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cgt201624a

  1. 1. ORIGINAL ARTICLE Physalis alkekengi and Alhagi maurorum ameliorate the side effect of cisplatin-induced nephrotoxicity S Changizi-Ashtiyani1 , M Alizadeh2 , H Najafi3 , S Babaei4 , M Khazaei2 , M Jafari2 , N Hossaini5 , A Avan6 and B Bastani7 Cisplatin is frequently being used for the treatment of different tumors, although the application of this agent is associated with nephrotoxicity. Here, we explored the antioxidant and anti-inflammatory activities of Physalis alkekengi and Alhagi maurorum; 400 mg kg− 1 per day P. alkekengi and 100 mg kg− 1 per day A. maurorum were administered in rats, orally for 10 days after a single dose of 7 mg kg− 1 intraperitoneal cisplatin. The concentrations of creatinine, urea-nitrogen, and relative and absolute excretion of sodium/potassium were evaluated before/after therapy. Levels of malondialdehyde (MDA) and ferric-reducing antioxidant power (FRAP) were measured to assess the oxidative stress induced by cisplatin. Moreover, tissues sections were used for histological analyses and evaluation of the degree of tissue damage. Cisplatin increased serum levels of creatinine and urea-nitrogen, relative/ absolute excretion of sodium/potassium, and MDA, whereas decreased FRAP level. Interestingly, P. alkekengi or A. maurorum were able to reduce the level of the renal function markers as well as the levels of sodium/potassium. This effect was more pronounced by P. alkekengi. Moreover, cisplatin induced pathological damage in kidney, whereas treatment with these agents improved this condition. Our findings demonstrate the potential therapeutic impact of P. alkekengi and A. maurorum for improving cisplatin- induced nephrotoxicity, supporting further investigations on the novel potential clinical application of these agents for patients being treated with cisplatin to ameliorate cisplatin-induced nephrotoxicity. Cancer Gene Therapy advance online publication, 3 June 2016; doi:10.1038/cgt.2016.24 INTRODUCTION Cisplatin is an anti-neoplastic drug that is being used in the treatment of different tumors.1–2 Although the increased dose could result in a remarkable increase in the therapeutic effect of cisplatin, it is associated with nephrotoxicity.3–5 It has been reported that approximately 20–30% of patients receiving cisplatin have the signs of nephrotoxicity.6,7 Several studies have been performed on the molecular mechanisms behind cisplatin- induced nephrotoxicity; indicating the key role of inflammation and oxidative stress in this condition.6,8–10 There is a growing body of evidence showing antioxidant and anti- inflammatory activities of Physalis alkekengi in a variety of human diseases. It has been suggested that alkaloids, glucocorticoids, lycopene and vitamin C are among its active ingredients.11 Moreover, several studies have been shown its antioxidant12 and anti-inflammatory properties.13–15 Another study suggested the antioxidant activity of Alhagi maurorum, which is enriched in flavonoids.16 Increasing evidence has shown the antioxidant activity of A. maurorum.17–20 Therefore, in the present study, we explored the anti-inflammatory and antioxidants effects of oral administration of P. alkekengi and A. maurorum extracts on cisplatin-induced nephrotoxicity in an in vivo model. MATERIALS AND METHODS Animals In this study, 28 male Sprague–Dawley rats (weighing 250–300 g) were used and kept in the central animal house of Arak University of Medical Sciences. The animals were housed under standard laboratory conditions and 12 h light/dark cycles at the temperature of 23 ± 2 °C with free access to food and water throughout the experiment. All tests and procedures were conducted according to the internationally accepted guidelines for the care and use of laboratory animals. The animal experiment was approved by the Ethics Committee at Arak University of Medical Sciences (AUMS) and performed according to a protocol approved by the AUMS, Iran and the Declaration of Helsinki. Extraction of P. alkekengi and A. maurorum P. alkekengi and A. maurorum were purchased from Arak University center and were confirmed by a botanist. P. alkekengi (#771230) and A. maurorum (#78549) was deposited in the herbarium of agriculture and natural resources research center of Arak, Iran. The aerial parts of the plants were dried in shade and used for extraction by maceration. Five hundred grams of dried plant powder was dissolved in 70% ethyl alcohol and was kept for 72 h at room temperature. The mixture was centrifuged and the solution was carefully isolated. This procedure was repeated three times and the resulting solution was concentrated in a vacuum evaporator (model R-1001-VN, Seoul, Korea) at 40 °C, and stored until use at − 20 °C. Treatment of animal The animals were randomly divided into four groups (n = 7, in each group). The sham group received a single intraperitoneal normal saline injection (1 ml), followed by daily normal saline gavages for 10 consecutive days. The second group received a single dose of cisplatin (intraperitoneal; 7 mg kg− 1 ), followed by 10 daily oral gavages of normal saline. The third group received a single dose of cisplatin (intraperitoneal; 7 mg kg− 1 ), followed by treatment with P. alkekengi (400 mg kg− 1 per day) orally for 10 days. The 1 Department of Physiology, Arak University of Medical Sciences, Arak, Iran; 2 Student Research Committee, Arak University of Medical Sciences, Arak, Iran; 3 Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran; 4 Department of Histology, Arak University of Medical Sciences, Arak, Iran; 5 Department of Medicinal Plants, University of Arak, Arak, Iran; 6 Molecular Medicine Group, Department of Modern Sciences and Technologies, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran and 7 Division of Nephrology, School of Medicine, Saint Louis University, Saint Louis, MO, USA. Correspondence: Dr B Bastani, Division of Nephrology, School of Medicine, Saint Louis University, 3635 Vista Avenue, Saint Louis, MO 63110, USA. E-mail: bastanib@slu.edu Received 2 April 2016; accepted 9 May 2016 Cancer Gene Therapy (2016), 1–6 © 2016 Nature America, Inc. All rights reserved 0929-1903/16 www.nature.com/cgt
  2. 2. fourth group received the same protocol as the third group, but the extract was A. maurorum at a dose of 100 mg kg− 1 per day. At the end of the 10-day period, rats were kept in metabolic cages for 6 h. Urine and blood samples were collected from all the animals. Right kidneys were removed and fixed in 10% formaldehyde to be stained with hematoxylin and eosin for histological study. The left kidneys were frozen in liquid nitrogen for the assessment of oxidative stress. Biochemical analyses The concentrations of plasma creatinine and urea-nitrogen were measured using an autoanalyzer (Technicon, RA-1000, Bayer, Tarrytown, NY, USA). The concentrations of sodium and potassium were evaluated in plasma and urine samples. Creatinine clearance and the relative and absolute excretion of sodium and potassium were calculated. For the assessment of oxidative stress, malondialdehyde (MDA) and ferric-reducing antioxidant power values were measured in kidney tissue using the methods by Ohkawa et al.21 and Benzie and Strain,22 as described in our previous studies.23–24 Histological analysis The degree of tissue damage was assessed by hematoxylin and eosin- stained tissue sections. In particular, renal histopathologic damages in at least 10 microscopic fields (magnification × 400) were quantified for evaluation of Bowman space, red blood cells in glomerular capillaries, tubular cell necrosis and their exfoliation into the tubular lumen, intracellular vacuolization, vascular congestion and proteinaceous casts. The Bowman space widening and reduced number of red blood cells in glomerular capillaries in rats showed the highest rate of changes, compared with the control group. Other changes such as cellular necrosis and exfoliation, intracellular vacuolization, vascular congestion and intra- tubular proteinaceous casts were calculated as a percentage of the total area. The degree of histological damages was scored as zero for no damage, 1 for 1–20% damage, 2 for 21–40%, 3 for 41–60%, 4 for 61–80% and 5 for 81–100%. The total histopathological score was calculated, which was equal to all scores of different damages in each group.23–26 Statistical analysis Data were analyzed by using SPSS-16 software and expressed as mean ± s.e.m. To compare the functional parameters as well as the data related to renal oxidative stress, one-way analysis of variance and Duncan's post hoc test were used; and the LSD test was used. Non-parametric Kruskal–Wallis and Mann–Whitney tests were carried out to compare histopathologic damages. Po0.05 was considered as significant. RESULTS The effects of P. alkekengi and A. maurorum on cisplatin-induced renal dysfunction In the present study, we first sought to explore the effect of P. alkekengi and A. maurorum on cisplatin-induced nephrotoxicity. Thus, we evaluated the effect of these extracts in an in vivo model. Our data showed that a single dose of cisplatin significantly increased the plasma creatinine and urea-nitrogen concentrations, compared with the sham group (Po0.05), whereas treatment with P. alkekengi or A. maurorum significantly reduced their levels, compared with the cisplatin group. Of note, the reduction in serum creatinine was greater in the group receiving P. alkekengi (Figures 1a and b). Moreover, the decreased creatinine clearance (Po0.01) and increased absolute and relative excretion of sodium and potassium caused by cisplatin were improved by the application of both A. maurorum and P. alkekengi (Table 1). 0 0.5 1 1.5 2 2.5 3 Sham Cisplatin Cis+Physalis Cis+Alhagi Experimental groups PlasmaCreatinineConcentration (mg/dl) *** †† ††† 0 5 10 15 20 25 30 35 40 45 50 Sham Cisplatin Cis+Physalis Cis+Alhagi Experimental groups PlasmaNitrogen-UreaConcentration (mg/dl) †† ** *** †† ** Figure 1. Effects of oral administration of P. alkekengi or A. maurorum extracts on plasma creatinine (a) and urea-nitrogen (b) concentra- tions in rats with cisplatin-induced nephrotoxicity. *Po0.05, **Po0.01, ***Po0.001 in comparison with the sham group. † Po0.05, †† Po0.01, ††† Po0.001 for comparison of Cisplatin group with Cis+Physal or Cis+Alhagi group. Table 1. The effects of oral administration of Physalis alkekengi or Alhagi maurorum on renal functional parameters induced by cisplatin Functional parameters Experimental groups Sham Cisplatin Cis+Physal Cis+Alhagi CCr (μl min− 1 KgW) 1128.8 ± 74.4 375.5 ± 36.4*** 751.5 ± 61.6**†† 734.9 ± 56.5**†† UNaVº (μmol min− 1 KgW) 4.6 ± 0.8 19.1 ± 2.9*** 6.0 ± 0.9††† 6.4 ± 0.9††† FENa (%) 2.3 ± 0.3 12.5 ± 1.4** 2.8 ± 0.5†† 5.7 ± 1.6†† UKVº (μmol min− 1 KgW) 1.8 ± 0.3 5.4 ± 1.7*** 1.9 ± 0.5††† 1.6 ± 0.3††† FEK (%) 26.7 ± 2.6 48.3 ± 3.4** 28.2 ± 2.1††† 34.5 ± 2.5†† Abbreviation: KgW, Kilogram body weight. Values are represented as mean ± s.e. for creatinine clearance (CCr), absolute excretion of sodium (UNaVº ) and potassium (UKVº ), and fractional excretion of sodium (FENa) and potassium (FEK) in rats receiving normal saline (Sham), Cisplatin, Cisplatin plus Physalis alkekengi (Cis+Physal) or Cisplatin plus Alhagi maurorum (Cis+Alhagi) extract. *Po0.05, **Po0.01, ***Po0.001 in comparison with the sham group. † Po0.05, †† Po0.01, ††† Po0.001 for comparison of Cisplatin group with Cis+Physal or Cis+Alhagi group. Protection from cisplatin-induced nephrotoxicity S Changizi-Ashtiyani et al 2 Cancer Gene Therapy (2016), 1 – 6 © 2016 Nature America, Inc.
  3. 3. The effect of P. alkekengi and A. maurorum extracts on oxidative stress induced by cisplatin We further evaluated the effect of P. alkekengi and A. maurorum on the oxidative stress parameter by analyzing MDA and ferric- reducing antioxidant power. As shown in Figures 2a and b, MDA level in kidney tissue of the cisplatin group was significantly increased, while administration of P. alkekengi and A. maurorum extracts significantly (Po0.05) reduced the level of MDA. Interestingly, MDA levels in P. alkekengi and A. maurorum groups were still higher than that in the sham group. On the other hand, cisplatin decreased the ferric-reducing antioxidant power level that was partially improved by P. alkekengi and A. maurorum (Figures 2a and b). The effects of P. alkekengi and A. maurorum on cisplatin-induced tissue damages Tissue damage in rats treated with cisplatin was determined by histological analyses. As shown in Table 2 and Figure 3, cisplatin resulted in the enlargement of Bowman space, necrotic epithelial cells in proximal tubule and thick ascending limb of loop of Henle and their exfoliation into the lumen, reduced number of red blood cells in the glomerular capillaries and vacuolization of proximal tubules cells. In the outer medulla, epithelial cells of pars recta and thick ascending limb of Henle's loop showed cellular necrosis and exfoliation, increased vascular congestion and intra-tubular proteinaceous casts (Table 2 and Figure 4). In the inner medulla, the degree of vascular congestion and intra-tubular proteinaceous casts was increased in compar- ison with the sham group. In particular, histopathologic score in the cisplatin group was 40, which was significantly greater than sham group. The administration of both P. alkekengi and A. maurorum extracts reduced the severity of the damages; in the P. alkekengi group, the total histopathologic score was reduced to 21.2. Also, in the A. maurorum group, the total histopathologic score was decreased compared with the cisplatin group. However, in both groups, the total histopathologic scores were significantly higher than the sham group (Table 2). DISCUSSION To the best of our knowledge, this is the first study showing the effects of oral administration of P. alkekengi and A. maurorum extracts and their mechanisms on cisplatin-induced nephrotoxi- city in rats. We demonstrated that the administration of cisplatin significantly decreased creatinine clearance, as an index of glomerular filtration rate, and increased plasma creatinine and urea-nitrogen concentrations. In agreement with our findings, several studies have suggested that cisplatin causes afferent vasoconstriction and altered ultra-filtration coefficient.27,28 In the present study, the reduced number of red blood cells in glomerular capillaries might be due to the afferent vasoconstric- tion. In line with our data, Somani et al.29 and Aydogan et al.30 showed that the reduction in ultra-filtration coefficient by cisplatin was related to the production of reactive oxygen species and reduction of glomerular filtration surface area. Furthermore, cisplatin increased tissue MDA and reduced ferric-reducing antioxidant power levels, indicating increased oxidative stress induced by this agent. The increased absolute excretion of sodium and potassium in the cisplatin group indicated a marked decrease in the renal tubular reabsorption capacity, which was further confirmed by the increasing rate of fractional excretion of these ions and tissue damages. Increasing evidence is 0 5 10 15 20 25 30 35 40 Sham Cisplatin Cis+Physalis Cis+Alhagi Experimental grops TissueMDA(nmol/gKW) †† ** † ** *** 0 2 4 6 8 10 12 14 16 18 Sham Cisplatin Cis+Physalis Cis+Alhagi Experimental groups TissueFRAP(µmol/gKW) *** † *** †† ** Figure 2. Effects of oral administration of P. alkekengi or A. maurorum extracts on tissue MDA (a) and ferric-reducing antioxidant power (b) levels in rats with cisplatin-induced nephrotoxicity. *Po0.05, **Po0.01, ***Po0.001 in comparison with the sham group. † Po0.05, †† Po0.01 in comparison with the Cisplatin group. Table 2. The effects of oral administration of Physalis alkekengi or Alhagi maurorum on renal histopathologic scores induced by cisplatin Experimental groups Histopathology cortex Cis +Alhagi Cis +Physalis Cisplatin Sham Bowman's space enlargement 2.2 2.4 5 0 Proximal tubule injury 2.2 2.6 3.2 0.4 Thick ascending limb injury 2.4 1.8 4.2 0.3 Reduced number of RBCs in glomerular capillaries 2.3 2.4 5 0 Intracellular vacuolization 2.8 2.2 3.8 0.3 Outer medulla Pars recta (S3) injury 3.2 1.8 3.4 0.5 Thick ascending limb injury 2.8 2 3.4 0 Vascular congestion 2.4 1.6 3.2 0.2 Intra-tubular proteinaceous casts 2.8 1.2 3.2 0.2 Inner medulla Vascular congestion 2.6 1.8 2.8 0 Intra-tubular proteinaceous casts 2.8 1.4 2.8 0 Total histopathologic score 28.5**†† 21.2*†† 40.0** 1.9 Abbreviation: RBC, red blood cell. Histopathological scores in rats receiving normal saline (sham), cisplatin, cisplatin plus Physalis alkekengi (Cis+Physal) or cisplatin plus Alhagi maurorum (Cis+Alhagi) extract. *Po0.05, **Po0.01 in comparison with sham group. †† Po0.01, for comparison of cisplatin group with Cis+Physal or Cis+Alhagi group. Protection from cisplatin-induced nephrotoxicity S Changizi-Ashtiyani et al 3 © 2016 Nature America, Inc. Cancer Gene Therapy (2016), 1 – 6
  4. 4. suggesting the role of cisplatin in increasing oxidative stress and decreasing the activity of antioxidant enzymes in kidney,29,31–36 as well as the stimulation of calcium-independent nitric oxide synthase,37–40 which are leading to increased production of NO and proxy nitrite (ONOO − ). Our findings revealed that P. alkekengi and A. maurorum were able improve this condition under treatment by cisplatin. In addition, it is known that cisplatin enters renal epithelial cells via organic cation transporter-2(OCT2)41–43 and copper transporter-1 (Ctr1),44 which causes mitochondrial and nuclear DNA damage. In the present study, we observed cell necrosis in the cortex and outer medulla of cisplatin-treated rats. However, treatment of animals by A. maurorum and P. alkekengi improved creatinine clearance, reduced plasma creatinine and urea-nitrogen concentrations, and reduced the levels of oxidative stress parameters. Also, tissue damage induced by cisplatin was reduced by both extracts, although the beneficial effects were more prominent in the group receiving P. alkekengi. Several previous studies have shown the biological effects of these agents. In particular, Hoshani and Aghdasi12 illustrated that P. alkekengi had an antioxidant property. More- over, several other studies have shown that P. alkekengi inhibited iNOS activity and reduced NO production. Anti- inflammatory activity of this extract was reported by inhibition of NF-κB and TNF-α and lipoxygenase-1activity.14,15 Moreover, several studies have shown the antioxidant activity,16,45 anti- inflammatory effect,18,19 urease inhibitory activity46 and litolitic properties20 of A. maurorum. CONCLUSION In aggregate, the present study expands the spectrum of the potential beneficial effects of A. maurorum and P. alkekengi as supplement agents for reducing the nephrotoxicity side effect of cisplatin. We found that both extracts reduced drug- induced nephrotoxicity. The protective mechanism was in part through reducing oxidative stress, inflammation and conversion of reactive oxygen species to reactive nitrogen species. Figure 3. Representing the histopathologic alterations in the cortex for Bowman's space widening and tubular necrosis in (a) sham group, (b) cisplatin group that received normal saline, (c) P. alkekengi or (d) A. maurorum extracts. Haematoxylin and eosin staining, magnification × 400. Protection from cisplatin-induced nephrotoxicity S Changizi-Ashtiyani et al 4 Cancer Gene Therapy (2016), 1 – 6 © 2016 Nature America, Inc.
  5. 5. CONFLICT OF INTEREST The authors declare no conflict of interest. ACKNOWLEDGEMENTS This paper is based on the results of research project No. 994 approved by the research deputy of Arak University of Medical Sciences. We wish to thank them for their financial support. This work was supported by a grant from Arak University of Medical Sciences. AUTHOR CONTRIBUTIONS Saeed Changizi-Ashtiyani, Mostafa Alizadeh, Houshang Najafi, Saeed Babaei, Mahdi Khazaei, Mostafa Jafari and Nasser Hossaini conceived, designed, contributed reagents, performed the experiments and analyzed the data. Saeed Changizi Ashtyani, Mostafa Alizadeh, Houshang Najafi, Saeed Babaei, Mahdi Khazaei, Mostafa Jafari, Nasser Hossaini, Amir Avan and Bahar Bastani contributed in writing of the manuscript. REFERENCES 1 Hartmann JT, Fels LM, Knop S, Stolt H, Kanz L, Bokemeyer C. A randomized trial comparing the nephrotoxicity of cisplatin/ifosfamide-based combination che- motherapy with or without amifostine in patients with solid tumors. Invest New Drugs 2000; 18: 281–289. 2 Hartmann JT, Lipp HP. Toxicity of platinum compounds. Expert Opin Pharmacother 2003; 4: 889–901. 3 Sastry J, Kellie SJ. Severe neurotoxicity, ototoxicity and nephrotoxicity following high-dose cisplatin and amifostine. Pediatr Hematol Oncol 2005; 22: 441–445. 4 Arany I, Safirstein RL. Cisplatin nephrotoxicity. Semin Nephrol 2003; 23: 460–464. 5 Boulikas T. Poly (ADP-ribose) synthesis in blocked and damaged cells and its relation to carcinogens. Anticancer Res 1992; 12: 885–898. 6 Saad SY, Arafah MM, Najjar TA. Effects of mycophenolate mofetil on cisplatin- induced renal dysfunction in rats. Cancer Chemother Pharmacol 2007; 59: 455–460. 7 Miller RP, Tadagavadi RK, Ramesh G, Reeves WB. Mechanisms of Cisplatin Nephrotoxicity. Toxins 2010; 2: 2490–2518. 8 Kuhad A, Pilkhwal S, Sharma S, Tirkey N, Chopra K. Effect of curcumin on inflammation and oxidative stress in cisplatin induced experimental nephrotoxi- city. J Agric Food Chem 2007; 12: 10150–10155. Figure 4. Representing the histopathologic alterations in medulla for cellular necrosis, tubular casts and vascular congestion in (a) sham group, (b) cisplatin group that received normal saline, (c) P. alkekengi or (d) A. maurorum extracts. Haematoxylin and eosin staining, magnification × 400. Protection from cisplatin-induced nephrotoxicity S Changizi-Ashtiyani et al 5 © 2016 Nature America, Inc. Cancer Gene Therapy (2016), 1 – 6
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