The Synergistic Influence of Polyflavonoids from Citrus aurantifolia on Diabetes Treatment and Their Modulation of the PI3K/AKT/FOXO1 Signaling Pathways: Molecular Docking Analyses and In Vivo Investigations
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemicals and Assay Kits
2.2. Preparation of Lemon Peel Extract (LPE)
2.3. High-Performance Liquid Chromatography (HPLC) Analysis
2.4. Molecular Docking Examination of Flavonoids in LPE
2.5. Physicochemical and Pharmacokinetic Protocol
2.6. In Vivo Investigations
Experimental Design and Induction of Diabetes
2.7. Blood Collection and Tissue Preparation
2.8. Biochemical Analysis
2.8.1. Lipid Profile Assay
2.8.2. Assessment of Oxidative Stress Biomarkers
2.8.3. Evaluation of Inflammatory Biomarkers
2.8.4. Glucose Transporter 2 (GLUT2) and GLUT4 and p-AKT
2.8.5. Quantitative Real-Time PCR (qRT-PCR) Analyses
2.9. Histopathological Examination
2.10. Statistical Analysis
3. Results
3.1. HPLC Study on Flavonoid Profiles
3.2. Potential Interaction of the PI3K Protein with LPE-Polyflavonoids
3.3. Pharmacokinetic Parameters and Drug-Likeness Prediction
3.4. Impact of LPE-Polyflavonoids on Serum Glucose, Insulin, Glycogen, and Liver Enzymes
3.5. Influence of LPE-Polyflavonoids on Hepatic Carbohydrate-Metabolizing Enzyme Activities
3.6. Effect of LPE-Polyflavonoids on Total Protein and Albumin Levels
3.7. Influence of LPE-Polyflavonoids on Serum Lipid Profile and AGEs
3.8. Effect of LPE-Polyflavonoids on Oxidative Stress Biomarkers in Pancreatic and Liver Tissues
3.9. Impact of LPE-Polyflavonoids on Liver and Pancreas Inflammatory Markers, NF-κB, and AFP
3.10. Effect of LPE-Polyflavonoids on GLUT4 and GLUT2 in Pancreas and Liver Tissues
3.11. Effect of LPE-Polyflavonoids on p-AKT in the Pancreas and Gene Expressions of PI3K, AMPK, and FOXO1 in Pancreatic and Hepatic Tissues
3.12. Histopathological Analysis of Pancreatic and Liver Tissues
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
References
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Gene | Forward Primer | Reverse Primer |
---|---|---|
PI3K | 5′-CCTGGTAACTGCAACACTTC-3′ | 5′-AACGAATTCAAACCTACCCG-3′ |
FOXO1 | 5′-TCATCCAATTGGTCTTGTGG-3′ | 5′-GTGTTTGCCTGTCTACCTTT-3′ |
AMPK | 5′-TGTGAAGATCGGACACTACG-3′ | 5′-TAACTGCCACTTTATGGCCT-3′ |
β-Actin | 5′-ATGTGGCTGAGGACTTTGATT-3′ | 5′-ATCTATGCCGTGGATACTTGG-3′ |
Flavonoid Compounds | R.T./min | Con. (mg/kg) |
---|---|---|
Diosmin | 22.878 | 62.75 |
Biochanin A | 17.477 | 62.35 |
Hesperidin | 6.254 | 59.18 |
Quercetin | 14.297 | 28.32 |
Hesperetin | 16.147 | 9.31 |
Lig I | Lig II | Lig III | Lig IV | Lig V | MYS Control | |
---|---|---|---|---|---|---|
Physicochemical properties | ||||||
Molecular weight (Da) | 608.54 | 284.26 | 610.56 | 302.24 | 302.28 | 318.24 |
Log Po/w (MLOGP) | −3.23 | 0.77 | −3.04 | −0.56 | 0.41 | |
Number of H-bond acceptors | 15 | 5 | 15 | 7 | 6 | 8 |
Number of H-bond donors | 8 | 2 | 8 | 5 | 3 | 6 |
Molar refractivity | 143.82 | 78.46 | 141.41 | 78.04 | 78.06 | 80.06 |
Number of rotatable bonds | 7 | 2 | 7 | 1 | 2 | 1 |
TPSA (Å2) | 238.2 | 79.9 | 234.29 | 131.36 | 151.59 | |
Pharmacokinetics | ||||||
Gastrointestinal (GI) absorption | Low | High | Low | High | High | Low |
Blood–brain barrier (BBB) permeant | No | No | No | No | No | No |
P-glycoprotein substrate | Yes | No | Yes | No | Yes | No |
Log Kp (skin permeation) | −9.91 | −5.91 | −10.12 | −7.05 | −6.3 | −7.4 |
Drug likeness | ||||||
Log S (ESOL) | −3.51 | −3.92 | −4.33 | −3.16 | −3.62 | −3.01 |
Water solubility class | Moderately soluble | Moderately soluble | Moderately soluble | Soluble | Soluble | Soluble |
Lipinski rule | No | Yes | No | Yes | Yes | Yes |
Ghose | No | Yes | No | Yes | Yes | Yes |
Veber | No | Yes | No | Yes | Yes | No |
Egan | No | Yes | No | Yes | Yes | No |
PAINs | 0 alerts | 0 alerts | 0 alerts | 1 alert: catechol_A | 0 alerts | 1 alert: catechol_A |
Bioavailability score | 0.17 | 0.55 | 0.17 | 0.55 | 0.55 | 0.55 |
Metabolism | ||||||
CYP1A2 inhibitor | No | Yes | No | Yes | Yes | Yes |
CYP2C19 inhibitor | No | No | No | No | No | No |
CYP2C9 inhibitor | No | No | No | No | No | No |
CYP2D6 inhibitor | No | Yes | No | Yes | No | No |
CYP3A4 inhibitor | No | Yes | No | Yes | Yes | Yes |
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Hassan, M.A.; Elmageed, G.M.A.; El-Qazaz, I.G.; El-Sayed, D.S.; El-Samad, L.M.; Abdou, H.M. The Synergistic Influence of Polyflavonoids from Citrus aurantifolia on Diabetes Treatment and Their Modulation of the PI3K/AKT/FOXO1 Signaling Pathways: Molecular Docking Analyses and In Vivo Investigations. Pharmaceutics 2023, 15, 2306. https://doi.org/10.3390/pharmaceutics15092306
Hassan MA, Elmageed GMA, El-Qazaz IG, El-Sayed DS, El-Samad LM, Abdou HM. The Synergistic Influence of Polyflavonoids from Citrus aurantifolia on Diabetes Treatment and Their Modulation of the PI3K/AKT/FOXO1 Signaling Pathways: Molecular Docking Analyses and In Vivo Investigations. Pharmaceutics. 2023; 15(9):2306. https://doi.org/10.3390/pharmaceutics15092306
Chicago/Turabian StyleHassan, Mohamed A., Ghada M. Abd Elmageed, Ibtehal G. El-Qazaz, Doaa S. El-Sayed, Lamia M. El-Samad, and Heba M. Abdou. 2023. "The Synergistic Influence of Polyflavonoids from Citrus aurantifolia on Diabetes Treatment and Their Modulation of the PI3K/AKT/FOXO1 Signaling Pathways: Molecular Docking Analyses and In Vivo Investigations" Pharmaceutics 15, no. 9: 2306. https://doi.org/10.3390/pharmaceutics15092306
APA StyleHassan, M. A., Elmageed, G. M. A., El-Qazaz, I. G., El-Sayed, D. S., El-Samad, L. M., & Abdou, H. M. (2023). The Synergistic Influence of Polyflavonoids from Citrus aurantifolia on Diabetes Treatment and Their Modulation of the PI3K/AKT/FOXO1 Signaling Pathways: Molecular Docking Analyses and In Vivo Investigations. Pharmaceutics, 15(9), 2306. https://doi.org/10.3390/pharmaceutics15092306