkar A, Sirtori CR, Mitro N, Ruscica M. PPAR agonists and metabolic syndrome: an established role? Int J Mol Sci 2018; 19: 1-21.
51.	Montaigne D, Butruille L, Staels B. PPAR control of metabolism and cardiovascular functions. Nat Rev Cardiol 2021; 18: 809-23. DOI PMID
52.	Ruscica M, Busnelli M, Runfola E, Corsini A, Sirtori CR. Impact of PPAR-Alpha polymorphisms-the case of metabolic disorders and atherosclerosis. Int J Mol Sci 2019; 20: 1-14.
53.	Glodowski M, Christen S, Saxon DR, Hegele RA, Eckel RH. Novel PPARG mutation in multiple family members with chylomicronemia. J Clin Lipidol 2021; 15: 431-4. DOI PMID
54.	Liu J, Wang Q, Wei Y, Zhang S, Chai E, Tang F. Calpain inhibitor prevents atherosclerosis in apolipoprotein E knockout mice by regulating mRNA expression of genes related to cholesterol uptake and efflux. Microvasc Res 2022; 140: 104276.
55.	Song Y, Li S, He C. PPAR gamma gene polymorphisms, metabolic disorders, and coronary artery disease. Front Cardiovasc Med 2022; 9: 808929.
56.	Qiu Y, Wang J, Li H, et al. Emerging views of OPTN (optineurin) function in the autophagic process associated with disease. Autophagy 2022; 18: 73-85.
57.	Gawrieh S, Noureddin M, Loo N, et al. Saroglitazar, a PPAR-alpha/gamma agonist, for treatment of NAFLD: a randomized controlled double-blind phase 2 trial. Hepatology 2021; 74: 1809-24. DOI PMID
58.	Jain N, Bhansali S, Kurpad AV, et al. Effect of a dual PPAR alpha/gamma agonist on insulin sensitivity in patients of type 2 diabetes with hypertriglyceridemia- randomized double-blind placebo-controlled trial. Sci Rep 2019; 9: 19017.
59.	Rastogi A, Dunbar RL, Thacker HP, Bhatt J, Parmar K, Parmar DV. Abrogation of postprandial triglyceridemia with dual PPAR alpha/gamma agonist in type 2 diabetes mellitus: a randomized, placebo-controlled study. Acta Diabetol 2020; 57: 809-18. DOI PMID
60.	van den Boomen DJH, Volkmar N, Lehner PJ. Ubiquitin-mediated regulation of sterol homeostasis. Curr Opin Cell Biol 2020; 65: 103-11. DOI PMID
61.	Williams MJ, Alsehli AM, Gartner SN, et al. The statin target hmgcr yegulates energy metabolism and food intake through central mechanisms. Cells 2022; 22: 427-37.
62.	Hosseini A, Razavi BM, Banach M, Hosseinzadeh H. Quercetin and metabolic syndrome: a review. Phytother Res 2021; 35: 5352-64. DOI PMID
63.	Yi H, Peng H, Wu X, et al. The therapeutic effects and mechanisms of Quercetin on metabolic diseases: pharmacological data and clinical evidence. Oxid Med Cell Longev 2021; 2021: 1-16.
64.	Chun JH, Henckel MM, Knaub LA, et al. (-)-Epicatechin improves vasoreactivity and mitochondrial respiration in thermoneutral-housed wistar rat vasculature. Nutrients 2022; 14: 1-16.
65.	Hid EJ, Mosele JI, Prince PD, Fraga CG, Galleano M. (-)-Epicatechin and cardiometabolic risk factors: a focus on potential mechanisms of action. Pflugers Arch 2022; 474: 99-115.
66.	Ponnian SMP. Preventive effects of (-) epicatechin on tachycardia, cardiac hypertrophy, and nuclear factor- kappa B inflammatory signaling pathway in isoproterenol-induced myocardial infarcted rats. Eur J Pharmacol 2022; 924: 174909.
67.	Alam W, Khan H, Shah MA, Cauli O, Saso L. Kaempferol as a dietary anti-inflammatory agent: current therapeutic standing. Molecules 2020; 25: 1-12.
68.	Dabeek WM, Marra MV. Dietary Quercetin and Kaempferol: bioavailability and potential cardiovascular-related bioactivity in humans. Nutrients 2019; 11: 1-19.

[1]	HUANG Jiaen, LUO Qing, DONG Gengting, PENG Weiwen, HE Jianhong, DAI Weibo. Xiahuo Pingwei San (夏藿平胃散) attenuated intestinal inflammation in dextran sulfate sodium-induced ulcerative colitis mice through inhibiting the receptor for advanced glycation end-products signaling pathway [J]. Journal of Traditional Chinese Medicine, 2025, 45(2): 311-325.
[2]	HAN Shuai, Du Zhikang, WANG Zirui, HUANG Tianfeng, GE Yali, SHI Jianwen, GAO Ju. Network pharmacology approach to unveiling the mechanism of berberine in the amelioration of morphine tolerance [J]. Journal of Traditional Chinese Medicine, 2025, 45(2): 376-384.
[3]	TAN Xiying, GU Ruxin, TAO Jing, ZHANG Yu, SUN RuiQian, YIN Gang, ZHANG Shuo, TANG Decai. Integrating network pharmacology and experimental validation to uncover the synergistic effects of Huangqi (Radix Astragali Mongolici)-Ezhu (Rhizoma Curcumae Phaeocaulis) with 5-fluorouracil in colorectal cancer models [J]. Journal of Traditional Chinese Medicine, 2025, 45(2): 385-398.
[4]	SHI Jinyu, PAN Fuwei, GE Haiya, YANG Zongrui, ZHAN Hongsheng. Mechanism of Qigu capsule (芪骨胶囊) as a treatment for sarcopenia based on network pharmacology and experimental validation [J]. Journal of Traditional Chinese Medicine, 2025, 45(2): 399-407.
[5]	YUAN Jianan, CHENG Kunming, LI Chao, ZHANG Xiang, DING Zeyu, LI Bing, ZHENG Yongqiu. Atractylenolide I ameliorates post-infectious irritable bowel syndrome by inhibiting the polymerase I and transcript release factor and c-Jun N-terminal kinase/inducible nitric oxide synthase pathway [J]. Journal of Traditional Chinese Medicine, 2025, 45(1): 57-65.
[6]	YAN Kai, WANG Wei, WANG Yan, GAO Huijuan, FENG Xingzhong. Network pharmacology-based study on the mechanism of Tangfukang formula (糖复康方) against type 2 diabetes mellitus [J]. Journal of Traditional Chinese Medicine, 2025, 45(1): 76-88.
[7]	ZHU Peixuan, SU Zeqi, FAN Qiongyin, ZHANG Cai, WANG Ting. Network pharmacology and animal experiments revealed the protective effects of Guilong prescription (归龙方) on chronic prostatitis and its possible mechanisms [J]. Journal of Traditional Chinese Medicine, 2025, 45(1): 89-99.
[8]	YANG Chunyan, LUO Jia, PENG Weijie, DAI Weibo. Huaiyu pill (槐榆片) alleviates inflammatory bowel disease in mice via blocking toll like receptor 4/ myeloid differentiation primary response gene 88/ nuclear factor kappa B subunit 1 pathway [J]. Journal of Traditional Chinese Medicine, 2024, 44(5): 916-925.
[9]	YU Siyun, ZHANG Shiwen, XIA Yu, LIU Xiaoqing, LIU Yajie, FU Jinrong. Network-based pharmacology and experimental validation to explore the mechanism of action of the Jiawei Pentongling formula (加味盆痛灵方) for the treatment of endometriosis-related pain [J]. Journal of Traditional Chinese Medicine, 2024, 44(5): 991-999.
[10]	SONG Zhenguang, YANG Bin, WANG Fei, YAN Dongmei, ZHOU Xiaoqing, HUANG Liping, GAO Xuemei, LI Bin, HUANG Luqi. Study on the four Qi of Pfaffia glomerata based on the metabolomics technology and comparison of Dangshen (Radix Codonopsis) in the equivalent substitution prescription [J]. Journal of Traditional Chinese Medicine, 2024, 44(4): 713-721.
[11]	YANG Qinjun, YIN Dandan, WANG Hui, GAO Yating, WANG Xinheng, WU Di, TONG Jiabing, WANG Chuanbo, LI Zegeng. Uncovering the action mechanism of Shenqi Tiaoshen formula (参芪调肾方) in the treatment of chronic obstructive pulmonary disease through network pharmacology, molecular docking, and experimental verification [J]. Journal of Traditional Chinese Medicine, 2024, 44(4): 770-783.
[12]	HU Yuanyuan, LIU Xinguang, ZHAO Peng, WU Jinyan, YAN Xinhua, HOU Runsu, WANG Xiangcheng, YANG Fan, TIAN Xinrong, LI Jiansheng. Integration of serum pharmacochemistry with network pharmacology to reveal the potential mechanism of Yangqing Chenfei formula (养清尘肺方) for the treatment of silicosis [J]. Journal of Traditional Chinese Medicine, 2024, 44(4): 784-793.
[13]	LUO Shan, YANG Fan, CHEN Yuanchun, ZHAO Ruoxi, LIU Haiye, GAO Fei, MA Wencan, GAO Weijuan, YU Wentao. Sanhua Tang (三化汤) protects against ischemic stroke by preventing blood-brain barrier injury: a network pharmacology and in vivo experiments [J]. Journal of Traditional Chinese Medicine, 2024, 44(4): 794-803.
[14]	WU Yijuan, SUN Xinghong, GUO Haixia, ZHANG Xiangan. Study on the effect and mechanism of Yanghe decoction Huacai (阳和汤化裁) on tissue repair of Yin syndrome after anal fistula surgery [J]. Journal of Traditional Chinese Medicine, 2024, 44(4): 813-821.
[15]	FENG Yanchen, LIU Yali, DANG Xue, LIN Zixuan, ZHANG Yunke, CHE Zhiying, LI Xiang, PAN Xiaolong, LIU Feixiang, ZHENG Pan. Exploring the multicomponent synergy mechanism of Zuogui Wan (左归丸) on postmenopausal osteoporosis by a systems pharmacology strategy [J]. Journal of Traditional Chinese Medicine, 2024, 44(3): 489-495.

Home

Online First

Author Center

Reviewer Center

Issues

Announcement

About Us

Hypolipidemic effect and mechanism of Hedan tablet (荷丹片) based on network pharmacology

RichHTML

PDF

Supplement

Knowledge

Abstract

Cite this article

share this article

Figures/Tables 6

References 68.

Related Articles 15

Recommended Articles

Metrics

Comments