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Plant-Derived Agents for Counteracting Cisplatin-Induced Nephrotoxicity.

1. Introduction

Cisplatin (CSP), chemically known as cis-diamminedichloroplatinum-II, is an anticancer agent used in the treatment of testicular, head and neck, ovarian, cervical, and non-small-cell lung cancers [1]. The major issues limiting the clinical use of CSP are its tendency to induce profound nephrotoxicity and ototoxicity [1]. The first occurrence of nephrotoxicity was documented in the clinical trial that evaluated the anticancer effects of CSP. It is estimated that 30% of patients treated with CSP could exhibit elevated serum creatinine levels and reduced glomerular filtration rate, reflecting the development of nephrotoxicity. In addition, these symptoms could occur as early as 10 days after the initiation of CSP chemotherapy. Moreover, nephrotoxicity is considered a determinant side effect of the use of anticancer medications. It is pertinent to note that approximately 50-60% of patients undergoing cancer chemotherapy acquire nosocomial acute kidney injury, which is associated with increased morbidity and mortality rates [1, 2].

The pathophysiological mechanisms purported to underlie CSP-induced nephrotoxicity have been extensively studied, and several hypotheses have been forwarded. To date, oxidative stress, inflammation, and apoptosis pathways have been widely considered as key pathomechanisms involved in the CSP-induced nephrotoxicity [3]. The identified scenario is that the accumulation of CSP in renal tissues results in massive oxidative stress that causes inflammatory damage to the tubular epithelium, which spreads to the renal microvasculature, impedes the blood flow by evoking ischemic injury, and decreases the glomerular filtration rate. These phenotypic events culminate in acute renal failure. To circumvent the CSP-induced nephrotoxicity, several analogs have been developed, which are expected to be less nephrotoxic. In addition, several clinical trials have examined the efficacy of mannitol and furosemide (osmotic and loop diuretics, resp.) in reducing the renal retention of CSP and, thereby, minimizing the noxious effects on naive tissue [4]. However, this approach has met with limited clinical success; while the induced nephrotoxicity has been milder, it has not been completely averted. Therefore, there is an urgent need to develop agents that confer renoprotection without compromising the anticancer activity of CSP [1, 5].

2. Phytochemicals as Leads for Attenuating CSP-Induced Nephrotoxicity

Phytochemicals are compounds that are distributed in various plant tissues and are responsible for imparting characteristics such as color and smell but do not possess nutritional value. Importantly, phytochemicals have been used in traditional medicine for several centuries for treating various ailments. There is considerable evidence from in vitro preclinical studies that phytochemicals extracted from various plant sources may retard tumor growth and elicit antioxidant and anti-inflammatory effects [6]. Most importantly, the anticancer agent Taxol (paclitaxel) is a phytochemical that was originally identified, extracted, and purified from the bark of the Pacific yew tree (Taxus brevifolia) [7]. Currently, most developed drugs are not from plants but are rather chemically synthesized. Recently there is a renewed interest in tapping into the potential of medicinal plants in drug discovery, since phytochemicals are chemically diverse in nature and a considerable receptacle of pharmacophores. This enthusiasm has led to significant research strides in the identification of several potential phytochemicals that are being investigated for their renoprotective actions in preclinical studies.

Extensive investigations over the past decade have provided significant insights into the pathophysiology of CSP-induced nephrotoxicity. A plethora of biochemical pathways and mechanisms have been purported to mediate CSP-elicited nephrotoxicity, including those involved in oxidative/nitrative stress, mitochondrial malfunction, inflammation, and cell death (reviewed in [8-10]). Recently, the involvement of endocannabinoid system has been implicated in the pathogenesis of CSP-induced nephrotoxicity [11,12].

In this context, we have discussed the developments made with the use of phytochemicals to attenuate the development CSP-induced nephrotoxicity in experimental models. The summary of the effects of phytochemicals in preclinical or ex vivo studies or both is provided in Table 1. The chemical structures of phytochemicals that have been tested for potential renoprotective actions against CSP-induced renal toxicity are presented in Table 2. Next, various biochemical pathways recruited by CSP in eliciting renal toxicity and the attenuation of these effects by phytochemicals are illustrated in Figure 1. Furthermore, in the following section, we systematically discussed the effects of various phytochemicals investigated for their potential renoprotection against CSP-induced nephrotoxicity.

2.1. 23-Hydroxytormentic Acid (23-HTA) and Niga-ichigoside [F.sub.1] (NI[F.sub.1]). 23-Hydroxytormentic acid (23-HTA), an aglycone of the triterpenoid glycoside niga-ichigoside [F.sub.1] (NI[F.sub.1]), has been isolated from the unripe fruit of Rubus coreanus, a perennial shrub found in southern parts of Korea [13]. Kim et al. [13] and Sohn et al. [14] have demonstrated that 23-HTA and NI[F.sub.1] attenuated CSP-induced nephrotoxicity by mitigating oxidative stress and inflammation in renal tissues. However, further mechanistic studies are required to confirm their renoprotective effects against CSP-induced renal toxicity.

2.2. 6-Gingerol. 6-Gingerol is a pungent ingredient of ginger (Zingiber officinale), which has demonstrated antiinflammatory, analgesic, antipyretic, antitumor, and antiproliferative properties [15, 16]. Kuhad et al. [17] reported that gingerol inhibited CSP-induced nephrotoxicity by suppressing oxidative stress. Similarly, another study reported that gingerol elicited renoprotective action by mitigating renal oxidative stress and inflammation [18]. However, further studies are warranted to delineate the precise molecular mechanisms of their renoprotective actions.

2.3. 6-Hydroxy-1-methylindole-3-acetonitrile (6-HMA). 6HMA is a phytochemical present in Brassica rapa roots. In traditional medicine, B. rapa has been used to treat a variety of conditions such as hepatitis, jaundice, furuncle, and sore throats [19]. 6-HMA has been demonstrated to improve renal function, augment endogenous antioxidant defenses, and protect kidneys from the noxious effects of CSP. Further, 6-HMA also inhibited CSP-induced death of LLC-PK1 cells (renal proximal tubular epithelial cells derived from porcine kidneys) [19].

2.4. [beta]-Caryophyllene (BCP). [beta]-Caryophyllene (BCP) is a natural sesquiterpene found in several essential oils of spices such as cinnamon, oregano, black pepper, basil, cloves, and other condiments [20]. BCP has been shown to elicit anti-inflammatory [20] and antioxidant effects [21, 22]. Horvath et al. [23] demonstrated that BCP attenuated CSPinduced nephrotoxicity by decreasing oxidative/nitrative stress, inflammation, and cell death pathway activation. Further, mechanistic studies revealed that the renoprotective actions of BCP against CSP-induced renal toxicity were mediated via activation of cannabinoid receptor-2 (C[B.sub.2]). It is pertinent to note that previous studies have also demonstrated the renoprotective role of C[B.sub.2] receptor activation [24]. In addition, several studies have documented the anti-inflammatory phenotype induced by C[B.sub.2] receptors activation in preclinical studies [25]. Considering the good safety and tolerability profile of BCP in human subjects, this has excellent prospects for further pharmaceutical development as a renoprotective agent.

2.5. Berberine. Berberine, an isoquinoline alkaloid present in the rhizome, root, and stem bark of several plant species, is especially highly concentrated in berries (Berberis vulgaris) [26]. Berberine has been documented to possess antioxidant, anti-inflammatory, and anticancer activities [26]. Berberine inhibited CSP-induced nephrotoxicity by reducing oxidative stress/nitrative stress, nuclear factor kappa-light-chain-enhancer of activated B-cells (NF[kappa]B) activation, and proinflammatory cytokine expression. In addition, berberine also inhibited apoptosis and diminished the cytochrome P450 (CYP) 2E1 expression in CSP-treated kidneys. CYP2E1 is the primary enzyme involved in the biotransformation of cisplatin, and previous studies have also demonstrated that genetic ablation of CYP2E1 imparted renoprotection against CSP-induce toxicity [27, 28].

2.6. Bixin. Bixin is the main carotenoid found in species of the tropical plant Annatto (Bixa orellana). Bixin inhibited CSP-induced nephrotoxicity by inhibiting lipid peroxidation and augmenting endogenous antioxidant defenses [29, 30]. However, further mechanistic studies are required to understand its renoprotective properties.

2.7. C-Phycocyanin (C-PC). C-Phycocyanin (C-PC) is a pigment from the blue-green algae, Spirulina maxima [31]. C-PC has been shown to mitigate CSP-induced nephrotoxicity via inhibition of oxidative stress, inflammation, and apoptosis. Furthermore, mechanistic studies revealed that C-PC blunted CSP-induced proapoptotic mitogen-activated protein kinase (MAPK) kinase (MEK), B-cell lymphoma 2- (Bcl2-) associated X protein (Bax)/Bcl2 ratio alterations, and caspase-3 activation in renal tissues [31, 32].

2.8. Caffeic Acid Phenethyl Ester (CAPE). Caffeic acid phenethyl ester (CAPE) is an active phenolic compound extracted from honeybee propolis [33]. CAPE treatment inhibited CSP-induced renal toxicity by suppressing oxidative stress, inflammation, and apoptosis. Further, CAPE also blunted CYP2E1 activation, thereby inhibiting the biotransformation of CSP [33, 34]. However, further studies are required to investigate whether CAPE provides renoprotection without compromising the anticancer effects of CSP.

2.9. Cannabidiol (CBD). Cannabidiol (CBD) is a phenolic compound and phytocannabinoid extracted from the Cannabis sativa (marijuana) plant, and it elicits antiinflammatory, immunomodulatory, and analgesic effects [35]. CBD attenuated CSP-induced nephrotoxicity by suppressing oxidative stress, inflammation, and apoptosis. It is also pertinent to note that CBD reversed the CSP-induced kidney injury when administered after the onset of renal tissue injury [36]. Furthermore, it is noteworthy that CBD is devoid of psychoactive properties since it does not bind to major cannabinoid receptors and has an excellent safety profile in human subjects. Recently, CBD was approved for the treatment of childhood epilepsy [25], and it could also be considered as a potent candidate for further development to counteract CSP-induced renal toxicity.

2.10. Capsaicin. Capsaicin is the major pungent ingredient in red peppers and has been used in pain sensation studies based on its stimulation of vanilloid receptor-1, an ion channel protein expressed by nociceptive primary afferent neurons [37]. Capsaicin has been demonstrated to inhibit oxidative stress, inflammation, and apoptosis in the renal tissues of CSP-treated animals. The renoprotective effects were in part due to the activation of heme oxygenase-1 (HO-1) [38, 39].

2.11. Cardamonin. Cardamonin is a flavone found in Alpinia plants and has been shown to affect cell-signaling pathways and to possess anticancer and anti-inflammatory properties [40]. Cardamonin increased endogenous antioxidants and decreased oxidative stress and inflammation [41-44].

2.12. Carnosic Acid. Carnosic acid is a naturally occurring polyphenolic diterpenoid molecule present in rosemary (Rosmarinus officinalis) [45]. Carnosic acid suppressed CSP-induced nephrotoxicity by mitigating oxidative stress and apoptosis in renal tissues [45]. However, additional studies are required to understand the molecular mechanisms purported to mediate its renoprotective actions.

2.13. Chrysin. Chrysin (5,7-dihydroxyflavone) is a flavonoid extracted from honeybee propolis. Chrysin has been reported to be a potent inhibitor of aromatase and anticancer properties [46]. Sultana et al. demonstrated that treatment of chrysin effectively diminished CSP-induced oxidative stress by improving antioxidant enzyme status and restored membrane integrity of tubular epithelial cells [47]. Furthermore, Khan et al. [48] reported that chrysin attenuated CSP-renal toxicity by inhibiting oxidative stress, p53 expression, DNA damage, and apoptosis.

2.14. CinnamicAcid and Cinnamaldehyde. The essential oil of cinnamon contains both cinnamic acid (CA) and cinnamaldehyde (CD). These phytochemicals have been documented to possess antioxidant, antibacterial, and anti-inflammatory effects [49]. CA and CD administration to rodents restored kidney function, suppressed oxidative stress, and mitigated the histopathological degeneration induced by CSP [49]. However, additional studies are required to understand the precise molecular mechanism underlying the renoprotective actions of CA and CD.

2.15. Curcumin. Curcumin is a principle curcuminoid (phenolic terpene compound) derived from the Indian curry spice turmeric (Curcuma longa) [50]. Curcumin treatment restored CSP-induced depletion of endogenous antioxidants [51-53] and reduced inflammation by suppressing NF[kappa]B activation, expression of proinflammatory cytokines, and adhesion molecules [54, 55]. Furthermore, curcumin has been reported to ameliorate CSP-induced renal toxicity by augmenting silent mating type information regulation 2 homolog-1 (SIRT-1) and nuclear factor erythroid-derived 2 (Nrf2), which enhanced endogenous antioxidant defenses and mitochondrial biogenesis [55, 56].

2.16. Cyanidin. Proanthocyanidins are polyphenol derivatives of flavan-3-ol flavonoids derived from grape seed. Proanthocyanidins are reported to possess antioxidant, anti-inflammatory, and antitumor activities [57]. Cyanidin treatment of rodents suppressed CSP-induced renal reactive oxygen species (ROS) generation and enhanced the activation of prosurvival kinases such as extracellular signal-regulated kinase (ERK) and Akt. Furthermore, cyanidin also suppressed CSP-induced renal apoptosis by blunting caspase-3/12 expression, the Bax/Bcl-2 ratio, p53 phosphorylation, and poly adenosine diphosphate (ADP) ribose polymerase (PARP) activation. In addition, cyanidin also suppressed CSP-induced endoplasmic reticulum stress in renal tissues [58]. Collectively these results suggest that cyanidin recruited several prosurvival pathways to counteract CSP-induced renal damage.

2.17. Decursin. Decursin is a natural pyranocoumarin compound isolated from the Korean herb Angelica gigas and is reported to possess anticancer activity [59]. Decursin treatment reduced CSP-induced renal toxicity by attenuating oxidative stress, inflammation, and apoptosis pathways in renal cancer cell lines and rodents [59, 60]. Recently, dose escalation studies were conducted to determine the pharmacokinetic profile of decursin in human subjects. From this study, it was inferred that decursin was well tolerated in both sexes and reached a peak plasma concentration in 812 h. These observations indicate the efficacy, safety, tissue distribution, and pharmacodynamic properties of decursin in human subjects [61].

2.18. Ellagic Acid. Ellagic acid is a naturally occurring phenolic compound found in fruits such as raspberries, strawberries, and pomegranates [62]. Ellagic acid treatment ameliorated CSP-induced renal toxicity by suppressing the kidney injury molecule (KIM-1) and clusterin protein expression (considered as early indicators of kidney injury) [63]. Furthermore, ellagic acid enhanced the glomerular filtration rate, which corroborated its reduction of inflammatory mediators and apoptotic markers in renal tissues [64]. These findings were correlated with the amelioration of CSP-induced tubular necrosis, degeneration, karyomegaly, and tubular dilatation [65].

2.19. Emodin. Emodin is the most abundant bioactive anthraquinone extracted from the Chinese culinary herb, Rhubarb (Rheum palmatum), and it possesses anticancer [66] and antioxidant activities [67]. Emodin treatment increased the cell viability after CSP treatment of normal human renal tubular epithelial cells [68]. In addition, emodin attenuated CSP-induced renal damage by suppressing the activity of N-acetyl-beta-D-glucosaminidase (NAG) [69], which is a lysosomal enzyme that is constitutively expressed in the proximal kidney tubule. Owing to its high molecular weight, under physiological conditions, NAG does not void via the kidneys because of its negligible glomerular filtration [70].

However, damage to the renal tubules causes the release of NAG in higher amounts than usual and, hence, it is excreted in the urine, and its serum accumulation is increased [70]. In a separate study, Liu et al. [71] demonstrated that emodin ameliorates CSP-induced apoptosis of rat renal tubular cells in vitro by modulating adenosine monophosphate-activated protein kinase (AMPK)/mechanistic target of rapamycin (mTOR) signaling pathways and activating autophagy and in vivo by suppressing caspase-3 activity and apoptosis in renal tissues.

2.20. Epigallocatechin-3-Gallate (EGCG). Epigallocatechin-3-gallate (EGCG) is a phenolic compound present in green tea [72] and is an effective ROS scavenger in vitro and in vivo [73, 74]. EGCG mitigated CSP-induced nephrotoxicity by inducing the expression of Nrf-2 and HO-1 and decreasing that of NF[kappa]B and proinflammatory cytokines [72]. Furthermore, EGCG also inhibited endoplasmic reticulum (ER) stress-induced apoptosis through the suppression of phosphorylated (p)-ERK, glucose-regulated protein 78 (GRP78), and the caspase-12 pathway [75]. Furthermore, EGCG inhibited the ligand of death receptor Fas (Fas-L); apoptosis regulator, Bax; and the tumor-suppressor protein, p53, while it increased the expression of Bcl-2 and, thereby, inhibited the extrinsic pathways of renal cell apoptosis [76]. All these studies collectively established the renoprotective actions of EGCG.

2.21. Genistein. Genistein is a polyphenol nonsteroidal isoflavonoid phytoestrogen extracted from soybean. Genistein treatment counteracted CSP-induced ROS generation and suppressed NF[kappa]B activation, proinflammatory cytokines expression, and apoptosis [77].

2.22. Ginsenosides Rh4 and Rk3. Ginseng is the root of Panax ginseng and is one of the most widely recommended and intensively studied herbal medicines. Ginsenosides are the secondary metabolites and unique constituents of Panax plants. Baek et al. [78] demonstrated that ginsenosides increased cell viability and prevented lactate dehydrogenase (LDH) leakage induced by CSP in normal renal proximal tubular epithelial cells. Furthermore, ginsenosides ameliorated CSP-induced renal damage by mitigating inflammation and apoptosis, which was evidenced by the suppression of DNA damage-induced apoptosis biomarkers such as phosphorylated c-Jun N-terminal kinase (JNK), p53, and cleaved caspase-3 expressions [79, 80].

2.23. Glycyrrhizic Acid. Glycyrrhizin and its aglycone glycyrrhetic acid (GA) are used for various therapeutic purposes in Chinese traditional medicine practice [81]. GA is the hydrophilic part of glycyrrhizin, an active compound found in licorice (Glycyrrhiza glabra), which is a conjugate of two molecules of glucuronic acid and GA. It is used as a flavoring agent in candies, pharmaceuticals, and tobacco products [82]. Furthermore, it has been reported to elicit anti-inflammatory, antioxidant, and antitumor activities [83]. GA treatment restored the antioxidant status and improved kidney function, as evidenced by diminished DNA fragmentation [82]. In addition, the renoprotective effects of GA were also associated with the upregulation of Nrf2 and downregulation of NF[kappa]B expression, resulting in decreased kidney damage [84].

2.24. Hesperidin. Hesperidin is a pharmacologically active bioflavonoid found in citrus fruits [85]. Hesperidin attenuated CSP-induced renal toxicity by ameliorating oxidative stress, inflammation, and apoptosis [85, 86]. However, additional studies are required to understand the exact molecular mechanism mediating the renoprotection induced by hesperidin.

2.25. Isoliquiritigenin (ISL). Isoliquiritigenin (ISL) is a flavonoid with a chalcone moiety extracted from several Glycyrrhiza species [87]. ISL has been shown to exert a variety of biological activities such as antiplatelet aggregation, antioxidant, and anti-inflammatory [88]. ISL exerted a remarkable renoprotective effect against CSP-induced renal toxicity by abrogating oxidative stress and apoptosis [87]. However, the precise molecular mechanisms purported to mediate the renoprotective activity of ISL needs to be explored.

2.26. Licochalcone A (LCA). Licochalcone A (LCA) is a species-specific phenolic constituent of Glycyrrhiza inflata. LCA administration to CSP-treated animals restored kidney function markers and decreased oxidative stress [89]. However, the exact mechanism underlying the renoprotection induced by LCA needs to be investigated.

2.27. Ligustrazine. Ligustrazine (tetramethylpyrazine) is an alkaloid compound extracted from the Chinese herb Chuanxiong (Ligusticum chuanxiong Hort) [90] and is extensively used in China for the management of myocardial and cerebral infarction [91]. Ligustrazine significantly diminished CSP-induced urinary NAG excretion and renal tubular injury in a dose-dependent manner. Furthermore, ligustrazine also suppressed renal oxidative stress, inflammation, and apoptosis by restoring the Bax/Bcl-2 ratio [90].

2.28. Luteolin. Luteolin is a flavone present in high concentrations in celery, green pepper, and chamomile, and it has been reported to display anti-inflammatory, antioxidant, and anticarcinogenic activities [92,93]. Luteolin treatment significantly reduced the pathophysiological changes induced by CSP in the kidneys by the suppression of oxidative/nitrative stress, inflammation, and apoptosis [92]. Moreover, luteolin also ameliorated tubular necrosis, which was confirmed using a terminal deoxynucleotidyl transferase (TdT) deoxyuridine 5'-triphosphate (dUTP) nick-end labeling (TUNEL) assay, and it diminished p53 activation and PUMA-a expression, as well as altering the Bax/Bcl-2 ratio [93].

2.29. Lycopene. Lycopene is a carotenoid pigment found in tomato [94]. Lycopene from dietary sources has been shown to reduce the risk of some chronic diseases including cancer and cardiovascular disorders [95]. The administration of lycopene significantly normalized the kidney function and antioxidant status of CSP-treated animals. Furthermore, lycopene also increased the expression of the organic anion and cation transporters (OAT and OCT, resp.) including OAT1, OAT3, OCT1, and OCT2 in the renal tissues [96-98]. In addition, lycopene also decreased the renal efflux transporters (multidrug resistance-associated protein [MRP]-2 and MRP4) levels and induced Nrf2 activation, which activated the antioxidant defense system [99]. Furthermore, lycopene protected against CSP-induced renal injury by modulating proapoptotic Bax and antiapoptotic Bcl-2 expressions and enhancing heat shock protein (HSP) expression [97].

2.30. Naringenin (NAR). Citrus fruits (such as oranges and grapefruits) are rich in the flavanone naringenin (NAR, aglycone) [100]. NAR diminished the extent of CSP-induced nephrotoxicity by improving renal function and antioxidant enzyme activity and diminishing lipid peroxidation [101]. However, the detailed molecular mechanism of the renoprotective action of NAR against CSP-induced renal tissue injury is still unknown and requires further investigation.

2.31. Paeonol. Paeonol is a major phenolic component of Moutan cortex [102]. In traditional medicine practice, paeonol is used to treat various diseases including atherosclerosis, infections, and other chronic inflammatory disorders [103]. Paeonol improved kidney function and suppressed the levels of proinflammatory cytokines, which attenuated the renal tissue injury induced by CSP [102]. However, additional mechanistic studies are warranted to understand the renoprotective activity of paeonol.

2.32. 1,2,3,4,6-Penta-O-galloyl-[beta]-D-glucose (PGG). 1,2,3,4,6-Penta-O-galloyl-[beta]-D-glucose (PGG) is a polyphenol and water-soluble gallotannin isolated from the Chinese herb Rhus chinensis [104]. PGG significantly blocked cytotoxicity and reduced the sub-G1 accumulation of human renal proximal tubular epithelial cells induced by CSP [105]. In addition, PGG suppressed PARP cleavage, caspase-3 activation, cytochrome c release, and upregulation of Bax and p53 expression, which diminished apoptosis in the renal tissues [106].

2.33. Platycodin D (PD). Triterpenoid saponins extracted from the roots of Platycodon grandiflorum exhibit a variety of pharmacological activities such as anti-inflammatory, anticancer, and immune-enhancing effects. The saponins in P. grandiflorum inhibited inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expressions by mitigating NF[kappa]B activation in CSP-treated kidneys [107]. Furthermore, PD also ameliorated CSP-induced renal injury as revealed by the decreased intraluminal cast formation and diminished epithelial desquamation. These effects were mediated in part by quenching ROS generation and suppressing the apoptosis cascade [108].

2.34. Quercetin. Quercetin is one of the most abundant flavonoids found in several plant species and exerts numerous beneficial effects on health including cardioprotection, anti-inflammatory, anti-proliferative, and anticancer activities [109]. Quercetin ameliorated CSP-induced nephrotoxicity by mitigating oxidative stress, inflammation, and cell death pathways. Specifically, quercetin diminished renal lipid peroxidation, MAPK, and NF[kappa]B activation, proinflammatory cytokine expression, and caspase activation, as well as decreasing apoptosis. The improvements in the molecular pathology induced by quercetin corroborated the improved renal function in CSP-treated animals [110-113].

2.35. Resveratrol. Resveratrol is a phenolic compound present in several botanical species such as mulberries, peanuts, red grapes, cranberries, and blueberries [114]. Resveratrol attenuated CSP-induced nephrotoxicity by augmenting the endogenous antioxidant defense system via SIRT1 and Nrf2 activation. Furthermore, it inhibited inflammatory cytokine production by blunting NF[kappa]B activation and immune cell infiltration in renal tissues. In addition, resveratrol also inhibited CSP-induced renal apoptosis by downregulating p53 expression and restoring the Bax/Bcl-2 ratio. Furthermore, resveratrol enhanced the chemosensitivity of CSP without compromising its antitumor activity [115-118].

2.36. Rosmarinic Acid. Rosmarinic acid is an ester of caffeic acid that is abundantly present in rosemary (Rosmarinus officinalis) [119]. Rosmarinic acid treatment diminished the CSP-induced renal toxicity by attenuating oxidative stress, and this effect was characterized by decreased accumulation of 4-hydroxynonenal (4-HNE) formation with improvement in superoxide dismutase (SOD) activity and glutathione (GSH) levels. The beneficial effects of rosmarinic acid, in part, were mediated by its inhibition of the expression and activity of CYP2E1. In addition, rosmarinic acid inhibited CSP-induced inflammation by blunting NF[kappa]B activation and apoptosis by reducing p53 activation and DNA damage [120].

2.37. Rutin. Rutin is a glycone of quercetin, which has been extracted from various citrus fruits [121]. The mechanism of the renoprotection induced by rutin against CSP toxicity is mediated by the suppression of oxidative stress, NF[kappa]B activation, inflammatory cytokine expression, and apoptosis [86, 122].

2.38. Schizandrin and Schizandrin B. Schizandrin is a lignan found in the Chinese berry (Schisandra chinensis) [123]. Giridharan et al. [124] documented that schizandrin B inhibited CSP-induced oxidative stress, inflammation, and apoptosis by attenuating NF[kappa]B, p53 accumulation, and cleaved caspase-3 expression. Furthermore, schizandrin B induced the activation of Nrf2 and its downstream target genes such as HO-1 and gamma-glutamylcysteine synthetase (GGCS), which is the rate-limiting enzyme involved in GSH synthesis. Furthermore, schizandrin B also inhibited CSP-induced nicotinamide adenine dinucleotide phosphate (NAD[P]H) dehydrogenase [quinone] 1 (NQO1) enzymatic activity. It is pertinent to note that NQO1 is involved in the one-electron reduction of quinones which produces superoxide and, thereby, propagates oxidative stress [125].

2.39. Silibinin. Silibinin is a flavonoid extracted from Silybum marianum, popularly known as the milk thistle [126]. Gaedeke et al. [127] demonstrated that silibinin inhibited CSP-renal damage by preserving the proximal tubular function and ameliorating proteinuria. However, the precise molecular mechanism underlying this action was not investigated. In another study, silibinin protected the kidneys against CSP-induced renal toxicity without compromising the antitumor activity of CSP in rodents [128].

2.40. Sulforaphane. Sulforaphane is an isothiocyanate present in cruciferous vegetables such as broccoli, Brussels sprout, and cabbage [129]. Sulforaphane inhibited CSP-induced renal dysfunction, structural damage, oxidative/nitrative stress, inflammation, and apoptosis. Mechanistically, sulforaphane attenuated MAPK and NF[kappa]B activation and stimulated Nrf2 activation [130, 131]. In addition, several synthetic analogs of sulforaphane also exerted renoprotective activity against CSP-induced nephrotoxicity by the aforementioned mechanisms [132].

2.41. Tannic Acid. Tannins belong to the class of polyphenols and have been shown to possess multiple biological activities including anticancer [133], antioxidant, and antimicrobial activities [134]. Yokozawa et al. [135] demonstrated that tannic acid administration restored antioxidant levels, decreased lipid peroxidation, and improve renal function. Tannic acid also decreased CSP-induced DNA fragmentation by diminishing p53 activation [136]. Furthermore, green tea tannin has been reported to restore the kidney function and synergistically enhance the cell death of ovarian cancer cells by CSP [137]. In addition, Tikoo et al. [138] reported that tannic acid decreased PARP cleavage, phosphorylation of p38, and hypoacetylation of histone H4, which diminished kidney injury, indicating the efficacy of tannic acid as a therapeutic drug for CSP-induced nephrotoxicity.

2.42. Thymoquinone. Thymoquinone is a bioactive compound derived from Nigella sativa popularly known as black seed oil. Thymoquinone has been shown to exert anti-inflammatory, antioxidant, and antineoplastic effects in both in vitro and in vivo studies [139]. Thymoquinone was shown to improve kidney function, diminish lipid peroxidation, and augment endogenous antioxidants [139]. In addition, thymoquinone has also been shown to increase the expression of various organic anion and cation transporters such as OAT1, OAT3, OCT1, and OCT2, which are necessary for the renal clearance of xenobiotic agents including toxins and commonly used drugs [140, 141].

2.43. Xanthorrhizol. Xanthorrhizol is one of the major constituents from the rhizomes of Curcuma xanthorrhiza, a medicinal plant native to Indonesia [142]. Kim et al. [143] demonstrated the renoprotective action of xanthorrhizol against CSP-induced nephrotoxicity mediated by inhibiting NF[kappa]B and activator protein-1 (AP-1) activation, proinflammatory cytokine expression, immune cell infiltration, and apoptosis. Furthermore, mechanistic studies revealed that xanthorrhizol suppressed CSP-induced phosphorylation of c-Jun N-terminal kinase (JNK) and p53, as well as the shutdown of the mitochondria-mediated apoptosis pathway [144].

2.44. Renoprotective Actions of Phytochemicals in Human Studies. The review of the published literature revealed that several preclinical studies reported the renoprotective properties of phytochemicals. Currently, there is no significant evidence from clinical trials indicating that phytochemicals show renoprotective efficacy in human subjects undergoing CSP chemotherapy. However, a recent open-labeled randomized clinical trial undertaken in a small patient population suggested that treatment with cystone (a herbomineral ayurvedic formulation) in combination with CSP chemotherapy improved renal function without compromising the anti-tumor effects of CSP. However, long-term follow-up data and survival rates were not presented in this study and, therefore, more stringent, well-designed, and controlled clinical trials are warranted to establish the clinical efficacy of cystone in combating CSP-induced nephrotoxicity [145].

3. Conclusion

The analysis of literature suggests that plant-derived agents (phytochemicals) are widely used to prevent the CSP-induced renal toxicity, and it is evident that these compounds exhibited potentially effective renal protection in preclinical studies. However, the major impediment to the clinical translation of these compounds for further pharmaceutical development pertains to the lack of convincing evidence of their bioavailability in human subjects [146, 147]. In addition, the therapeutic indexes for various phytochemicals are presently unknown. Therefore, future studies should investigate the analogs and derivatives of phytochemicals with demonstrable bioavailability in human subjects, and these molecules should be thoroughly investigated in preclinical models for further pharmaceutical development. In addition, most studies reported in the literature demonstrated the prophylactic action of phytochemicals in combating CSP-induced renal tissue injury. However, this approach has major limitations because clinically patients require treatment after and not before the onset of kidney damage. Therefore, future studies should essentially investigate the therapeutic effect of phytochemicals against CSP-induced nephrotoxicity in preclinical models. Specifically, studies must report the effect of phytochemical administration after the establishment of renal tissue injury and present the survival rate of the animal models. Finally, to establish the renoprotective actions of phytochemicals, studies need to be conducted in rodents harboring tumors that are sensitive to CSP. This is to ascertain that the beneficial effects of the phytochemicals do not compromise or interfere with the antitumor activity of CSP.
Abbreviations

CSP:              Cisplatin
C[B.sub.2]:       Cannabinoid receptor-2
NF-[kappa]B:      Nuclear factor
                  kappa-light-chain-enhancer of activated
                  B-cells
CYP2E1:           Cytochrome P450 2E1
MAPK:             Mitogen-activated protein kinase
Bax:              B-cell lymphoma 2- (Bcl-2-) associated X
                  protein
Bcl-2:            B-cell lymphoma 2
HO-1:             Heme oxygenase-1
p53:              Tumor-suppressor protein p53
SIRT, Sirtuin:    Silent mating type information regulation
                  2 homolog
Nrf2:             Nuclear factor erythroid-derived 2
ROS:              Reactive oxygen species
ERK:              Extracellular signal-regulated kinases
Akt:              Serine/threonine-specific protein kinase
                  (synonym: protein kinase B)
PARP:             Poly adenosine diphosphate (ADP) ribose
                  polymerase
KIM-1:            Kidney injury molecule-1
NAG:              N-acetyl-D-glucosamine
AMPK:             Adenosine monophosphate-activated
                  protein kinase
mTOR:             Mechanistic target of rapamycin
GRP-78:           78 kDa glucose-regulated protein
Fas-L:            Fas ligand [synonym: cluster of
                  differentiation antigen 95 (CD95) ligand]
LDH:              Lactate dehydrogenase
JNK:              c-Jun N-terminal kinases
TUNEL:            Terminal deoxynucleotidyl transferase
                  deoxyuridine 5'-triphosphate (dUTP)
                  nick-end labeling
PUMA:             p53-upregulated modulator of apoptosis
OAT:              Organic anion transporter
OCT:              Organic cation transporter
MRP:              Multidrug resistance-associated proteins
HSP:              Heat shock protein
iNOS:             Inducible nitric oxide synthase
COX-2:            Cyclooxygenase-2
4-HNE:            4-Hydroxynonenal
SOD:              Superoxide dismutase
GSH:              Glutathione (reduced)
GCLC:             Gamma-glutamyl cysteine synthetase
NQO1:             NAD(P)H dehydrogenase [quinone] 1
AP-1:             Activator protein-1
BUN:              Blood urea nitrogen
MDA:              Malondialdehyde
CAT:              Catalase
GR:               Glutathione reductase
NOX:              NADPH (nicotinamide adenine
                  dinucleotide phosphate-oxidase) oxidase
3-NT/3-NY:        3-Nitrotyrosine
TNF-[alpha]:      Tumor necrosis factor alpha
GPx:              Glutathione peroxidase
p38:              p38 MAPK
NO:               Nitric oxide
IL-1[beta]:       Interleukin 1 beta
NAMPT:            Nicotinamide phosphoribosyl transferase
MCP-1:            Monocyte chemoattractant protein-1
ICAM-1:           Intercellular adhesion molecule-1
TBARS:            Thiobarbituric acid reactive substances
IL:               Interleukin
TAC:              Total antioxidant capacity
GST:              Glutathione S-transferase
XO:               Xanthine oxidase
TOS:              Total oxidant status
LPO:              Lipid peroxidation
H2O2:             Hydrogen peroxide
ALP:              Alkaline Phosphatase
GSSG:             Glutathione disulfide
ICAM:             Intercellular adhesion molecule
VCAM:             Vascular cell adhesion protein
MPO:              Myeloperoxidase
G6PD:             Glucose-6-phosphate dehydrogenase
QR:               Quinone reductase
I.P.:             Intraperitoneal injection
I.V.:             Intravenous administration
LLC-PK1:          Renal epithelial cells derived from normal
                  pig kidney
HK-2 cells:       Proximal tubular epithelial cells from
                  normal human kidney
HRCs:             Human primary epithelial cells from
                  cortex and glomeruli
ETC:              Electron transport chain
XOR:              Xanthine oxidoreductase
CXCL1:            Chemokine (C-X-C motif) ligand 1
ER:               Endoplasmic reticulum
PMN:              Polymorphonuclear (neutrophil).


http://dx.doi.org/10.1155/2016/4320374

Competing Interests

There is no conflict of interests to disclose.

Authors' Contributions

Shreesh Ojha and Balaji Venkataraman contributed equally to this article.

Acknowledgments

Mohanraj Rajesh, Shreesh Ojha, and Bassem Sadek were supported by intermural funds from the College of Medicine and Health Sciences and the Office of Graduate Studies and Research, UAE University.

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Shreesh Ojha, (1) Balaji Venkataraman, (1) Amani Kurdi, (2) Eglal Mahgoub, (1) Bassem Sadek, (1) and Mohanraj Rajesh (1)

(1) Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 17666, UAE

(2) Department of Pharmacology and Therapeutics, Beirut Arab University, Beirut, Lebanon

Correspondence should be addressed to Mohanraj Rajesh; rajm@uaeu.ac.ae

Received 8 June 2016; Accepted 23 August 2016

Academic Editor: Renata Szymanska

Caption: Figure 1: Scheme showing various pathways mediating cisplatin- (CSP-) induced nephrotoxicity and mitigation of this cascade by phytochemicals.
Table 1: Phytochemicals investigated for renoprotective actions
against cisplatin- (CSP-) induced nephrotoxicity.

                      Dose, duration, and
Phytochemical         route of administration   Animal model

NI[F.sub.1] and 23-   10 mg/kg/day, orally      Sprague Dawley (SD)
hydroxytormentic      (PO) for 14 days          rats
acid                  intraperitoneally (i.p.)

6-Gingerol            12.5, 25, and 50 mg/kg    Wistar rats
                      for 5 days (before and
                      after treatment), i.p.

6-Hydroxy-1-          5 and 10 mg/kg, single    LLC-PK1 cells and SD
methylindole-3-       dose, PO                  rats
acetonitrile

[beta]-Caryophyllene  1/10 mg/kg, i.p. single   C57BL/6J mice
                      dose

Berberine             1/3 mg/kg, single dose,   BALB/cN mice
                      i.p.

Bixin                 2.5 and 5 mg/kg for 3     Wistar rats
                      days, i.p.

C-Phycocyanin         5-50 mg/kg, i.p.          C57BL/6J and CD1 mice

Caffeic acid          10 [micro]M/kg,           Wistar Albino rats
phenethyl ester       single dose, i.p.

Cannabidiol           2.5/10 mg/kg, i.p.        C57BL/6J mice
                      (before and after
                      treatment)

Capsaicin             5 and 10 mg/kg, PO for 6  SD rats
                      days, i.p.

                      2.5, 5, and 10 mg/kg for  C57BL/6 mice
                      5 days, i.p.

Cardamonin            10 and 30 mg/kg, PO for   Albino rats
                      2 weeks

Carnosic acid         100 mg/kg, PO for 10      Wistar rats
                      days

Chrysin               25 or 50 mg/kg 14 days,   Wistar rats
                      i.p.

Cinnamic acid (CA)    CA, 50mg/kg CD, 40 mg/    SD rats
and cinnamaldehyde    kg, PO for 7 days
(CD)

Curcumin              100 mg/kg 10 days, i.p.   Wistar rats

                      100 mg/kg, i.p.           C57BL/6J mice

                      8 mg/kg                   Wistar rats

Cyanidin              10, 20, and 40 [micro]g/  HK-2 cells
                      mL

Decursin              20-80 mM                  Primary HRCs

                      10-40 mg/kg 3 days, i.p.  SD rats

Ellagic acid          10 and 30 mg/kg 9 days,   SD rats
                      i.p.

                      10 mg/kg 10 days, i.p.    SD rats

Emodin                10 mg/kg for 9 days,      Wistar rats
                      i.p.

Epigallocatechin-     l00 mg orally, 2 days     Wistar rats
3-gallate

                      100 mg/kg i.p.,           C57BL/6 mice
                      single dose

Genistein             10 mg/kg 3 days           C57BL/6 mice
                      25 [micro]g/L             HK-2 cells

Ginsenosides          10-60 [micro]g/mL         LLC-PK1 cells

Glycyrrhizic acid     75 and 150 mg/kg for 7    BALB/c and Swiss Albino
                      days, i.p.                mice

Hesperidin            100 and 200 mg/kg 10      Wistar rats
                      days, i.p.

Isoliquiritigenin     1 mg/kg for               BALB/c mice
                      15 days, i.p.

Licochalcone A        1 mg/kg for               BALB/c mice
                      15 days, i.p.

Ligustrazine          50 and 100 mg/kg,         SD rats
                      7 days, i.p.

Luteolin              10 mg/kg                  BALB/cN mice
                      3 days, i.p.

                      50 mg/kg 3 days, i.p.     C57BL/6J mice

Lycopene              6 mg/kg                   Wistar rats
                      10 days, i.p.

                      4 mg/kg 5 days, i.p.      SD and Wistar rats

Naringenin            20 mg x [kg.sup.-1] x     Wistar Albino rats
                      [day.sup.-1], PO for 10
                      days

Paeonol               20 mg/kg 3 days, i.p.     BALB/c mice

Penta- O-galloyl-     20-80 [micro]M            Primary HRC
[beta]-D-glucose

Platycodin D          0.1, 1, and 5 mg/kg for   ICR mice
                      3 days, i.p.

Quercetin             100 mg/kg 30 days         Albino rats

                      50 mg/kg 3 days           Wistar rats

                      50 and 100 mg/kg 9 days,  Fischer-F344 rats
                      i.p.

Resveratrol           25 mg/kg single dose,     Albino mice
                      i.p.

                      10 mg/kg, 7 days          C57BL/6 mice and
                                                Fischer rat kidney
                      30 [micro]g/mL, i.p.      in vitro

Rosmarinic acid       1, 2, and 5 mg/kg 2       BALB/cN mice
                      days, i.p.

Rutin                 75 and 150 mg/kg 21 days  Wistar rats

                      30 mg/kg 14 days          SD rats

Schizandrin and       10, 25, 50 mg/kg 15       BALB/c mice
schizandrin B         days, i.p.

Silibinin             200 mg/kg single dose,    Wistar rats
                      i.p.

Sulforaphane          500 [micro]g/kg/day i.v.  Wistar rats
                      for 3 days

                      500 [micro]g/kg/day i.p.  Wistar rats
                      for 3 days

Tannic acid           40 and 80 mg/kg 7 days,   Swiss Albino mice
                      i.p.

Thymoquinone          50 mg/L in drinking       Wistar Albino rats and
                      water for 5 days          Swiss Albino mice

Xanthorrhizol         100 and 200 mg/kg for 4   ICR mice
                      days, i.p.

                      Cisplatin dose and
                      route of
Phytochemical         administration       Key findings

NI[F.sub.1] and 23-                        [down arrow] BUN and
hydroxytormentic      7 mg/kg, i.p.        serum creatinine
acid
                                           [down arrow] MDA
                                           production and GSH
                                           depletion

6-Gingerol            5 mg/kg, i.p.        [down arrow] oxidative
                                           stress

6-Hydroxy-1-          7 mg/kg, i.p.        [down arrow] BUN,
methylindole-3-                            creatinine, and urinary
acetonitrile                               LDH

                                           [up arrow] HO-1
                                           expression, activities
                                           of SOD, CAT, GR, MDA, and
                                           GSH

[beta]-Caryophyllene  25 mg/kg, i.p.       [down arrow]
                                           inflammation and
                                           dysfunction

                                           [down arrow] NOX-2 and
                                           NOX-4 expression, 4-
                                           HNE, 3-NT accumulation,
                                           and cell death

Berberine             13 mg/kg, i.p.       [down arrow] BUN,
                                           creatinine, and
                                           oxidative/nitrosative
                                           stress

                                           [down arrow] NF-
                                           [kappa]B, TNF-[alpha],
                                           COX-2, iNOS, and
                                           histopathological
                                           changes

                                           [down arrow] p53 and
                                           active caspase-3

Bixin                 5 mg/kg, i.p.        [down arrow] lipid
                                           peroxidation and renal
                                           glutathione depletion

                                           [down arrow] chromosome
                                           aberrations

C-Phycocyanin         12-18 mg/kg, i.p.    [down arrow] BUN,
                                           creatinine, oxidative
                                           stress, and apoptosis

                                           [down arrow] p-ERK, p-
                                           JNK, and p-p38
                                           expression and Bax,
                                           caspase-9, and caspase-
                                           3 activation

Caffeic acid          7 mg/kg, i.p.        [down arrow] BUN,
phenethyl ester                            tubular damage, and
                                           oxidative tissue damage

                                           [down arrow] antioxidant
                                           enzymes

Cannabidiol           20 mg/kg, i.p.       [down arrow] BUN,
                                           creatinine, ROS
                                           formation, and 3-NT

                                           [down arrow] PARP,
                                           caspase-3/7, and DNA
                                           fragmentation

                                           [down arrow] mRNA of
                                           TNF-[alpha] and IL1 and
                                           iNOS and protein
                                           expression

Capsaicin             5 mg/kg, i.p.        [down arrow] BUN,
                                           creatinine, MDA, and
                                           renal damage

                      5 mg/kg, i.p.        [down arrow] HO-1
                                           expression

Cardamonin            7 mg/kg, i.p.        [up arrow] SOD, GSH

                                           [down arrow] NOX/1,
                                           caspase/3 expression,
                                           and Bax/Bcl-2 ratio

Carnosic acid         7.5 mg/kg, i.p.      [down arrow] BUN,
                                           creatinine, and MDA

                                           [down arrow] GSH levels,
                                           catalase, SOD, GST, GPx,
                                           and GR activities

                                           [down arrow] caspase-3
                                           activity, apoptosis, and
                                           renal damage

Chrysin               7.5 mg/kg, i.p.      [down arrow] oxidative
                                           stress and apoptosis

Cinnamic acid (CA)    5 mg/kg, i.p.        [down arriw] urea,
and cinnamaldehyde                         creatinine, and MDA
(CD)                                       content

                                           [up arrow] GSH levels,
                                           SOD, CAT, and GPx
                                           activities

Curcumin              7 mg/kg, i.p.        [down arrow] MDA

                      20 mg/kg, i.p.       [up arrow] NAMPT, SIRT1,
                                           SIRT3, and SIRT4 levels

                      5 mg/kg, i.p.        [down arrow] renal TNF-
                                           [alpha], MCP-1, and
                                           ICAM-1 mRNA expression

                                           [down arrow] creatinine,
                                           TBARS, and MDA

Cyanidin              8 [micro]g/mL        [down arrow] BUN,
                                           creatinine, MDA, renal
                                           index, and IL-6

                                           [down arrow] GRP78,
                                           p-ERK, caspase-12, and
                                           PARP cleavage

                                           [down arrow] apoptosis,
                                           DNA damage, ERK
                                           activation, and AKT
                                           inhibition

Decursin              20-80 mM             [up arrow] catalase,
                                           SOD, and GPx activities

                      5.2 mg/kg, i.p.      [down arrow] caspases 3
                                           and 9, PARP, DNA
                                           fragmentation, and
                                           apoptosis

                                           [down arrow] BUN and
                                           creatinine

Ellagic acid          6 mg/kg, i.p.        [down arrow] creatinine,
                                           urea, and kidney injury

                      7 mg/kg, i.p.        [down arrow] total
                                           antioxidant status and
                                           GSH

                                           [down arrow] MDA levels
                                           and improved antioxidant
                                           enzymes

                                           [down arrow] tubular
                                           necrosis and tubular
                                           dilatation

Emodin                6 mg/kg, i.p.        [up arrow] GSH, TAC,
                                           GST, GPx, GR, SOD,
                                           and CAT

                                           [down arrow] NAG,
                                           creatinine, and urea
                                           concentration

Epigallocatechin-     7 mg/kg, i.p.        [up arrow] SOD, CAT,
3-gallate                                  GPx, and GSH

                      20 mg/kg, i.p.       [down arrow] NF-
                                           [kappa]B and 4HNE

                                           [down arrow] p-ERK,
                                           GRP78, caspase-12, Fas-
                                           L, BAX, and apoptosis

Genistein             20 mg/kg, i.p.       [down arrow] BUN,
                      1 [micro]g/mL        creatinine, ROS
                                           production, tubular
                                           damage, and necrosis
                                           score

                                           [down arrow] ICAM-1 and
                                           MCP-1 expression and NF-
                                           [kappa]B activation

                                           [down arrow] apoptosis
                                           and p53 induction

Ginsenosides          25 and               [down arrow] LDH
                      500 [micro]M         leakage, renal damage,
                                           and apoptosis

Glycyrrhizic acid     7 mg/kg, i.p.        [up arrow] GSH, GR, GST,
                                           catalase, and GPx
                                           activities

                                           [down arrow] BUN and
                                           creatinine

Hesperidin            7.5 mg/kg, i.p.      [down arrow] BUN,
                                           creatinine, and DNA
                                           degradation

                                           [up arrow] SOD, GPx,
                                           GST, GR, GSH, and
                                           catalase activities and
                                           vitamin C levels

                                           [down arrow] renal TNF-
                                           [alpha] levels

Isoliquiritigenin     5 mg/kg, i.p.        [down arrow] BUN,
                                           creatinine, nitrite, and
                                           tissue MDA and ROS

Licochalcone A        5 mg/kg, i.p.        [down arrow] BUN,
                                           creatinine, nitrite, and
                                           MDA

Ligustrazine          8 mg/kg, i.p.        [down arrow] urinary
                                           protein excretion, NAG
                                           excretion, creatinine,
                                           and BUN

                                           [up arrow] GSH levels,
                                           SOD, and GST activities

                                           [down arrow] tubular
                                           cell apoptosis

Luteolin              10 and 20 mg/        [down arrow] renal
                      kg, i.p.             dysfunction, tubular
                                           injury, oxidative
                                           stress, BUN, and
                                           creatinine

                                           [up arrow] GSH, SOD, and
                                           catalase

                                           [down arrow] p53
                                           activation and
                                           PUMA-[alpha] protein
                                           expression

                      20 mg/kg, i.p.       [down arrow] CYP2E1,
                                           Bcl-2, 4-HNE, 3-NT,
                                           NF-[kappa]B, and
                                           caspase-3

                                           [down arrow] MRP4 and
                                           MRP2 expression

Lycopene              7 mg/kg, i.p.        [down arrow] urea and
                                           creatinine and MRP2 and
                                           MRP4 expression

                                           [up arrow] OAT1, OAT3,
                                           OCT1, OCT2, Nrf2, and
                                           Bcl-2 expression

                                           [up arrow] catalase,
                                           GPx, and SOD activities

                                           [down arrow] NF-
                                           [kappa]B, HSP 60 and HSP
                                           70, and Bax expression

Naringenin            7 mg/kg,             [down arrow] urea,
                      intravenous          creatinine, sodium
                      (i.v.)               excretion, and renal
                                           lipid peroxides

                                           [up arrow] GST activity
                                           and renal antioxidant
                                           enzymes

Paeonol               10-30 mg/kg I.P.     [down arrow] creatinine,
                                           BUN, TNF-[alpha], and
                                           IL-1[beta]

Penta- O-galloyl-     40 [micro]M          [down arrow]
[beta]-D-glucose                           cytotoxicity, apoptosis,
                                           PARP cleavage, Bax, and
                                           caspase-3

                                           [down arrow] cytochrome
                                           C translocation and ROS
                                           production

Platycodin D          20 mg/kg, i.p.       [down arrow] BUN,
                                           creatinine, TBARS, NF-
                                           [kappa]B activation, [up
                                           arrow] GSH, GPx, and SOD

Quercetin             12 mg/kg i.p.        [up arrow] GSH, GPX,
                                           SOD, CAT, GR, XO, TOS,
                                           and TAC

                                           [down arrow] BUN,
                                           creatinine, LPO,
                                           [H.sub.2][O.sub.2], and
                                           tubular cell necrosis

                      5 mg/kg, i.p.        [down arrow] Na and K
                                           excretion, NAG, LDH,
                                           ALP, GGT, and KIM-1

                                           [down arrow] GSH-GSSG
                                           ratio, NF[kappa]B, iNOS,
                                           ICAM-1, VCAM-1, and
                                           renal MPO

                      7.5 mg/kg, i.p.      [down arrow] caspase-3/
                                           7 activity and DNA
                                           fragmentation

Resveratrol           5 mg/kg, i.p.        [down arrow] creatinine,
                                           MDA, and LDH leakage

                      20 mg/kg, i.p.       [down arrow]
                                           inflammation and
                      7.5/15 [micro]g/     necrosis
                      mL, i.p.
                                           [down arrow] acetylation
                                           of p53 and SIRT1

Rosmarinic acid       13 mg/kg, i.p.       [down arrow] creatinine
                                           and BUN

                                           [down arrow] CYP2E1, HO-
                                           1, and 4-HNE expression

                                           [down arrow] NF[kappa]B
                                           and cleaved caspase-3
                                           expression

Rutin                 7 mg/kg, i.p.        [down arrow] BUN,
                                           creatinine,
                                           [H.sub.2][O.sub.2], LDH,
                                           caspase-3, NF[kappa]B,
                                           and TNF-[alpha] level

                      5 mg/kg, i.p.        [down arrow] membrane
                                           integrity, GSH, XO, and
                                           GGT

Schizandrin and       10 mg/kg, i.p.       [down arrow] NF[kappa]B
schizandrin B                              activation and p53
                                           activation

Silibinin             5 mg/kg, i.p.        [up arrow] creatinine
                                           clearance

                                           [up arrow] glomerular
                                           and proximal tubular
                                           function

Sulforaphane          7.5 mg/kg, i.p.      [down arrow] p38 MAPK
                                           and renal adhesion
                                           molecule expressions

                      10 mg/kg, i.p.       [down arrow]
                                           inflammatory cell
                                           infiltration

Tannic acid           7 mg/kg, i.p.        [down arrow] BUN,
                                           creatinine, p38 MAPK
                                           phosphorylation, and
                                           PARP cleavage

                                           [down arrow] XOR and
                                           LPO; [up arrow] G6PD,
                                           QR, and catalase
                                           activities

Thymoquinone          5, 7, and 14 mg/kg   [down arrow] urea,
                      i.v. in rats i.p.    creatinine, MDA, 8-
                      in mice              isoprostane, MRP2, and
                                           MRP4

                                           [up arrow] OAT1, OAT3,
                                           OCT1, and OCT2 and
                                           survival rate of animals

Xanthorrhizol         45 mg/kg, i.p.       [down arrow] BUN,
                                           creatinine, and lipid
                                           peroxides

Phytochemical         Reference

NI[F.sub.1] and 23-
hydroxytormentic      [14]
acid

6-Gingerol            [17]

6-Hydroxy-1-
methylindole-3-       [19]
acetonitrile

[beta]-Caryophyllene  [23]

Berberine             [27]

Bixin                 [29, 30]

C-Phycocyanin         [31, 32]

Caffeic acid          [33]
phenethyl ester

Cannabidiol           [36]

Capsaicin             [38]

                      [39]

Cardamonin            [41]

Carnosic acid         [45]

Chrysin               [47]

Cinnamic acid (CA)    [49]
and cinnamaldehyde
(CD)

Curcumin              [56]

                      [54]

                      [51]

Cyanidin              [58]

Decursin              [59]

                      [60]

Ellagic acid          [63] [65]

Emodin                [69]

Epigallocatechin-     [72]
3-gallate

                      [75, 76]

Genistein             [77]

Ginsenosides          [78-80]

Glycyrrhizic acid     [82, 84]

Hesperidin            [85, 86]

Isoliquiritigenin     [87]

Licochalcone A        [89]

Ligustrazine          [90]

Luteolin              [92]

                      [93]

Lycopene              [96, 97]

                      [98]

Naringenin
                      [101]

Paeonol               [102]

Penta- O-galloyl-     [106]
[beta]-D-glucose

Platycodin D          [108]

Quercetin             [110]

                      [111]

                      [148]

Resveratrol           [115] [116]

                      [117]

Rosmarinic acid       [120]

Rutin                 [122]

                      [86]

Schizandrin and       [124]
schizandrin B

Silibinin             [127,128]

Sulforaphane          [130]

                      [131]

Tannic acid
                      [136]

Thymoquinone          [139]

Xanthorrhizol         [143]

Table 2: Structures of phytochemicals investigated for renoprotective
action against cisplatin- (CSP-) induced nephrotoxicity.

Phytochemical          Structure                   Chemical class

23-Hydroxytormentic    [formula expression not     Carboxylic acid
acid                   reproducible]

6-Gingerol             [formula expression not     Decanone
                       reproducible]

6-Hydroxy-l-           [formula expression not     Nitrile
methylindole-3-        reproducible]
acetonitrile

Caffeic acid           [formula expression not     Ester
phenylethyl ester      reproducible]

Cannabidiol            [formula expression not     Monoterpene
                       reproducible]

[beta]-Caryophyllene   [formula expression not     Bicyclic alkene
                       reproducible]

Cinnamaldehyde         [formula expression not     Aldehyde
                       reproducible]

Curcumin               [formula expression not     Diketone
                       reproducible]

Berberine              [formula expression not     Isoquinoline
                       reproducible]

Bixin                  [formula expression not     Apocarotenoid
                       reproducible]

C-Phycocyanin          [formula expression not     Phycobiliprotein
                       reproducible]

Capsaicin              [formula expression not     Amide
                       reproducible]

Cardamonin             [formula expression not     Chalconoid
                       reproducible]

Carnosic acid          [formula expression not     Benzenediol abietane
                       reproducible]               diterpene

Chrysin                [formula expression not     Flavonoid
                       reproducible]

Cinnamic acid          [formula expression not     Carboxylic acid
                       reproducible]

Cyanidin               [formula expression not     Anthocyanidin
                       reproducible]

Decursin               [formula expression not     Coumarin
                       reproducible]

Ellagic acid           [formula expression not     Chromene-5,10-dione
                       reproducible]

Emodin                 [formula expression not     Anthraquinone
                       reproducible]

Epigallocatechin-      [formula expression not     Polyphenol
3-gallate              reproducible]

Genistein              [formula expression not     Isoflavone
                       reproducible]

Ginsenoside            [formula expression not     Triterpene-saponin
                       reproducible]

Glycyrrhizic acid      [formula expression not     Triterpenoid saponin
                       reproducible]

Hesperidin             [formula expression not     Licorice chalconoid
                       reproducible]

Isoliquiritigenin      [formula expression not     Chalconoid
                       reproducible]

Licochalcone A         [formula expression not     Chalconoid
                       reproducible]

Ligustrazine           [formula expression not     Pyrazine Flavanone
Luteolin               reproducible]

Lycopene               [formula expression not     Carotenoid
                       reproducible]

Naringenin             [formula expression not     Flavanone
                       reproducible]

Paeonol                [formula expression not     Acetophenone
                       reproducible]

Penta-O-galloyl-       [formula expression not     Glycoside
B-D-glucose            reproducible]

Platycodin D           [formula expression not     Saponin
                       reproducible]

Quercetin              [formula expression not     Flavonol
                       reproducible]

Resveratrol            [formula expression not     Stilbenoid
                       reproducible]

Rosmarinic acid        [formula expression not     Caffeic acid
                       reproducible]

Rutin                  [formula expression not     Chroman-4-one
                       reproducible]

Schizandrin            [formula expression not     Cycloocta[l',2':4,5]
                       reproducible]               benzo[l,2-d]
                                                   [l,3]dioxole

Silibinin              [formula expression not     Chroman-4-one
                       reproducible]

Sulforaphane           [formula expression not     Isothiocyanate
                       reproducible]

Tannic acid            [formula expression not     Polyphenol
                       reproducible]

Thymoquinone           [formula expression not     1,4-Quinone
                       reproducible]

Xanthorrhizol          [formula expression not     Sesquiterpene
                       reproducible]
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Author:Ojha, Shreesh; Venkataraman, Balaji; Kurdi, Amani; Mahgoub, Eglal; Sadek, Bassem; Rajesh, Mohanraj
Publication:Oxidative Medicine and Cellular Longevity
Date:Jan 1, 2016
Words:12772
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