Nobiletin, as a Novel PDE4B Inhibitor, Alleviates Asthma Symptoms by Activating the cAMP-PKA-CREB Signaling Pathway
Abstract
:1. Introduction
2. Results
2.1. Nobiletin Decreased the Levels of Inflammation in Bronchoalveolar Lavage Fluid (BALF) and the Content of Specific IgE in Serum
2.2. Nobiletin Attenuated Enhanced Pause (Penh) in Asthmatic Mice
2.3. Effect of Nobiletin on Pathological Changes in Lung Tissue in Asthmatic Mice
2.4. Molecular Docking and Molecular Dynamics (MD) between Nobiletin and PDE4B
2.5. The Binding of the PDE4B Protein with Nobiletin
2.6. The Inhibitory Effect of Nobiletin on PDE4B
2.7. Effect of Nobiletin on the cAMP-PKA-CREB and NF-κB Signaling Pathways
2.8. Nobiletin Decreased the Level of Inflammation in RAW264.7 Cells
2.9. Effects of Nobiletin on the cAMP-PKA-CREB Signaling Pathway in RAW264.7 Cells
2.10. Nobiletin Decreased the Proliferation of ASM Cells Induced by TGF-β1
2.11. Effects of Nobiletin on the cAMP-PKA-CREB Signaling Pathway in ASM Cells Induced by TGF-β1
2.12. Nobiletin Played a Role in Increasing cAMP Levels by Depending on PDE4B
3. Discussion
4. Materials and Methods
4.1. Drugs and Reagents
4.2. Animals
4.3. Animal Experimental Protocol
4.4. BALF Collection and Leukocyte Counts
4.5. Determination of IL-5, IL-13, IL-6, and OVA-IgE Levels
4.6. Detection of Airway Hyperresponsiveness
4.7. Histopathologic Evaluation of the Lung Tissue
4.8. Ligand Profiling and Molecular Docking
4.9. MD Simulation
4.10. SPR
4.11. PDE4B Inhibition Assay
4.12. Immunohistochemical Staining
4.13. Cell Culture and Treatments
4.14. MTT Assay
4.15. Measurement of NO, TNF-α, and IL-6
4.16. Immunofluorescence Analysis
4.17. Cell Proliferation Assay
4.18. Cell Migration Assay
4.19. Measurement of cAMP Levels
4.20. siRNA Transfection
4.21. Western Blotting Analysis
4.22. Statistical Analysis
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
MTT | 3-(4:5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide |
FBS | fetal bovine serum |
BALF | bronchoalveolar lavage fluid |
OVA | ovalbumin |
LPS | lipopolysaccharide |
TGF-β1 | transforming growth factor β1 |
SPR | surface plasmonic resonance |
ASM | airway smooth muscle |
PDE4B | phosphodiesterase 4B |
MD | molecular dynamics. |
Penh | enhanced pause |
cAMP | 3′,5′-cyclic adenosine monophosphate |
PKA | protein kinase A |
CREB | cyclic-AMP response binding protein |
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Zhang, Y.; Yang, Y.; Liang, H.; Liang, Y.; Xiong, G.; Lu, F.; Yang, K.; Zou, Q.; Zhang, X.; Du, G.; et al. Nobiletin, as a Novel PDE4B Inhibitor, Alleviates Asthma Symptoms by Activating the cAMP-PKA-CREB Signaling Pathway. Int. J. Mol. Sci. 2024, 25, 10406. https://doi.org/10.3390/ijms251910406
Zhang Y, Yang Y, Liang H, Liang Y, Xiong G, Lu F, Yang K, Zou Q, Zhang X, Du G, et al. Nobiletin, as a Novel PDE4B Inhibitor, Alleviates Asthma Symptoms by Activating the cAMP-PKA-CREB Signaling Pathway. International Journal of Molecular Sciences. 2024; 25(19):10406. https://doi.org/10.3390/ijms251910406
Chicago/Turabian StyleZhang, Yan, Yaping Yang, Huicong Liang, Yuerun Liang, Guixin Xiong, Fang Lu, Kan Yang, Qi Zou, Xiaomin Zhang, Guanhua Du, and et al. 2024. "Nobiletin, as a Novel PDE4B Inhibitor, Alleviates Asthma Symptoms by Activating the cAMP-PKA-CREB Signaling Pathway" International Journal of Molecular Sciences 25, no. 19: 10406. https://doi.org/10.3390/ijms251910406