Mitochondria-mediated mitigatory role of curcumin in cisplatin-induced nephrotoxicity

Mitochondria-mediated mitigatory role of curcumin incisplatin-induced nephrotoxicity

Mohammad Waseem†, Pooja Kaushik† and Suhel Parvez*

Department of Medical Elementology and Toxicology, Jamia Hamdard (Hamdard University), New Delhi, India

Cisplatin (CP) is one of the most potent chemotherapeutic anti-tumour drugs, and it has been implicated in renal toxicity. Oxidative stress hasbeen proven to be involved in CP-induced toxicity including nephrotoxicity. However, there is paucity of literature involving role ofmitochondria in mediating CP-induced renal toxicity, and its underlying mechanism remains unclear. Therefore, the present study wasundertaken to examine the antioxidant potential of curcumin (CMN; a natural polyphenolic compound) against the mitochondrial toxicityof CP in kidneys of male rats. Acute toxicity was induced by a single intra-peritoneal injection of CP (6mgkg�1). We studied the ameliorativeeffect of CMN pre-treatment (200mg kg�1) on the toxicity of CP in rat kidney mitochondria. CP caused a significant elevation in themitochondrial lipid peroxidation (LPO) levels and protein carbonyl (PC) content. Pre-treatment of rat with CMN significantly replenishedthe mitochondrial LPO levels and PC content. It also restored the CP-induced modulatory effects on altered enzymatic and non-enzymaticantioxidants in kidney mitochondria. We hypothesize that the reno-protective effects of CMN may be related to its predisposition toscavenge free radicals, and upregulate antioxidant machinery in kidney mitochondria. Copyright © 2013 John Wiley & Sons, Ltd.

key words—curcumin; cisplatin; oxidative stress; mitochondria; nephrotoxicity; biomarkers

INTRODUCTION

Cisplatin (CP), a platinum-based drug, is one of the mostfrequently used anti-neoplastic agents to treat a variety ofcancers. It has a potent chemotherapeutic action against broadrange of malignancies, including bladder, ovarian, testicular,cervical and lung cancers as well as solid tumours resistant toother treatment regimens.1,2 The major dose-limiting side effectof CP is its nephrotoxicity and hepatotoxicity. It has been inves-tigated that nephrotoxicity can result in severe nephropathy,which may lead to acute renal failure.3 The kidney selectivelyaccumulates CP and to higher degree than other organs, prob-ably through mediated transport.4–6 Once inside the cell, CPinteracts with a variety of other molecules besides DNAincluding sulphur-containing macromolecules, e.g. glutathione,that sequester CP and remove it from the cell.7–10

Defects in mitochondria in relation to oxidative damageseems to play pivotal role in cell death induced by CP.11,12

A direct link between mitochondrial dysfunction and toxicexposure of anticancer drugs has been established.13–15

CP-induced nephrotoxicity studies suggest that augmentedreactive oxygen species (ROS) generation, with consequentimpairment of mitochondrial function and structure, may bea detrimental factor.16,17 Oxidative stress is involved in theearly stage of CP-induced nephrotoxicity.18–20

Natural compounds have been studied to diminish severeside effects as well as increase anti-tumour activities of anticancer drugs.21 Curcumin (CMN) is the chief component ofthe spice turmeric and is derived from rhizome of the EastIndian plant Curcuma longa.22 The purpose of CMN has beenaccounted as a therapeutic agent to modulate various kinds oftoxicity including hepatotoxicity, cardiotoxicity, neurotoxicityand nephrotoxicity.23–26 Pre-treatment with CMN was foundto mitigate mitochondrial dysfunction in rodents.27 Thecompound has been depicted to possess a variety of pharmaco-logical and biological activities including anti-inflammatory,antimicrobial, antioxidant and anticancer activities.28–31 It alsohas a protective effect against adverse effects of CP.32,33

It has been postulated that the cytotoxic effect of CPoccurs via a mitochondrial injury. CMN has been shownto protect mitochondria against various oxidative stressconditions.34 The aims of the present study were to determinethe level of oxidative stress resulting from mitochondrialdysfunction in CP-mediated nephrotoxicity and to investigatethe possible modulatory effect of CMN on CP-inducedalteration in antioxidant armamentarium of rats.

MATERIALS AND METHODS

Chemicals

Bovine serum albumin, butylated hydroxy toluene (BHT),1-chloro-2,4-dinitrobenzene (CDNB), 2,4-dinitrophenylhydrazine (DNPH), 5,50-dithiobis (2-nitrobenzoic acid)

*Correspondence to: Suhel Parvez, Department of Medical Elementologyand Toxicology, Jamia Hamdard (Hamdard University), New Delhi 110062, India.E-mail: [email protected]†Contributed equally to this work.

Received 25 October 2012Revised 30 November 2012Accepted 2 January 2013Copyright © 2013 John Wiley & Sons, Ltd.

cell biochemistry and functionCell Biochem Funct 2013; 31: 678–684.Published online 13 February 2013 in Wiley Online Library(wileyonlinelibrary.com) DOI: 10.1002/cbf.2955

(DTNB), ethylenediaminetetraacetic acid (EDTA), epinephrine,oxidized glutathione (GSSG), reduced glutathione (GSH),hydrogen peroxide (H2O2), nicotinamide adenine dinucleotidephosphate reduced tetrasodium salt, o-phoshoric acid (OPA),sulfosalicylic acid, thiobarbituric acid (TBA) and trichloroacetic acid (TCA) were purchased from Sigma ChemicalsCo. (St. Louis, MO, USA). Other routine chemicals wereobtained from Hi-Media Labs and Merck Limited (Mumbai,India). CP and CMN were obtained from Dr Reddy’s Lab(Hyderabad, India) and Hi-Media Labs (Mumbai, India),respectively.

Animals and experimental design

Adult male Wistar rats weighing between 100 and 120 g wereused in the experiments. Animals were maintained andutilized under the guidelines of Institutional Animals EthicsCommittee. Animals were stabilized for 7 days prior to theexperiments on standard rat pellet diet with free access towater. They were kept at temperature 22� 2 �C with relativehumidity at 65� 10% and at a photoperiod of 12 h light/darkcycle. Animals were randomly assigned to four groups, andeach group consisted of six animals (n = 6). CP was admi-nistered intraperitoneally (i.p.) and CMN by oral gavage.Control animals (group I) were administered normal saline(1ml kg�1). CMN alone (200mg kg�1, orally) was given ina single dose (group II). Group III (CP +CMN) rats wereadministered CMN treatment (200mg kg�1, orally) 24 hprior to the administration of CP (6mg kg�1, i.p.) and usedas a pre-treatment group. In group IV, CP alone (6mg kg�1)was given as a single i.p. dose. Dosing was performed insuch a way that all the animals were sacrificed on the sameday. The CP and CMN dose schedules were based on thepreliminary investigation involving a dose and also frompreviously published reports.35,36 At the end of the experi-mental period (after 24 h of the administration of CP), therats were anesthetized and sacrificed by cervical decapita-tion. Their kidneys were quickly excised and washed inice-cold saline to remove blood. The effect of CP and roleof CMN on the oxidative stress biomarkers were investi-gated in kidney mitochondria.

Mitochondrial preparation

Rat kidney mitochondria were isolated by differential centri-fugation method.35,37 Briefly, the kidneys from the adult ratswere separated and homogenized by using mechanicallydriven Teflon-fitted Potter-Elvehjem type homogenizer inan ice-cold isolation buffer containing 0�25mol 1�1 sucroseand 1mmol 1�1 EDTA adjusted by Tris to pH 7�4, centri-fuged at 800 g for 5min. The supernatant was centrifugedat 5100 g for 4min. Thereafter, the obtained pellet wasresuspended again in a 0�25mol 1�1 sucrose mediumadjusted by Tris to pH 7�4 and centrifuged at 12 300 g for2min. Finally, the pellet was resuspended in a 0�25mol1�1 sucrose medium adjusted by Tris to pH 7�4, centrifugedat 12 300 g for 10min, and resuspended in a buffer containing0�25mol 1�1 sucrose and 0�5mmol 1�1 EDTA adjustedby Tris to pH 7�4. The protein concentration of the stock

suspension was 2–3mgml�1 as determined using theLowry method.38

Biochemical analysis

Assessment of oxidative stress biomarkers. Assay ofmitochondrial lipid peroxidation (LPO). LPO was measuredusing the procedure of Tabassum et al.39 The mixtureconsisted of 10mmol 1�1 BHT, 0�67% TBA, 1% chilledOPA and mitochondrial preparation (2–3mg protein ml�1).The mixture was incubated at 90 �C for 45min. The absorb-ance of supernatant was measured at 535 nm. The rate ofLPO was determined as micromoles of TBA reactivesubstances (TBARS) formed per hour per gram tissue usinga molar extinction coefficient of 1�56� 105M�1 cm�1.

Measurement of mitochondrial protein oxidation. Proteinoxidation in kidney mitochondria was measured as theconcentration of protein carbonyls (PCs) by using DNPHassay. PC content was assayed using the procedure of Floorand Wetzel.40 The mitochondrial preparations were treatedwith 10mmol l�1 DNPH in 2mol l�1 hydrochloric acid for1 h at room temperature and precipitated with 6% TCA.The pelleted protein was washed thrice by resuspension inethanol/ethyl acetate (1:1). Proteins were then solubilizedin 6mol l�1 guanidine hydrochloride and 50% formic acidand centrifuged at 16 000 g for 5min to remove any traceof insoluble material. The carbonyl content was measuredspectrophotometrically at 360 nm. Results were expressedas nanomoles of DNPH incorporated per milligram proteinusing molar extinction coefficient of 21 000M�1 cm�1.

Evaluation of mitochondrial non-enzymatic antioxidants

Mitochondrial GSH estimation. Reduced glutathione contentwas estimated according to the method of Tabassum et al.41

In this method, DTNB is reduced by –SH groups to form2-nitro-5-mercaptobenzoic acid per mole of SH. The nitromercaptobenzoic acid anion released has an intense yellowcolour and can be used to measure –SH groups at 412 nm.Mitochondrial suspension was precipitated with 1ml ofsulphosalicylic acid (4%). The samples were kept at 4 �C for1 h and then centrifuged at 1200 g for 15min at 4 �C. Theassay mixture contained 0�4ml of mitochondrial suspension,2�2ml of sodium phosphate buffer (0�1mol l�1, pH7�4) and0�4ml DTNB in a total volume of 3ml. The absorbance ofreaction product was read at 412 nm on a double beamspectrophotometer. The GSH content was expressed as micro-moles GSH per gram tissue.

Determination of mitochondrial antioxidant enzyme activity

Measurement of catalase activity. Catalase (CAT) activitywas analysed using the method of Claiborne, as modified byZafeer et al.42,43 This method is based on the disappearanceof H2O2 at 240 nm. The reaction volume contained 0�1moll�1 sodium phosphate buffer (pH7�4), 0�05mol l�1 H2O2

and 0�05ml mitochondria prepared from 10% homogenateof kidney tissue. Change in absorbance was recorded

679curcumin as antioxidant

Copyright © 2013 John Wiley & Sons, Ltd. Cell Biochem Funct 2013; 31: 678–684.

kinetically at 240 nm. The enzyme activity was calculated asmicromoles H2O2 consumed per minute per milligram proteinby using a molar extinction coefficient of 39�6M�1 cm�1.

Measurement ofmanganese superoxide dismutase activity. Man-ganese superoxide dismutase (MnSOD) activities weremeasured according to the method of Govil et al.44 Theassay was based on the ability of SOD to inhibit the auto-oxidation of epinephrine at alkaline pH. The mitochondrialsuspension (0�2ml) was treated with 0�8ml of 50mmol l�1

glycine buffer (pH 10�4) and 0�020ml epinephrine.MnSOD activity was measured kinetically at 480 nm. Theactivity was measured indirectly by the oxidized productof epinephrine, i.e. adrenochrome. MnSOD activity wasexpressed as nanomoles of (�)epinephrine protected fromoxidation per minute per milligram protein by using a molarextinction coefficient of 4020M�1 cm�1.

Measurement of glutathione-S-transferase activity. Meas-urement of glutathione-S-transferase (GST) activity wascarried out using the method of Habig et al.45 This reactionis measured by observing the conjugation of CDNB withGSH forming a coloured conjugate glutathione 2,4-dinitro-benzene. For GST activity measurement, the reactionmixture contained 1�575ml of 0�1mol l�1 sodium phosphatebuffer (pH 7�4), 0�2ml GSH (10mmol l�1), 0�025ml(10mmol l�1) CDNB and 0�2ml mitochondrial suspension.The enzyme activity was calculated as nanomoles of CDNBconjugate formed per minute per milligram protein by usinga molar extinction coefficient of 9�6� 103M�1 cm�1 at340 nm.

Protein estimation. Mitochondrial protein content wasdetermined using Lowry’s method.38

Statistical analysis

Data were expressed as means� SE. All data were analysedusing one-way ANOVA followed by Tukey’s test formultiple comparisons of group means. Values of p< 0�05were considered as significant. All the statistical analyses wereperformed using GRAPH PAD PRISM 5 software (Graph PadSoftware, Inc., San Diego, CA, USA).

RESULTS

Oxidative stress biomarkers

CMN prevented enhancement of LPO level in CP-treatedrats. The LPO status in kidney mitochondria of variousgroups is shown in Figure 1. A significant increase (p< 0�001)in the level of LPOwas observed in CP-treated group in kidneymitochondria as compared with that in the control animals.CMN pre-treatment significantly (p< 0�001) decreased thelevel of LPO products in kidney mitochondria as comparedwith that in CP-treated animals. CMN treatment caused nosignificant alteration in kidney mitochondria as compared withthat in the control animals.

CMN prevented increases in PC content in CP-treatedrats. Cisplatin treatment led to a significant elevation(p< 0�001) in PC content of kidney mitochondria as comparedwith that in the control group (Figure 2). The PC content inCMN-alone treatment showed a significant (p< 0�001) changein kidney mitochondria as compared with that in the controlanimals. In the group administered with CP combined withCMN, the content of kidney mitochondrial PC was signifi-cantly (p< 0�001) lower than that of CP-alone-treated animals.

Non-enzymatic antioxidant profile

CMN provides protection against elevation in GSH contentsin CP-treated rats. A single dose of CP caused a significant(p< 0�001) increase in GSH content in kidney mitochondriaof animals when compared with that in the control animals.CMN pre-treatment in CP-treated group caused a significant(p< 0�001) restoration inGSH contents of kidneymitochondria

Figure 1. Effect of CMN and CP on LPO in kidney mitochondria of rats.Values were expressed as micromoles of TBARS formed per hour per gramtissue. Each value is represented as mean�SE (n= 6). Significant differ-ences were indicated by ***p< 0�001 when compared with control, andsignificant differences were indicated by ###p< 0�001 when compared withCP-treated animals

Figure 2. Effect of CMN and CP on PC content in kidney mitochondria ofrats. Values were expressed as nanomoles of DNPH incorporated per milli-gram protein. Each value is represented as mean�SE (n= 6). Significantdifferences were indicated by ***p< 0�001 when compared with control,and ###p< 0�001 was used to show significance when compared with CP-treated animals

680 m. waseem ET AL.


when compared with that of the CP group. CMN-alone-treatedanimals did not show any significant change in GSH contentin kidney mitochondria as compared with that in the controlanimals (Figure 3).

Enzymatic antioxidant profile

CMN ameliorated the decrease in CAT activity in CP-treatedrats. Cisplatin treatment caused a significant decline (p< 0�001)in CAT activity of kidney mitochondria as compared with thatin the control group (Figure 4). CMN pre-treatment withCP-treated group was significantly (p< 0�001) greater inCAT activity as compared with that in CP-alone-treatedgroups. CAT activity in the CMN-alone treatment wassignificantly (p< 0�001) changed as compared with that inthe control group.

CMN alleviated the CP-induced inhibition of MnSOD activityin rats. Cisplatin administration significantly (p< 0�001)increased on MnSOD activity in kidney mitochondria as

compared with that in the control. CP treatment in CMN-supplemented animals showed significant depletion (p< 0�001)in the activity ofMnSOD in kidneymitochondria as comparedwith that in the CP-alone-treated group (Figure 5). A signifi-cant (p< 0�001) change was also observed inMnSOD activityin kidney mitochondria of the CMN-treated group whencompared with that in the control.

CMN partially modulated the CP-induced inhibition of GSTactivity in rats. Cisplatin treatment caused a significantenhancement (p< 0�05) on the activity of GST in kidneymitochondria as compared with that in the control (Figure 6).These effects were significantly (p< 0�01) mitigated by CMNpre-treatment in kidney as compared with that in theCP-treated group. GST activity in CMN-alone-treated groupremained significantly (p< 0�01) lower as compared with thatin the control group.

DISCUSSION

Chemotherapeutic agents such as CP continue to be anirreplaceable therapy against various malignancies, despiteits side effects such as nephrotoxicity. The exact mechanismunderlying CP-induced nephrotoxicity is not well known.The treatment of kidney mitochondria with CP provokesseveral responses including membrane peroxidation anddysfunction of mitochondria.20,46 The current study demon-strates that CMN provides protection against CP-inducednephrotoxicity in rats. The data obtained in our studyconfirm that acute intoxication with CP causes a significantincrease of LPO concentration in the kidney mitochondria ofrats. LPO is probably the most largely considered productproduced by free radicals and hence is regarded as an excel-lent biomarker of oxidative stress. Free radical generation oroxidative stress develops when there is an imbalancebetween pro-oxidants and antioxidants, leading to the

Figure 3. Effect of CMN and CP on level of GSH in kidneymitochondria ofrats. Values were expressed as micromoles GSH per gram tissue. Each valuerepresented as mean�SE (n=6). Significant differences were indicatedby ***p< 0�001 when compared with control. Significant differences,###p< 0�001, were shown when compared with CP-treated animals

Figure 4. Effect of CMN and CP on CAT activity in kidneymitochondria ofrat. Values were expressed as micromoles of H2O2 consumed per minute permilligram protein. Each value is represented as mean�SE (n=6). Significantdifferences were indicated by ***p < 0�001 when compared with control andby ###p< 0�001 when compared with CP-administered animals

Figure 5. Effect of CMN and CP on MnSOD activity in kidney mitochon-dria of rats. Values were expressed as nanomoles of (�)epinephrine pro-tected from oxidation per minute per milligram protein. Each value isrepresented as mean�SE (n= 6). Significant differences were indicatedby ***p< 0�001 when compared with control and by ###p< 0�001 whencompared with CP-administered animals



generation of ROS.37,47 The increase in LPO reported heremay be the result of increased production of ROS or a decreasein antioxidant status. A high concentration of polyunsaturatedfatty acids in the mitochondrial membrane increases suscepti-bility to lipid peroxidative degradation. The enhanced LPO inmitochondria may decrease mitochondrial membrane fluidity,increase the negative surface charge distribution and altermembrane ionic permeability including proton permeability,which uncouples oxidative phosphorylation.48 In our study,CMN pre-treatment significantly reversed the LPO and alteredantioxidant status. It has been documented that CMN declinedoxidative stress marker LPO by scavenging ROS.23

In our results, CMN could reinforce a constructive actionagainst LPO, which may act as an added compensation mech-anism to retain cell integrity and protection against free radicaldamage. Reduced LPO may result from free radical-inducedinactivation and glycation of the antioxidant enzymes.49

Protein oxidation has been studied in several humandisorders.50 Oxidative damage to proteins modified itssymmetrical arrangement via aggregation, fragmentationand formation of cross-linkages in the polypeptide chain,which further amplified the generation of superoxideanions.51 PC is a ubiquitously preferable biomarker and,so far, the most frequently used indicator of PC accumulationand protein oxidation. We observed that CP enhanced proteinoxidation in kidney mitochondria, which is advocated by theincreased production of superoxide radicals.17,39,52 CMN iswidely considered to be responsible for its modulatory effectsin different tissues including renal tissue.34 CMN has beenreported to act as an electrophilic scavenger, as well as anantioxidant.53–55 In our results, CMN pre-treatment preventedthe increase of kidney PC content caused by CP.Glutathione is one of the essential compounds for regulation

of variety of cell functions maintaining cell integrity and cellprotection against a variety of toxins such as free radicalsand their accompanied oxidative injury because of its reducingproperties and participation in cell metabolism. It has a directantioxidant function by reacting with superoxide radicals,

peroxy radicals and singlet oxygen followed by the formationof GSSG and other disulfides.6 GSH, a universal antioxidant,is synthesized in the cytoplasm and then transported intomitochondria.39 The thiol (SH) portion is very reactive withseveral compounds, mainly with alkylating agents such asCP.56,57 In our study, a single dose of CP caused marked renaldamage, characterized by a significant increase in GSH levels.This shows induction of oxidative stress and enervation of thecellular antioxidant defence mechanisms leading to activeparticipation of GSH in cellular defence against ROS.44

The increased values of GSH indicate the non-enzymaticantioxidant response to being subjected to oxidative stress.Earlier research has shown that supplementation of CMNmarkedly altered the GSH or thiol ratio in anticanceragent-induced oxidative stress.23 Mitochondrial GSH playsa key role in mitochondria functionality and has a moresignificant role than cytosolic GSH in determining cellularfunction and viability.58 In our results, pre-treatment withCMNmodulated the GSH levels, thereby protecting againstCP-induced oxidative damage.Catalase, an antioxidant enzyme, decomposes H2O2 into

O2 and H2O. These reactions constitute a mutually supportiveteam of defence against ROS.59 CP administration caused amarked deterioration of the endogenous antioxidant profile,as evidenced by the significant decrease in mitochondrialCAT activities in rodents.59,60 In our study, CP treatmentshowed a declined activity of CAT in kidney mitochondria.CMN administration was able to reverse the activities ofCAT in kidney mitochondria of CP-exposed animals. Theactivity of CAT could reflect the adverse effects of CP, andwith CMN pre-treatment, a restoration of balanced antioxidantsystem may be visualized.Manganese superoxide dismutase is a key antioxidant

enzyme inmitochondria that protects mitochondria from super-oxide anions generated during oxidative phosphorylation.61

MnSOD resides in the matrix of mitochondria. About1–2% of inhaled O2 may be shifted to superoxide anionin mitochondria. In our study, CP treatment showed anincreased activity of MnSOD in kidney mitochondria.Reports have indicated elevated MnSOD activity in theisolated mitochondria of liver and brain.62,63 Our resultindicates that elevated MnSOD activity may be due toan increase in superoxide radical formation. CMN pre-treatment restored MnSOD activity in kidney mitochondria.These results could explain the ability of CMN to enhancethe inactivation and scavenging of H2O2 and hydroxylradical.49

Glutathione-S-transferase is a group of enzymes thatcatalyses the conjugation of GSH via the sulfhydryl group,to electrophilic centers on a wide variety of substrates. Thisactivity is useful in the detoxification of endogenouscompounds such as peroxidised lipids, as well as themetabolism of xenobiotics.6 Mitochondrial GST activityis induced by ROS because of sulfhydryl group oxidation.Enhanced mitochondrial GST activity may be related to anincrease in ROS production in tissue injury.63,64 In ourresults, CP treatment showed an increased activity ofGST in kidney mitochondria. CMN pre-treatment in

Figure 6. Effect of CMN and CP on GST activity in kidney mitochondria ofrats. GST activity was expressed as nanomoles of CDNB conjugate formed perminute per milligram protein. Each value is represented as mean�SE (n=6).Significant differences were shown by **p< 0�01 and *p< 0�05 whencompared with control. Significant differences were indicated by ##p< 0�01when compared with CP-treated animals



mitochondria has restored the enhanced activity of GST.This in turn will help in providing protection fromoxidative stress produced by excess O2 and H2O2.

CONCLUSION

In summary, the current biochemical data confirm that CMNmay protect against acute CP-induced oxidative stress via itsantioxidant and free radical-scavenging properties. In thepresent study, we assessed whether the mitochondrial oxida-tive effects caused by acute administration to CP could beameliorated by pre-treatment with CMN.Our findings providebiochemical evidence for the efficacy of CMN in modulatingthe adverse effects of CP in kidney mitochondria of rats.Moreover, CMN is a natural polyphenolic compound that isused clinically and is approved as a safe food additive. Ourresults clearly demonstrated that CMN provides protectionagainst CP-induced mitochondrial nephrotoxicity throughantioxidants and oxidative stress biomarkers. Future studiesshould examine the hypothesis that CMN administration is asafe and effective approach to attenuating broad systemictoxicity, which is mediated via mitochondrial oxidative stress.An antioxidant therapy targeted to renal mitochondrialdamage induced by CP may constitute an interesting strategyto mitigate renal toxicity at molecular level.

CONFLICT OF INTEREST

The authors have declared that there is no conflict of interest.

ACKNOWLEDGMENTS

University Grants Commission, Government of India, isgratefully acknowledged for providing funding under theMajor Research Project to S. P. M.W. was supported by afellowship from Research Promotion Grant of JamiaHamdard (Hamdard University), New Delhi, India.

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Mitochondria-mediated mitigatory role of curcumin in cisplatin-induced nephrotoxicity