Investigation of the Lipid-Lowering Activity and Mechanism of Three Extracts from Astragalus membranaceus, Hippophae rhamnoides L., and Taraxacum mongolicum Hand. Mazz Based on Network Pharmacology and In Vitro and In Vivo Experiments
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemicals and Reagents
2.2. LC-MS Analysis Conditions
2.3. AHT Chemical Composition Screening and Target Prediction
2.4. Prediction of Targets for Hyperlipidemia
2.5. Construction of Drug Target Network and Pathways
2.6. Pancreatic Lipase Inhibition Test and Combined Index Analysis
2.7. Cell Culture and MTT Assay
2.8. Establishment of High-Fat Model and Administration Regimen
2.9. Oil Red O Staining
2.10. Determination of Lipid-Lowering Levels in HepG2 Cells by AHT
2.11. Western Blot Analysis
2.12. Animal Experiments
2.13. Determination of Serum Biochemical Indicators
2.14. Statistical Analysis
3. Results
3.1. Analysis of AHT Active Ingredients
3.2. Potential Target Prediction of AHT and HLP
3.3. Target Network Construction for AHT and HLP
3.4. Construction of PPI Network
3.5. Enrichment Analysis of GO and KEGG Pathways
3.6. Determination of AHT Compounding Ratio
3.7. Combination Index Analysis of AHT, AME, HRE, and TME
3.8. The Effects of AHT, AME, HRE, and TME on HepG2 Cell Proliferation and Oleic Acid Staining
3.9. The Lipid-Lowering Effect of AHT on Oleic Acid-Induced HepG2 Cells
3.10. The Effect of AHT on the Lipid-Lowering Mechanism Induced by Oleic Acid in HepG2 Cells
3.11. The Effect of AHT on Body Weight, Food Intake, and Organ Index in Mice
3.12. The Effect of AHT on Serum Biochemical Indicators in High-Fat Mice
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
List of Abbreviations
ALT | Alanine aminotransferase |
AST | Aspartate aminotransferase |
AME | Astragalus membranaceus extract |
AHT | Astragalus membranaceus extract: Hippophae rhamnoides L. extract: Taraxacum mongolicum Hand. Mazz extract = 3:1:2 |
HDL-C | High-density lipoprotein cholesterol |
HRE | Hippophae rhamnoides L. extract |
LC-MS | Liquid chromatography–mass spectrometry |
LDL-C | Low-density lipoprotein cholesterol |
OMIM | Online Mendelian Inheritance in Man |
PPI | Protein–protein interaction |
SOD | Superoxide dismutase |
TME | Taraxacum mongolicum Hand. Mazz extract |
TCMSP | Traditional Chinese Medicine System Pharmacology Analysis Platform |
T-AOC | Total antioxidant capacity |
TC | Total cholesterol |
TG | Triglycerides |
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No. | Name | Molecule ID | Molecule Name | OB (%) | DL |
---|---|---|---|---|---|
1 | Luteolin | MOL000006 | Luteolin | 36.16 | 0.25 |
2 | Quercetin | MOL000098 | Quercetin | 46.43 | 0.28 |
3 | Isorhamnetin | MOL000354 | Isorhamnetin | 49.6 | 0.31 |
4 | Kaempferol | MOL000422 | Kaempferol | 41.88 | 0.24 |
5 | Phaseollidin | MOL000457 | Phaseollidin | 52.04 | 0.53 |
6 | Cholesterol | MOL000953 | CLR | 37.87 | 0.68 |
7 | Ellagic acid | MOL001002 | Ellagic acid | 43.06 | 0.43 |
8 | Pelargonidin | MOL001004 | Pelargonidin | 37.99 | 0.21 |
9 | Dihydrochelerythrine | MOL001461 | Dihydrochelerythrine | 32.73 | 0.81 |
10 | Dihydrosanguinarine | MOL001463 | Dihydrosanguinarine | 59.31 | 0.86 |
11 | Sanguinarine | MOL001474 | Sanguinarine | 37.81 | 0.86 |
12 | Chelerythrine | MOL001478 | Toddaline | 25.99 | 0.81 |
13 | Scopolamine | MOL001554 | Scopolamine | 67.97 | 0.27 |
14 | (+)-Sesamin | MOL001558 | Sesamin | 56.55 | 0.83 |
15 | Acacetin | MOL001689 | Acacetin | 34.97 | 0.24 |
16 | Diphyllin | MOL001699 | Diphyllin | 36.23 | 0.75 |
17 | Podofilox | MOL001714 | Podophyllotoxin | 59.94 | 0.86 |
18 | Linarin | MOL001790 | Linarin | 39.84 | 0.71 |
19 | Scopolin | MOL002218 | Scopolin | 56.45 | 0.39 |
20 | Hesperetin | MOL002341 | Hesperetin | 70.31 | 0.27 |
21 | Medicarpin | MOL002565 | Medicarpin | 49.22 | 0.34 |
22 | Baicalein | MOL002714 | Baicalein | 33.52 | 0.21 |
23 | Melilotoside | MOL004101 | Melilotoside | 36.85 | 0.26 |
24 | Corydaline | MOL004195 | CORYDALINE | 65.84 | 0.68 |
25 | Kaempferide | MOL004564 | Kaempferid | 73.41 | 0.27 |
26 | Glabranin | MOL004910 | Glabranin | 52.9 | 0.31 |
27 | Artemetin | MOL005229 | Artemetin | 49.55 | 0.48 |
28 | Arachidonic acid | MOL005320 | Arachidonate | 45.57 | 0.2 |
29 | Citromitin | MOL005815 | Citromitin | 86.9 | 0.51 |
30 | Papaverine | MOL006980 | Papaverine | 64.04 | 0.38 |
31 | Codeine | MOL006982 | Codeine | 45.48 | 0.56 |
32 | Cirsimaritin | MOL007274 | Skrofulein | 30.35 | 0.3 |
33 | Artemisinin | MOL007424 | Artemisinin | 49.88 | 0.31 |
34 | Corynoline | MOL008636 | Corynoline | 30.53 | 0.85 |
35 | Camptothecin | MOL009830 | EHD | 61.04 | 0.81 |
36 | Leucocyanidin | MOL010489 | Resivit | 30.84 | 0.27 |
37 | Estrone | MOL010921 | Estrone | 53.56 | 0.32 |
38 | Lobelanine | MOL012208 | Lobelanine | 54.13 | 0.32 |
39 | Uridine 5’-monophosphate | MOL012820 | 5’-Uridylic acid | 40.25 | 0.2 |
40 | Fustin | MOL013296 | Fustin | 50.91 | 0.24 |
41 | Garbanzol | MOL013305 | Garbanzol | 83.67 | 0.21 |
Peak No. | Proposed Compound | RT/s | Precursor m/z | Error (ppm) | Formula |
---|---|---|---|---|---|
1 | Luteolin | 290 | 285.0761 | 2.606 | C15H10O6 |
2 | Quercetin | 287 | 303.0498 | 0.420 | C15H10O7 |
3 | Isorhamnetin | 303.7 | 315.0515 | 1.512 | C16H12O7 |
4 | Kaempferol | 282 | 285.0391 | 4.770 | C15H10O6 |
5 | Phaseollidin | 224 | 325.1379 | 17.003 | C20H20O4 |
6 | CLR | 412.7 | 369.3588 | 19.607 | C27H46O |
7 | Ellagic acid | 116.6 | 324.9999 | 13.574 | C14H6O8 |
8 | Pelargonidin | 57.5 | 543.1263 | 4.175 | C15H11O5 |
9 | Dihydrochelerythrine | 63.8 | 332.1285 | 1.169 | C21H19NO4 |
10 | Dihydrosanguinarine | 48.1 | 665.1907 | 3.352 | C20H15NO4 |
11 | Sanguinarine | 116.9 | 289.1103 | 1.990 | C20H14NO4 |
12 | Toddaline | 83.9 | 332.1315 | 10.197 | C21H18NO4 |
13 | Scopolamine | 301.9 | 285.1163 | 10.784 | C17H21NO4 |
14 | Sesamin | 48.5 | 337.1115 | 13.218 | C20H18O6 |
15 | Acacetin | 336.1 | 283.0606 | 2.098 | C16H12O5 |
16 | Diphyllin | 46.8 | 381.0936 | 8.594 | C21H16O7 |
17 | Podophyllotoxin | 58.8 | 829.2688 | 1.687 | C22H22O8 |
18 | Linarin | 240.2 | 653.184 | 17.888 | C28H32O14 |
19 | Scopolin | 81.8 | 335.0758 | 4.287 | C16H18O9 |
20 | Hesperetin | 241.6 | 301.071 | 2.518 | C16H14O6 |
21 | Medicarpin | 240.9 | 254.0728 | 11.289 | C16H14O4 |
22 | Baicalein | 297.6 | 269.0448 | 2.767 | C15H10O5 |
23 | Melilotoside | 81.8 | 371.0968 | 4.221 | C15H18O8 |
24 | CORYDALINE | 226.1 | 387.2221 | 14.781 | C22H27NO4 |
25 | Kaempferid | 302.1 | 299.0567 | 1.977 | C16H12O6 |
26 | Glabranin | 385.4 | 369.1471 | 4.907 | C20H20O4 |
27 | Artemetin | 61.3 | 345.1367 | 9.972 | C20H20O8 |
28 | Arachidonate | 447.9 | 303.2351 | 7.121 | C20H32O2 |
29 | Citromitin | 206.6 | 405.1339 | 18.738 | C21H24O8 |
30 | Papaverine | 66.5 | 322.127 | 4.678 | C20H21NO4 |
31 | Codeine | 219.3 | 300.1587 | 2.372 | C18H21NO3 |
32 | Skrofulein | 252 | 359.073 | 11.803 | C17H14O6 |
33 | Artemisinin | 260.9 | 343.1382 | 4.764 | C15H22O5 |
34 | Corynoline | 254.3 | 350.1458 | 3.569 | C21H21NO5 |
35 | EHD | 260.3 | 330.2363 | 11.189 | C20H16N2O4 |
36 | Resivit | 267.9 | 288.0443 | 14.498 | C15H14O7 |
37 | Estrone | 292.4 | 269.079 | 10.881 | C18H22O2 |
38 | Lobelanine | 276 | 336.1978 | 5.963 | C22H25NO2 |
39 | 5’-Uridylic acid | 41.1 | 323.0274 | 3.682 | C9H13N2O9P |
40 | Fustin | 326.2 | 333.0473 | 15.279 | C15H12O6 |
41 | Garbanzol | 252.4 | 273.0805 | 17.407 | C15H12O5 |
NO. | Symbol ID | Protein Name | Pathways |
---|---|---|---|
1 | TP53 | Tumor protein p53 | hsa05417, hsa04010, hsa04151 |
2 | PPARG | Peroxisome proliferator-activated receptor gamma | hsa05417 |
3 | ESR1 | Estrogen receptor | hsa05207 |
4 | TNF | Tumor necrosis factor | hsa05417, hsa04933, hsa04010 |
5 | CCL2 | C-C motif chemokine 2 | hsa05417, hsa04933, hsa05418 |
6 | AKT1 | Potassium channel AKT1 | hsa05417, hsa04933, hsa04010, hsa04151 |
7 | RELA | Transcription factor p65 | hsa05417, hsa04933, hsa04010, hsa04151 |
8 | MAPK1 | Mitogen-activated protein kinase 1 | hsa05417, hsa04933, hsa04010, hsa04151 |
9 | IL6 | Interleukin-6 | hsa05417, hsa04933, hsa04151 |
10 | CXCL8 | Interleukin-8 | hsa05417, hsa04933 |
11 | IL1A | Interleukin-1 alpha | hsa04933, hsa04010, hsa05418 |
12 | IL4 | Interleukin-4 | hsa04151 |
13 | IL10 | Interleukin-10 | - |
14 | IL1B | Interleukin-1 beta | hsa05417, hsa04933, hsa04010 |
15 | IFNG | Interferon gamma | hsa05418 |
ID | Description | p-Value | Gene ID | Count |
---|---|---|---|---|
hsa05200 | Pathways in cancer | 29.15 | GSK3B, CXCL8, PTEN, CASP9, CASP8, CCND1, MYC, CASP3, AKT1, NCOA1, CHUK, PRKCB, MMP1, MMP2, FOS, MMP9, AR, IFNG, BIRC5, PPARG, RAF1, TP53, PPARD, PTGS2, HIF1A, EGFR, RELA, RXRB, MAPK8, RXRA, ERBB2, E2F1, HMOX1, MAPK1, RXRG, TGFB1, NOS2, CDKN2A, EGF, STAT1, IGF2, ESR1, ESR2, IL2, VEGFA, MAPK10, IL4, IL6, CDK4, BCL2, MDM2, BAX, NFE2L2 | 53 |
hsa05417 | Lipid and atherosclerosis | 30.27 | GSK3B, CXCL8, TNF, CXCL2, RELA, ICAM1, CASP9, RXRB, PPP3CA, MAPK8, CASP8, CYP2B6, RXRA, CASP3, CCL2, AKT1, MAPK1, OLR1, RXRG, VCAM1, CHUK, MMP1, NOS3, MMP3, NFATC1, FOS, MAPK14, SELE, MMP9, MAPK10, IL6, CD40LG, IL1B, CYP1A1, BCL2, BAX, PPARG, TP53, NFE2L2 | 39 |
hsa04933 | AGE-RAGE signaling pathway in diabetic complications | 31.05 | CXCL8, SERPINE1, TNF, RELA, ICAM1, THBD, MAPK8, CCND1, CASP3, CCL2, AKT1, MAPK1, TGFB1, VCAM1, PRKCB, NOS3, STAT1, MMP2, NFATC1, MAPK14, SELE, F3, VEGFA, MAPK10, IL1A, COL3A1, IL6, CDK4, IL1B, BCL2, BAX | 31 |
hsa05167 | Kaposi sarcoma-associated herpesvirus infection | 20.65 | GSK3B, CXCL8, PTGS2, HIF1A, CXCL2, RELA, PIK3CG, ICAM1, CASP9, PPP3CA, MAPK8, CASP8, CCND1, MYC, CASP3, E2F1, AKT1, MAPK1, CHUK, STAT1, NFATC1, FOS, MAPK14, VEGFA, MAPK10, IL6, CDK4, BAX, RAF1, TP53 | 30 |
hsa05207 | Chemical carcinogenesis—receptor activation | 19.50 | NR1I3, ADRB1, AHR, ADRB2, CYP3A4, RELA, EGFR, RXRB, CYP2B6, RXRA, CCND1, MYC, E2F1, AKT1, MAPK1, RXRG, UGT1A1, PRKCB, EGF, FOS, ESR1, ESR2, VEGFA, AR, CYP1A1, BCL2, BIRC5, PGR, RAF1, PPARA | 30 |
hsa05163 | Human cytomegalovirus infection | 17.81 | GSK3B, CXCL8, PTGS2, TNF, RELA, EGFR, CASP9, PPP3CA, CASP8, CCND1, MYC, CASP3, E2F1, CCL2, AKT1, MAPK1, CHUK, CDKN2A, PRKCB, NFATC1, MAPK14, VEGFA, IL6, CDK4, IL1B, MDM2, BAX, RAF1, TP53 | 29 |
hsa04010 | MAPK signaling pathway | 12.69 | HSPB1, TNF, RELA, EGFR, PPP3CA, MAPK8, MYC, CASP3, ERBB2, AKT1, MAPK1, TGFB1, CHUK, PRKCB, EGF, INSR, IGF2, NFATC1, FOS, MAPK14, VEGFA, MAPK10, IL1A, RASA1, IL1B, RAF1, TP53 | 27 |
hsa04151 | PI3K-Akt signaling pathway | 10.81 | GSK3B, PTEN, RELA, EGFR, PIK3CG, CASP9, RXRA, CCND1, MYC, ERBB2, SPP1, AKT1, MAPK1, CHUK, EGF, NOS3, INSR, IGF2, IL2, VEGFA, IL4, IL6, CDK4, BCL2, MDM2, RAF1, TP53 | 27 |
hsa05418 | Fluid shear stress and atherosclerosis | 19.75 | PLAT, TNF, RELA, ICAM1, THBD, MAPK8, CCL2, AKT1, HMOX1, VCAM1, CHUK, NOS3, CAV1, MMP2, FOS, MAPK14, SELE, MMP9, VEGFA, MAPK10, IL1A, IFNG, IL1B, BCL2, TP53, NFE2L2 | 26 |
hsa05161 | Hepatitis B | 18.15 | CXCL8, TNF, RELA, CASP9, MAPK8, CASP8, MYC, CASP3, E2F1, AKT1, MAPK1, TGFB1, CHUK, PRKCB, STAT1, NFATC1, FOS, MAPK14, MMP9, MAPK10, IL6, BCL2, BAX, BIRC5, RAF1, TP53 | 26 |
Group | AME | HRE | TME | Inhibition Rate% |
---|---|---|---|---|
1 | 1 | 1 | 1 | 80.71 ± 0.83 |
2 | 1 | 2 | 2 | 79.84 ± 0.80 |
3 | 1 | 3 | 3 | 72.11 ± 1.94 |
4 | 2 | 1 | 2 | 94.25 ± 1.10 |
5 | 2 | 2 | 3 | 86.08 ± 0.86 |
6 | 2 | 3 | 1 | 89.64 ± 1.23 |
7 | 3 | 1 | 3 | 96.72 ± 1.30 |
8 | 3 | 2 | 1 | 95.87 ± 0.25 |
9 | 3 | 3 | 2 | 96.47 ± 0.32 |
k1 | 77.55 | 90.56 | 88.74 | |
k2 | 89.99 | 87.26 | 90.19 | |
k3 | 96.35 | 86.07 | 84.97 | |
R | 18.80 | 4.49 | 5.13 | |
Best combination | A3H1T2 |
Group | NC | MC | PC | LD | MD | HD |
---|---|---|---|---|---|---|
Heart (%) | 0.693 ± 0.11 | 0.672 ± 0.11 | 0.602 ± 0.10 | 0.707 ± 0.19 | 0.660 ± 0.09 | 0.613 ± 0.10 |
Liver (%) | 4.554 ± 0.47 | 4.527 ± 0.35 | 3.847 ± 1.40 | 4.750 ± 0.67 | 4.483 ± 0.66 | 4.548 ± 0.74 |
Spleen (%) | 0.327 ± 0.03 | 0.309 ± 0.05 | 0.253 ± 0.06 | 0.306 ± 0.08 | 0.282 ± 0.10 | 0.321 ± 0.09 |
Kidney (%) | 1.462 ± 0.18 | 1.367 ± 0.13 | 1.357 ± 0.17 | 1.463 ± 0.19 | 1.334 ± 0.23 | 1.271 ± 0.14 |
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Yang, X.; Jia, M.; Luo, J.; An, Y.; Chen, Z.; Bao, Y. Investigation of the Lipid-Lowering Activity and Mechanism of Three Extracts from Astragalus membranaceus, Hippophae rhamnoides L., and Taraxacum mongolicum Hand. Mazz Based on Network Pharmacology and In Vitro and In Vivo Experiments. Foods 2024, 13, 2795. https://doi.org/10.3390/foods13172795
Yang X, Jia M, Luo J, An Y, Chen Z, Bao Y. Investigation of the Lipid-Lowering Activity and Mechanism of Three Extracts from Astragalus membranaceus, Hippophae rhamnoides L., and Taraxacum mongolicum Hand. Mazz Based on Network Pharmacology and In Vitro and In Vivo Experiments. Foods. 2024; 13(17):2795. https://doi.org/10.3390/foods13172795
Chicago/Turabian StyleYang, Xue, Mingjie Jia, Jiayuan Luo, Yuning An, Zefu Chen, and Yihong Bao. 2024. "Investigation of the Lipid-Lowering Activity and Mechanism of Three Extracts from Astragalus membranaceus, Hippophae rhamnoides L., and Taraxacum mongolicum Hand. Mazz Based on Network Pharmacology and In Vitro and In Vivo Experiments" Foods 13, no. 17: 2795. https://doi.org/10.3390/foods13172795