Abstract
Cyclophosphamide (CPA) is used in the management of autoimmune conditions and malignant illnesses. However, its therapeutic use is limited because of its severe side effects, especially hepatotoxicity attributed to oxidative stress. Nasturtium officinale R. Br (watercress or WC) has pharmacological properties, such as anti-inflammation, and antioxidant activities. Therefore, the present study was design to assess effects of WC or its active ingredient, quercetin (QE), against CPA-induced hepatotoxicity. For this study, 49 male Wistar rats (200–250 g) were randomly selected and categorized into seven equal groups. The animals were pre- and post-treated with both hydroalcoholic extract of WC (500 mg/kg) and quercetin (75 mg/kg) for 10 consecutive days, and intraperitoneal administration of CPA (200 mg/kg) was performed on only day 10, one hour before the last dose of WC or quercetin. On day 11, all the animals were sacrificed, and their blood and liver were gathered for evaluation of the liver enzyme, hepatic oxidative stress markers, antioxidant enzymes activity, and hematoxylin and eosin staining. CPA significantly increased malondialdehyde (MDA), protein carbonyl (PCO) and nitric oxide (NO) levels and liver biomarkers. Otherwise, hepatic catalase (CAT), reduced glutathione (GSH), total thiol content (tSH), and ferric reducing antioxidant power (FRAP) were considerably lower than the control group. Results showed that WC has the ability to reduce the changes (MDA, PCO, FRAP, CAT, ALT and AST) and QE (MDA, PCO, AST) induced by CPA (p < 0.05). Histopathological finding confirmed the indicated results. These findings propose that WC and QE have protective effect against the CPA-induced hepatotoxicity by decreasing oxidative stress.
Graphic abstract
Similar content being viewed by others
References
Shokrzadeh M, Chabra A, Ahmadi A, Naghshvar F, Habibi E, Salehi F, Assadpour S (2015) Hepatoprotective effects of Zataria multiflora ethanolic extract on liver toxicity induced by cyclophosphamide in mice. Drug Res 65:169–175. https://doi.org/10.2165/00003495-199142050-00005
Capel ID, Jenner M, Dorrell HM, Williams DC (1979) Hepatic function assessed (in rats) during chemotherapy with some anti-cancer drugs. Clin Chem 25:1381–1383. https://doi.org/10.1093/clinchem/25.8.1381
Fraiser LH, Kanekal S, Kehrer JP (1991) Cyclophosphamide toxicity. Drugs 42:781–795. https://doi.org/10.2165/00003495-199142050-00005
Dollery C (2003) Therapeutic drugs. Churchill Livingstone, Edinburgh, pp C349–C354
Alenzi FQ, El-Bolkiny YE-S, Salem ML (2010) Protective effects of Nigella sativa oil and thymoquinone against toxicity induced by the anticancer drug cyclophosphamide. Br J Biomed Sci 67:20–28. https://doi.org/10.1080/09674845.2010.11730285
Weijl NI, Cleton FJ, Osanto S (1997) Free radicals and antioxidants in chemotherapyinduced toxicity. Cancer Treat Rev 23:209–240. https://doi.org/10.1016/S0305-7372(97)90012-8
Bhattacharya A, Lawrence RA, Krishnan A, Zaman K, Sun D, Fernandes G (2003) Effect of dietary n-3 and n-6 oils with and without food restriction on activity of antioxidant enzymes and lipid peroxidation in livers of cyclophosphamide treated autoimmune-prone NZB/W female mice. J Am Coll Nutr 22:388–399. https://doi.org/10.1080/07315724.2003.10719322
Azarmehr N, Afshar P, Moradi M, Sadeghi H, Sadeghi H, Alipoor B, Khalvati B, Barmoudeh Z, Abbaszadeh-Goudarzi K, Doustimotlagh AH (2019) Hepatoprotective and antioxidant activity of watercress extract on acetaminophen-induced hepatotoxicity in rats. Heliyon 5:e02072. https://doi.org/10.1016/j.heliyon.2019.e02072
Karami M, Mostafazadeh M, Sadeghi H, Sadeghi H, Mehraban F, Panahi Kokhdan E, Sayahi M, Abtahi SR (2018) Nephroprotective effect of Nasturtium officinale (Watercress) ethanol extract and vitamin E on vancomycin-induced nephrotoxicity in rats. Jundishapur J Nat Pharm 13:e67178. https://doi.org/10.5812/jjnpp.67178
Klimek-Szczykutowicz M, Szopa A, Ekiert H (2018) Chemical composition, traditional and professional use in medicine, application in environmental protection, position in food and cosmetics industries, and biotechnological studies of Nasturtium officinale (watercress): a review. Fitoterapia 129:283–292. https://doi.org/10.1016/j.fitote.2018.05.031
Latifian E, Arslanoğlu ŞF (2018) Traditional medicinal plants of Azerbaijan province of Iran. Agric Sci 9:157. https://doi.org/10.4236/as.2018.91012
Pandey Y, Bhatt SS, Debbarma N (2018) Watercress (Nasturtium Officinale): a potential source of nutraceuticals. Int J Curr Microbiol Appl Sci 7:2685–2691. https://doi.org/10.1186/s40064-015-1514-5
Bahramikia S, Yazdanparast R (2010) Antioxidant efficacy of Nasturtium officinale extracts using various in vitro assay systems. J Acupunct Meridian Stud 3:283–290. https://doi.org/10.1016/S2005-2901(10)60049-0
Fenton-Navarro B, Martínez MU, Castro BF, Castillo OM, López-Rodríguez M, Arellanes SP, Hernández AV (2018) Antioxidant and hypoglycemic effects of watercress (Nasturtium officinale) extracts in diabetic rats. Afr J Tradit Complement Altern Med 15:68–79. https://doi.org/10.21010/ajtcam.v15i2.9
Bahramikia S, Yazdanparast R (2008) Effect of hydroalcoholic extracts of Nasturtium officinale leaves on lipid profile in high-fat diet rats. J Ethnopharmacol 115:116–121. https://doi.org/10.1016/j.jep.2007.09.015
Obi RK (2011) Antiviral potential of vegetables: can they be cost-effective agents for human disease? In: Watson RR (ed) Nutrients, dietary supplements, and nutriceuticals. Springer, New York, pp 259–276
Sadeghi H, Mostafazadeh M, Sadeghi H, Naderian M, Barmak MJ, Talebianpoor MS, Mehraban F (2014) In vivo anti-inflammatory properties of aerial parts of Nasturtium officinale. Pharm Biol 52:169–174. https://doi.org/10.3109/13880209.2013.821138
Ozen T (2009) Investigation of antioxidant properties of Nasturtium officinale (watercress) leaf extracts. Acta Pol Pharm 66:187–193
Shahrokhi N, Hadad MK, Keshavarzi Z, Shabani M (2009) Effects of aqueous extract of water cress on glucose and lipid plasma in streptozotocin induced diabetic rats. Pak J Physiol 5:6–10
Mousa-Al-Reza Hadjzadeh ZR, Moradi R, Ghorbani A (2015) Effects of hydroalcoholic extract of watercress (Nasturtium officinale) leaves on serum glucose and lipid levels in diabetic rats. Indian J Physiol Pharmacol 59:223–230
Natanzi AE, Ghahremani MH, Monsef-Esfahani HR, Minaei B, Nazarian H, Sabzevari O (2009) An experimental model for study of the hepatoprotective activity of Nasturtium officinale (Watercress) against acetaminophen toxicity using in situ rat liver system. Eur J Sci Res 38:556–564
Gill CIR, Haldar S, Boyd LA, Bennett R, Whiteford J, Butler M, Pearson JR, Bradbury I, Rowland IR (2007) Watercress supplementation in diet reduces lymphocyte DNA damage and alters blood antioxidant status in healthy adults. Am J Clin Nutr 85:504–510. https://doi.org/10.1093/ajcn/85.2.504
Casanova NA, Simoniello MF, López Nigro MM, Carballo MA (2017) Modulator effect of watercress against cyclophosphamide-induced oxidative stress in mice. Medicina (B. Aires) 77:201–206
Giallourou N, Oruna-Concha MJ, Harbourne N (2016) Effects of domestic processing methods on the phytochemical content of watercress (Nasturtium officinale). Food Chem 212:411–419. https://doi.org/10.1016/j.foodchem.2016.05.190
Martínez-Sánchez A, Gil-Izquierdo A, Gil MI, Ferreres F (2008) A comparative study of flavonoid compounds, vitamin C, and antioxidant properties of baby leaf Brassicaceae species. J Agric Food Chem 56:2330–2340. https://doi.org/10.1021/jf072975+
Haro G, Iksen I, Rumanti RM, Marbun N, Sari RP, Gultom RPJ (2018) Evaluation of antioxidant activity and minerals value from watercress (Nasturtium officinale R. Br.). Rasayan J Chem 11:232–237. https://doi.org/10.7324/RJC.2018.1112011
Mazandarani M, Momeji A, Zarghami MP (2013) Evaluation of phytochemical and antioxidant activities from different parts of Nasturtium officinale R. Br. in Mazandaran. Iran J Plant Physiol 659:659–664
Flora SJ (2009) Structural, chemical and biological aspects of antioxidants for strategies against metal and metalloid exposure. Oxid Med Cell Longev 2:191–206. https://doi.org/10.4161/oxim.2.4.9112
Lin S-Y, Wang Y-Y, Chen W-Y, Chuang Y-H, Pan P-H, Chen C-J (2014) Beneficial effect of quercetin on cholestatic liver injury. J Nutr Biochem 25:1183–1195. https://doi.org/10.1016/j.jnutbio.2014.06.003
Doustimotlagh A, Taheri S, Mansourian M, Eftekhari M (2019) Extraction and identification of two flavonoids in Phlomoides hyoscyamoides as endemic plant of Iran: the role of quercetin in the activation of the glutathione peroxidase, the improvement of the hydroxyproline and protein oxidation in bile duct-ligated rats. Curr Comput-Aid Drug. https://doi.org/10.2174/1573409915666190903163335
Pullar JM, Thomson SJ, King MJ, Turnbull CI, Midwinter RG, Hampton MB (2004) The chemopreventive agent phenethyl isothiocyanate sensitizes cells to Fas-mediated apoptosis. Carcinogenesis 25:765–772. https://doi.org/10.1093/carcin/bgh063
Arabi M, Ostovan A, Asfaram A, Ghaedi M (2018) Development of an eco-friendly approach based on dispersive liquid–liquid microextraction for the quantitative determination of quercetin in Nasturtium officinale, Apium graveolens, Spinacia oleracea, Brassica oleracea var. sabellica, and food samples. New J Chem 42:14340–14348. https://doi.org/10.1039/C8NJ02485E
Panahi Kokhdan E, Ahmadi K, Sadeghi H, Sadeghi H, Dadgary F, Danaei N, Aghamaali MR (2017) Hepatoprotective effect of Stachys pilifera ethanol extract in carbon tetrachloride-induce hepatotoxicity in rats. Pharm Biol 55:1389–1393. https://doi.org/10.1080/13880209.2017.1302484
Mahmoudi R, Ardakani MT, Verdom BH, Bagheri A, Mohammad-Beigi H, Aliakbari F, Salehpour Z, Alipour M, Afrouz S, Bardania H (2019) Chitosan nanoparticles containing Physalis alkekengi-l extract: preparation, optimization and their antioxidant activity. Bull Mater Sci. https://doi.org/10.1007/s12034-019-1815-3
Goudarzi M, Khodayar MJ, Hosseini Tabatabaei SMT, Ghaznavi H, Fatemi I, Mehrzadi S (2017) Pretreatment with melatonin protects against cyclophosphamide-induced oxidative stress and renal damage in mice. Fundam Clin Pharmacol 31:625–635. https://doi.org/10.1111/fcp.12303
Karami M, Mostafazadeh M, Sadeghi H, Sadeghi H, Mehraban F, Kokhdan EP, Sayahi M, Abtahi SR (2018) Nephroprotective effect of Nasturtium officinale (Watercress) ethanol extract and vitamin E on vancomycin-induced nephrotoxicity in rats. Jundishapur J Nat Pharm 13:e67178. https://doi.org/10.5812/jjnpp.67178
Takizawa S, Fukuyama N, Hirabayashi H, Kohara S, Kazahari S, Shinohara Y, Nakazawa H (2003) Quercetin, a natural flavonoid, attenuates vacuolar formation in the optic tract in rat chronic cerebral hypoperfusion model. Brain Res 980:156–160. https://doi.org/10.1016/S0006-8993(03)03009-9
Sadeghi H, Jahanbazi F, Sadeghi H, Omidifar N, Alipoor B, Kokhdan EP, Mousavipoor SM, Mousavi-Fard SH, Doustimotlagh AH (2019) Metformin attenuates oxidative stress and liver damage after bile duct ligation in rats. Res Pharm Sci 14(2):122. https://doi.org/10.4103/1735-5362.253359
Doustimotlagh AH, Dehpour AR, Nourbakhsh M, Golestani A (2014) Alteration in membrane protein, antioxidant status and hexokinase activity in erythrocytes of CCl4-induced cirrhotic rats. Acta Med Iran 52:795–803
Doustimotlagh AH, Dehpour AR, Etemad-Moghadam S, Alaeddini M, Ostadhadi S, Golestani A (2018) A study on OPG/RANK/RANKL axis in osteoporotic bile duct-ligated rats and the involvement of nitrergic and opioidergic systems. Res Pharm Sci 13(3):239. https://doi.org/10.4103/1735-5362.228954
Kokhdan EP, Sadeghi H, Ghafoori H, Sadeghi H, Danaei N, Javadian H, Aghamaali MR (2018) Cytotoxic effect of methanolic extract, alkaloid and terpenoid fractions of Stachys pilifera against HT-29 cell line. Res Pharm Sci 13:404–412. https://doi.org/10.4103/1735-5362.236833
Benzie IF, Strain JJ (1996) The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: the FRAP assay. Anal Biochem 239:70–76. https://doi.org/10.1006/abio.1996.0292
Ohkawa H, Ohishi N, Yagi K (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358. https://doi.org/10.1016/0003-2697(79)90738-3
Moradi Z, Alipanahpour Dil E, Asfaram A (2019) Dispersive micro-solid phase extraction based on Fe3O4@SiO2@Ti-MOF as a magnetic nanocomposite sorbent for the trace analysis of caffeic acid in the medical extracts of plants and water samples prior to HPLC-UV analysis. Analyst 144:4351–4361. https://doi.org/10.1039/C9AN00120D
Germoush MO, Mahmoud AM (2014) Berberine mitigates cyclophosphamide-induced hepatotoxicity by modulating antioxidant status and inflammatory cytokines. J Cancer Res Clin Oncol 140:1103–1109. https://doi.org/10.1007/s00432-014-1665-8
Lata S, Singh S, NathTiwari K, Upadhyay R (2014) Evaluation of the antioxidant and hepatoprotective effect of Phyllanthus fraternus against a chemotherapeutic drug cyclophosphamide. Appl Biochem Biotechnol 173:2163–2173. https://doi.org/10.1016/j.intimp.2018.05.007
Sherif IO (2018) The effect of natural antioxidants in cyclophosphamide-induced hepatotoxicity: role of Nrf2/HO-1 pathway. Int Immunopharmacol 61:29–36. https://doi.org/10.1016/j.intimp.2018.05.007
Yazdanparast R, Bahramikia S, Ardestani A (2008) Nasturtium officinale reduces oxidative stress and enhances antioxidant capacity in hypercholesterolaemic rats. Chem-Biol Interact 172:176–184. https://doi.org/10.1016/j.cbi.2008.01.006
Sheweita SA, El-Hosseiny LS, Nashashibi MA (2016) Protective effects of essential oils as natural antioxidants against hepatotoxicity induced by cyclophosphamide in mice. PLoS ONE 11:e0165667. https://doi.org/10.1371/journal.pone.0165667
Alou-El-Makarem MM, Moustafa MM, Fahmy MA-A, Abdel-Hamed AM, El-fayomy KN, Darwish MMA-S (2014) Evaluation of carbonylated proteins in hepatitis c virus patients. Mod Chem Appl 2:1000130. https://doi.org/10.4172/2329-6798.1000130
Abraham P, Rabi S, Selvakumar D (2009) Protective effect of aminoguanidine against oxidative stress and bladder injury in cyclophosphamide-induced hemorrhagic cystitis in rat. Cell Biochem Funct 27:56–62. https://doi.org/10.1002/cbf.1534
Goudarzi M, Khodayar MJ, Hosseini Tabatabaei SMT, Ghaznavi H, Fatemi I (2017) Pretreatment with melatonin protects against cyclophosphamide-induced oxidative stress and renal damage in mice. Fundam Clin Pharmacol 31:625–635. https://doi.org/10.1111/fcp.12303
Sadeghi H, Azarmehr N, Razmkhah F, Sadeghi H, Danaei N, Omidifar N, Vakilpour H, Pourghadamyari H, Doustimotlagh AH (2019) The hydroalcoholic extract of watercress attenuates protein oxidation, oxidative stress, and liver damage after bile duct ligation in rats. J Cell Biochem 120:14875–14884. https://doi.org/10.1002/jcb.28749
Bryan NS (2018) Functional nitric oxide nutrition to combat cardiovascular disease. Curr Atheroscler Rep 20:21. https://doi.org/10.1007/s11883-018-0723-0
Akbari Bazm M, Khazaei M, Khazaei F, Naseri L (2019) Nasturtium Officinale L. hydroalcoholic extract improved oxymetholone-induced oxidative injury in mouse testis and sperm parameters. Andrologia 51:e13294. https://doi.org/10.1111/and.13294
Shahani S, Behzadfar F, Jahani D, Ghasemi M, Shaki F (2017) Antioxidant and anti-inflammatory effects of Nasturtium officinale involved in attenuation of gentamicin-induced nephrotoxicity. Toxicol Mech Method 27:107–114. https://doi.org/10.1080/15376516.2016.1258748
Llorach R, Martínez-Sánchez A, Tomás-Barberán FA, Gil MI, Ferreres F (2008) Characterisation of polyphenols and antioxidant properties of five lettuce varieties and escarole. Food Chem 108:1028–1038. https://doi.org/10.1016/j.foodchem.2007.11.032
Boligon AA, Janovik V, Boligon AA, Pivetta CR, Pereira RP, Rocha JBTD, Athayde ML (2013) HPLC analysis of polyphenolic compounds and antioxidant activity in Nasturtium officinale. Int J Food Prop 16:61–69. https://doi.org/10.1080/10942912.2010.528111
Rose P, Faulkner K, Williamson G, Mithen R (2000) 7-Methylsulfinylheptyl and 8-methylsulfinyloctyl isothiocyanates from watercress are potent inducers of phase II enzymes. Carcinogenesis 21:1983–1988. https://doi.org/10.1093/carcin/21.11.1983
Oneill M, Carroll Y, Corridan B, Olmedilla B, Granado F, Blanco I, Van den Berg H, Hininger I, Rousell A-M, Chopra M (2001) A European carotenoid database to assess carotenoid intakes and its use in a five-country comparative study. Br J Nutr 85:499–507. https://doi.org/10.1079/BJN2000284
Zeb A (2015) Phenolic profile and antioxidant potential of wild watercress (Nasturtium officinale L.). SpringerPlus 4:714. https://doi.org/10.1186/s40064-015-1514-5
Amiri H (2012) Volatile constituents and antioxidant activity of flowers, stems and leaves of Nasturtium officinale R Br. Nat Prod Res 26:109–115. https://doi.org/10.1080/14786419.2010.534998
Asfaram A, Arabi M, Ostovan A, Sadeghi H, Ghaedi M (2018) Simple and selective detection of quercetin in extracts of plants and food samples by dispersive-micro-solid phase extraction based on core-shell magnetic molecularly imprinted polymers. New J Chem 42:16144–16153. https://doi.org/10.1039/c8nj03349h
Acknowledgements
The authors acknowledge the financial support from the Yasuj University of Medical Sciences, Yasuj, Iran.
Author information
Authors and Affiliations
Contributions
HS—designed the research. AA, EPK, HV and BK—carried out the experiments. AA—performed HPLC analysis of Nasturtium officinale R.Br extract. MJB—performed histopathological analysis. AHD and AA—wrote the manuscript. HS, AHD and AA—revised the manuscript. All the listed authors have read and approved the submitted manuscript.
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare no conflict of interest.
Ethical approval
This study was performed in animal models.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Doustimotlagh, A.H., Kokhdan, E.P., Vakilpour, H. et al. Protective effect of Nasturtium officinale R. Br and quercetin against cyclophosphamide-induced hepatotoxicity in rats. Mol Biol Rep 47, 5001–5012 (2020). https://doi.org/10.1007/s11033-020-05556-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-020-05556-7