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. 2021 Mar 20;11(3):886.
doi: 10.3390/ani11030886.

Date Palm Pollen Extract Avert Doxorubicin-Induced Cardiomyopathy Fibrosis and Associated Oxidative/Nitrosative Stress, Inflammatory Cascade, and Apoptosis-Targeting Bax/Bcl-2 and Caspase-3 Signaling Pathways

Samar S Elblehi  1 , Yasser S El-Sayed  2 , Mohamed Mohamed Soliman  3 , Mustafa Shukry  4
Affiliations

Date Palm Pollen Extract Avert Doxorubicin-Induced Cardiomyopathy Fibrosis and Associated Oxidative/Nitrosative Stress, Inflammatory Cascade, and Apoptosis-Targeting Bax/Bcl-2 and Caspase-3 Signaling Pathways

Samar S Elblehi et al. Animals (Basel). .

Abstract

Doxorubicin (DOX) has a potent antineoplastic efficacy and is considered a cornerstone of chemotherapy. However, it causes several dose-dependent cardiotoxic results, which has substantially restricted its clinical application. This study was intended to explore the potential ameliorative effect of date palm pollen ethanolic extract (DPPE) against DOX-induced cardiotoxicity and the mechanisms underlying it. Forty male Wistar albino rats were equally allocated into Control (CTR), DPPE (500 mg/kg bw for 4 weeks), DOX (2.5 mg/kg bw, intraperitoneally six times over 2 weeks), and DPPE + DOX-treated groups. Pre-coadministration of DPPE with DOX partially ameliorated DOX-induced cardiotoxicity as DPPE improved DOX-induced body and heart weight changes and mitigated the elevated cardiac injury markers activities of serum aminotransferases, lactate dehydrogenase, creatine kinase, and creatine kinase-cardiac type isoenzyme. Additionally, the concentration of serum cardiac troponin I (cTnI), troponin T (cTnT), N-terminal pro-brain natriuretic peptide (NT-pro BNP), and cytosolic calcium (Ca+2) were amplified. DPPE also alleviated nitrosative status (nitric oxide) in DOX-treated animals, lipid peroxidation and antioxidant molecules as glutathione content, and glutathione peroxidase, catalase, and superoxide dismutase activities and inflammatory markers levels; NF-κB p65, TNF-α, IL-1β, and IL-6. As well, it ameliorated the severity of histopathological lesions, histomorphometric alteration and improved the immune-staining of the pro-fibrotic (TGF-β1), pro-apoptotic (caspase-3 and Bax), and anti-apoptotic (Bcl-2) proteins in cardiac tissues. Collectively, pre-coadministration of DPPE partially mitigated DOX-induced cardiac injuries via its antioxidant, anti-inflammatory, anti-fibrotic, and anti-apoptotic potential.

Keywords: Bax; Bcl-2; TGF-β1; cardiac injury markers; date palm (pollen extract); doxorubicin; histopathology; oxidative stress.

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Conflict of interest statement

The authors declared no competing conflict of interest.

Figures

Figure 1
Figure 1
A schematic overview of the experimental protocol. CTR, Control group; DPPE, date palm pollen ethanolic extract-treated group; DOX, doxorubicin-treated group, DPPE + DOX, date palm pollen ethanolic extract- and doxorubicin treated group. * DPPE was given an hour before DOX administration.
Figure 2
Figure 2
Histopathological changes of rats’ cardiac tissues (H&E, ×400). A rat from the control (a) and a rat from date palm pollen ethanolic extract-treated (b) groups, respectively showing normal histoarchitecture of the cardiomyocytes with well-organized and branched cardiac myofibers (black arrow), centrally located oval nuclei (white arrow), and minimal interstitial connective tissue with few interstitial fibroblasts (red arrow) in between. Doxorubicin-treated rats (c–g) showing vacuolization of the sarcoplasm (black arrowhead), Zenker’s necrosis (black arrow), wavy muscle fibers (orange arrowhead), loss of myofibrils (orange arrow), myocardial necrosis (star), mononuclear inflammatory cells infiltrations (yellow arrow), fibroblasts proliferation (red arrow), and hyperemic interstitial blood vessels (green arrow). DPPE + DOX-treated rat (h) showing marked improvement in muscle fibers striation, which almost looks like the control. However, minute areas of myocardial necrosis with inflammatory cells infiltration (yellow arrow) and hyperemic interstitial blood vessels (green arrow) are still evident. (n = 7). Each value is the average of seven observations.
Figure 3
Figure 3
Histopathological changes of rats’ cardiac tissues (Masson’s trichrome, ×400, arrows: green stained collagen fibers). Rats from the control (a,e) and DPPE (b,f) groups, respectively showing scanty collagen fibers deposition. DOX treated rat (c,g) showing increased collagen deposition. DPPE + DOX-treated rat (d,h) showed a relative reduction in collagen deposition. Quantification of collagen volume fraction (CVF%), and perivascular collagen area (PVCA%) (i,j), respectively, ×400 across 10 different fields/section), n = 7 rat/group. Mean values were statistically differ from CTR (# p < 0.05), DPPE (* p < 0.05), DOX ($ p < 0.05) groups.
Figure 4
Figure 4
Immunohistochemical staining of transforming growth factor β1 (TGF-β1) in the experimental rats’ cardiac cells (IHC, ×400). A control (a), DPPE-treated (b) DOX-treated (c) and DPP + DOX-treated (d) rats. (e) Quantification of TGF-β1 expression, the immunohistochemical staining of TGF-β1 was measured as area percent (%) across 10 different fields/section, n = 7 rat/group. Mean values were statistically differed from CTR (# p < 0.05), DPPE (* p < 0.05), DOX ($ p < 0.05) group.
Figure 5
Figure 5
Immunohistochemical staining of cysteine aspartate specific protease-3 (cleaved caspase-3) in the cardiac cells of the experimental rats (IHC, ×400). A control (a), DPPE-treated (b) DOX-treated (c) and DPP + DOX-treated (d) rats. (e) Quantification of caspase-3 expression, the immunohistochemical staining of cleaved caspase-3 was measured as area percent (%) across 10 different fields/section, n = 7 rat/group. Mean values were statistically different from the CTR (# p < 0.05), DPPE (* p < 0.05), and DOX ($ p < 0.05) groups.
Figure 6
Figure 6
Immunohistochemical staining of Bcl2 associated X protein (Bax) in the experimental rats’ cardiac cells (IHC, ×400). A control (a), DPPE-treated (b) DOX-treated (c) and DPP + DOX-treated (d) rats. (e) Quantification of Bax expression, the immunohistochemical staining of Bax was measured as area percent (%) across 10 different fields/section, n = 7 rat/group. Mean values were statistically different from the CTR (# p < 0.05), DPPE (* p < 0.05), and DOX ($ p < 0.05) groups.
Figure 7
Figure 7
Immunohistochemical staining of B-cell lymphoma-2 (Bcl-2) in cardiac cells of the experimental rats (IHC, ×400). A control (a), DPPE-treated (b) DOX-treated (c) and DPP + DOX-treated (d) rats. (e) Quantification of Bcl-2 expression, the immunohistochemical staining of Bcl-2 was measured as area percent (%) across 10 different fields/section, n = 7 rat/group. Mean values were statistically different from the CTR (# p < 0.05), DPPE (* p < 0.05), and DOX ($ p < 0.05) groups.
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