Molecular Rescue of Dyrk1A Overexpression Alterations in Mice with Fontup® Dietary Supplement: Role of Green Tea Catechins
Abstract
:1. Introduction
2. Results
2.1. Quantification of FontUp® Polyphenols
2.2. In Vitro Inhibition and Molecular Docking of DYRK1A
2.3. Effects of Low, Intermediate and High Doses of FontUp® Administration on Plasma Biomarkers Linked with DYRK1A
2.4. Effects of the Higher Dose of FontUp® Administration on Liver and Cardiac Biomarkers
2.5. Effects of the Intermediate Dose of FontUp® Administration on Brain Biomarkers Linked with DYRK1A
3. Discussion
4. Materials and Methods
4.1. Quantification of FontUp® Polyphenols
4.2. Experimental Mice Model
4.3. FontUp® Treatment
4.4. Preparation of Serum Samples, Tissue Collection, and Plasma Assays
4.5. Protein Extraction and Analysis
4.6. Expression and Purification of Truncated DYRK1A (DYRK1A-ΔC)
4.7. DYRK1A Inhibition Assays
4.8. Quantification of FontUp® Polyphenols in Plasma and Brain Samples
4.9. Molecular Docking
4.10. Data Analysis
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
Akt | Protein kinase B |
ALT | Alanine aminotransferase |
αSMA | α Smooth muscle actin |
BBB | Blood-brain barrier |
BDNF | Brain derived neurotrophic factor |
DAD | Diode array detection |
DS | Down syndrome |
DYRK1A | Dual-specificity tyrosine phosphorylation-related kinase 1A |
EC | Epicatechin |
ECG | Epicatechin gallate |
EGC | Epigallocatechin |
EGCG | Epigallocatechin-3-gallate |
Erk | Extracellular signal-regulated kinase |
GSH | Glutathione |
HPLC | High-performance liquid chromatography |
hcy | Homocysteine |
PAkt | Phosphor-Akt |
Perk | Phosphor-Erk |
RNF216 | Ring Finger Protein 216 |
Truncated DYRK1A | Truncated dual-specificity tyrosine phosphorylation-related kinase 1A |
WT | Wild type |
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Compound | Structure | DYRK1A-ΔC Remaining Activity at 0.1 µM (%) | DYRK1A-ΔC Remaining Activity at 1 µM (%) | DYRK1A-ΔC Remaining Activity at 10 µM (%) | DYRK1A-ΔC Remaining Activity at 100 µM (%) |
---|---|---|---|---|---|
ECG | 78.1 ± 3.6 (n = 8) | 27.1 ± 7.3 (n = 8) | 11.8 ± 4.2 (n = 8) | 7.6 ± 2.3 (n = 8) | |
EGC | 99.5 ± 3.2 (n = 4) | 93.6 ± 2.6 (n = 4) | 80.6 ± 11.4 (n = 4) | 81.4 ± 12.8 (n = 4) | |
EGCG | 71.3 ± 4.6 (n = 13) | 16.3 ± 2.3 (n = 13) | 6.4 ± 1.1 (n = 13) | 3.5 ± 0.8 (n = 13) | |
EC | 89.2 ± 9.5 (n = 4) | 84.1 ± 9.1 (n = 4) | 95.6 ± 8.1 (n = 4) | 88.7 ± 8.2 (n = 4) |
Compound | Structure | DYRK1A Remaining Activity at 0.1 µM (%) | DYRK1A Remaining Activity at 1 µM (%) | DYRK1A Remaining Activity at 10 µM (%) | DYRK1A Remaining Activity at 100 µM (%) |
---|---|---|---|---|---|
ECG | 69.9 ± 3.9 (n = 4) | 12.5 ± 2.4 (n = 4) | 4.6 ± 0.9 (n = 4) | 2.3 ± 0.5 (n = 4) | |
EGCG | 67.5 ± 9.4 (n = 7) | 10 ± 2 (n = 7) | 3.4 ± 0.6 (n = 7) | 2.1 ± 0.5 (n = 7) |
Compound | DYRK1A-ΔC Remaining Activity With 200 µM ATP (%) | DYRK1A-ΔC Remaining Activity with 400 µM ATP (%) | DYRK1A-ΔC Remaining Activity with 800 µM ATP (%) |
---|---|---|---|
ECG (10 µM) | 8.0 ± 0.8 (n = 4) | 6.5 ± 0.9 (n = 4) | 4.0 ± 0.5 (n = 4) |
EGCG (10 µM) | 11.0 ± 3.1 (n = 4) | 9.6 ± 2.1 (n = 4) | 5.4 ± 1.3 (n = 4) |
Compound | DYRK1A Remaining Activity with 200 µM ATP (%) | DYRK1A Remaining Activity with 400 µM ATP (%) | DYRK1A Remaining Activity with 800 µM ATP (%) |
---|---|---|---|
ECG (10 µM) | 9.4 ± 1.4 (n = 4) | 7.0 ± 1.1 (n = 4) | 5.4 ± 0.9 (n = 4) |
EGCG (10 µM) | 6.3 ± 0.9 (n = 4) | 5.1 ± 0.9 (n = 4) | 4.0 ± 0.7 (n = 4) |
WT CTL | WT D1 | WT D2 | WT D3 | |
---|---|---|---|---|
EGCG (nM) | 0 | 28 ± 0.0003 | 63 ± 10.8 | 104 ± 11.2 |
hcy (µM) | 2.7 ± 0.1 | 2.9 ± 0.3 | 3.6 ± 0.3 * | 2.7 ± 0.2 |
GSH (µM) | 66.4 ± 3.5 | 71.2 ± 2.6 | 75.2 ± 3.3 ** | 88.4 ± 2.7 *** |
ALT (mU/mL) | 27.4 ± 7.1 | 17.1 ± 5 | 14.9 ± 4.3 * | 27.1 ± 4.9 |
Galectin-3 (pg/mL) | 5.1 ± 0.3 | 5.2 ± 0.2 | 4.9 ± 0.25 | 5.1 ± 0.15 |
WT | TgDyrk1A | |
---|---|---|
Plasma EGCG (µM) | 0.065 ± 0.023 | 0.036 ± 0.011 |
Brain EGCG (µM) | 0.025 ± 0.007 | 0.050 ± 0. 01 $ |
Kp | 1.2 ± 0.33 | 3.6 ± 0.82 |
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Gu, Y.; Moroy, G.; Paul, J.-L.; Rebillat, A.-S.; Dierssen, M.; de la Torre, R.; Cieuta-Walti, C.; Dairou, J.; Janel, N. Molecular Rescue of Dyrk1A Overexpression Alterations in Mice with Fontup® Dietary Supplement: Role of Green Tea Catechins. Int. J. Mol. Sci. 2020, 21, 1404. https://doi.org/10.3390/ijms21041404
Gu Y, Moroy G, Paul J-L, Rebillat A-S, Dierssen M, de la Torre R, Cieuta-Walti C, Dairou J, Janel N. Molecular Rescue of Dyrk1A Overexpression Alterations in Mice with Fontup® Dietary Supplement: Role of Green Tea Catechins. International Journal of Molecular Sciences. 2020; 21(4):1404. https://doi.org/10.3390/ijms21041404
Chicago/Turabian StyleGu, Yuchen, Gautier Moroy, Jean-Louis Paul, Anne-Sophie Rebillat, Mara Dierssen, Rafael de la Torre, Cécile Cieuta-Walti, Julien Dairou, and Nathalie Janel. 2020. "Molecular Rescue of Dyrk1A Overexpression Alterations in Mice with Fontup® Dietary Supplement: Role of Green Tea Catechins" International Journal of Molecular Sciences 21, no. 4: 1404. https://doi.org/10.3390/ijms21041404