A Novel Based-Network Strategy to Identify Phytochemicals from Radix Salviae Miltiorrhizae (Danshen) for Treating Alzheimer’s Disease
Abstract
:1. Introduction
2. Results and Discussion
2.1. Target Identification and Validation
2.2. Network Construction and Analysis
2.3. Anti-AD Effect Analysis of Danshen Component
2.3.1. Score Ranking
2.3.2. CMap Validation
2.3.3. Anti-AD Drug Candidates from Danshen
2.4. Experimental Evaluation of Neuroprotective Effects
2.4.1. SMP Protects against H2O2-Treated PC12 Cells
2.4.2. SMP Increased Ach Levels in H2O2-Stimulated PC12 Cells
2.4.3. SMP Suppresses Apoptosis in H2O2-stimulated PC12 Cells
2.4.4. SMP Reduced the H2O2-Stimulated Reactive Oxygen Species (ROS) Generation in PC12 Cells
2.4.5. SMP Ameliorated H2O2-Induced Oxidative Stress in PC12 Cells
2.4.6. Effects of M308 and SMP on mRNA Expressions of PSEN1, DRD2, and APP in H2O2-Stimulated PC12 Cells
3. Materials and Methods
3.1. Data Mining
3.1.1. AD-Associated Genes Screening
3.1.2. Danshen Compounds Absorbed in Plasma and Their Putative Targets
3.2. In Silico Target Validation by Molecular Docking
3.2.1. Intersectional Analysis
3.2.2. Molecular Docking
3.3. Construction of AD Network Treated by Danshen
3.3.1. Construction of AD Background Network
3.3.2. Extraction of the Danshen-Treated Subnetwork
3.3.3. Function Enrichment Analysis
3.4. Anti-AD Effect Ranking of Active Ingredient
3.4.1. Network Scoring of Anti-AD Effects of Compounds
3.4.2. Z-Score
3.4.3. FDA-Approved Anti-AD Drugs
3.5. Network Scores Validated by CMap Analysis
3.5.1. Differentially Expressed Genes
3.5.2. Connectivity Map
3.6. Experimental Validation
3.6.1. Materials and Chemicals
3.6.2. Animals
3.6.3. Cell Culture and Treatment
3.6.4. Determination of Cell Viability
3.6.5. Determination of ACh Levels in PC12 Cells
3.6.6. Apoptosis Assay by Dual AO/EB Staining
3.6.7. Assessment of Mitochondrial Membrane Potential
3.6.8. Determination of Intracellular ROS Accumulation in PC12 Cells
3.6.9. Determination of MDA, SOD, GSH-Px, and CAT in H2O2-Induced PC12 Cells
3.6.10. UPLC-Q-TOF/MS Analysis
3.6.11. RT-qPCR Assay
3.7. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Sample Availability
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Molecule | CAS | Category | Target | Affinity |
---|---|---|---|---|
M001 | 76822-21-4 | Phenolic acids | PLAU | −6.7 |
M019 | 20283-92-5 | Phenolic acids | APP | −4.41 |
M029 | 96574-01-5 | Phenolic acids | APP | −5.5 |
M031 | 28831-65-4 | Phenolic acids | APP | −4.6 1 |
M081 | 491-70-3 | Phenolic acids | ACHE/APP/MPO | −4.9 1/−4.8 1/−10 |
M095 | 21967-41-9 | Phenolic acids | ACHE | −6.3 |
M187 | 99-50-3 | Volatile oil | MPO | −6.3 |
M206 | 568-73-0 | Tanshinones | NOS3 | −12 |
M208 | 568-72-9 | Tanshinones | DRD1 | −10.6 |
M216 | 18887-19-9 | Tanshinones | ACHE/HTR2C | −5.3/−9.9 |
M218 | 146362-71-2 | Tanshinones | ACHE | −5.3 |
M219 | 142694-58-4 | Tanshinones | ACHE/ADAM10/ HTR2A/HTR2C/ NCSTN/PSEN1 | −5.2/−6.4/−10.1/ −9.4/−6.1/−8.1 |
M229 | 126979-84-8 | Tanshinones | ACHE | −5 |
M230 | 87205-99-0 | Tanshinones | ACHE/HTR2C | −5.3/−10.9 |
M231 | 27210-57-7 | Tanshinones | ACHE | −4.6 1 |
M234 | 105037-82-9 | Tanshinones | ACHE/APP/DRD2/ HTR2A/NCSTN/ PSEN1/SLC6A4 | −5/−5.1/−10.1/−9.1/−6.1/−7.7/−9.3 |
M237 | 119963-50-7 | Tanshinones | ACHE/HTR2A/ HTR2C | −4.9 1/−9.5/−9.9 |
M239 | 35825-57-1 | Tanshinones | ACHE/HTR2A/ HTR2C | −5.2/−9.7/−9.5 |
M253 | 189290-30-0 | Tanshinones | NCSTN/PSEN1 | −5.9/−7.4 |
M260 | 76843-23-7 | Tanshinones | ACHE/MPO | −5/−9.8 |
M263 | 121077-35-8 | Tanshinones | ACHE | −4.9 1 |
M308 | 98873-76-8 | Tanshinones | DRD2/HTR2A/ NCSTN/PSEN1 | −9/−8.9/−6.4/−8 |
M378 | 13850-16-3 | Triterpenoids | SLC6A4 | −7.5 |
M380 | 4373-41-5 | Triterpenoids | SLC6A4 | −8.6 |
M389 | 4547-24-4 | Triterpenoids | SLC6A4 | −7.8 |
Molecule | Count | Score | Z-Value |
---|---|---|---|
M234 | 7 | 0.6473 | 5.7989 |
M308 | 4 | 0.5563 | 4.9337 |
M081 | 3 | 0.0909 | 0.5071 |
M219 | 6 | 0.0697 | 0.3055 |
M237 | 3 | 0.0617 | 0.2294 |
M239 | 3 | 0.0617 | 0.2294 |
M216 | 2 | 0.0611 | 0.2244 |
M230 | 2 | 0.0611 | 0.2244 |
M260 | 2 | 0.0517 | 0.1351 |
M095 | 1 | 0.0517 | 0.1347 |
M218 | 1 | 0.0517 | 0.1347 |
M229 | 1 | 0.0517 | 0.1347 |
M231 | 1 | 0.0517 | 0.1347 |
M263 | 1 | 0.0517 | 0.1347 |
M019 | 1 | 0.0391 | 0.0151 |
M029 | 1 | 0.0391 | 0.0151 |
M031 | 1 | 0.0391 | 0.0151 |
M253 | 2 | 0.0067 | −0.2930 |
M206 | 1 | 0.0021 | −0.3371 |
M001 | 1 | 0.0002 | −0.3546 |
M208 | 1 | 0.0002 | −0.3550 |
M378 | 1 | 0.0002 | −0.3555 |
M380 | 1 | 0.0002 | −0.3555 |
M389 | 1 | 0.0002 | −0.3555 |
M187 | 1 | 0.0000 | −0.3566 |
Memantine | 2 | 0.3077 | 2.5696 |
Donepezil | 4 | 0.2782 | 2.2884 |
Normal | Model | Low Dose | Middle Dose | High Dose |
---|---|---|---|---|
38.13 ± 4.64 ** | 12.00 ± 2.03 | 17.80 ± 2.30 | 30.97 ± 6.66 ** | 50.35 ± 3.14 ** |
Gene Name | Forward (5′-3′) | Reverse (5′-3′) |
---|---|---|
PSEN1 | TGCACCTTTGTCCTACTTCCA | GCTCAGGGTTGTCAAGTCTCTG |
DRD2 | GAGCCAACCTGAAGACACCA | GCATCCATTCTCCGCCTGTT |
APP | TCCGAGAGGTGTGCTCTGAA | CCACATCCGCCGTAAAAGAATG |
GAPDH | AGGTCGGTGTGAACGGATTTG | TCCACCACCCTGTTGCTGTA |
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Li, B.; Wu, Y.-R.; Li, L.; Liu, Y.; Yan, Z.-Y. A Novel Based-Network Strategy to Identify Phytochemicals from Radix Salviae Miltiorrhizae (Danshen) for Treating Alzheimer’s Disease. Molecules 2022, 27, 4463. https://doi.org/10.3390/molecules27144463
Li B, Wu Y-R, Li L, Liu Y, Yan Z-Y. A Novel Based-Network Strategy to Identify Phytochemicals from Radix Salviae Miltiorrhizae (Danshen) for Treating Alzheimer’s Disease. Molecules. 2022; 27(14):4463. https://doi.org/10.3390/molecules27144463
Chicago/Turabian StyleLi, Bo, Yu-Rui Wu, Lan Li, Yu Liu, and Zhu-Yun Yan. 2022. "A Novel Based-Network Strategy to Identify Phytochemicals from Radix Salviae Miltiorrhizae (Danshen) for Treating Alzheimer’s Disease" Molecules 27, no. 14: 4463. https://doi.org/10.3390/molecules27144463