Synergistic Differential DNA Demethylation Activity of Danshensu (Salvia miltiorrhiza) Associated with Different Probiotics in Nonalcoholic Fatty Liver Disease
Abstract
:1. Introduction
2. Materials and Methods
2.1. In Vitro Study of Danshensu Extracts
2.2. Total Polyphenol Content (TPC)
2.3. Determination of Total Flavonoids (TFs)
2.4. Measurement of Antioxidant Properties
2.5. Total Reduction Capability
2.6. ABTS Radical Cation Decolorization Assay
2.7. Hydrogen Peroxide (H2O2) Radical Scavenging Activity
2.8. Nitric Oxide (NO) Radical Scavenging Assay
2.9. In Vitro Lipid Peroxidation (LPO) Assay
2.9.1. Preparation of Rat Liver Homogenate
2.9.2. TBARS Assay
2.10. In Vivo Study
2.10.1. Animals and Experimental Design
2.10.2. Acute Toxicity Study
2.10.3. Induction of Hyperlipidemia
2.10.4. Collection of the Body Organs (Heart, Liver, and Serum)
2.10.5. Preparation of Tissue Homogenate
2.11. Biochemical Analysis
2.11.1. Blood Lipid Profile Analysis
2.11.2. Determination of HMG-CoA Reductase Activity
2.11.3. Determination of Hepatic and Fecal Lipids
2.11.4. Measurement of Fecal Bile Acids
2.11.5. Evaluation of Tissue Markers of Oxidative Stress
2.12. Quantitative RT-PCR
2.13. In Silico Study
2.13.1. Ligand Preparation
2.13.2. Receptor Preparation
2.13.3. Molecular Docking
2.13.4. ADMET and Drug-Likeness Properties
2.14. Statistical Analysis
3. Results
3.1. Phytochemical Analysis
3.2. In Vitro Antioxidant Activities of Danshensu
3.2.1. DPPH Radical Scavenging Activity
3.2.2. Total Reduction Capability
3.2.3. ABTS Radical Cation Decolorization Assay
3.2.4. Hydrogen Peroxide (H2O2) Radical Scavenging Activity
3.2.5. Nitric Oxide (NO) Radical Scavenging Activity
3.2.6. Inhibition of Lipid Peroxidation (LPO)
3.3. In Vivo Study
3.3.1. Acute Toxicity of Danshensu on Animals
3.3.2. Danshensu Combined with PROBIOTICS—Effect on Body Weight
3.3.3. Biochemical Parameters
3.3.4. Oxidative Stress Markers
3.3.5. Serum
3.3.6. Heart
3.3.7. Liver
3.3.8. Determination of HMG-CoA Reductase Activity
3.3.9. Determination of Hepatic and Fecal Lipids and Fecal Bile Acids
3.3.10. Histopathological Changes
Liver
Kidney
Pancreatic
Coronary Blood Vessels
3.4. Quantitative RT-PCR
3.5. In Silico Study
3.5.1. Molecular Docking
3.5.2. ADMET and Drug-Likeness Properties
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Primer | Sequence (5′-3′) |
---|---|
DNMT-1 | F: AGGAATGTGTGAAGGAGAAATTG |
R: CTTGAACGCTTAGCCTCTCCATC | |
MS | F: AGAAGAGGATTATGGTGCTGGATG |
R: TCTTAATTCCTGTCTGGAGAGTT | |
STAT-3 | F: ACCCAACAGCCGCCGTAG |
R: CAGACTGGTTGTTTCCATTCAGAT | |
TET1 | F: ACTCCCTGAGGTCTGTCCTGGGA |
R: GGATCGAGACATAGCTACAGAGT | |
GAPDH | F: CAGGTTGTCTCCTGCGACTT |
R: TATGGG GGTCTGGGATGGAA |
Parameter | Danshensu Extracts |
---|---|
Total Polyphenol Content (TPC) | 111.9 ± 216 mg GAE g−1 |
Total flavonoids (TF) | 33.79 ± 1.89 mg QE g−1 |
Group | Initial Body Weight-1st Day (g) | Final Body Weight-28th Day (g) |
---|---|---|
NC | 170.5 ± 2.31 | 182 ± 2.8 |
HCF | 185.2 ± 2.75 | 225 ± 3.22 * |
HCF + FF | 176.2 ± 3.93 | 181 ± 2.89 |
HCF + DSS | 175.3 ± 3.43 | 202 ± 3.11 * |
HCF + DSS + L. acidophillius | 177.22 ± 2.31 | 190 ± 3.61 |
HCF + DSS + L. casei | 174.22 ± 3.91 | 187 ± 2.3 |
Parameters (mg/dL) | NC | HCF | HCF + FF | HCF + DSS | HCF + DSS + L. acidophillius | HCF + DSS + L. casei |
---|---|---|---|---|---|---|
TC | 73.04 ± 2.21 | 153.44 ± 3.21 | 126.12 ± 5.1 * | 112 ± 3.7 * | 94 ± 2.9 | 91 ± 1.67 |
TG | 61.43 ± 2.31 | 121.21 ± 2.1 | 103.31 ± 3.97 * | 94.18 ± 2.3 | 81.47 ± 2.1 | 77.31 ± 3.6 |
HDL | 62.59 ± 3.62 | 33.54 ± 4.85 | 41.18 ± 2.1 | 50.45 ± 3.6 | 56.12 ± 3.4 | 61.11 ± 1.9 |
LDL | 51 ± 2.33 ** | 141.32 ± 3.66 | 89.37 ± 5.9 | 63.17 ± 2.8 | 56.41 ± 1.6 | 52.17 ± 3.6 |
VLDL | 15.86 ± 2.73 | 23.37 ± 3.97 | 20.47 ± 4.1 | 18.3 ± 1.09 | 16.8 ± 1.03 * | 15.9 ± 0.97 * |
Parameters | NC | HCF | HCF + FF | HCF + DSS | HCF + DSS + L. acidophillius | HCF + DSS + L. casei | |
---|---|---|---|---|---|---|---|
Serum | SOD a | 39.1 ± 1.14 | 17.2 ± 2 ++ | 25 ± 3.6 | 29.6 ± 4.5 | 34.1 ± 3.4 | 38.6 ± 2.6 ++ |
GSH b | 137 ± 4.5 | 203 ± 5.7 | 113 ± 3.1 | 121 ± 1.6 | 129 ± 4.3 | 135 ± 6.5 | |
TBARS c | 26.2 ± 1.1 | 41.8 ± 4.1 | 36.3 ± 3.81 | 31.23 ± 2.2 | 29.1 ± 1.8 | 27.3 ± 2.1 | |
NO d | 28.12 ± 1.32 | 51.4 ± 1.36 | 22.91 ± 1.51 | 36.23 ± 2.6 | 30.19 ± 1.23 | 25.31 ± 3.1 | |
Liver | SOD a | 88 ± 1.3 | 51 ± 1.2 + | 69 ± 1.4 | 73 ± 1.2 | 79 ± 1.1 | 84 ± 1.3 ** |
GSH b | 339 ± 8.6 | 265 ± 6.1 | 302 ± 5.7 | 309 ± 4.4 | 329 ± 5.7 | 343 ± 6.4 | |
TBARS c | 96.4 ± 5.2 | 161 ± 7.6 ++ | 142 ± 8.39 | 116 ± 5.6 | 104 ± 6.5 | 89.2 ± 7.4 ** | |
NO d | 21.3 ± 2.3 | 43.2 ± 2.1 | 27.1 ± 3.4 | 21.2 ± 2.1 | 16.1 ± 2.3 | 14.3 ± 0.6 | |
Heart | SOD a | 69.4 ± 3.6 | 35.1 ± 1.4 + | 61.1 ± 2.5 | 62.2 ± 1.5 | 68.13 ± 0.98 | 69.1 ± 1.31 * |
GSH b | 123 ± 4.3 | 81 ± 3.4 ++ | 95 ± 4.3 | 101 ± 2.3 * | 112 ± 5.8 ** | 117 ± 6.4 *** | |
TBARS c | 36.2 ± 1.4 | 53.4 ± 4.3 | 41.1 ± 2.1 | 34.1 ± 3.2 | 30 ± 2.3 | 29 ± 2.1 | |
NO d | 15.1 ± 1.3 | 25.2 ± 1.4 | 21.16 ± 2.2 | 17.14 ± 1.6 | 15.10 ± 1.5 | 12.12 ± 1.1 |
Compound | Protein | ∆G (kcal/mol) | 2D | Interactions |
---|---|---|---|---|
Danshensu | DNAT-1 | 5.9 | Hydrogen bond (GLU 1329, ALA 1587 and, EDO1721), Pi-sigma LEU1591), Pi-Alkyl (LEU 1594 and, PRO1080), unfavorable acceptor -acceptor bond (GLU 1591) | |
Danshensu | MS | −5.7 | Hydrogen bond (ARG 1172, TYR1227 and, SER1179), Pi-sigma (LEU1591), Pi-Alkyl(PRO1178), and Pi-Pi Stacked (TYR 1177) | |
Danshensu | STAT-3 | −5.3 | Hydrogen bond (GLN 247, GLN326 GLU 324 and, CYS 251), Pi-sigma (LEU1591), Pi-Alkyl(ALA 250), and Pi-Pi Sigma (ILE 258) Unfavorable Donor -Donor bond (GLN 326) | |
Danshensu | TET-1 | −4.0 | Van der Waals bond (CYS 14, LEU 12, TYR 12), Hydrogen bond (HIS 9, LEU 10)), Pi-sigma (LEU10), Pi-Alkyl (LEU 13) and, Unfavorable acceptor -acceptor bond (HIS 9) | |
Danshensu | HMG | −5.0 | Hydrogen bond (MET 336, VAL483 GLY 446) and, Carbon Hydrogen Bond (CLY 484) |
Compound | Absorption Intestinal Human Absorption | Distribution | Metabolism | AMES Toxicity | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Log p | Log S | CYP2D6 Substrate | CYP3A4 Substrate | CYP1A2 Inhibitior | CYP2C19 Inhibitior | CYP2C9 Inhibitior | CYP2D6 Inhibitior | CYP3A4 Inhibitior | Total Clearance | |||
Danshensu | 41.771 | 0.0858 | −1.40 | No | No | No | No | No | No | No | 0.444 | No |
Compound | Molecular Weight | HBA | HBD | mlogP | Synthetic Accessibility | Bioavailability | Lipinski Violation | Drug Likeness |
---|---|---|---|---|---|---|---|---|
Danshensu | 470.518 g/mol | 5 | 4 | −0.04 | 1.91 | 0.56 | 0 | Yes |
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Hassan, A.; Rijo, P.; Abuamara, T.M.M.; Ali Lashin, L.S.; Kamar, S.A.; Bangay, G.; Al-Sawahli, M.M.; Fouad, M.K.; Zoair, M.A.; Abdalrhman, T.I.; et al. Synergistic Differential DNA Demethylation Activity of Danshensu (Salvia miltiorrhiza) Associated with Different Probiotics in Nonalcoholic Fatty Liver Disease. Biomedicines 2024, 12, 279. https://doi.org/10.3390/biomedicines12020279
Hassan A, Rijo P, Abuamara TMM, Ali Lashin LS, Kamar SA, Bangay G, Al-Sawahli MM, Fouad MK, Zoair MA, Abdalrhman TI, et al. Synergistic Differential DNA Demethylation Activity of Danshensu (Salvia miltiorrhiza) Associated with Different Probiotics in Nonalcoholic Fatty Liver Disease. Biomedicines. 2024; 12(2):279. https://doi.org/10.3390/biomedicines12020279
Chicago/Turabian StyleHassan, Amr, Patrícia Rijo, Tamer M. M. Abuamara, Lashin Saad Ali Lashin, Sherif A. Kamar, Gabrielle Bangay, Majid Mohammed Al-Sawahli, Marina K. Fouad, Mohammad A. Zoair, Tamer I. Abdalrhman, and et al. 2024. "Synergistic Differential DNA Demethylation Activity of Danshensu (Salvia miltiorrhiza) Associated with Different Probiotics in Nonalcoholic Fatty Liver Disease" Biomedicines 12, no. 2: 279. https://doi.org/10.3390/biomedicines12020279
APA StyleHassan, A., Rijo, P., Abuamara, T. M. M., Ali Lashin, L. S., Kamar, S. A., Bangay, G., Al-Sawahli, M. M., Fouad, M. K., Zoair, M. A., Abdalrhman, T. I., Elebeedy, D., Ibrahim, I. A., Mohamed, A. F., & Abd El Maksoud, A. I. (2024). Synergistic Differential DNA Demethylation Activity of Danshensu (Salvia miltiorrhiza) Associated with Different Probiotics in Nonalcoholic Fatty Liver Disease. Biomedicines, 12(2), 279. https://doi.org/10.3390/biomedicines12020279