Potential Hepatoprotective Effects of Chamaecyparis lawsoniana against Methotrexate-Induced Liver Injury: Integrated Phytochemical Profiling, Target Network Analysis, and Experimental Validation
Abstract
:1. Introduction
2. Materials and Methods
2.1. Plant Material and Extraction
2.2. Analysis of CLAE Using UPLC-ESI-MS/MS Technique
2.3. Network Pharmacology
2.3.1. Selection of the Bioactive Compounds of CLAE and Associated Targets
2.3.2. Identification of DILI-Associated Targets
2.3.3. The Establishment of the Protein–Protein Interaction (PPI) and Compound–Target Networks
2.3.4. Analysis of Gene Ontology and KEGGs Pathway Enrichment
2.4. Molecular Docking
2.4.1. Protein and Ligand Preparation
2.4.2. Determination of the Grid Coordinates of the Active Sites
2.4.3. Docking Simulation and Visualization
2.5. In Vivo Experiments
2.5.1. Animals
2.5.2. Ethical Statement
2.5.3. Drugs and Vehicles
2.5.4. Experimental Protocol
Induction of MTX-Hepatotoxicity
Study Groups
2.5.5. Blood and Tissue Samples Preparation
2.5.6. Assessment of Serum Biomarkers
Liver Function Biomarkers
2.5.7. Assessment of Hepatic Biomarkers
Oxidative Stress Biomarkers
Proinflammatory Cytokines
Apoptotic Biomarkers
2.5.8. Immunohistochemical Staining
2.5.9. Histopathological Examination
2.5.10. Statistical Analysis
3. Results
3.1. UPLC-ESI-MS/MS Profiling
No. | Rt. | [M-H]− | MS2 Fragments (m/z) | Tentative Identification | Class | Ref. |
---|---|---|---|---|---|---|
1. | 1.068 | 133.014 | 115, 71 | Malic acid | Carboxylic acid | [58] |
2. | 1.119 | 173.045 | 155, 111, 137, 73, 93 | Shikimic acid | Carboxylic acid | [59] |
3. | 1.158 | 135.030 | 117, 99, 73, 75 | L-Threonic acid | Sugar acid | [59] |
4. | 1.163 | 329.091 | 167 | Vanillic acid glucoside | Phenolic acid glycoside | [60] |
5. | 1.183 | 191.056 | 173, 85 | Quinic acid | Carboxylic acid | [29] |
6. | 1.211 | 335.054 | 299, 191, 137 | Caffeoylshikimic acid | Phenolic acid derivatives | [61] |
7. | 1.237 | 377.086 | 341 | Disaccharid adduct | Disaccharid | [62] |
8. | 1.275 | 315.071 | 153 | Protocatechuic acid hexoside | Phenolic acid glycoside | [29] |
9. | 1.301 | 355.116 | 193, 149, 175, 134 | Ferulic acid-O-glucoside | Phenolic acid glycoside | [63] |
10. | 1.379 | 341.109 | 59, 71, 89, 101, 113, 143 | Sucrose | Disaccharid | [62] |
11. | 1.405 | 337.092 | 191, 163, 119 | Coumaroylquinic acid | Phenolic acid derivatives | [64] |
12. | 1.458 | 357.119 | 195 | Dihydro-ferulic acid hexoside | Phenolic acid glycoside | [65] |
13. | 4.162 | 507.164 | 345 | Syringetin-3-O-glucoside | Flavonol glycoside | [66] |
14. | 5.339 | 489.143 | 313, 283 | 5,7-Dihydroxy-8,2’-dimethoxyflavone 7-glucuronide | Flavone glucuronide | [67] |
15. | 5.537 | 385.186 | 223, 153 | Roseoside | Norisoprenoid glucoside | [64] |
16. | 5.564 | 385.186 | 223, 179 | Sinapoyl D-glucoside | Phenolic acid glycoside | [68] |
17. | 5.645 | 431.192 | 385, 223, 153 | Roseoside (formate adduct) | Norisoprenoid glucoside | [64] |
18. | 5.648 | 593.153 | 447, 431, 285 | kaempferol-3-O-glucoside-7-O-rhamnoside | Flavonol glycoside | [69] |
19. | 5.751 | 623.158 | 487, 477, 461, 443, 315, 297 | Verbascoside | Phenylethanoid glycosides | [70] |
20. | 5.775 | 525.197 | 329, 507 | Tricin-4′-O-(erythro-β-guaiacylglyceryl) ether (Salcolin A) | Flavone derv. | [71] |
21. | 5.777 | 623.160 | 477, 315 | Isorhamnetin-3-O-rutinoside | Flavonol glycoside | [72] |
22. | 5.777 | 623.160 | 461, 477 | Isorhamnetin 3-O-glucoside-7-O-rhamnoside | Flavonol glycoside | [73] |
23. | 6.110 | 373.149 | 327 | Pinopalustrin (Nortrachelogenin) | Dibenzylbutyrolactone lignan | [74] |
24. | 6.433 | 609.146 | 463, 447, 301 | Quercetin 3-rhamnoglucoside | Flavonol glycoside | [75] |
25. | 6.615 | 463.088 | 301, 300, 179, 271, 255, 151 | Quercetin-3-O-glucoside | Flavonol glycoside | [64] |
26. | 6.633 | 609.111 | 447, 285 | kaempferol dihexoside | Flavonol glycoside | [76] |
27. | 6.860 | 593.152 | 431, 385, 311, 269 | Apigenin diglucoside | Flavone glycoside | [77] |
28. | 6.882 | 363.144 | 315, 179, 167 | (7R,8R)-3-Methoxy-3’,4,7,9,9’-pentahydroxy-8,4’-oxyneolignan | Lignan | [78] |
29. | 7.264 | 447.092 | 301, 179, 151, 271 | Quercitrin (Quercetin -3-O-rhamnoside) | Flavonol glycoside | [64] |
30. | 7.316 | 477.103 | 315, 314, 285 | Isorhamnetin 3-O-Glucoside | Flavonol glycoside | [79] |
31. | 7.416 | 327.217 | 327, 229, 211, 171, 113 | 9,12,13-trihydroxyoctadeca-10,15-dienoic acid (Malyngic acid) | Fatty Acid | [80] |
32. | 7.518 | 287.056 | 259, 151 | Dihydrokaempferol (Aromadendrin) | Flavanonol | [72] |
33. | 7.538 | 699.135 | Agathisflavone -O-hexoside | Biflavonoid glycoside | [81] | |
34. | 7.586 | 577.156 | 269, 225, 201, 149 | Apigenin 7-O-neohesperidoside (rhoifolin) | Flavone glycoside | [82] |
35. | 7.861 | 329.138 | 314, 299 | 3,7-dimethylquercetin | Flavonol | [83] |
36. | 7.862 | 341.141 | 311, 283, 257 | 4’,5,6,7-Tetramethoxyflavone (Scutellarein tetramethyl ether) | Flavone | [84] |
37. | 7.887 | 435.149 | 273, 167 | Phlorizin (phloretin glucoside) | Dihydrochalcone glycoside | [29] |
38. | 7.976 | 461.107 | 461, 299, 284 | Dihydro-methoxyisoflavone O-hexoside (Tectoridin) | Flavone glycoside | [85] |
39. | 8.052 | 461.108 | 315, 314 | Isorhamnetin-O-rhamnoside | Flavonol glycoside | [86] |
40. | 8.220 | 519.187 | 459, 357, 315, 314, 299, 285 | Hexosyl-acyl-isorhamnetin | Flavonol glycoside | [87] |
41. | 8.283 | 417.082 | 285, 284, 255 | Kaempferol-3-O-arabinoside | Flavonol glycoside | [88] |
42. | 8.692 | 557.244 | 539, 509, 361 | Secoisolariciresinol guaiacylglyceryl ether | Butanediol lignan | [89] |
43. | 8.865 | 555.224 | 525, 507, 329, 195, 165 | Lariciresinol-4’-guaiacylglyceryl ether | Tetrahydrofuranolignan | [89] |
44. | 9.366 | 537.273 | 417, 375, 399 | Agathisflavone | Biflavonoid | [81] |
45. | 9.639 | 543.276 | 335 | Pharboside C | Diterpene acid glycoside | [90] |
46. | 9.948 | 271.062 | 151 | Naringenin | Flavanone | [72] |
47. | 10.454 | 137.024 | 93 | Protocatechualdehyde | Phenolic aldehyde | [91] |
48. | 10.955 | 521.087 | 329, 359 | Lariciresinol glucoside | Tetrahydrofuranolignan glycoside | [92] |
49. | 11.580 | 551.096 | 457, 431, 413, 389, 345 | 7-O-methylamentoflavone (Sequoiaflavone) | Biflavonoid | [93] |
50. | 11.629 | 551.097 | 457, 431, 413, 389, 390, 345 | 4′-O-methylamentoflavone (Bilobetin) | Biflavonoid | [94] |
51. | 14.081 | 333.258 | 315 | 8alpha-8-Hydroxy-12-oxo-13-abieten-18-oic acid | Diterpene acid | [95] |
52. | 14.433 | 302.911 | 259, 219 | Copalic acid | Diterpene acid | [74] |
53. | 16.038 | 565.115 | 533, 389, 374 | Isoginkgetin (4′,4″ dimethylamentoflavone) | Biflavonoid | [94] |
54. | 16.416 | 564.773 | 471, 445, 403 | Robustaflavone 7,4′-dimethyl ether | Biflavonoid | [94] |
55. | 16.715 | 357.099 | 342, 313 | Matairesinol | Dibenzylbutyrolactone lignans | [96] |
56. | 17.152 | 359.222 | 344, 313 | Cyclolariciresinol | Aryltetralin diol lignan | [89] |
57. | 18.682 | 329.175 | 285, 313, 311 | Carnosol | Phenolic diterpene | [74] |
58. | 21.153 | 317.212 | 299, 205 | 3-Hydroxysandaracopimaric acid | Diterpene acid | [97] |
59. | 21.191 | 317.212 | 299 | 12alpha-hydroxy-8,15-isopimaradien-18-oic acid | Diterpene acid | [98] |
60. | 21.202 | 301.218 | 253, 205 | ent-kaurenoic acid | Diterpene acid | [99] |
61. | 21.269 | 715.328 | 641, 375, 301 | Ganoleucoin J | lanostane triterpenoid | [100] |
3.1.1. Identification of Phenolic, Carboxylic, Sugar, Diterpene Acid and Fatty Acids
3.1.2. Identification of Flavonoid and Glycosides
3.1.3. Identification of Lignans and Their Glycosides
3.1.4. Identification of Miscellaneous Compounds
3.2. Network Pharmacology-Based Analysis
3.2.1. Identification of Bioactive Constituents of CLAE
3.2.2. Determination of the Overlapping Molecular Targets of CLAE Bioactive Compounds and DILI
3.2.3. PPI Network of the Common Targets
3.2.4. Top CLAE Compounds Associated with DILI Targets
3.2.5. Enrichment Analysis of the Common Targets
3.3. Molecular Docking Simulation
3.4. In Vivo Validation
3.4.1. CLAE Improved Liver Function
3.4.2. CLAE Alleviated Hepatic Oxidative Stress
3.4.3. CLAE Reduced Hepatic Inflammation
3.4.4. CLAE Attenuated Apoptosis (Immunostaining and Biochemical Findings)
3.4.5. CLAE Improved Liver Histology (Histopathological Findings)
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Rank | Target Name | Score |
---|---|---|
1 | TP53 | 59 |
2 | IL6 | 50 |
3 | TNF | 46 |
3 | HSP90AA1 | 46 |
5 | EGFR | 44 |
6 | IL1B | 43 |
7 | BCL2 | 42 |
8 | CASP3 | 37 |
8 | JUN | 37 |
10 | ALB | 36 |
11 | MMP9 | 35 |
12 | HIF1A | 34 |
13 | ESR1 | 30 |
14 | PTGS2 | 29 |
15 | STAT1 | 28 |
16 | MAPK3 | 26 |
17 | ERBB2 | 25 |
18 | MAPK1 | 24 |
19 | MAPK8 | 23 |
19 | JAK2 | 23 |
Rank | Compound | Score |
---|---|---|
1 | Sequoiaflavone | 105 |
2 | 3-Hydroxysandaracopimaric acid | 104 |
2 | 3,7-Dimethylquercetin | 104 |
4 | 12α-hydroxy-8,15-isopimaradien-18-oic acid | 103 |
5 | Robustaflavone 7,4′-dimethyl ether | 102 |
6 | Bilobetin | 100 |
6 | 4′,5,6,7-Tetramethoxyflavone (Scutellarein tetramethyl ether) | 100 |
8 | 8alpha-8-Hydroxy-12-oxo-13-abieten-18-oic acid | 99 |
8 | Carnosol | 99 |
10 | Isoginkgetin | 97 |
11 | Matairesinol | 94 |
12 | Caffeoylshikimic acid | 93 |
13 | secoisolariciresinol guaiacylglyceryl ether | 92 |
14 | ent-Kaurenoic acid | 90 |
15 | Ferulic acid O-glucoside | 89 |
15 | Roseoside | 89 |
17 | lariciresinol-4′-guaiacylglyceryl ether | 88 |
17 | cyclolariciresinol | 88 |
19 | Sinapoyl D-glucoside | 87 |
19 | Malyngic Acid | 87 |
21 | Copalic acid | 86 |
21 | Naringenin | 86 |
23 | Coumaroylquinic acid | 82 |
24 | Pinopalustrin (Nortrachelogenin) | 80 |
24 | Kaempferol-3-O-arabinoside | 80 |
26 | Aromadendrin | 77 |
27 | Quinic acid | 76 |
28 | Phlorizin | 74 |
29 | Vanillic acid glucoside | 68 |
30 | L-Threonic acid | 59 |
31 | Protocatechualdehyde | 42 |
Target Protein | Ligand | Docking Score (kcal/mol) | Interacting Amino Acid Residues | Bond Type |
---|---|---|---|---|
TP53 (8DC4) | Sequoiaflavone | −9.060 | Glu221 Ser229 Leu145 and Val147 Val147, Pro151, Pro222, and Pro223 Pro223 Cys220 | Amide-Pi Stacked Carbon–Hydrogen Conventional Hydrogen Pi-Alkyl Pi-Sigma Pi-Sulfur |
3-Hydroxysandaracopimaric acid | −6.291 | Pro151, Pro222, and Pro223 Val147 | Alkyl Conventional Hydrogen | |
3,7-Dimethylquercetin | −7.112 | Leu145 and Val147 Glu221 Cys220 and Thr230 Val147, Pro151, and Pro222 Pro222 and Pro223 Cys220 Gly154 and Thr155 | Alkyl Amide-Pi Stacked Conventional Hydrogen Pi-Alkyl Pi-Sigma Pi-Sulfur Unfavorable Donor–Donor | |
Co-crystallized ligand | −7.040 | Pro223 Glu221 Cys220 Val147, Pro151, Pro222, and Pro223 Thr230 Val147 Cys220 | Alkyl Amide-Pi Stacked Conventional Hydrogen Pi-Alkyl Pi-Donor–Hydrogen Pi-Sigma Pi-Sulfur | |
IL6 (4NI9) | Sequoiaflavone | −7.444 | Leu33 Lys41 and Arg40 Arg168 and Lys171 Ser37 | Alkyl Pi-Alkyl Pi-Cation Pi-Donor–Hydrogen |
3-Hydroxysandaracopimaric acid | −4.837 | Leu33, Arg40, and Lys171 | Alkyl | |
3,7-Dimethylquercetin | −6.277 | Leu33 Ser37 Arg40, Arg168, and Lys171 Lys171 Ser37 Arg168 | Alkyl Carbon–Hydrogen Pi-Alkyl Pi-Cation Pi-Donor–Hydrogen Unfavorable Donor–Donor | |
* TNF-α (2AZ5) | Sequoiaflavone | −9.429 | ProA117 LysB98 and IleB118 GlnA61 and TyrB119 LysA98 TyrA119 TyrB119 | Alkyl Carbon–Hydrogen Conventional Hydrogen Pi-Cation Pi-Pi Stacked Pi-Pi T-shaped |
3-Hydroxysandaracopimaric acid | −8.56 | SerB60 and TyrB151 TyrA119 and TyrB119 TyrA119 | Conventional Hydrogen Pi-Alkyl Pi-Sigma | |
3,7-Dimethylquercetin | −7.258 | LeuA57 and IleA155 GlyA121, TyrA151, and TyrB151 TyrA59 TyrA59 | Alkyl Conventional Hydrogen Pi-Alkyl Pi-Pi Stacked | |
Co-crystallized ligand | −9.076 | GlyA121 TyrB59, TyrB119, and TyrB151 TyrA119 | Halogen (Fluorine) Pi-Alkyl Pi-Sigma | |
HSP90AA1 (8AGI) | Sequoiaflavone | −10.27 | Asn51 Ser50 and Gly97 Ala55, Met98, and Val 168 Asp54 Asn51 Met98 Ser52 | Amide-Pi Stacked Conventional Hydrogen Pi-Alkyl Pi-Anion Pi-Donor–Hydrogen Pi-Sigma Van Der Waals |
3-Hydroxysandaracopimaric acid | −6.905 | Ala55, Lys58, and Met98 Gly132 Gly132 Gly135 | Alkyl Conventional Hydrogen Unfavorable Acceptor–Acceptor Carbon–Hydrogen | |
3,7-Dimethylquercetin | −7.945 | Lys58 and Ile96 Asn51 Asn51 Ala55 and Met98 Met98 | Alky Carbon–Hydrogen Conventional Hydrogen Pi-Alkyl Pi-Sulfur | |
Co-crystallized ligand | −9.931 | Ile96, Met98, and Leu107 Asp93, Gly97, Asn106, and Thr184 Phe138 Ala55 Met98 | Alkyl Conventional Hydrogen Pi-Alkyl Pi-Sigma Pi-Sulfur | |
EGFR (7T4I) | Sequoiaflavone | −10.14 | Lys745 Leu718, Thr790, Met793, and Thr854 Val726 and Ala743 Leu718, Val726, and Leu844 Cys797 Phe723 | Carbon–Hydrogen Conventional Hydrogen Pi-Alkyl Pi-Sigma Pi-Sulfur Pi-Pi T-shaped |
3-Hydroxysandaracopimaric acid | −8.331 | Leu718, Val726, Ala743, and Leu844 Thr790 and Thr854 | Alkyl Conventional Hydrogen | |
3,7-Dimethylquercetin | −7.868 | Leu718 Thr790, Met793, and Thr854 Val726, Ala743, and Leu844 Leu718 | Carbon–Hydrogen Conventional Hydrogen Pi-Alkyl Pi-Sigma | |
Co-crystallized ligand | −9.079 | Leu718, Val726, Ala743, Lys745, and Leu792 Asp800 and Glu804 Leu718, Gln791, and Asp800 Thr790, Met793, Phe795, Cys797, and Thr854 Val726 and Ala743 Leu718, Val726, and Leu844 | Alkyl Attractive Charge Carbon–Hydrogen Conventional Hydrogen Pi-Alkyl Pi-Sigma | |
IL1B (1T4Q) | Sequoiaflavone | −8.833 | Ala1 Val3 Val3, Asn7, Lys65, Lys88, and Ser153 Lys63 and Pro91 Ser43 Asn7 | Alkyl Carbon–Hydrogen Conventional Hydrogen Pi-Alkyl Pi-Donor–Hydrogen Unfavorable Donor–Donor |
3-Hydroxysandaracopimaric acid | −6.477 | Ser5 Ser43 Tyr68 | Carbon–Hydrogen Conventional Hydrogen Pi-Alkyl | |
3,7-Dimethylquercetin | −6.588 | Pro87 Ser43, Glu64, Leu62, and Lys65 Pro91 Val3 Ser5 | Alkyl Conventional Hydrogen Pi-Alkyl Unfavorable Acceptor–Acceptor Unfavorable Donor–Donor | |
BCL2 (7LHB) | Sequoiaflavone | −10.13 | Glu152 Glu136 Arg146 and Ala149 Tyr108 Leu137 Met115 Phe153 | Amide Pi-Stacked Conventional Hydrogen Pi-Alkyl Pi-Pi T-shaped Pi-Sigma Pi-Sulfur Van Der Waals |
3-Hydroxysandaracopimaric acid | −7.917 | Met115, Leu137, Ala149, and Val156 Glu136 Phe104, Phe112, and Phe153 Glu136 | Alkyl Conventional Hydrogen Pi-Alkyl Unfavorable Acceptor–Acceptor | |
3,7-Dimethylquercetin | −7.394 | Leu137 and Ala149 Ala100, Phe104, and Arg146 Arg146, Val148, and Ala149 Phe104 | Alkyl Conventional Hydrogen Pi-Alkyl Pi-Pi T-shaped | |
Co-crystallized ligand | −12.78 | Ala100, Val133, Leu137, and Val156 Gly145 Arg107 and Asp111 Ala100, Asp103, and Asp111 Asp103 and Asn143 Glu152 Ala100, Phe112, Met115, Arg146, Val148, and Ala149 Tyr202 Tyr202 | Alkyl Amide Pi-Stacked Attractive Charge Carbon–Hydrogen Conventional Hydrogen Halogen (Cl, Br, I) Pi-Alkyl Pi-Donor–Hydrogen Pi-Pi Stacked | |
CASP3 (3KJF) | Sequoiaflavone | −8.477 | Trp214 Trp214 Asp253 Arg207 Asn208 and Phe250 Phe256 | Conventional Hydrogen Pi-Alkyl Pi-Anion Pi-Cation Pi-Donor–Hydrogen Pi-Pi Stacked |
3-Hydroxysandaracopimaric acid | −6.334 | Phe250 Asn208 and Phe250 Phe250 | Carbon–Hydrogen Conventional Hydrogen Pi-Alkyl | |
3,7-Dimethylquercetin | −6.261 | Arg207 and Ser251 Phe256 Trp206 Trp214 | Conventional Hydrogen Pi-Alkyl Pi-Pi T-shaped Unfavorable Donor–Donor | |
Co-crystallized ligand | −8.20 | Arg207 Arg207, Asn208, Ser209, Trp214, and Phe250 Arg207, Asn208, and Ser251 Phe250 and Phe252 Phe256 | Attractive Charge Conventional Hydrogen Carbon–Hydrogen Pi-Alkyl Pi-Pi Stacked/3.72 |
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Fikry, E.; Orfali, R.; El-Sayed, S.S.; Perveen, S.; Ghafar, S.; El-Shafae, A.M.; El-Domiaty, M.M.; Tawfeek, N. Potential Hepatoprotective Effects of Chamaecyparis lawsoniana against Methotrexate-Induced Liver Injury: Integrated Phytochemical Profiling, Target Network Analysis, and Experimental Validation. Antioxidants 2023, 12, 2118. https://doi.org/10.3390/antiox12122118
Fikry E, Orfali R, El-Sayed SS, Perveen S, Ghafar S, El-Shafae AM, El-Domiaty MM, Tawfeek N. Potential Hepatoprotective Effects of Chamaecyparis lawsoniana against Methotrexate-Induced Liver Injury: Integrated Phytochemical Profiling, Target Network Analysis, and Experimental Validation. Antioxidants. 2023; 12(12):2118. https://doi.org/10.3390/antiox12122118
Chicago/Turabian StyleFikry, Eman, Raha Orfali, Shaimaa S. El-Sayed, Shagufta Perveen, Safina Ghafar, Azza M. El-Shafae, Maher M. El-Domiaty, and Nora Tawfeek. 2023. "Potential Hepatoprotective Effects of Chamaecyparis lawsoniana against Methotrexate-Induced Liver Injury: Integrated Phytochemical Profiling, Target Network Analysis, and Experimental Validation" Antioxidants 12, no. 12: 2118. https://doi.org/10.3390/antiox12122118
APA StyleFikry, E., Orfali, R., El-Sayed, S. S., Perveen, S., Ghafar, S., El-Shafae, A. M., El-Domiaty, M. M., & Tawfeek, N. (2023). Potential Hepatoprotective Effects of Chamaecyparis lawsoniana against Methotrexate-Induced Liver Injury: Integrated Phytochemical Profiling, Target Network Analysis, and Experimental Validation. Antioxidants, 12(12), 2118. https://doi.org/10.3390/antiox12122118