Protective Effects of Processed Ginseng and Its Active Ginsenosides on Cisplatin-Induced Nephrotoxicity: <i>In Vitro</i> and <i>in Vivo</i> Studies

Park, Jun Yeon; Choi, Pilsoon; Kim, Taejung; Ko, Hyeonseok; Kim, Ho-kyong; Kang, Ki Sung; Ham, Jungyeob

doi:10.1021/acs.jafc.5b00782

Cited by 70 publications

(81 citation statements)

References 33 publications

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“…Besides, for the time being more attentions was paid on cortex in cisplatin nephrotoxicity, and medulla seemed to be ignored. In in vitro studies, renal cortical slices, primary cells or passage cells (including NRK-52E, normal rat kidney proximal cell; LLC-PK1, porcine kidney epithelial cell line; HK-2, human renal proximal tubule epithelial cell) derived from cortex were most routinely used for cytotoxicity test, while no cell model originated from medulla was established and adopted4546474849. In the future, cell lines derived from medullar part could be established for cytotoxicity researches.…”

Section: Discussionmentioning

confidence: 99%

Renal Medulla is More Sensitive to Cisplatin than Cortex Revealed by Untargeted Mass Spectrometry-Based Metabolomics in Rats

Zhang

Chen

Huang

et al. 2017

Sci Rep

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Nephrotoxicity has long been the most severe and life-threatening side-effect of cisplatin, whose anticancer effect is therefore restricted. Previous pathological studies have shown that both renal cortex and medulla could be injured by cisplatin. Our TUNEL (terminal deoxynucleotidyl transferasemediated dUTP nick end-labeling) assay results further uncovered that medulla subjected more severe injury than cortex. In order to depict the underlying metabolic mechanism of spatial difference in response to cisplatin, in the present study, mass spectrometry-based untargeted metabolomics approach was applied to profile renal cortex and medulla metabolites of rat after receiving a single dose of cisplatin (2.5, 5 or 10 mg/kg). Eventually, 53 and 55 differential metabolites in cortex and medulla were screened out, respectively. Random forest, orthogonal partial least squares-discriminant analysis and metabolic cumulative fold change analysis revealed that metabolic changes in medulla were more obviously dose-dependent than those in cortex, which confirmed the conclusion that medulla was more sensitive to cisplatin exposure. Furthermore, 29 intermediates were recognized as the most contributive metabolites for the sensitivity difference. Metabolic pathways interrupted by cisplatin mainly included amino acid, energy, lipid, pyrimidine, purine, and creatine metabolism. Our findings provide new insight into the mechanism study of cisplatin-induced nephrotoxicity.Cisplatin [cis-diamminedichloroplatinum(II)] is an effective antineoplastic agent that was widely applied in the treatment of various types of solid tumors in the past several decades 1-3 . However, due to poor selectivity, cisplatin could cause neurotoxicity, nephrotoxicity, nausea and vomiting, and ototoxicity et al. in clinical [4][5][6][7][8][9][10] . As the principal excretory organ for cisplatin, kidney accumulates and retains platinum to a greater degree than other organs 11,12 . Therefore, nephrotoxicity has long been the most severe and life-threatening toxicity among these side-effects 13,14 . Statistics showed there were about 25-35% patients experienced a significant decline in renal function after receiving a single dose of cisplatin 13,15 . The declines manifested clinically as lower glomerular filtration rate, reduced serum magnesium and potassium levels et al. 13,16 . Research over the past few years has gained significant insights into the mechanisms regarding cisplatin nephrotoxicity, which mainly involved apoptosis, inflammation and oxidative stress et al. [17][18][19][20][21][22] . However, how the toxicity occurs and develops, and how various types of mechanisms are integrated to induce distinct kidney pathology, remain largely unknown.Metabolomics is an emerging -omics approach that could provide information of holistic and time-dependent metabolic variation in response to xenobiotic interventions 23,24 . At present, metabolomics analysis encompasses different strategies depending on the objective of study, namely target analysis of a group of c...

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Section: Discussionmentioning

confidence: 99%

Renal Medulla is More Sensitive to Cisplatin than Cortex Revealed by Untargeted Mass Spectrometry-Based Metabolomics in Rats

Zhang

Chen

Huang

et al. 2017

Sci Rep

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“…We carried out in vitro kidney cell protection screening to compare the protective effect of raw ginseng, BG, and FBG on LLC-PK1 pig kidney epithelial cells. The kidney cell protection assay conditions were established using the LLC-PK1 cell line, which is commonly used to evaluate nephrotoxicity [32]. The potent protective effect by ameliorating reduced cell viability due to cisplatin was observed only after treatment with FBG.…”

Section: Discussionmentioning

confidence: 99%

“…The renoprotective effect against oxidative renal cell damage was evaluated using LLC-PK1 cells [32], [33]. The LLC-PK1 (pig kidney epithelium, CL-101) cells were purchased from the American Type Culture Collection (Rockville, MD, USA), and cultured in Dulbecco's modified Eagle's medium, supplemented with 10% fetal bovine serum, 1% penicillin/streptomycin, and 4mM l -glutamine at 37°C with 5% CO 2 in air.…”

Section: Methodsmentioning

confidence: 99%

Preventive effect of fermented black ginseng against cisplatin-induced nephrotoxicity in rats

Jung

Eom

et al. 2017

Journal of Ginseng Research

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BackgroundFermented black ginseng (FBG) is processed ginseng by the repeated heat treatment and fermentation of raw ginseng. The protective effect and mechanism of FBG on cisplatin-induced nephrotoxicity was investigated to evaluate its therapeutic potential.MethodsThe free radical scavenging activity of FBG was measured using 1,1-diphenyl-2-picrylhydrazyl (DPPH). In addition, the protective effect against cisplatin-induced renal damage was tested in rats. FBG was orally administered every day at a dose of 150 mg/kg body weight for 10 d, and a single dose of cisplatin was administered intraperitoneally (7.5 mg/kg body weight) with 0.9% saline on the 4th d.ResultsThe DPPH radical-scavenging activity of FBG (IC50 = 384 μg/mL) was stronger than that of raw ginseng. The improved DPPH radical-scavenging activity was mediated by the generation phenolic compounds. The decreased cell viability by cisplatin was recovered significantly after treatment with FBG in a dose-dependent manner. Then, the protective effect of FBG on cisplatin-induced oxidative renal damage was investigated in rats. The decreased creatinine clearance levels, which are a reliable marker for renal dysfunction in cisplatin-treated rats, were reduced to the normal level after the administration of FBG. Moreover, FBG showed protective effects against cisplatin-induced oxidative renal damage in rats through the inhibition of NF-κB/p65, COX-2, and caspase-3 activation.ConclusionThese results collectively show that the therapeutic evidence for FBG ameliorates the nephrotoxicity via regulating oxidative stress, inflammation, and apoptosis.

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“…Ginsenosides Rg1 and Re, which are the precursors of Rk3 and Rh4, exhibit protective effects against ischemic brain injury, glutamate-induced lung injury, ROS-induced astrocyte injury, as well as complement-induced podocyte injury through restoration of the antioxidant defense enzyme activities or inhibition of ROS generation [36], [37], [38], [39]. Ginsenosides Rg3, Rg5, and Rk1 reduced cisplatin-induced toxicity through inactivation of JNK and p53 [40]. Despite the structural differences in many ginsenosides, ginsenosides exert diverse protective effects on many disease models.…”

Section: Discussionmentioning

confidence: 99%

Protective effect of ginsenosides Rk3 and Rh4 on cisplatin-induced acute kidney injury in vitro and in vivo

Baek

Shin

Kim

et al. 2017

Journal of Ginseng Research

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BackgroundNephrotoxicity is the major side effect in cisplatin chemotherapy. Previously, we reported that the ginsenosides Rk3 and Rh4 reduced cisplatin toxicity on porcine renal proximal epithelial tubular cells (LLC-PK1). Here, we aimed to evaluate the protective effect of ginsenosides Rk3 and Rh4 on kidney function and elucidate their antioxidant effect using in vitro and in vivo models of cisplatin-induced acute renal failure.MethodsAn enriched mixture of ginsenosides Rk3 and Rh4 (KG-KH; 49.3% and 43.1%, respectively) was purified from sun ginseng (heat processed Panax ginseng). Cytotoxicity was induced by treatment of 20μM cisplatin to LLC-PK1 cells and rat model of acute renal failure was generated by single intraperitoneal injection of 5 mg/kg cisplatin. Protective effects were assessed by determining cell viability, reactive oxygen species generation, blood urea nitrogen, serum creatinine, antioxidant enzyme activity, and histopathological examination.ResultsThe in vitro assay demonstrated that KG-KH (50 μg/mL) significantly increased cell viability (4.6-fold), superoxide dismutase activity (2.8-fold), and glutathione reductase activity (1.5-fold), but reduced reactive oxygen species generation (56%) compared to cisplatin control cells. KG-KH (6 mg/kg, per os) also significantly inhibited renal edema (87% kidney index) and dysfunction (71.4% blood urea nitrogen, 67.4% creatinine) compared to cisplatin control rats. Of note, KG-KH significantly recovered the kidney levels of catalase (1.2-fold) and superoxide dismutase (1.5-fold).ConclusionConsidering the oxidative injury as an early trigger of cisplatin nephrotoxicity, our findings suggest that ginsenosides Rk3 and Rh4 protect the kidney from cisplatin-induced oxidative injury and help to recover renal function by restoring intrinsic antioxidant defenses.

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Protective Effects of Processed Ginseng and Its Active Ginsenosides on Cisplatin-Induced Nephrotoxicity: In Vitro and in Vivo Studies

Cited by 70 publications

References 33 publications

Renal Medulla is More Sensitive to Cisplatin than Cortex Revealed by Untargeted Mass Spectrometry-Based Metabolomics in Rats

Renal Medulla is More Sensitive to Cisplatin than Cortex Revealed by Untargeted Mass Spectrometry-Based Metabolomics in Rats

Preventive effect of fermented black ginseng against cisplatin-induced nephrotoxicity in rats

Protective effect of ginsenosides Rk3 and Rh4 on cisplatin-induced acute kidney injury in vitro and in vivo

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