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Ginsenoside Rg5 Ameliorates Cisplatin-Induced Nephrotoxicity in Mice through Inhibition of Inflammation, Oxidative Stress, and Apoptosis

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ABSTRACT

Although cisplatin is an effective anti-cancer agent that is widely used for treating various types of malignant solid tumors, the nephrotoxicity induced by cisplatin severely limits its clinical application. The present study was designed to explore the potential protective effect of ginsenoside Rg5, a rare ginsenoside generated during steaming ginseng, on cisplatin-induced nephrotoxicity in a mouse experimental model. The possible mechanisms underlying this nephroprotective effect were also investigated for the first time. Rg5 was given at doses of 10 and 20 mg/kg for 10 consecutive days. On Day 7, a single nephrotoxic dose of cisplatin (25 mg/kg) was injected to mice. Cisplatin administration resulted in renal dysfunction as evidenced by increase in serum creatinine (CRE) and blood urea nitrogen (BUN) levels. In addition, cisplatin increased the level of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), the makers of lipid peroxidation, and depleted glutathione (GSH) content and superoxide dismutase (SOD) activity in renal tissues. These effects were associated with the significantly increased levels of cytochrome P450 E1 (CYP2E1), 4-hydroxynonenal (4-HNE), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, nuclear factor-kappa B (NF-κB) p65, and cyclooxygenase-2 (COX-2) in renal tissues. However, pretreatment with ginsenoside Rg5 significantly attenuated the renal dysfunction, oxidative stress and inflammation response induced by cisplatin. Furthermore, ginsenoside Rg5 supplementation inhibited activation of apoptotic pathways through increasing Bcl-2 and decreasing Bax expression levels. Histopathological examination further confirmed the nephroprotective effect of Rg5. Collectively, these results clearly suggest that Rg5-mediated alleviation of cisplatin-induced nephrotoxicity may be related to its anti-oxidant, anti-apoptotic and anti-inflammatory effects.

No MeSH data available.


Histological examination of morphological changes in kidney tissues. Renal tissues stained with TUNEL (100× & 400×) (A). The presence of TUNEL positive cells were measured by the image analyzer (B). All data were expressed as mean ± S.D., n = 8. ** p < 0.01 vs. normal group; #p < 0.05, ##p < 0.01 vs. cisplatin group.
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nutrients-08-00566-f008: Histological examination of morphological changes in kidney tissues. Renal tissues stained with TUNEL (100× & 400×) (A). The presence of TUNEL positive cells were measured by the image analyzer (B). All data were expressed as mean ± S.D., n = 8. ** p < 0.01 vs. normal group; #p < 0.05, ##p < 0.01 vs. cisplatin group.

Mentions: To further determine whether apoptosis would coexist with necrosis in cisplatin-induced nephrotoxicity, the apoptosis in renal tubular cells was confirmed and quantified using TUNEL staining. As depicted in Figure 8, almost no apoptotic cells were observed in renal tissues of normal groups. Compared to normal group, the number of TUNEL positive cells was significantly increased in the cisplatin-induced group. However, Rg5 pretreatment (20 mg/kg) significantly reduced the number of TUNEL positive cells in renal tissues.


Ginsenoside Rg5 Ameliorates Cisplatin-Induced Nephrotoxicity in Mice through Inhibition of Inflammation, Oxidative Stress, and Apoptosis
Histological examination of morphological changes in kidney tissues. Renal tissues stained with TUNEL (100× & 400×) (A). The presence of TUNEL positive cells were measured by the image analyzer (B). All data were expressed as mean ± S.D., n = 8. ** p < 0.01 vs. normal group; #p < 0.05, ##p < 0.01 vs. cisplatin group.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5037551&req=5

nutrients-08-00566-f008: Histological examination of morphological changes in kidney tissues. Renal tissues stained with TUNEL (100× & 400×) (A). The presence of TUNEL positive cells were measured by the image analyzer (B). All data were expressed as mean ± S.D., n = 8. ** p < 0.01 vs. normal group; #p < 0.05, ##p < 0.01 vs. cisplatin group.
Mentions: To further determine whether apoptosis would coexist with necrosis in cisplatin-induced nephrotoxicity, the apoptosis in renal tubular cells was confirmed and quantified using TUNEL staining. As depicted in Figure 8, almost no apoptotic cells were observed in renal tissues of normal groups. Compared to normal group, the number of TUNEL positive cells was significantly increased in the cisplatin-induced group. However, Rg5 pretreatment (20 mg/kg) significantly reduced the number of TUNEL positive cells in renal tissues.

View Article: PubMed Central - PubMed

ABSTRACT

Although cisplatin is an effective anti-cancer agent that is widely used for treating various types of malignant solid tumors, the nephrotoxicity induced by cisplatin severely limits its clinical application. The present study was designed to explore the potential protective effect of ginsenoside Rg5, a rare ginsenoside generated during steaming ginseng, on cisplatin-induced nephrotoxicity in a mouse experimental model. The possible mechanisms underlying this nephroprotective effect were also investigated for the first time. Rg5 was given at doses of 10 and 20 mg/kg for 10 consecutive days. On Day 7, a single nephrotoxic dose of cisplatin (25 mg/kg) was injected to mice. Cisplatin administration resulted in renal dysfunction as evidenced by increase in serum creatinine (CRE) and blood urea nitrogen (BUN) levels. In addition, cisplatin increased the level of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), the makers of lipid peroxidation, and depleted glutathione (GSH) content and superoxide dismutase (SOD) activity in renal tissues. These effects were associated with the significantly increased levels of cytochrome P450 E1 (CYP2E1), 4-hydroxynonenal (4-HNE), tumor necrosis factor (TNF)-&alpha;, interleukin (IL)-1&beta;, nuclear factor-kappa B (NF-&kappa;B) p65, and cyclooxygenase-2 (COX-2) in renal tissues. However, pretreatment with ginsenoside Rg5 significantly attenuated the renal dysfunction, oxidative stress and inflammation response induced by cisplatin. Furthermore, ginsenoside Rg5 supplementation inhibited activation of apoptotic pathways through increasing Bcl-2 and decreasing Bax expression levels. Histopathological examination further confirmed the nephroprotective effect of Rg5. Collectively, these results clearly suggest that Rg5-mediated alleviation of cisplatin-induced nephrotoxicity may be related to its anti-oxidant, anti-apoptotic and anti-inflammatory effects.

No MeSH data available.