Potential of Pumpkin Pulp Carotenoid Extract in the Prevention of Doxorubicin-Induced Cardiotoxicity
Abstract
1. Introduction
2. Materials and Methods
2.1. Extraction Procedure
2.2. Total Carotenoid Content
2.3. Determination of Carotenoid Profiles Using High-Performance Liquid Chromatography (HPLC)
2.4. Experimental Animals and Ethical Statement
2.5. In Vivo Experimental Design
- Negative control group (C): they received daily, once a day, per os (orogastric tube), 1 mL of saline from the 1st to the 20th day of the experiment (0.9% NaCl);
- NADES solvent (C8:C10) (N): they received daily, once a day, per os (orogastric tube), 1 mL of NADES solvent from the 1st to the 20th day of the experiment;
- Pumpkin pulp extract (P): they received daily, once a day, per os (orogastric tube), 900 µg/kg of pumpkin pulp extract from the 1st to the 20th day of the experiment;
- Positive control group—doxorubicin (D): they received daily, once a day, per os (orogastric tube), 1 mL of saline from the 1st to the 20th day of the experiment (0.9% NaCl), as well as 4 doses of doxorubicin (2 mg/kg, intraperitoneally) on the 8th, 12th, 16th, and 20th day of the experiment;
- NADES solvent (C8:C10) and doxorubicin (ND): they received daily, once a day, per os (orogastric tube), 1 mL of NADES solvent from the 1st to the 20th day of the experiment, as well as 4 doses of doxorubicin (2 mg/kg, intraperitoneally) on the 8th, 12th, 16th, and 20th day of the experiment;
- Pumpkin pulp extract and doxorubicin (PD): they received daily, once a day, per os (orogastric tube), 900 µg/kg of pumpkin pulp extract from the 1st to the 20th day of the experiment, as well as 4 doses of doxorubicin (2 mg/kg, intraperitoneally) on the 8th, 12th, 16th, and 20th day of the experiment. On days when both doxorubicin and the extract were applied, the interval between the two substances was 4 h.
2.6. General Condition, Body Weight, Heart Weight, and Sacrifice of Animals
2.7. Examination of Biochemical Markers
2.8. Histological Processing of Tissues and Immunohistochemical Staining of Preparations
2.9. Semiquantitative Analysis of H&E Preparations
- negative DDS score (score < 2), i.e., absence of myocardial damage caused by doxorubicin, or
- positive DDS score (score 2–7), existence of damage caused by doxorubicin, namely:
- mild damage (score 2–3.99),
- moderate damage (score 4–5.99), or
- high grade damage of a strong/pronounced degree (score 6–7).
2.10. Semiquantitative Analysis of Immunohistochemically Stained Preparations
- maximum staining intensity (Imax): the strongest staining intensity among all stained cells—mild (1), moderate (2), and strong (3);
- dominant staining intensity (Idom): staining intensity observed in the largest number of stained cells—mild (1), moderate (2), and strong (3);
- staining extent (Iext): percentage of cells showing positive staining—<25% of cells are positive (1), 25–50% of cells are positive (2), 50–75% of cells are positive (3), and >75% of cells are positive (4).
2.11. Statistical Processing and Analysis of the Obtained Results
3. Results
3.1. Qualitative and Quantitative Analysis
3.2. General Condition of Animals
3.3. Body Weight (BW) and Heart Weight (HW)
Group | BW (1-Day) (g) | BW (21-Day) (g) | ∆BW | HW (g) |
---|---|---|---|---|
C | 429.00 ± 31.25 | 475.88 ± 30.43 | 46.88 | 1.48 ± 0.21 |
N | 301.38 ± 25.12 | 380.25 ± 51.63 | 78.87 | 1.56 ± 0.19 # |
P | 301.13 ± 23.87 | 339.13 ± 43.69 | 38 | 1.23 ± 0.18 * |
D | 401.13 ± 37.84 | 419.50 ± 32.47 | 18.37 * | 1.32 ± 0.16 |
ND | 320.88 ± 38.45 | 334.38 ± 40.71 | 13.5 | 1.05 ± 0.20 *,# |
PD | 304.00 ± 26.15 | 317.50 ± 50.32 | 13.5 | 1.64 ± 1.35 |
3.4. Assessment of Cardiovascular Biomarkers (NT-proBNP, CK-MB, hsTnT)
3.5. Doxorubicin Damage Score (DDS)
3.6. Immunohistochemistry
3.6.1. Anti-Cardiac Troponin I (TnI)
3.6.2. Anti-Nrf2 (Nrf2)
3.6.3. Anti-Bcl-2 (Bcl2)
3.6.4. Anti-Caspase-3 (Casp3), Anti-COX2 (COX2), and Anti-Ki67 (Ki67)
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
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Average Number of Casp3+ per VP | Median Expression Intensity (Casp3+) | Average Number of COX2+ per VP | Median Expression Intensity (COX2+) | Average Number of Ki67+ per VP | Median Expression Intensity (Ki67+) | |
---|---|---|---|---|---|---|
C | 3.38 ± 0.75 | 1 | 3.78 ± 1.03 | 1 | 1.90 ± 0.75 | 1 |
N | 3.98 ± 0.54 # | 1 # | 3.91 ± 0.84 # | 1 # | 2.23 ± 0.27 # | 1 # |
P | 3.54 ± 0.84 # | 1 # | 3.84 ± 0.72 # | 1 # | 2.14 ± 0.42 # | 1 # |
D | 6.81 ± 1.02 * | 2 * | 5.91 ± 1.11 * | 2 * | 11.18 ± 1.39 * | 2 * |
ND | 4.90 ± 0.49 *,# | 1 # | 4.33 ± 0.59 # | 1 | 9.70 ± 1.43 *,# | 2 * |
PD | 3.84 ± 0.799 # | 1 # | 4.39 ± 0.49 # | 1 # | 7.75 ± 0.52 # | 2 * |
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Bosanac, M.; Stupar, A.; Cvetković, B.; Miljković, D.; Čanković, M.; Andrejić Višnjić, B. Potential of Pumpkin Pulp Carotenoid Extract in the Prevention of Doxorubicin-Induced Cardiotoxicity. Pharmaceutics 2025, 17, 977. https://doi.org/10.3390/pharmaceutics17080977
Bosanac M, Stupar A, Cvetković B, Miljković D, Čanković M, Andrejić Višnjić B. Potential of Pumpkin Pulp Carotenoid Extract in the Prevention of Doxorubicin-Induced Cardiotoxicity. Pharmaceutics. 2025; 17(8):977. https://doi.org/10.3390/pharmaceutics17080977
Chicago/Turabian StyleBosanac, Milana, Alena Stupar, Biljana Cvetković, Dejan Miljković, Milenko Čanković, and Bojana Andrejić Višnjić. 2025. "Potential of Pumpkin Pulp Carotenoid Extract in the Prevention of Doxorubicin-Induced Cardiotoxicity" Pharmaceutics 17, no. 8: 977. https://doi.org/10.3390/pharmaceutics17080977
APA StyleBosanac, M., Stupar, A., Cvetković, B., Miljković, D., Čanković, M., & Andrejić Višnjić, B. (2025). Potential of Pumpkin Pulp Carotenoid Extract in the Prevention of Doxorubicin-Induced Cardiotoxicity. Pharmaceutics, 17(8), 977. https://doi.org/10.3390/pharmaceutics17080977