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In Vivo Protective Effects of Diosgenin against Doxorubicin-Induced Cardiotoxicity.

Chen CT, Wang ZH, Hsu CC, Lin HH, Chen JH - Nutrients (2015)

Bottom Line: DOX treatment led to a significant decrease in the ratio of heart weight to body weight, and increases in the blood pressure and the serum levels of lactate dehydrogenase (LDH), creatine phosphokinase (CPK) and creatine kinase myocardial bound (CK-MB), markers of cardiotoxicity.Molecular data showed that the protective effects of diosgenin might be mediated via regulation of protein kinase A (PKA) and p38.Our data imply that diosgenin possesses antioxidant and anti-apoptotic activities, and cGMP modulation effect, which in turn protect the heart from the DOX-induced cardiotoxicity.

View Article: PubMed Central - PubMed

Affiliation: School of Nutrition, Chung Shan Medical University, Taichung City 40201, Taiwan. thomas.chen@unitybiotech.com.

ABSTRACT
Doxorubicin (DOX) induces oxidative stress leading to cardiotoxicity. Diosgenin, a steroidal saponin of Dioscorea opposita, has been reported to have antioxidant activity. Our study was aimed to find out the protective effect of diosgenin against DOX-induced cardiotoxicity in mice. DOX treatment led to a significant decrease in the ratio of heart weight to body weight, and increases in the blood pressure and the serum levels of lactate dehydrogenase (LDH), creatine phosphokinase (CPK) and creatine kinase myocardial bound (CK-MB), markers of cardiotoxicity. In the heart tissue of the DOX-treated mice, DOX reduced activities of antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GPx), were recovered by diosgenin. Diosgenin also decreased the serum levels of cardiotoxicity markers, cardiac levels of thiobarbituric acid relative substances (TBARS) and reactive oxygen species (ROS), caspase-3 activation, and mitochondrial dysfunction, as well as the expression of nuclear factor kappa B (NF-κB), an inflammatory factor. Moreover, diosgenin had the effects of increasing the cardiac levels of cGMP via modulation of phosphodiesterase-5 (PDE5) activity, and in improving myocardial fibrosis in the DOX-treated mice. Molecular data showed that the protective effects of diosgenin might be mediated via regulation of protein kinase A (PKA) and p38. Our data imply that diosgenin possesses antioxidant and anti-apoptotic activities, and cGMP modulation effect, which in turn protect the heart from the DOX-induced cardiotoxicity.

No MeSH data available.


Related in: MedlinePlus

Effect of diosgenin on the activation of caspase-3 (A); the release of cytochrome c (B); and mRNA expressions of NF-κB and TGF-β (C) in heart tissues of mice treated with DOX for four weeks. Values are mean ± SD, n = 10. a,b Means in a row without a common letter differ, p < 0.05. The protein expressions of cytochrome c (cyto. c) from mitochondrial (Mito., line 1–2) and cytosolic (Cyto., line 3–4) fractions. COX IV and β-actin, respectively, served as an internal control of Mito. and Cyto. fractions. The protein levels above the figures represent relative density of the bands normalized to COX IV (upper panel) or β-actin (bottom panel). Determined expression of the protein was subsequently quantified by densitometric analysis with that of control being 1.00-fold, as shown just below the gel data. Results are representative of at least three independent experiments.
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nutrients-07-04938-f002: Effect of diosgenin on the activation of caspase-3 (A); the release of cytochrome c (B); and mRNA expressions of NF-κB and TGF-β (C) in heart tissues of mice treated with DOX for four weeks. Values are mean ± SD, n = 10. a,b Means in a row without a common letter differ, p < 0.05. The protein expressions of cytochrome c (cyto. c) from mitochondrial (Mito., line 1–2) and cytosolic (Cyto., line 3–4) fractions. COX IV and β-actin, respectively, served as an internal control of Mito. and Cyto. fractions. The protein levels above the figures represent relative density of the bands normalized to COX IV (upper panel) or β-actin (bottom panel). Determined expression of the protein was subsequently quantified by densitometric analysis with that of control being 1.00-fold, as shown just below the gel data. Results are representative of at least three independent experiments.

Mentions: To investigate whether the protective effect of diosgenin against DOX occurred because it inhibited apoptotic pathways, we further studied the change in the expression of caspase-3, one marker of apoptosis, in the heart tissue (Figure 2A). Caspase-3 is a cytosolic protein that exists normally as an inactive precursor with a higher molecular weight (about 32 kDa). It is cleaved proteolytically into low molecular weights (11, 17, and 20 kDa) when a cell undergoes apoptosis [31]. In this study, treatment with DOX induced significantly an increase in cleavage of caspase-3 to 1.53-fold of that of control. In the diosgenin co-treated group, the active fragment was decreased (Figure 2A). As shown in Figure 2B (lane 2), DOX increased significantly the cytosolic concentration of cytochrome c, with a concomitant decrease in the mitochondria, implicating mitochondrial dysfunction due to DOX toxicity [32]. Quantitative data showed that the cytosolic concentration of cytochrome c was increased to 1.87-fold of that of control in the heart tissues of the DOX-treated mice. This effect was significantly suppressed in the DOX plus diosgenin group (lane 3, Figure 2B). The DOX-induced release of cytochrome c from mitochondria was inhibited by 81.6% in the DOX plus diosgenin group. In addition, mRNA expressions of NF-κB and transforming growth factor-beta (TGF-β), two factors that are related to inflammation, were measured by real-time PCR. DOX treatment augmented the cardiac mRNA expression of NF-κB, but not TGF-β. However, when mice were co-treated with diosgenin, concomitant decreases in their expressions were observed, as compared to the DOX treated group (p < 0.05).


In Vivo Protective Effects of Diosgenin against Doxorubicin-Induced Cardiotoxicity.

Chen CT, Wang ZH, Hsu CC, Lin HH, Chen JH - Nutrients (2015)

Effect of diosgenin on the activation of caspase-3 (A); the release of cytochrome c (B); and mRNA expressions of NF-κB and TGF-β (C) in heart tissues of mice treated with DOX for four weeks. Values are mean ± SD, n = 10. a,b Means in a row without a common letter differ, p < 0.05. The protein expressions of cytochrome c (cyto. c) from mitochondrial (Mito., line 1–2) and cytosolic (Cyto., line 3–4) fractions. COX IV and β-actin, respectively, served as an internal control of Mito. and Cyto. fractions. The protein levels above the figures represent relative density of the bands normalized to COX IV (upper panel) or β-actin (bottom panel). Determined expression of the protein was subsequently quantified by densitometric analysis with that of control being 1.00-fold, as shown just below the gel data. Results are representative of at least three independent experiments.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4488824&req=5

nutrients-07-04938-f002: Effect of diosgenin on the activation of caspase-3 (A); the release of cytochrome c (B); and mRNA expressions of NF-κB and TGF-β (C) in heart tissues of mice treated with DOX for four weeks. Values are mean ± SD, n = 10. a,b Means in a row without a common letter differ, p < 0.05. The protein expressions of cytochrome c (cyto. c) from mitochondrial (Mito., line 1–2) and cytosolic (Cyto., line 3–4) fractions. COX IV and β-actin, respectively, served as an internal control of Mito. and Cyto. fractions. The protein levels above the figures represent relative density of the bands normalized to COX IV (upper panel) or β-actin (bottom panel). Determined expression of the protein was subsequently quantified by densitometric analysis with that of control being 1.00-fold, as shown just below the gel data. Results are representative of at least three independent experiments.
Mentions: To investigate whether the protective effect of diosgenin against DOX occurred because it inhibited apoptotic pathways, we further studied the change in the expression of caspase-3, one marker of apoptosis, in the heart tissue (Figure 2A). Caspase-3 is a cytosolic protein that exists normally as an inactive precursor with a higher molecular weight (about 32 kDa). It is cleaved proteolytically into low molecular weights (11, 17, and 20 kDa) when a cell undergoes apoptosis [31]. In this study, treatment with DOX induced significantly an increase in cleavage of caspase-3 to 1.53-fold of that of control. In the diosgenin co-treated group, the active fragment was decreased (Figure 2A). As shown in Figure 2B (lane 2), DOX increased significantly the cytosolic concentration of cytochrome c, with a concomitant decrease in the mitochondria, implicating mitochondrial dysfunction due to DOX toxicity [32]. Quantitative data showed that the cytosolic concentration of cytochrome c was increased to 1.87-fold of that of control in the heart tissues of the DOX-treated mice. This effect was significantly suppressed in the DOX plus diosgenin group (lane 3, Figure 2B). The DOX-induced release of cytochrome c from mitochondria was inhibited by 81.6% in the DOX plus diosgenin group. In addition, mRNA expressions of NF-κB and transforming growth factor-beta (TGF-β), two factors that are related to inflammation, were measured by real-time PCR. DOX treatment augmented the cardiac mRNA expression of NF-κB, but not TGF-β. However, when mice were co-treated with diosgenin, concomitant decreases in their expressions were observed, as compared to the DOX treated group (p < 0.05).

Bottom Line: DOX treatment led to a significant decrease in the ratio of heart weight to body weight, and increases in the blood pressure and the serum levels of lactate dehydrogenase (LDH), creatine phosphokinase (CPK) and creatine kinase myocardial bound (CK-MB), markers of cardiotoxicity.Molecular data showed that the protective effects of diosgenin might be mediated via regulation of protein kinase A (PKA) and p38.Our data imply that diosgenin possesses antioxidant and anti-apoptotic activities, and cGMP modulation effect, which in turn protect the heart from the DOX-induced cardiotoxicity.

View Article: PubMed Central - PubMed

Affiliation: School of Nutrition, Chung Shan Medical University, Taichung City 40201, Taiwan. thomas.chen@unitybiotech.com.

ABSTRACT
Doxorubicin (DOX) induces oxidative stress leading to cardiotoxicity. Diosgenin, a steroidal saponin of Dioscorea opposita, has been reported to have antioxidant activity. Our study was aimed to find out the protective effect of diosgenin against DOX-induced cardiotoxicity in mice. DOX treatment led to a significant decrease in the ratio of heart weight to body weight, and increases in the blood pressure and the serum levels of lactate dehydrogenase (LDH), creatine phosphokinase (CPK) and creatine kinase myocardial bound (CK-MB), markers of cardiotoxicity. In the heart tissue of the DOX-treated mice, DOX reduced activities of antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GPx), were recovered by diosgenin. Diosgenin also decreased the serum levels of cardiotoxicity markers, cardiac levels of thiobarbituric acid relative substances (TBARS) and reactive oxygen species (ROS), caspase-3 activation, and mitochondrial dysfunction, as well as the expression of nuclear factor kappa B (NF-κB), an inflammatory factor. Moreover, diosgenin had the effects of increasing the cardiac levels of cGMP via modulation of phosphodiesterase-5 (PDE5) activity, and in improving myocardial fibrosis in the DOX-treated mice. Molecular data showed that the protective effects of diosgenin might be mediated via regulation of protein kinase A (PKA) and p38. Our data imply that diosgenin possesses antioxidant and anti-apoptotic activities, and cGMP modulation effect, which in turn protect the heart from the DOX-induced cardiotoxicity.

No MeSH data available.


Related in: MedlinePlus