Thymol Protects against 5-Fluorouracil-Induced Hepatotoxicity via the Regulation of the Akt/GSK-3β Pathway in In Vivo and In Silico Experimental Models
Abstract
:1. Introduction
2. Results
2.1. Protective Effect of Thymol against 5-FU-Induced Histopathological Changes in Liver Tissues
2.2. Effects of Thymol and 5-FU on Liver Enzymes and Oxidative Stress Markers in Liver Tissues
2.3. Effect of Thymol and 5-Fluorouracil on Apoptotic Marker Expression in Liver Tissues
2.4. Effect of Thymol and 5-Fluorouracil on Akt1/ GSK-3α/β Signaling Pathway Protein Expression in Liver Tissues
2.5. Docking Studies of Thymol
3. Discussion
4. Materials and Methods
4.1. Materials
4.1.1. Drugs and Chemicals
4.1.2. Animals
4.2. Methods
4.2.1. Experiment Design
4.2.2. Blood and Liver Sample Collection
4.2.3. Histopathological Examination
4.2.4. Assessment of Serum Liver Enzymes and Oxidative Stress Markers in Liver Tissues
4.2.5. Assessment of Apoptotic Markers in Liver Tissues
4.2.6. Western Blot Analysis
4.2.7. Assessing the Binding Affinities Using In Silico Modeling
4.3. Statistics
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Groups | Liver Enzymes | Oxidative Stress Markers | |||||
---|---|---|---|---|---|---|---|
AST (U/L) | ALT (U/L) | ALP (U/L) | LDH (U/L) | Glutathione (µg/mg Protein) | TBARSs (nmol/mg Protein) | SOD (U/mg Protein) | |
Control | 92.49 ± 2.02 | 47.58 ± 3.91 | 15.89 ± 1.32 | 166.80 ± 1.92 | 1.70 ± 0.03 | 0.37 ± 0.02 | 3.93 ± 0.12 |
5-FU | 131.20 ± 4.39 x | 89.21 ± 1.16 x | 37.80 ± 1.66 x | 330.60 ± 11.58 x | 0.63 ± 0.04 x | 2.60 ± 0.07 x | 0.95 ± 0.049 x |
5-FU + Thymol (60 mg/kg) | 112.00 ± 6.88 x,y | 48.25 ± 2.73 y | 15.03 ± 0.85 y | 288.00 ± 11.58 x,y | 1.11 ± 0.04 x,y | 1.68 ± 0.03 x,y | 2.35 ± 0.08 x,y |
5-FU + Thymol (120 mg/kg) | 84.58 ± 2.29 y,z | 31.60 ± 4.30 x,y,z | 11.35 ± 0.59 y | 182.00 ± 2.55 y,z | 1.55 ± 0.07 y,z | 0.67 ± 0.05 x,y,z | 3.52 ± 0.08 x,y,z |
Protein | pdb ID | Binding Energy Kcal/mol | RMSD (Å) | Amino Acid Residues of Interaction | Types of Bonds |
---|---|---|---|---|---|
Caspase-3 | 3kjf | −4.16 | 1.48 | PHE 250 ASN 208 PHE 250 | H-donor pi-H pi-H |
Gsk-3β | 1Q5K | −5.28 | 1.08 | VAL 135 | H-donor |
Bax | 4S0P | −4.6 | 1.49 | - | - |
Description | |
---|---|
Control | Normal rats received the vehicle (0.5% DMSO in normal saline) once daily by oral gavage. |
5-FU | Rats serving as the positive control group were given the vehicle orally (0.5% DMSO in normal saline) once daily and two doses of 5-FU (150 mg/kg, intraperitoneally (ip)) on days 6 and 7 to induce hepatic toxicity [15,77]. |
5-FU + Thymol 60 | Rats were given thymol daily (60 mg/kg in 0.5% DMSO in normal saline, orally) and 5-FU (150 mg/kg, ip) on days 6 and 7 [15,78]. |
5-FU + Thymol 120 | Rats were given thymol daily (120 mg/kg in 0.5% DMSO in normal saline, orally) and 5-FU (150 mg/kg, ip) on days 6 and 7 [15,24] |
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© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
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Mahran, Y.F.; Badr, A.M.; Al-Kharashi, L.A.; Alajami, H.N.; Aldamry, N.T.; Bayoumy, N.M.; Elmongy, E.I.; Soliman, S. Thymol Protects against 5-Fluorouracil-Induced Hepatotoxicity via the Regulation of the Akt/GSK-3β Pathway in In Vivo and In Silico Experimental Models. Pharmaceuticals 2024, 17, 1094. https://doi.org/10.3390/ph17081094
Mahran YF, Badr AM, Al-Kharashi LA, Alajami HN, Aldamry NT, Bayoumy NM, Elmongy EI, Soliman S. Thymol Protects against 5-Fluorouracil-Induced Hepatotoxicity via the Regulation of the Akt/GSK-3β Pathway in In Vivo and In Silico Experimental Models. Pharmaceuticals. 2024; 17(8):1094. https://doi.org/10.3390/ph17081094
Chicago/Turabian StyleMahran, Yasmen F., Amira M. Badr, Layla A. Al-Kharashi, Hanaa N. Alajami, Nouf T. Aldamry, Nervana Moustafa Bayoumy, Elshaymaa I. Elmongy, and Sahar Soliman. 2024. "Thymol Protects against 5-Fluorouracil-Induced Hepatotoxicity via the Regulation of the Akt/GSK-3β Pathway in In Vivo and In Silico Experimental Models" Pharmaceuticals 17, no. 8: 1094. https://doi.org/10.3390/ph17081094