Cleistocalyx nervosum var. paniala Berry Seed Protects against TNF-α-Stimulated Neuroinflammation by Inducing HO-1 and Suppressing NF-κB Mechanism in BV-2 Microglial Cells
Abstract
:1. Introduction
2. Results
2.1. Characterization of Phytochemical Components in CNSE
2.2. In Silico Evaluation of Identified Compounds in CNSE against Inflammatory-Related Transcription Factors
2.3. In Silico Evaluation of Identified Compounds in CNSE against iNOS Protein
2.4. In Silico Evaluation of Identified Compounds in CNSE against COX-2 Protein
2.5. Lipinski’s Rule of Five Parameters and ADMET Properties of Bioactive Components in CNSE
2.6. Effect of CNSE on the Viability of BV-2 Cells
2.7. Effect of CNSE on the Morphological Changes of BV-2 Cells
2.8. Inhibitory Effect of CNSE on Levels of Proinflammatory Cytokines
2.9. Effect of CNSE on MAPKs Signaling Activation
2.10. Effect of CNSE on NF-κB Signaling Activation
2.11. Effect of CNSE on HO-1 Activation
3. Discussion
4. Materials and Methods
4.1. Materials and Reagents
4.2. CNSE Extraction
4.3. Liquid Chromatography-Mass Spectrometry (LC-MS) Analysis
4.4. Molecular Docking
4.4.1. Protein Preparation
4.4.2. Ligand Preparation
4.4.3. Method Validation
4.4.4. Molecular Docking of Candidate Ligands
4.5. Lipinski’s Rule and Pharmacokinetic Property Analysis
4.6. Cell Culture
4.7. Cell Viability Assay
4.8. Cell Morphological Analysis
4.9. Quantitative Real-Time PCR Analysis
4.10. Immunoblotting Analysis
4.11. Enzyme-Linked Immunosorbent Assay (ELISA)
4.12. Dual-Luciferase Assay
4.13. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Ligand | Binding Energy (kcal/mol) | Inhibition Constant (μM) | Amino Acid Interaction | ||
---|---|---|---|---|---|
Hydrogen Bond | Hydrophobic Bond | Other | |||
3,5-dimethyl-4-[(2-nitrophenyl)diazenyl]pyrazole-1-carbothioamide (native inhibitor) | −6.33 | 22.78 | ARG246 (3) GLN247 | LYS218 (2) VAL248 ARG246 (2) ALA192 | - |
Ellagic acid | −7.31 | 4.41 | ARG33 (2) LYS218 (2) ARG187 | LYS218 (2) ARG187 (2) ALA192 | - |
Alpinetin | −6.17 | 30.19 | ARG33 (2) ASN186 GLU193 ASP217 | ALA192 ARG187 | - |
Aurentiacin | −6.01 | 39.06 | ASN186 (2) LYS218 (2) ARG246 GLU193 | ALA192 (2) LYS218 ARG187 | ASP217 |
Brassitin | −5.11 | 178.17 | ARG33 (2) ASP217 | ARG33 ALA192 | - |
Ferulic acid | −4.52 | 488.99 | ASN186 LYS218 (2) ASP217 ARG187 | ALA192 (2) LYS218 | ASN186 |
Ligand | Binding Energy (kcal/mol) | Inhibition Constant (μM) | Amino Acid Interaction | ||
---|---|---|---|---|---|
Hydrogen Bond | Hydrophobic Bond | Other | |||
1-[[6-methoxy-2-(2-thienyl)quinazolin-4-yl]amino]-3-methyl-pyrrole-2,5-dione (native inhibitor) | −9.29 | 0.016 | SER16 ARG17 LYS20 (2) DG208 DA209 (3) | ALA13 ARG17 (4) LYS20 (3) LEU21 (2) DG208 (4) | ARG17 LYS20 DA209 (2) |
Aurentiacin | −7.69 | 2.32 | LYS20 DG208 | ARG17 (3) LEU21 (2) LYS20 (2) DG208 DA209 | ARG17 LYS20 DA209 |
Alpinetin | −7.22 | 5.06 | ARG17 DG208 | ARG17 (2) LYS20 LEU21 DG208 | ARG17 LYS20 |
Ellagic acid | −7.06 | 6.67 | ARG17 (2) LYS20 DG208 (2) DA209 (3) DC210 | ALA192 (2) ARG17 (4) LYS20 (2) | ARG17 (2) LYS20 |
Ferulic acid | −6.72 | 11.81 | ARG17 (2) LYS20 DA209 | ARG17 (2) LYS20 LEU21 | LYS20 |
Brassitin | −6.7 | 12.26 | SER16 LYS20 DG208 | ALA13 ARG17 (3) LYS20 LEU21 DT207 DG208 (2) | LYS20 (2) DG208 (3) |
Ligand | Binding Energy (kcal/mol) | Inhibition Constant (μM) | Amino Acid Interaction | ||
---|---|---|---|---|---|
Hydrogen Bond | Hydrophobic Bond | Other | |||
Ethyl 4-[(4-methylpyridin-2-yl) amino] piperidine-1-carboxylate (native inhibitor) | −6.91 | 8.64 | TYR347 VAL352 | TRP346 (2) TYR347 PRO350 (2) VAL352 ASN370 | - |
Ellagic acid | −6.32 | 23.46 | ILE265 (2) ARG266 (2) ALA351 TYR373 GLU377 ARG388 | GLN263 | ASP382 (2) |
Aurentiacin | −6.13 | 32.37 | TYR347 ALA351 TYR373 GLU377 (2) | TRP346 (2) PRO350 VAL352 TYR373 ARG381 | - |
Alpinetin | −6.11 | 33.02 | VAL352 TRP372 | PRO350 (2) PHE369 | - |
Brassitin | −5.63 | 75.29 | TYR347 ALA351 GLU377 | PRO350 (2) VAL352 TYR373 (2) | TYR347 TYR373 |
Ferulic acid | −4.71 | 323.29 | ARG199 CYS200 GLY202 PRO350 | PRO350 VAL352 | CYS200 |
Ligand | Binding Energy (kcal/mol) | Inhibition Constant (μM) | Amino Acid Interaction | ||
---|---|---|---|---|---|
Hydrogen Bond | Hydrophobic Bond | Other | |||
Tolfenamic acid (native inhibitor) | −8.13 | 1.1 | TYR385 SER530 | VAL116 VAL349 (2) LEU352 VAL523 ALA527 (4) LEU531 (2) | - |
Alpinetin | −8.14 | 1.08 | TYR355 SER530 | VAL349 (2) LEU352 LEU359 PHE518 GLY526 ALA527 (2) LEU531 | MET522 |
Aurentiacin | −8.03 | 1.3 | ARG120 TYR355 | MET113 VAL116 (2) VAL349 (3) LEU352 TYR355 LEU359 TRP387 GLY526 ALA527 (3) LEU531 (2) | MET522 |
Ellagic acid | −6.89 | 8.94 | TYR355 SER530 | VAL349 (2) LEU352 (4) VAL523 (2) GLY526 (3) ALA527 (6) | - |
Brassitin | −6.29 | 24.61 | SER530 | PHE205 TYR348 LEU352 (2) TYR385 PHE518 VAL523 (2) GLY526 (2) ALA527 (3) | TYR348 TYR385 MET522 |
Ferulic acid | −5.07 | 193.72 | TYR355 SER353 | LEU352 PHE381 TYR385 MET522 VAL523 (2) GLY526 ALA527 (2) | MET522 |
Compound | Molecular Weight (≤500) | #H-Bond Acceptors (≤10) | #H-Bond Donors (≤5) | MLOGP (≤4.15) | Lipinski #Violations (≤1) |
---|---|---|---|---|---|
Alpinetin | 194.18 | 4 | 2 | 1 | 0 |
Aurentiacin | 298.33 | 4 | 1 | 2.31 | 0 |
Brassitin | 302.19 | 8 | 4 | 0.14 | 0 |
Ellagic acid | 220.29 | 1 | 2 | 1.4 | 0 |
Ferulic acid | 270.28 | 4 | 1 | 1.52 | 0 |
Pharmacokinetic Property | Alpinetin | Aurentiacin | Brassitin | Ellagic Acid | Ferulic Acid |
---|---|---|---|---|---|
GI absorption | High | High | High | High | High |
Pgp substrate | Yes | No | No | No | No |
log Kp (skin permeation) (cm/s) | −6.07 | −5.14 | −6.22 | −7.36 | −6.41 |
BBB permeant | Yes | Yes | Yes | No | Yes |
CYP1A2 inhibitor | Yes | Yes | Yes | Yes | No |
CYP2C19 inhibitor | Yes | Yes | Yes | No | No |
CYP2C9 inhibitor | No | Yes | No | No | No |
CYP2D6 inhibitor | No | Yes | No | No | No |
CYP3A4 inhibitor | Yes | Yes | No | No | No |
Carcinogenicity (mouse) | Negative | Negative | Negative | Negative | Negative |
hERG inhibition | Medium risk | Medium risk | Medium risk | Low risk | Medium risk |
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Janpaijit, S.; Sillapachaiyaporn, C.; Theerasri, A.; Charoenkiatkul, S.; Sukprasansap, M.; Tencomnao, T. Cleistocalyx nervosum var. paniala Berry Seed Protects against TNF-α-Stimulated Neuroinflammation by Inducing HO-1 and Suppressing NF-κB Mechanism in BV-2 Microglial Cells. Molecules 2023, 28, 3057. https://doi.org/10.3390/molecules28073057
Janpaijit S, Sillapachaiyaporn C, Theerasri A, Charoenkiatkul S, Sukprasansap M, Tencomnao T. Cleistocalyx nervosum var. paniala Berry Seed Protects against TNF-α-Stimulated Neuroinflammation by Inducing HO-1 and Suppressing NF-κB Mechanism in BV-2 Microglial Cells. Molecules. 2023; 28(7):3057. https://doi.org/10.3390/molecules28073057
Chicago/Turabian StyleJanpaijit, Sakawrat, Chanin Sillapachaiyaporn, Atsadang Theerasri, Somsri Charoenkiatkul, Monruedee Sukprasansap, and Tewin Tencomnao. 2023. "Cleistocalyx nervosum var. paniala Berry Seed Protects against TNF-α-Stimulated Neuroinflammation by Inducing HO-1 and Suppressing NF-κB Mechanism in BV-2 Microglial Cells" Molecules 28, no. 7: 3057. https://doi.org/10.3390/molecules28073057