Temperate Propolis Has Anti-Inflammatory Effects and Is a Potent Inhibitor of Nitric Oxide Formation in Macrophages
Abstract
:1. Introduction
2. Results
2.1. The Effect of Propolis on NO Production and Cytokine Production by Macrophages
2.2. Propolis Does Not Affect Cell Viability
2.3. The Effect of Propolis on the Metabolomic Profile of Macrophages
2.3.1. Propolis Treatment Inhibits NO Formation
2.3.2. Propolis Treatment May Promote Energy Metabolism and Stimulate the Formation of High Energy Phosphates
2.3.3. Propolis Treatment Stimulates Formation of Amino Sugars
2.3.4. Propolis Treatment Lowers Citrate and Increases Itaconate
2.4. Propolis Treatment Increases GSH Levels
2.5. Propolis Treatment Increases Fatty Acid Metabolism
3. Discussion
4. Materials and Methods
4.1. Chemicals and Reagents
4.2. Preparation of Propolis Extracts
4.3. Generation of Bone Marrow-Derived Macrophages (BMMs)
4.4. Flow Cytometry
4.5. Effect of Propolis Treatment on LPS-Activated Macrophages
4.6. Measurement of Cell Viability
4.7. Measurement of NO Production in BMMs
4.8. Cytokine Assays
4.9. Liquid Chromatography/Mass Spectroscopy (LC/MS)
4.10. Metabolomic Data Analysis
4.11. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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Anova Tukey’s HSD | m/z | Rt min | Metabolite | P LM | L/M | P224L | 224/L | P225L | 225/L |
---|---|---|---|---|---|---|---|---|---|
Nitric oxide biosynthesis | |||||||||
4.8 × 10−14 ¥ | 176.103 | 16.0 | l-Citrulline * | 0.001 | 31.765 | 0.002 | 0.199 | 0.009 | 0.432 |
1.8 × 10−18 ¥ | 191.114 | 22.5 | N-(Omega)-Hydroxyarginine | 0.001 | 18030.784 | 0.002 | 0.056 | 0.002 | 0.157 |
1.0 × 10−14 ¥ | 247.140 | 14.3 | N2-(d-1-Carboxyethyl)-l-Arginine | 0.002 | 4.929 | <0.001 | 6.081 | <0.001 | 10.833 |
3.3 × 10−15 ¥ | 291.129 | 16.8 | N-(l-Arginino) Succinate | 0.002 | 24.687 | 0.002 | 3.091 | 0.001 | 5.223 |
Glycolysis/TCA cycle | |||||||||
1.9 × 10−8 ¥ | 129.018 | 14.9 | Itaconic Acid * | 0.000 | 125.289 | 0.002 | 4.069 | 0.001 | 5.428 |
8.0 × 10−8 ¥ | 168.990 | 16.0 | Glyceraldehyde 3-Phosphate * | 0.003 | 150.353 | 0.001 | 10.092 | 0.001 | 12.626 |
1.3 × 10−7 ¥ | 173.021 | 15.7 | Sn-Glycerol 3-Phosphate * | 0.002 | 12.756 | 0.005 | 0.289 | 0.006 | 0.331 |
1.4 × 10−6 ¥ | 179.0552 | 14.7 | d-Glucose * | <0.001 | 0.429 | 0.002 | 0.268 | <0.001 | 0.094 |
3.0 × 10−16 ¥ | 191.0189 | 18.1 | Citrate * | <0.001 | >1000 | <0.001 | 0.024 | <0.001 | 0.017 |
3.7 × 10−9 ¥ | 666.131 | 13.3 | NADH * | 0.009 | 2.221 | 0.001 | 2.477 | 0.001 | 3.351 |
6.1 × 10−7 # | 810.131 | 12.3 | Acetyl-CoA | 0.004 | 4.363 | 0.480 | 1.213 | <0.001 | 2.257 |
Oxidative stress/glutathione metabolism | |||||||||
1.3 × 10−13 ¥ | 76.040 | 15.9 | Glycine * | 0.005 | 2.367 | <0.001 | 7.222 | <0.001 | 8.452 |
6.5 × 10−12 ¥ | 122.027 | 14.1 | l-Cysteine * | 0.027 | 20.174 | 0.001 | 14.423 | <0.001 | 26.437 |
4.8 × 10−9 ¥ | 241.031 | 16.1 | l-Cystine * | 0.009 | 0.492 | 0.005 | 0.108 | 0.005 | 0.159 |
6.1 × 10−17 ¥ | 251.069 | 14.1 | Gamma-l-Glutamyl-l-Cysteine | 0.001 | 14.204 | <0.001 | 8.063 | 0.001 | 14.927 |
6.4 × 10−11 ¥ | 148.060 | 14.6 | l-Glutamate * | 0.012 | 0.729 | <0.001 | 3.126 | <0.001 | 4.074 |
1.8 × 10−16 ¥ | 308.090 | 14.2 | Glutathione * | 0.000 | 3.903 | 0.001 | 6.268 | <0.001 | 8.205 |
1.6 × 10−11 ¥ | 336.087 | 14.6 | S-Formylglutathione | <0.001 | 4.273 | <0.001 | 0.536 | <0.001 | 0.518 |
5.3 × 10−15 ¥ | 338.0488 | 17.3 | S-Sulfanylglutathione | 0.080 | >1000 | 0.006 | 326.271 | 0.005 | 320.140 |
1.8 × 10−22 ¥ | 380.111 | 12.1 | S-Lactoylglutathione * | 0.001 | >1000 | <0.001 | 7.408 | <0.001 | 10.455 |
2.4 × 10−18 ¥ | 613.159 | 17.4 | Glutathione Disulphide * | 0.001 | 5.952 | <0.001 | 24.600 | <0.001 | 20.853 |
High-energy phosphate metabolism | |||||||||
1.1 × 10−10 ¥ | 212.043 | 15.1 | Phosphocreatine * | 0.001 | 2.157 | 0.006 | 1.768 | 0.002 | 2.739 |
4.5 × 10−10 ¥ | 348.070 | 16.6 | AMP * | 0.035 | 4.217 | 0.007 | 3.455 | 0.007 | 5.228 |
1.8 × 10−10 ¥ | 322.0446 | 16.0 | CMP * | 0.002 | 1.795 | 0.001 | 2.107 | <0.001 | 2.095 |
1.9 × 10−11 ¥ | 489.114 | 15.3 | CDP–Choline * | 0.001 | 22.575 | 0.001 | 0.142 | 0.001 | 0.191 |
9.6 × 10−13 ¥ | 484.975 | 17.9 | UTP * | 0.001 | 0.534 | <0.001 | 7.534 | <0.001 | 11.550 |
8.2 × 10−11 ¥ | 508.002 | 16.6 | ATP * | 0.002 | 1.987 | 0.001 | 2.006 | 0.001 | 2.416 |
5.7 × 10−10 ¥ | 523.997 | 19.3 | GTP * | <0.001 | 7.584 | 0.060 | 1.485 | 0.002 | 2.214 |
4.8 × 10−10 § | 565.0477 | 16.1 | UDP–Glucose * | 0.897 | 1.058 | 0.002 | 24.657 | 0.007 | 50.760 |
8.4 × 10−10 ¥ | 606.0744 | 15.0 | UDP–N-Acetyl-d-glucosamine * | 0.107 | 3.312 | 0.008 | 33.266 | 0.016 | 46.857 |
Fatty acid metabolism | |||||||||
3.5 × 10−9 § | 185.117 | 3.9 | 10-Oxodecanoate | 0.318 | 0.702 | <0.001 | 100.192 | 0.001 | 90.767 |
3.0 × 10−9 ¥ | 204.123 | 11.1 | O-Acetylcarnitine * | <0.001 | 4.658 | <0.001 | 0.002 | 0.490 | 0.002 |
1.7 × 10−7 € | 218.138 | 9.9 | O-Propanoylcarnitine | <0.001 | 0.321 | <0.001 | 2.871 | <0.001 | 2.967 |
1.9 × 10−9 § | 227.201 | 4.2 | Tetradecanoic Acid | <0.001 | 2.432 | 0.004 | 1.413 | <0.001 | 1.464 |
9.2 × 10−10 § | 225.186 | 4.2 | Tetradecenoic Acid | 0.126 | 2.130 | 0.025 | 2.131 | <0.001 | 5.490 |
3.5 × 10−14 § | 269.212 | 4.2 | Oxo-Hexadecanoic Acid | 0.323 | 1.305 | 0.003 | 38.013 | <0.001 | 257.413 |
3.4 × 10−10 § | 271.228 | 3.8 | Hydroxypalmitate | 0.193 | 0.610 | <0.001 | 129.447 | <0.001 | 132.527 |
1.7 × 10−9 § | 279.231 | 4.0 | Linoleate | 0.350 | 0.340 | <0.001 | 20.934 | <0.001 | 22.371 |
4.1 × 10−8 § | 283.264 | 3.8 | Octadecanoic Acid | <0.001 | 1.779 | <0.001 | 0.589 | <0.001 | 0.537 |
1.7 × 10−9 § | 295.227 | 3.8 | Hydroxyoctadecadienoic Acid | 0.293 | 1.227 | 0.008 | 41.194 | <0.001 | 102.576 |
1.4 × 10−7 § | 299.259 | 3.9 | Hydroxyoctadecanoic Acid | 0.829 | 0.937 | 0.020 | 29.732 | <0.001 | 68.922 |
1.7 × 10−6 § | 301.217 | 4.0 | Eicosapentaenoic Acid | 0.001 | 1.822 | 0.001 | 0.585 | 0.001 | 0.583 |
1.7 × 10−10 § | 303.233 | 4.0 | Eicosatetraenoic Acid | 0.267 | 0.938 | <0.001 | 0.511 | <0.001 | 0.509 |
3.8 × 10−8 § | 309.280 | 3.7 | Eicosenoic Acid | <0.001 | 3.417 | 0.006 | 0.699 | 0.001 | 0.660 |
1.2 × 10−9 § | 327.233 | 3.7 | Docosahexaenoic Acid | 0.001 | 1.905 | <0.001 | 0.336 | <0.001 | 0.395 |
7.8 × 10−9 § | 333.280 | 3.7 | Docosatrienoic Acid | <0.001 | 2.118 | <0.001 | 0.485 | <0.001 | 0.468 |
2.2 × 10−8 # | 386.289 | 4.9 | Hydroxytetradecenoylcarnitine | 0.002 | 9.282 | 0.107 | 1.459 | <0.001 | 6.815 |
7.1 × 10−9 § | 414.320 | 4.9 | Hydroxyhexadecenoylcarnitine | 0.002 | 29.177 | 0.014 | 2.715 | <0.001 | 4.851 |
4.0 × 10−10 § | 428.373 | 4.6 | Stearoylcarnitine | 0.005 | 1.898 | 0.001 | 2.351 | 0.003 | 1.699 |
4.3 × 10−22 § | 442.352 | 7.6 | Hydroxyoctadecenoylcarnitine | 0.001 | >1000 | <0.001 | 13.029 | <0.001 | 11.175 |
Phospholipid biosynthesis | |||||||||
1.4 × 10−3 € | 104.107 | 14.5 | Choline * | <0.001 | 4.826 | <0.001 | 0.407 | <0.001 | 0.379 |
8.8 × 10−13 ¥ | 184.073 | 15.0 | Choline Phosphate * | 0.001 | 2.530 | <0.001 | 2.827 | 0.001 | 2.582 |
2.0 × 10−9 ¥ | 258.110 | 14.5 | Sn-Glycero-3-Phosphocholine * | <0.001 | 5.060 | 0.001 | 0.427 | 0.001 | 0.400 |
1.9 × 10−11 ¥ | 568.339 | 4.6 | LPC 22:6 | 0.009 | 2.501 | <0.001 | 3.014 | <0.001 | 2.920 |
5.0 × 10−8 € | 810.526 | 3.8 | PS 38:5 | <0.001 | 3.432 | <0.001 | 0.186 | <0.001 | 0.291 |
6.0 × 10−5 ¥ | 820.619 | 4.1 | PC40:5 | 0.034 | 1.269 | 0.002 | 0.618 | 0.001 | 0.572 |
Purines and pyrimidines | |||||||||
1.1 × 10−13 § | 136.062 | 9.7 | Adenine * | <0.001 | 4.250 | <0.001 | 1.708 | <0.001 | 2.160 |
1.5 × 10−10 § | 137.046 | 8.3 | Hypoxanthine * | 0.002 | 2.386 | 0.002 | 4.181 | <0.001 | 6.198 |
3.4 × 10−8 ¥ | 243.062 | 12.0 | Uridine * | 0.624 | 1.141 | <0.001 | 3.804 | <0.001 | 4.458 |
8.6 × 10−11 § | 251.0784 | 9.6 | Deoxyinosine | 0.072 | 2.383 | 0.007 | 21.680 | <0.001 | 35.912 |
5.3 × 10−10 § | 284.098 | 12.7 | Guanosine * | 0.046 | 13.235 | 0.001 | 23.082 | <0.001 | 29.869 |
8.3 × 10−09 ¥ | 384.114 | 14.4 | Succinyladenosine | 0.050 | >1000 | 0.006 | 3.782 | 0.006 | 2.794 |
Aminosugars | |||||||||
1.5 × 10−7 € | 180.086 | 18.1 | d-Glucosamine * | <0.001 | 6.336 | <0.001 | 0.210 | <0.001 | 0.148 |
1.2 × 10−9 ¥ | 222.098 | 12.7 | N-Acetyl-d-Glucosamine * | 0.018 | 21.617 | <0.001 | 5.012 | 0.003 | 6.840 |
4.6 × 10−14 § | 266.0895 | 11.2 | Neuraminic Acid | 0.164 | 2.320 | <0.001 | 62.644 | <0.001 | 97.751 |
8.8 × 10−15 ¥ | 300.0489 | 15.0 | N-Acetyl-d-Glucosamine 6-Phosphate * | 0.003 | 0.428 | <0.001 | 27.336 | <0.001 | 26.704 |
3.2 × 10−6 § | 310.113 | 13.2 | N-Acetylneuraminate | 0.013 | 2.197 | 0.002 | 0.170 | 0.004 | 0.297 |
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Alanazi, S.; Alenzi, N.; Fearnley, J.; Harnett, W.; Watson, D.G. Temperate Propolis Has Anti-Inflammatory Effects and Is a Potent Inhibitor of Nitric Oxide Formation in Macrophages. Metabolites 2020, 10, 413. https://doi.org/10.3390/metabo10100413
Alanazi S, Alenzi N, Fearnley J, Harnett W, Watson DG. Temperate Propolis Has Anti-Inflammatory Effects and Is a Potent Inhibitor of Nitric Oxide Formation in Macrophages. Metabolites. 2020; 10(10):413. https://doi.org/10.3390/metabo10100413
Chicago/Turabian StyleAlanazi, Samyah, Naif Alenzi, James Fearnley, William Harnett, and David G. Watson. 2020. "Temperate Propolis Has Anti-Inflammatory Effects and Is a Potent Inhibitor of Nitric Oxide Formation in Macrophages" Metabolites 10, no. 10: 413. https://doi.org/10.3390/metabo10100413