Bone-Marrow-Derived Mesenchymal Stem Cells, Their Conditioned Media, and Olive Leaf Extract Protect against Cisplatin-Induced Toxicity by Alleviating Oxidative Stress, Inflammation, and Apoptosis in Rats
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemicals
2.2. Experimental Animal
2.3. Experimental Design
2.4. Stem Cells Isolation, Culture, and Expansion
2.5. Phenotypic Characterization of BM-MSCs
2.6. Assessment of Viability, Cell Count and Transplantation of BM-MSCs
2.7. Collection and Preparation of BM-MSCs Conditioned Media (CM-MSC)
2.8. Tissues Harvesting and Samples Collection
2.9. Assessment of the Body, Liver, and Kidney Weights
2.10. Assessment of Liver Necrosis and Hepatic Functions Markers
2.11. Measurement of Renal Function Markers
2.12. Estimation of the Markers of Oxidative Stress and Antioxidants in Hepatic and Renal Tissues
2.13. Assessment of the Levels of Pro-Inflammatory Markers (IL-1β, IL-6, and TNF-α)
2.14. Quantification of 8-Hydroxy-2-Deoxyguanosine (8-OH-dG) Level in Serum
2.15. Assessment of Lactate Dehydrogenase Enzyme (LDH) Activity
2.16. Assessment of Lysozyme Activity
2.17. Assessment of Nitric Oxide (NO)
2.18. Micronucleus Assay
2.19. Histopathological Investigation
2.20. Immunohistochemical Investigation
2.21. Morphometric Analysis
2.22. Tracking of Donner Male BM-MSCs in Female Tissues
2.23. PCR Analysis for Bcl-2, Bax, and Caspase-3 Genes
2.24. Statistical Analysis
3. Results
3.1. The Effect of Cis, OLE, CM-MSC, and MSC on Body, Liver, and Kidney Weights
3.2. The Effect of Cis, OLE, CM-MSC, and MSC on Liver and Renal Functions Markers
3.3. The Effect of Cis, OLE, CM-MSC, and MSC on Liver and Renal Oxidative/Antioxidants Status
3.4. The Effect of Cis, OLE, CM-MSC, and MSC on Liver and Renal Inflammatory Markers
3.5. The Effect of Cis, OLE, CM-MSC, and MSC on Genotoxicity and Cytotoxicity and Im-Munotoxicity Biomarkers
3.6. Morphological and Phenotypic Characterization of the Isolated BM-MSCs
3.7. Red Blood Cells Micronucleus Test
3.8. Histopathological and Immunohistochemical Assessment of Liver Sections
3.9. Histopathological and Immunohistochemical Assessment of Kidney Sections
3.10. Histopathological and Immunohistochemical Assessment of Thymus Sections
3.11. Histopathological and Immunohistochemical Assessment of Spleen Sections
3.12. Quantitative Real-Time Polymerase Chain Reaction (RT-PCR) Analysis of Bcl-2, Bax, and Caspase-3 Genes
3.13. Polymerase Chain Reaction Analysis of Sry Gene
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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Gene | Primer Sequence |
---|---|
Bcl-2 | Forward: 5′-GGATGACTTCTCTCGTCGCTACCGT-3′ |
Reverse: 5′-ATCCCTGAAGAGTTCCTCCACCAC-3′ | |
Bax | Forward: 5′-CCAGGACGCATCCACCAAGAAGC-3′ |
Reverse: 5′-TGCCACACGGAAGAAGACCTCTCG-3′ | |
Caspase-3 | Forward: 5′-GCAGCAGCCTCAAATTGTTGACTA-3′ |
Reverse: 5′-TGCTCCGGCTCAAACCATC-3′ | |
β-actin | Forward: 5′-TCCTCCTGAGCGCAAGTACTCT-3′ |
Reverse: 5′-GCTCAGTAACAGTCCGCCTAGAA-3′ |
Parameters | Control | OLE | Cis | Cis + OLE | Cis + CM-MSC | Cis + MSC |
---|---|---|---|---|---|---|
Initial body weight(g) | 206.33 ± 7.66 | 208.00 ± 7.07 | 204.50 ± 5.21 | 205.17 ± 5.23 | 206.67 ± 6.65 | 205.67 ± 5.28 |
Final body weight (g) | 226.33 ± 8.52 | 232.17 ± 9.35 | 194.17 ± 12.83 ab | 212.50 ± 19.10 c | 218.67 ± 13.78 c | 225.00 ± 10.64 c |
RBW | 109.83 ± 6.10 | 111.68 ± 4.66 | 94.93 ± 5.46 ab | 103.62 ± 9.39 c | 105.78 ± 4.99 c | 109.51 ± 6.85 c |
Liver weight (g) | 7.22 ± 0.48 | 7.32 ± 0.40 | 5.72 ± 0.59 ab | 6.37 ± 0.61 c | 6.58 ± 0.40 c | 6.90 ± 0.53 c |
RLW | 3.20 ± 0.28 | 3.16 ± 0.21 | 2.96 ± 0.43 ab | 3.0 ± 0.11 c | 3.03 ± 0.36 c | 3.07 ± 0.29 c |
Kidney weight (g) | 0.69 ± 0.08 | 0.68 ± 0.08 | 0.88 ± 0.07 ab | 0.78 ± 0.05 c | 0.74 ± 0.08 c | 0.70 ± 0.10 c |
RKW | 0.30 ± 0.03 | 0.29 ± 0.04 | 0.45 ± 0.06 ab | 0.37 ± 0.04 c | 0.34 ± 0.05 c | 0.31 ± 0.05 c |
Parameters | Control | OLE | Cis | Cis + OLE | Cis + CM-MSC | Cis + MSC |
---|---|---|---|---|---|---|
Liver | ||||||
ALT (U/L) | 29.50 ± 3.94 | 29.17 ± 3.60 | 142.17 ± 7.05 ab | 70.67 ± 5.47 abc | 66.33 ± 4.93 c | 48.33 ± 3.83 c |
AST(U/L) | 30.90 ± 4.06 | 33.17 ± 3.71 | 132.50 ± 3.94 ab | 77.00 ± 4.98 abc | 57.33 ± 4.46 c | 50.67 ± 5.28 c |
ALP(U/L) | 147.50 ± 5.24 | 153.67 ± 7.94 | 198.67 ± 5.28 ab | 179.83 ± 4.26 abc | 164.17 ± 2.64 c | 154.33 ± 6.28 c |
TP(g/dL) | 6.62 ± 0.71 | 6.70 ± 0.69 | 4.45 ± 0.46 ab | 5.17 ± 0.26 abc | 5.63 ± 0.32 c | 6.10 ± 0.33 c |
Albumin (g/dL) | 4.43 ± 0.37 | 4.30 ± 0.41 | 2.83 ± 0.34 ab | 3.10 ± 0.17 abc | 3.37 ± 0.39 c | 3.98 ± 0.22 c |
Total Bilirubin (mg/dL) | 0.29 ± 0.04 | 0.24 ± 0.03 | 0.84 ± 0.08 ab | 0.56 ± 0.04 abc | 0.47 ± 0.09 c | 0.33 ± 0.05 c |
Kidney | ||||||
Urea(mg/dL) | 27.38 ± 3.50 | 26.83 ± 3.66 | 45.17 ± 4.54 ab | 35.50 ± 4.64 abc | 31.33 ± 5.92 c | 29.50 ± 5.24 c |
Creatinine (mg/dL) | 0.75 ± 0.04 | 0.74 ± 0.04 | 1.04 ± 0.18 ab | 0.85 ± 0.08 abc | 0.81 ± 0.04 c | 0.77 ± 0.08 c |
Parameters | Control | OLE | Cis | Cis + OLE | Cis + CM-MSC | Cis + MSC |
---|---|---|---|---|---|---|
Liver | ||||||
CAT | 348.00 ± 20.45 | 351.00 ± 20.69 | 210.50 ± 14.52 ab | 295.33 ± 12.48 abc | 298.17 ± 10.28 c | 309.83 ± 8.54 c |
SOD | 288.17 ± 6.21 | 296.67 ± 3.33 | 227.17 ± 7.36 ab | 258.50 ± 7.89 abc | 264.67 ± 4.80 c | 284.33 ± 5.32 c |
GSH | 6.51 ± 0.29 | 6.61 ± 0.38 | 4.32 ± 0.20 ab | 5.21 ± 0.48 abc | 5.42 ± 0.26 c | 6.00 ± 0.45 c |
TAC | 88.33 ± 6.59 | 90.17 ± 5.88 | 37.50 ± 8.89 ab | 65.67 ± 6.53 abc | 77.67 ± 9.52 c | 83.33 ± 8.62 c |
MDA | 49.00 ± 4.60 | 46.17 ± 4.45 | 86.17 ± 4.79 ab | 65.83 ± 5.74 abc | 62.83 ± 3.19 c | 53.83 ± 3.54 c |
Renal | ||||||
CAT | 341.50 ± 17.01 | 343.17 ± 15.16 | 214.00 ± 11.10 ab | 299.00 ± 7.85 abc | 321.67 ± 16.38 c | 338.83 ± 10.87 c |
SOD | 286.00 ± 6.51 | 283.33 ± 6.15 | 234.83 ± 7.81 ab | 254.67 ± 11.20 abc | 264.33 ± 7.00 c | 281.67 ± 7.92 c |
GSH | 6.78 ± 0.32 | 6.67 ± 0.49 | 4.18 ± 0.33 ab | 5.17 ± 0.42 abc | 5.65 ± 0.45 c | 6.48 ± 0.34 c |
TAC | 87.5 ± 6.19 | 85.7 ± 4.18 | 39.8 ± 4.49 ab | 66.5 ± 5.43 abc | 72.8 ± 6.11 c | 82.2 ± 3.76 c |
MDA | 46.33 ± 5.50 | 47.67 ± 5.01 | 82.67 ± 6.25 ab | 56.50 ± 5.13 abc | 49.50 ± 4.04 c | 48.50 ± 4.55 c |
Parameters | Control | OLE | Cis | Cis + OLE | Cis + CM-MSC | Cis + MSC |
---|---|---|---|---|---|---|
Liver | ||||||
IL-1β | 11.05 ± 0.34 | 11.08 ± 0.21 | 26.33 ± 0.47 ab | 18.78 ± 0.56 abc | 17.07 ± 0.62 c | 12.72 ± 0.57 c |
IL-6 | 110.83 ± 2.64 | 112.33 ± 4.23 | 176.50 ± 5.43 ab | 129.17 ± 6.62 abc | 121.50 ± 6.47 c | 118.50 ± 5.05 c |
TNF-α | 2562.00 ± 22.30 | 2552.00 ± 16.70 | 3457.33 ± 14.47 ab | 2975.67 ± 17.73 abc | 2764.33 ± 33.18 c | 2602.17 ± 22.68 c |
Renal | ||||||
IL-1β | 13.77 ± 1.00 | 14.07 ± 0.81 | 30.6 ± 0.75 ab | 20.15 ± 1.01 abc | 18.0 ± 1.11 c | 16.4 ± 0.69 c |
IL-6 | 99.00 ± 5.06 | 97.7 ± 6.06 | 164.7 ± 6.92 ab | 114.5 ± 8.24 abc | 110.0 ± 7.24 c | 105.2 ± 6.43 c |
TNF-α | 2365.5 ± 53.63 | 2351.8 ± 45.96 | 3268.5 ± 46.47 ab | 2733.5 ± 30.09 abc | 2526.0 ± 31.55 c | 2410.3 ± 41.37 c |
Parameters | Control | OLE | Cis | Cis + OLE | Cis + CM-MSC | Cis + MSC |
---|---|---|---|---|---|---|
8-OH-dG (ng/mL) | 4.15 ± 0.10 | 4.47 ± 0.28 | 17.18 ± 0.75 ab | 9.23 ± 0.67 c | 7.93 ± 0.48 c | 6.02 ± 0.69 c |
LDH (µ/L) | 2280 ± 51 | 2323 ± 64 | 3912 ± 55 ab | 2620 ± 63 c | 2433 ± 85 c | 2403 ± 78 c |
Lysozyme activity (µg/mL) | 284.33 ± 4.76 | 289.50 ± 5.32 | 226.83 ± 4.58 ab | 265.17 ± 4.17 c | 269.83 ± 4.62 c | 279.50 ± 6.22 c |
NO (ng/mL) | 8.55 ± 0.55 | 8.95 ± 0.29 | 19.50 ± 2.43 ab | 13.62 ± 1.23 c | 11.70 ± 1.10 c | 9.63 ± 1.20 c |
Parameters | Control | OLE | Cis | Cis + OLE | Cis + CM-MSC | Cis + MSC |
---|---|---|---|---|---|---|
Mean ± SD | 166.1 ± 24.2 | 170.3 ± 40.4 | 188.4 ± 40.8 * | 173.9 ± 29 *# | 175.2 ± 34 *# | 174.4 ± 32.1 *# |
Parameters | Control | OLE | Cis | Cis + OLE | Cis + CM-MSC | Cis + MSC |
---|---|---|---|---|---|---|
Mean ± SD | 175.8 ± 26.3 | 173.4 ± 27.7 | 149.3 ± 43.4 * | 164.5 ± 30.2 *# | 164.7 ± 37.9 *# | 165.2 ± 32.1 *# |
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Ibrahim, M.A.; Khalifa, A.M.; Mohamed, A.A.; Galhom, R.A.; Korayem, H.E.; Abd El-Fadeal, N.M.; Abd-Eltawab Tammam, A.; Khalifa, M.M.; Elserafy, O.S.; Abdel-Karim, R.I. Bone-Marrow-Derived Mesenchymal Stem Cells, Their Conditioned Media, and Olive Leaf Extract Protect against Cisplatin-Induced Toxicity by Alleviating Oxidative Stress, Inflammation, and Apoptosis in Rats. Toxics 2022, 10, 526. https://doi.org/10.3390/toxics10090526
Ibrahim MA, Khalifa AM, Mohamed AA, Galhom RA, Korayem HE, Abd El-Fadeal NM, Abd-Eltawab Tammam A, Khalifa MM, Elserafy OS, Abdel-Karim RI. Bone-Marrow-Derived Mesenchymal Stem Cells, Their Conditioned Media, and Olive Leaf Extract Protect against Cisplatin-Induced Toxicity by Alleviating Oxidative Stress, Inflammation, and Apoptosis in Rats. Toxics. 2022; 10(9):526. https://doi.org/10.3390/toxics10090526
Chicago/Turabian StyleIbrahim, Mahrous A., Athar M. Khalifa, Alaa A. Mohamed, Rania A. Galhom, Horeya E. Korayem, Noha M. Abd El-Fadeal, Ahmed Abd-Eltawab Tammam, Mohamed Mansour Khalifa, Osama S. Elserafy, and Rehab I. Abdel-Karim. 2022. "Bone-Marrow-Derived Mesenchymal Stem Cells, Their Conditioned Media, and Olive Leaf Extract Protect against Cisplatin-Induced Toxicity by Alleviating Oxidative Stress, Inflammation, and Apoptosis in Rats" Toxics 10, no. 9: 526. https://doi.org/10.3390/toxics10090526