Biomedicine & Pharmacotherapy 83 (2016) 241–246

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10-DHGD ameliorates cisplatin-induced nephrotoxicity in rats Mohamed M. Elseweidy* , Mohamed S. Zaghloul, Nahla N. Younis Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt

A R T I C L E I N F O

Article history: Received 16 April 2016 Received in revised form 11 June 2016 Accepted 20 June 2016 Keywords: Nephrotoxicity Cisplatin Renal fibrosis 10-Dehydrogingerdione

A B S T R A C T

Organs subjected to chronic injuries may develop tissue fibrosis. Several factors contribute to the combat injurious stimuli to repair, heal and alleviate any disturbance. Secretion of chemokines, migration of inflammatory cells to the affected site and activation of fibroblast for production of extracellular matrix (ECM) are examples. Recently, few studies have delt with 10-dehydrogingerdione (10-DHGD), one of the active constituent of ginger extracts that has been published. This constituent proved to be potent antioxidant, anti-inflammatory, cholesterol ester transfer protein (CETP) inhibitor, indeed, a hypolipemic agent. It has been selected in the present study as a natural anti-inflammatory agent to combat inflammation, nephrotoxicity and renal fibrosis–induced by cisplatin. Renal fibrosis state demonstrated a significant increase in creatinine, urea, nuclear factor kappa (NF-kB), insulin like growth factor I (IGF-I), fibroblast growth factor-23 (FGF-23) along with a significant decrease of hepatocytes growth factor (HGF), renal glutathione (GSH) and in confirm to histopathological examination of kidney tissue. Administration of 10-DHGD orally daily for 4 weeks resulted in a significant improvement of both the biomarkers studied in addition to the histopathological profile of the renal tissues. Conclusion: 10-DHGD exhibited a marked anti-inflammatory potential, alleviated to a great extent of nephrotoxicity and renal fibrosis induced by cisplatin. ã 2016 Elsevier Masson SAS. All rights reserved.

1. Introduction Cisplatin (cis-diamminedichlor-oplatinum II, CDDP) is widely used as potentially an effective anticancer drug for solid tumors. However, its use is limited because of its multiorgan toxicity, namely nephrotoxicity and its preferential accumulation in renal tubular cells. In response to injurious stimuli, affected tissues undergo a cascade of events in an attempt to repair, heal and a subsequent recovery [1]. This wound healing process includes the production and the secretion of chemokines, cytokines, migration of inflammatory cells to the injured sites, the activation of fibroblasts to produce extracellular matrix (ECM), the regeneration of destroyed tissue via cell proliferation, the differentiation and the matrix remodeling [2]. Wounded tissues can react in an imprudent way leading to a maladaptation which is characterized by the over production of ECM, formation of fibrotic lesions and tissue scarring [3]. In other words, tissue fibrosis is a final step outcome when organs face chronic sustained injuries. Fibrosis is characterized by an excessive deposition of matrix components compromising

* Corresponding author. E-mail address: [email protected] (M.M. Elseweidy). http://dx.doi.org/10.1016/j.biopha.2016.06.032 0753-3322/ã 2016 Elsevier Masson SAS. All rights reserved.

organ functions due to the replacement of normal organ tissues as fibrosis can affect tissues with common inflammation such as the lung, the liver and the kidney [4,5]. In the kidney, chronic fibrosis is the final common pathway of glomerular, vascular or interstitial inflammations often leads to the last stage of renal failure (ESRF) [5,6]. Similar to wound healing, renal fibrosis probably initiates a beneficial response to injury. If an injurious condition is sustained, like in most progressive renal diseases, pathological fibrosis results in glomerulosclerosis, tubular atrophy, dilatation, tubule interstitial fibrosis and refraction of the glomerular in addition to the peritubular capillaries [7]. As progressive fibrosis might be a driving force for the disruption of glomerular and tubular architecture, inhibition of the major mediators responsible for matrix accumulation might slow or arrest the progression of fibrosis [8]. Several studies which have been done in animal models may support this concept. Therefore, trials to inhibit factors that promote fibrosis such as the fibroblast growth factor (FGF) and the connective tissue growth factor (CTGF) [9–13] or enhancing factors that attenuate fibrosis such as the hepatocyte growth factor (HGF) and the bone morphogenetic protein-7 (BMP-7) to improve renal architecture and/or function are requested [14,15]. The current study was therefore undertaken to evaluate the effect of 10-DHGD as a

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potential anti-inflammatory agent to ameliorate inflammation, to combat nephrotoxicity and renal fibrosis in cisplatin rat model. 2. Materials and methods 2.1. Animals Twenty four adult male Wistar albino rats weighing 200  20 g, supplied from The Egyptian Organization for Biological products and Vaccines (Cairo, Egypt), were utilized in the present study. Rats were housed in rodent cages under environmentally controlled conditions and were allowed one week for acclimatization at room temperature with a 12 h dark/light cycle. Rats were fed rodent chow (El-Nasr Pharmaceuticals and Chemicals Industry, Egypt), and were allowed free access of drinking water. The protocols for animal experimentation and the handling of animals were in accordance with the Animal Welfare Act and the Guide for the Care and the Use of Laboratory Animals established by Zagazig University, Zagazig, Egypt.

Biopharma AU Ltd (Adelaide, Australia), Quantikine R and D systems Inc (Minneapolis USA) and EIAab Science Co., Ltd (Wuhan, China), respectively. Kidney MDA [18] and GSH [19] were determined colorimetrically by using Bio-Diagnostics Kits, (Biodiagnostics Co. Giza, Egypt). 2.7. TNF-a and TGF-b1 gene expression analysis by using real-time PCR

Renal fibrosis was induced via a single dose of cisplatin (4 mg/ kg) intraperitoneally for each rat and renal fibrosis was evaluated through Masson’s Trichrome stain of kidney sections to verify the incidence of fibrosis after 1 week prior to be involved in the study. All rats were divided into 3 groups (n = 8 rats each); normal control (NC) group; normal rats received drug free vehicle, diseased control (DC) group; renal fibrotic rats received drug free vehicle and 10-dehydrogingerdione (10-DHGD) group; in a daily dose level of 10 mg/kg orally for 4 weeks.

Total RNA was extracted from kidney samples by using Qiagen tissue extraction kit (Qiagen, USA), reverse transcribed into cDNA by using high capacity cDNA reverse transcription kit (Fermentas, USA) and amplified by PCR by using RT-PCR kit (Stratagene, USA). Real-time qPCR amplification and analysis were performed by using an Applied Biosystem with software version 3.1 (StepOneTM, USA). The qPCR assay with the primer sets were optimized at the annealing temperature. Reactions were performed in a 25 ml final volume (12.5 ml SYBR Green Mix (2x), 5 ml cDNA, 2 ml primer pair mix, 5.5 ml H2O). PCR reaction was: 50  C for 2 min (1 cycle) and 40 cycles of 95  C for 15 s, 60  C for 1 min and 72  C for 1 min. Relative gene expression was calculated by using 2-DDCt method. PCR primers were designed with Gene Runner Software (Hasting Software, Inc., Hasting, NY) by using RNA sequences from GenBank. The sequences of forward and reverse primers were as follows: TNF-a (forward: 50 CATTGAGGTGTATTTCACGG-30 and reverse: 50 - GGCAAGTGGCCATTGTGTTC-30 ), TGF-b1 (forward: 50 0 0 CCTTGCCTCTAAGCCTTTGC-3 and reverse: 5 - GCCCTCCAGAAGTGGTCATT-30 ) and GAPDH (forward: 50 - GATGCTGGTGCTGAGTATGTCG-30 and reverse: 50 -GTGGTGCAGGATGCATTGCTGA30 ).

2.3. Isolation and identification of 10-dehydrogingerdione

2.8. Histopathological examination

Fresh rhizomes of ginger (Zingiber officinale) were purchased from the herbal market, Mansoura, Egypt. The isolation and identification of 10-DHGD were carried out as described before [16,17].

The fixed kidney specimens were dehydrated with a series of ascending grade ethanol from 75 to 100%. Tissues were placed thereafter in xylol and embedded in paraffin. Cross sections of about 2 mm thickness were sliced using a microtome (Leica RM 2155, England), stained with Hematoxylin, eosin (H&E) and Masson's Trichrome stains [20] for microscopical examination. Fibrosis was quantified by measuring Masson’s Trichrome stained area using Image J software and expressed as a percentage of total analyzed areas.

2.2. Experimental protocol

2.4. Blood sampling Blood samples were collected after 4 weeks of drugs administration and centrifuged directly for serum separation. Samples were processed instantly for the determination of creatinine, urea, total protein, fibroblast growth factor-23 (FGF23), insulin like growth factor I (IGF-I), nuclear factor kappa (NFkB) and HGF. 2.5. Tissue collection Following blood collection, rats were killed by decapitation. Kidneys were removed instantly, rinsed with cold normal saline and dried with filter paper. One specimen was quickly frozen in liquid nitrogen (170  C) and stored at 80  C for the determination of malondialdehyde (MDA) and reduced glutathione (GSH). Other kidney specimens were kept in 10% formalin-saline at 4  C for at least 1 week (1ry fixation) and processed for histopathological examination. 2.6. Analytical methods Serum creatinine, urea and total protein were determined by using commercial kits supplied by Diamond Diagnostics, Cairo, Egypt. Serum FGF-23, IGF-I, HGF and NF-kB were determined by using commercially available ELISA kits, supplied by AMS Biotechnology (Europe) Ltd (Abingdon, UK), Novozymes

2.9. Statistical analyses Statistics of data were made by Graphpad Prism 5, CA, USA. Results were expressed as means  standard deviation and statistical differences were done by ANOVA one way analysis of varience followed by Newman keul's post hoc test taken p < 0.05 as a confident interval. 3. Results 3.1. Metabolic parameters Kidney function tests and the oxidative stress status in kidney tissue were measured in our experimental groups where renal fibrotic group (DC) demonstrated a significant increase in serum creatinine, urea, total protein, renal lipid peroxidation content (MDA) along with a significant decrease in kidney GSH content as compared with NC group. Administration 10-DHGD improved these changes as distinguished by a significant decrease in serum creatinine, urea and total protein and renal MDA as compared with DC group while GSH demonstrated a significant increase (Table 1).

M.M. Elseweidy et al. / Biomedicine & Pharmacotherapy 83 (2016) 241–246 Table 1 Effect of 10-dehydrogingerdione on kidney functions’ parameters.

243

[a]

Parameter

NC

DC

10-DHGD

Serum creatinine (mg/dl) Serum urea (mg/dl) Serum total protein (g/dl) Kidney MDA (nmol/g.tissue) Kidney GSH (mmol/g.tissue)

0.11  0.01 8.25  1.20 1.20  0.25 9.63  3.01 5.19  0.76

0.85  0.24* 40.96  3.80* 6.20  0.19* 48.59  2.93* 1.67  0.38*

0.60  0.09# 30.57  2.40# 4.80  0.26# 20.45  2.83# 3.27  0.05#

Results were expressed as mean  SD, n = 8. * Significant from NC and # significant from DC.

7

5 4

NF-kβ (ng/ml) 3

3.2. Inflammatory and fibrotic parameters

2

Inflammation and fibrosis are common nephrotoxic side effects of cisplatin administration. DC group demonstrated a significant increase in NF-kB (Fig. 1a), IGF-I (Fig. 1b), FGF-23 (Fig. 1c) and a significant decrease in HGF (Fig. 1d) as compared with NC group. 10-DHGD administration resulted in a significant decrease in NFkB, IGF-I and FGF-23 along with a significant increase in HGF as compared with renal fibrotic (DC) group at p < 0.05. The gene expression of both TGF-b1 and TNF-a was upregulated in DC group by 7.7 and 8.7 folds respectively as compared to NC group. Treatment with 10-DHGD significantly down regulated these genes as compared to DC.

1

#

0

NC

250

*

Series1 IGF-1 (pg/ml) Series2 FGF-23 (ng/ml)

200

Series3 HGF (pg/ml)

Serum conc.

150

# # #

100

*

50 0

NC

DC

10-DHGD

[c] 14

10 Relave gene 8 expression 6

The improvement in renal function tests (a decrease in urea and creatinine) was associated with a strong correlation with growth regulatory molecules and proinflammatory NF-kB and negatively with HGF (Table 2).

2 0

TNF-α

*

12

4

Renal fibrosis is the final common manifestation of chronic kidney disease (CKD), mostly characterized by progressive tissue scarring that leads to glomerulosclerosis and tubulointerstitial fibrosis [8,21]. Considerable evidence that proteinuria activates the elaboration of profibrotic mediators [7,22,23] was reported in a renal fibrosis study which used cisplatin model. [24]. Our results indicated that cisplatin administration significantly deteriorated kidney function (increased urea and creatinine) which is a widely

10-DHGD

*

3.4. Correlation studies

4. Discussion

DC

[b]

3.3. Histopathological findings The studied biochemical changes were confirmed by the histopathological changes in all studied groups. As compared with normal group (Fig. 2a & b), renal fibrosis group (DC) showed a massive necrosis of renal parenchyma joined with fibrosis and collagen deposits usually seen intraglomerular (mesangial matrix), periglomerular, interstitial and perivascular in both cortex and medulla (Fig. 2c). It also showed collagen fibers as demonstrated by Masson’s trichrome (MT) stain in different sites of renal parenchyma (Fig. 2d). Glomeruli exhibited a state of hypercellularity or appeared sclerotic from extensive fibrosis (lesion score +3) as well. 10-DHGD group demonstrated mild thin immature fibrous tissue bands radiated from the renal cortex toward the medulla with apparently normal parenchyma (Fig. 2e) then showed a few strands stained blue could be seen mainly perivascular, interstitial and within a few glomeruli (Fig. 2f) lesion score +2 too. Percent of fibrosis expressed as Masson’s Trichromestained area relative to total analyzed areas was shown in Fig. 2g. NC showed the lowest level (0.48  0.1%), while DC-rats showed the highest level (24.5  0.2%) of collagen deposition. A significant reduction in collagen deposition was observed in 10-DHGD group (8.2  0.2%) as compared to DC group.

*

6

TGF-β1

* # #

NC

DC

10-DHGD

Fig. 1. Serum levels of [a] NF-kb (ng/ml), [b] IGF-1 (pg/ml), FGF-23 (ng/ml) and HGF (pg/ml) and [c] the renal gene expression of TNF-a and TGF-b1. Results were expressed as mean  SD, n = 8. * Significant difference from NC group and # significant difference from DC group.

well-known reported side effect of cisplatin nephrotoxicity as previously reported [25–27]. These results are suggested to be due to multiple intracellular effects including direct toxicity with reactive oxygen species which is increased in renal tissue following cisplatin adminstration. Renal injury as well as the significant degree of renal fibrosis were also an evident in our cisplatin rat

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Fig. 2. Histopathological examination of kidney tissue from [a] NC group rats showing normal renal parenchyma, H&E (X1200), [b] normal renal parenchyma without fibrous tissues, MT (X300), [c] DC group rats showing massive diffuse fibrosis and necrosis in renal parenchyma (star) H&E (X1200), [d] abundant perivascular, periglomerular and interstitial fibrosis in renal cortex (arrow) MT (X300), [e] 10-DHGD group rats showing thin immature fibrous tissue forming bands radiating from the renal cortex toward medulla (arrow), H&E (X1200), [f] little fibrous tissue in the renal glomeruli, perivascular and interstitial tissue, MT(X300) and [g] percent of fibrosis (mean  SD) quantified in Masson’s Trichrome stained area relative to total analyzed areas (n = 12 fields for each group). * Significant difference from NC group and # significant difference from DC group.

Table 2 The correlation between kidney function and growth regulatory molecules and NFkB (n = 24).

NF-kB IGF-1 FGF-23 HGF

Urea

Creatinine

0.88 (p < 0.001) 0.88 (p < 0.001) 0.91 (p < 0.001) 0.44 (p < 0.05)

0.82 0.82 0.84 0.38

(p < 0.001) (p < 0.001) (p < 0.001) (p < 0.05)

model as architectural damage, increased inflammation and fibrosis were seen. The underlying mechanism of renal inflammation involved the NF-kB pathway. The latter has long been considered as a prototypical proinflammatory signaling pathway due to its role in the expression of pro-inflammatory gene including cytokines, chemokines and adhesion molecules. Therefore, NF-kB has been expressed as a target for the new antiinflammatory drugs [28]. In cisplatin-induced nephrotoxicity, the activation of multiple pro-inflammatory cytokines and the

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infiltration of the inflammatory cells in the kidney were involved and were reported [26,27,29,30]. Cisplatin induced the phosphorylation, the subsequent translocation of NF-kB to the nucleus through the degradation of the inhibitory protein IkB a [29]. Within the nucleous activation, NF-kB led to the transcription of inflammatory mediators including TNF-a [30]. The latter induced the expression of other inflammatory cytokines, recruitment of macrophages and inflammatory cells into the kidney tissues [31]. The inflammatory state (increased circulating NF-kB level and renal TNF-a mRNA expression) which was seen in our cisplatin model was in accordance with previous studies [26,27,29,30]. The acquired state of oxidative stress (increased MDA and decreased GSH) in the kidney tissues induced by cisplatin may encourage the activation of myofibroblasts causing the release of profibrogenic cytokines including TGF-b1 and in accordance with the previous studies [26,27]. The latter is profibrogenic cytokine which induced the recruitment of inflammatory cells and fibroblasts into the injury area, stimulated these cells to produce further cytokines (TNF-a), enhanced ECM synthesis and inhibited ECM degradation [26]. Exaggerated proliferation of fibroblasts and myofibroblasts are one of the hallmarks of fibrosis and many approaches to interfere with this process along with overproduction of ECM had been described [32]. Various growth of factors were previously reported to either induce or inhibit fibrosis in various tissues; from this IGF1 which was known as a mitogenic factor that promotes ECM accumulation in various cell types including fibroblasts [33–35] and consequently increasing the collagen synthesis [36–38], in addition to the overexpression of IGF-1 which induces renal and glomerular hypertrophy [39–41]. On the other hand, HGF, a multifunctional polypeptide protected renal epithelial cells from apoptotic cell death induced by cisplatin [42,43]. It represents another known intrinsic antifibrotic factor which directly antagonizes the profibrotic actions of TGF-b1 [1,44,45] as indicated by the negative correlation between HGF and TGF-b1 mRNA expression. In other words, HGF acts as endogenous regulators that safe guard normal tissues from the development of fibrotic lesions after injury and highlighting its potential use as a novel therapeutic arsenal in combating various fibrotic disorders [1]. Incresaed IGF-1 and depleted HGF in our cisplatin rat model were accounted for the developed fibrosis that was similar to the previous report [25]. FGF-23 is another growth factor that was extensively reported to be increased in different renal disorders then showed an increase in our cisplatin-induced nephrotoxicity. The circulating levels of FGF-23 increase in association with renal function decrease that may reach high concentrations in ESRD. FGF-23 effects are mediated through FGF receptors in the kidneys and exist in membrane bound as well as soluble forms [8,46]. From our cisplatin model, nephrotocicity and fibrosis were associated by oxidative stress and inflammation. Owing to its antioxidant and anti-inflammatory activities [17,47,48], 10-DHGD was selected in the present study. Administration of 10-DHGD reversed all changes induced by cisplatin as it improved the kidney functions and resolved renal fibrosis. It significantly decreased renal MDA, circulated NF-kB and down regulated TNF-a while increased renal GSH as compared to DC. The anti-oxidant effects of 10-DHGD reported by the current study as well as previous studies [17] were principally responsible for the beneficial effects induced by 10-DHGD. 10-DHGD inhibited inflammation through the suppression of NF-kB by regulating the expression of inflammatory genes [47,48]. Suppression of oxidative stress and thus the inhibition of the NF-kB pathway lead in turn to attenuation of renal injury and inflammation [48]. The anti-inflammatory activity of 10-DHGD was also reported earlier [17,47,48].

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The current study is the first to report anti-fibrotic effect of 10DHGD. The anti-fibrotic effect was mediated via inhibition of profibrotic TGF-b1, IGF-1 while increasing HGF. The increase in HGF has antagonized the profibrotic actions of TGF-b1 [1,44,45] and therefore has protected renal tissue from fibrosis. The inhibition of IGF-1 may offer a way to inhibit the development or progression of renal injury [49]. Our study in turn suggested that the overall modulation of these growth regulatory molecules by 10-DHGD protected renal tissue from fibrosis and also promoted cellular repair. Improved histological architecture as well as resolution in renal fibrosis in accordance with the biochemical data were obtained. The improvement in kidney function by 10DHGD was proved to be a function of its modulatory effect on growth regulatory molecules and anti-inflammatory effect mediated via NF-kB pathway. 5. Conclusion Presentation of certain agent of natural origin product to interrupt the harmful effect exerted by cisplatin that remains necessary. The protective effect of 10-DHGD against cisplatininduced nephrotoxicity was mediated via anti-oxidant, antiinflammatory and antifibrotic effects. Prospective trials are needed to elucidate a potential role for 10-DHGD in adjunctive therapy and to confirm the adequate dose for enhanced renal outcomes in fibrosis. References [1] Y. Liu, Hepatocyte growth factor in kidney fibrosis: therapeutic potential and mechanisms of action, Am. J. Physiol. Renal Physiol. 287 (1) (2004) F7–16. [2] A. Eddy, Molecular basis of renal fibrosis, Pediatr. Nephrol. 15 (2000) 290–301. [3] S. Klahr, J. Morrissey, Obstructive nephropathy and renal fibrosis, Am. J. Physiol. Renal Physiol. (2002) 283. [4] A.A. Eddy, Molecular insights into renal interstitial fibrosis, J. Am. Soc. Nephrol.: JASN 7 (12) (1996) 2495–2508. [5] F. Strutz, et al., Basic fibroblast growth factor expression is increased in human renal fibrogenesis and may mediate autocrine fibroblast proliferation, Kidney Int. 57 (4) (2000) 1521–1538. [6] A.M. Nahas, et al., Renal fibrosis: insights into pathogenesis and treatment, Int. J. Biochem. Cell Biol. 29 (1) (1997) 55–62. [7] P. Boor, T. Ostendorf, J. Floege, Renal fibrosis: novel insights into mechanisms and therapeutic targets, Nat. Rev. Nephrol. 6 (11) (2010) 643–656. [8] A.E. Decleves, K. Sharma, Novel targets of antifibrotic and anti-inflammatory treatment in CKD, Nat. Rev. Nephrol. 10 (5) (2014) 257–267. [9] F.N. Ziyadeh, et al., Long-term prevention of renal insufficiency: excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-beta antibody in db/db diabetic mice, Proc. Natl. Acad. Sci. U. S. A. 97 (14) (2000) 8015–8020. [10] S. Chen, et al., Reversibility of established diabetic glomerulopathy by antiTGF-beta antibodies in db/db mice, Biochem. Biophys. Res. Commun. 300 (1) (2003) 16–22. [11] Q. Guan, et al., Reduction of chronic rejection of renal allografts by antitransforming growth factor-beta antibody therapy in a rat model, Am. J. Physiol. Renal Physiol. 305 (2) (2013) F199–F207. [12] S.J. Williams, et al., 3',4'-Bis-difluoromethoxycinnamoylanthranilate (FT061): an orally-active antifibrotic agent that reduces albuminuria in a rat model of progressive diabetic nephropathy, Bioorg. Med. Chem. Lett. 23 (24) (2013) 6868–6873. [13] K. Sharma, P. McCue, S.R. Dunn, Diabetic kidney disease in the db/db mouse, Am. J. Physiol. Renal Physiol. 284 (6) (2003) F1138–44. [14] A.L. Negri, Prevention of progressive fibrosis in chronic renal diseases: antifibrotic agents, J. Nephrol. 17 (4) (2004) 496–503. [15] M. Zeisberg, R. Kalluri, Reversal of experimental renal fibrosis by BMP7 provides insights into novel therapeutic strategies for chronic kidney disease, Pediatr. Nephrol. 23 (9) (2008) 1395–1398. [16] S.Y. Choi, et al., The conformation and CETP inhibitory activity of [10]dehydrogingerdione isolated from Zingiber officinale, Arch. Pharm. Res. 34 (5) (2011) 727–731. [17] M.M. Elseweidy, et al., 10-Dehydrogingerdione raises HDL-cholesterol through a CETP inhibition and wards off oxidation and inflammation in dyslipidemic rabbits, Atherosclerosis 231 (2) (2013) 334–340. [18] H. Ohkawa, N. Ohishi, K. Yagi, Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction, Anal. Biochem. 95 (2) (1979) 351–358. [19] E. Beutler, O. Duron, B.M. Kelly, Improved method for the determination of blood glutathione, J. Lab. Clin. Med. 61 (1963) 882–888.

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