Abstract
To investigate the influence of Moringa seed extract (MSE) on the cerebral Nrf2/NQO1 signaling in TiO2-NPs–induced brain damage, 80 male albino rats were divided into four groups (n = 20); group I was used as a control, group II received TiO2-NPs (500 mg/kg b.w/day orally) for 14 days, group III received MSE (100 mg/kg b.w/day orally) for 30 days, and group IV received MSE an hour before TiO2-NPs administration with the same doses as before. Administration of TiO2-NPs was started on the 17th day for both groups (II) and (IV). Administration of MSE significantly increased the cerebral mitochondrial viability and Nrf2 level with a simultaneous increase of NQO1 mRNA expression. This designates a powerful antioxidant effect of MSE which is indicated by a significant reduction of INOS expression, MDA, TOS, OSI levels, and DNA fragmentation % with a significant increase of GSH concentration, SOD activities, and TAC. MSE possesses an anti-inflammatory effect by a significant reduction of IL-1β and TNF-α levels, and anti-apoptotic effect manifested by a significant reduction of caspase-3 and Fas levels. In harmonization, dopamine, serotonin concentrations, and acetylcholinesterase activities return back to normal as compared to control group. These results were confirmed by the histopathological features which were alleviated with MSE administration. In conclusion, Nrf2 plays a pivotal role in the mechanism of TiO2-NPs cerebral toxicity and MSE as a Nrf2 activator can provide a powerful cerebroprotective effect, whereas MSE increased the Nrf2 expression and consequently restore the antioxidant activity of brain cells by increasing NQO1 gene expression and cerebral mitochondrial viability as well as inhibition of pro-inflammatory and apoptotic mediators.
Similar content being viewed by others
Change history
31 July 2019
The original publication of this paper contains a mistake. The correct title is shown in this paper.
References
Ansar S, Abudawood M, Hamed SS, Aleem MM (2017) Exposure to zinc oxide nanoparticles induces neurotoxicity and proinflammatory response: amelioration by hesperidin. Biol Trace Elem Res 17:360–366
Bancroft JD, Gamble M (2002) Theory and practice of histological techniques, 5th edn. Churchill Livingstone, New York, London, New York & Sydney, pp 377–694
Beutler E, Duron O, Kelly BM (1963) Improved method for the determination of blood glutathione. J Lab Clin Med 61:882–888
Brand MD, Nicholls DG (2011) Assessing mitochondrial dysfunction in cells. Biochem J 435(2):297e312
Buege JA, Aust SD (1978) Microsomal lipid peroxidation. Methods Enzymol 52:302–310
Burton K (1956) The study of the conditions and mechanisms of the diphenylamine reaction for the calorimetric estimation of deoxyribonucleic acid. Biochem J 62:615–623
Chen Q, Wang N, Zhu M, Lu J, Zhong H, Xue X, Guo S, Li M, Wei X, Tao Y, Yin H (2018) TiO2 nanoparticles cause mitochondrial dysfunction, activate inflammatory responses, and attenuate phagocytosis in macrophages: a proteomic and metabolomic insight. Redox Biol 15:266–276
Chivapat S, Sincharoenpokai P, Suppajariyawat P, Rungsipipat A, Phattarapornchaiwat S, Chantarateptawan V (2012) Safety evaluations of ethanolic extract of Moringa oleifera Lam. seed in experimental animals. Thai J Vet Med 42(3):343–352
Clements CM, McNally RS, Conti BJ, Ma TW, Ting JP (2006) DJ-1, a cancer- and Parkinson’s disease–associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proc Natl Acad Sci U S A 103:15091–15096
Culei I (1964) Practical manual on the industrial utilization of medicinal plants. University of Bucharest, Romania, pp 56–71
De Moura MB, dos Santos LS, Van Houten B (2010) Mitochondrial dysfunction in neurodegenerative diseases and cancer. Environ Mol Mutagen 51:391e405
Dinkova-Kostova AT, Abramov AY (2015) The emerging role of Nrf2 in mitochondrial function. Free Radic Biol Med 88(B):179–188
Dinkova-Kostova AT, Talalay P (2000) Persuasive evidence that quinone reductase type 1 (DT diaphorase) protects cells against the toxicity of electrophiles and reactive forms of oxygen. Free Radic Biol Med 29(3–4):231–240
Dinkova-Kostova AT, Liby KT, Stephenson KK, Holtzclaw WD, Gao X, Suh N, Williams C, Risingsong R, Honda T, Gribble GW, Sporn MB, Talalay P (2005) Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. Proc Natl Acad Sci U S A 102:4584–4589
Dinkova-Kostova AT, Kostov RV, Kazantsev AG (2018) The role of Nrf2 signaling in counteracting neurodegenerative diseases. FEBS J 285(19):3576–3590
Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35:495–516
El-Shemy HA, Aboul-Enein AM, Aboul-Enein KM, Fujita K (2007) Willow leaves’ extracts contain anti-tumor agents effective against three cell types. PLoS One 2(1):e178
Erel O (2005) A new automated colorimetric method for measuring total oxidant status. Clin Biochem 38:1103–1111
Fabian E, Landsiedel R, Ma-Hock L, Wiench K, Wohlleben W, van Ravenzwaay B (2008) Tissue distribution and toxicity of intravenously administered titanium dioxide nanoparticles in rats. Arch Toxicol 82:151–157
Fernandes ES, Passos GF, Medeiros R, da Cunha FM, Ferreira J, Campos MM, Pianowski LF, Calixto JB (2007) Anti-inflammatory effects of compounds alpha-humulene and (-)-trans-caryophyllene isolated from the essential oil of Cordia verbenacea. Eur J Pharmacol 569(3):228–236
Fleury C, Mignotte B, Vayssiere JL (2002) Mitochondrial reactive oxygen species in cell death signaling. Biochimie 84:131–141
Franco JL, Braga HC, Stringari J, Missau FC, Posser T, Mendes BG, Leal RB, Santos AR, Dafre AL, Pizzolatti MG, Farina M (2007) Mercurial-induced hydrogen peroxide generation in mouse brain mitochondria: protective effects of quercetin. Chem Res Toxicol 20:1919–1926
Fujisawa S, Muraoka E, Nakazato Y, Okada N (2005) Effects of visible light irradiation on eugenol-treated oral mucosa. Dent Mater J 24:202–206
Ghiridhari WA, Malhati D, Geetha K (2011) Anti-diabetic properties of drumstick (Moringa oleifera) leaf tablets. Int J Health Nutr 2:1–5
Gorrini C, Harris IS, Mak TW (2013) Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov 12:931–947
Gurr JR, Wang AS, Chen CH, Jan KY (2005) Ultrafine titanium dioxide particles in the absence of photoactivation can induce oxidative damage to human bronchial epithelial cells. Toxicology 213:66–73
Gusev AI (2007) Nanomaterials, nanostructures, and nanotechnologies (in Russian) Fizmatlit Moscow 416
Gusev AI, Kurlov AS (2008) Production of nanocrystalline powders by high-energy ball milling: model and experiment. Nanotechnology 19(26):265–302
Han D, Hanawa N, Saberi B, Kaplowitz N (2006) Mechanisms of liver injury. III. Role of glutathione redox status in liver injury. Am J Physiol Gastrointest Liver Physiol 291(1):G1–G7
Harangi M, Seres I, Varga Z, Emri G, Szilvássy Z, aragh G (2004) Atorvastatin effect on high-density lipoprotein-associated paraoxonase activity and oxidative DNA damage. Eur J Clin Pharmacol 60:685–691
Harborne JB (1973) Phytochemical methods: a guide to modern techniques of plant analysis. Chapman and Hall Ltd, London, pp 49–188
Harlow ED, Lane DP (1999) Using antibodies. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York
Hond T, Honda Y, Favaloro FG, Gribble GW, Suh N, Place AE, Rendi MH, Sporn MB (2002) A novel dicyanotriterpenoid, 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-onitrile, active at picomolar concentrations for inhibition of nitric oxide production. Bioorg Med Chem Lett 12:1027–1030
Hu R, Gong X, Duan Y, Li N, Che Y, Cui Y, Zhou M, Liu C, Wang H, Hong F (2010) Neurotoxicological effects and the impairment of spatial recognition memory in mice caused by exposure to TiO2 nanoparticles. Biomaterials 31(31):8043–8050
Hu R, Zheng L, Zhang T, Gao G, Cui Y, Cheng Z, Cheng J, Hong M, Tang M, Hong F (2011) Molecular mechanism of hippocampal apoptosis of mice following exposure to titanium dioxide nanoparticles. J Hazard Mater 191:32–40
Huerta-Garcıa E, Perez-Arizti JA, Marquez-Ram S, Gırez et al (2014) Titanium dioxide nanoparticles induce strong oxidative stress and mitochondrial damage in glial cells. Free Radic Biol Med 73:84–94
IARC (1985) Monographs on the evaluation of the carcinogenic risk of chemicals to humans: allyl compounds, aldehydes, epoxides and peroxides. World Health Organization, International Agency for Research on Cancer, Lyon, pp 163–177
Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, Oyake T, Hayashi N, Satoh K, Hatayama I, Yamamoto M, Nabeshima Y (1997) An Nrf2 small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun 236:313–322
Katsube T, Tabata H, Ohta Y, Yamasaki Y, Anuurad E, Shiwaku K, Yamane Y (2004) Screening for antioxidant activity in edible plant products: comparison of low-density lipoprotein oxidation assay, DPPH radical scavenging assay, and Folin-Ciocalteu assay. J Agric Food Chem 52:2391–2396
Kaya H, Akbulut M (2015) Effects of waterborne lead exposure in Mozambiquetilapia: oxidative stress, osmoregulatory responses, and tissue accumulation. J Aquat Anim Health 27:77–87. https://doi.org/10.1080/08997659.2014.1001533. https://www.ncbi.nlm.nih.gov/pubmed/25951052
Kobayashi A, Kang MI, Watai Y, Tong KI, Shibata T, Uchida K, Yamamoto M (2006) Oxidative and electrophilic stresses activate Nrf2 through inhibition of ubiquitination activity if Keap1. Mol Cell Biol 26:221–229
Koracevic D, Koracevic G, Djordjevic V, Andrejevic S, Cosic V (2001) Method for the measurement of antioxidant activity in human fluids. J Clin Pathol 54:356–361
Kovarik Z, Radić Z, Berman HA, Simeon-Rudolf V, Reiner E, Taylor P (2003) Acetyl cholinesterase active centre and gorge conformations analyzed by combinatorial mutations and enantiomeric phosphonates. Biochem J 1(73):33–40
Kundu A, Saha S, Walia S, Ahluwalia V, Kaur C (2013) Antioxidant potential of essential oil and cadinene sesquiterpenes of Eupatorium adenophorum. Toxicol Environ Chem 95(1):127–137
Li Y, Paonessa JD, Zhang Y (2012) Mechanism of chemical activation of Nrf2. PLoS One 7:e35122
Li X, Fang P, Mai J, Choi ET, Wang H, Yang XF (2013) Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers. J Hematol Oncol 2744:6e19
Lin JY, Tang CY (2006) Determination of total phenolic and flavonoid contents in selected fruits and vegetables, as well as their stimulatory effects on mouse splenocyte proliferation. Food Chem 101(1):140–147
Liu J, Wu KC, Lu YF, Ekuase E, Klaassen CD (2013) NRF2 protection against liver injury produced by various hepatotoxicants. Oxid Med Cell Longev 2013:305861. https://doi.org/10.1155/2013/305861
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C (T)) Method. Methods 25(4):402–408
Long TM, Tajuba J, Sama P, Saleh N, Swartz C, Parker J, Hester S, Lowry GV, Veronesi B (2007) Nanosize titanium dioxide stimulates reactive oxygen species in brain microglia and damages neurons in vitro. Environ Health Perspect 115(11):1631–1637
Ma L, Liu J, Li N, Wang J, Duan Y, Yan J, Liu H, Wang H, Hong F (2010) Oxidative stress in the brain of mice caused by translocated nanoparticulate TiO2 delivered to the abdominal cavity. Biomaterials 31:99–105
Mbikay M (2012) Therapeutic potential of Moringa oleifera leaves in chronic hyperglycemia and dyslipidemia: a review. Front Pharmacol 3:24
McCoy MK, Cookson MR (2011) DJ-1 regulation of mitochondrial function and autophagy through oxidative stress. Autophagy 7:531–532
Meng B, Li J, Cao H (2013) Antioxidant and antiinflammatory activities of curcumin on diabetes mellitus and its complications. Curr Pharm Des 19:2101–2113
Moscovitz O, Tsvetkov P, Hazan N, Michaelevski I, Keisar H, Ben-Nissan G, Shaul Y, Sharon M (2012) A mutually inhibitory feedback loop between the 20S proteasome and its regulator, NQO1. Mol Cell 47:76–86
Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65(1–2):55–63
Munoz-Castaneda JK, Montilla P, Padillo FJ, Bujalance I, Munoz MC, Muntane J, Tunez I (2006) Role of serotonin in cerebral oxidative stress in rats. Acta Neurobiol Exp 66(1):1–6
Nabavi SM, Ebrahimzadeh MA, Nabavi SF, Hamidinia A, Bekhradnia AR (2008) Determination of antioxidant activity, phenol and flavonoids content of Parrotia persica Mey. Pharmacol Online 2:560–567
Nishikimi M, Rao NA, Yagi K (1972) The occurrence of superoxide anion in the reaction of reduced phenazine methosulphate and molecular oxygen. Biochem Biophys Res Commun 46(2):849–854
Niska K, Pyszka K, Tukaj C, Wozniak M, Radomski MW, Inkielewicz-Stepniak I (2015) Titanium dioxide nanoparticles enhance production of superoxide anion and alter the antioxidant system in human osteoblast cells. Int J Nanomedicine 4(10):1095–1107
Okwu ED, Ighodaro UB (2010) GC-MS evaluation of bioactive compounds and antibacterial activity of the oil fraction from the leaves of Alstoniaboonei. De Wild, Der Pharma Chemica 2(1):261–262
Panda S, Kar A, Sharma P, Sharma A (2013) Cardioprotective potential of N,alpha-l-rhamnopyranosyl vincosamide, an indole alkaloid, isolated from the leaves of Moringa oleifera in isoproterenol induced cardiotoxic rats: in vivo and in vitro studies. Bioorg Med Chem Lett 23:959–962
Pink JJ, Planchon SM, Tagliarino C, Varnes ME, Siegel D, Boothman DA (2000) NAD(P)H:Quinone oxidoreductase activity is the principal determinant of beta-lapachone cytotoxicity. J Biol Chem 275:5416–5424
Pradeep HA, Khan S, Ravikumar K, Ahmed MF, Rao MS, Kiranmai M, Reddy DS, Ahamed SR, Ibrahim M (2009) Hepatoprotective evaluation of Anogeissus latifolia: in vitro and in vivo studies. World J Gastroenterol 15(38):4816–4822
Prieto P, Pineda M, Aguilar M (1999) Spectrophotometric quantitation of antioxidant capacity through the formation of a phosphomolybdenum complex: specific application to the determination of vitamin E. Anal Biochem 269:337–341
Rajappa R, Bovilla V, Madhunapantula SV (2017) Naturally occurring Nrf2 activators in the management of diabetes. Nutr Food Sci Int J 2(4):1–10
Rizk MZ, Ali SA, Hamed MA, El-Rigal NS, Aly HF, Salah HH (2017) Toxicity of titanium dioxide nanoparticles: effect of dose and time on biochemical disturbance, oxidative stress and genotoxicity in mice. Biomed Pharmacother 90:466–472
Rockwood JL, Anderson BG, Casamatta DA (2013) Potential uses of Moringa oleifera and an examination of antibiotic efficacy conferred by M. oleifera seed and leaf extracts using crude extraction techniques available to underserved indigenous populations. Int J Phytotherapy Res 3:61–71
Sadrieh N, Wokovich AM, Gopee NV, Zheng J, Haines D, Parmiter D, Siitonen PH, Cozart CR, Patri AK, McNeil SE, Howard PC, Doub WH, Buhse LF (2010) Lack of significant dermal penetration of titanium dioxide from sunscreen formulations containing nano- and submicron-size TiO2 particles. Toxicol Sci 115:156–166
Sermakkani M, Thangapandian V (2012) GC-MS analysis of Cassia italic leaf methanol extract. Asian J Pharm Clin Res 5(2):90–94
Sharma HS, Sharma A (2010) Conference scene: nanoneuroprotection and nanoneurotoxicity: recent progress and future perspectives. Nanomedicine 5:533–537 https://www.futuremedicine.com/doi/abs/10.2217/nnm.10.25
Shi H, Magaye R, Castranova V, Zhao J (2013) Titanium dioxide nanoparticles: a review of current toxicological data. Part Fibre Toxicol 10:15
Shi Z, Niu Y, Wang Q, Shi L, Guo H, Liu Y et al (2015) Reduction of DNA damage induced by titanium dioxide nanoparticles through Nrf2 in vitro and in vivo. J Hazard Mater 15(298):310–319
Shih AY, Imbeault S, Barakauskas V, Erb H, Jiang L, Li P, Murphy TH (2005) Induction of the Nrf2-driven antioxidant response confers neuroprotection during mitochondrial stress in vivo. J Biol Chem 280(24):22925–22936
Shukla RK, Sharma V, Pandey AK, Singh S, Sultana S, Dhawan A (2011) ROS-mediated genotoxicity induced by titanium dioxide nanoparticles in human epidermal cells. Toxicol in Vitro 25:231–241
Siegel D, Bolton EM, Burr JA, Liebler DC, Ross D (1997) The reduction of alpha-tocopherol quinone by human NAD(P)H: quinone oxidoreductase: the role of alpha-tocopherol hydroquinone as a cellular antioxidant. Mol Pharmacol 52:300–305
Song B, Liu J, Feng X, Wei L, Sha L (2015) A review on potential neurotoxicity of titanium dioxide nanoparticles. Nanoscale Res Lett 10:342
Sun GY, Horrocks LA, Farooqui AA (2007) The roles of NADPH oxidase and phospholipases A2 in oxidative and inflammatory responses in neurodegenerative diseases. J Neurochem 103(1):1–16
Tietz NW (1995) Clinical guide to laboratory tests (ELISA), 3rd edn. W.B. Saunders, Co, Philadelphia, pp 22–23
Totsuka Y, Ishino K, Kato T, Goto S, Tada Y, Nakae D, Watanabe M, Wakabayashi K (2014) Magnetite nanoparticles induce genotoxicity in the lungs of mice via inflammatory response. Nanomaterials 4:175–188
Trouiller B, Reliene R, Westbrook A, Solaimani P, Schiestl RH (2009) Titanium dioxide nanoparticles induce DNA damage and genetic instability in vivo in mice. Cancer Res 69:8784–8789
Tsyganova NA, Khairullin NA, Terentyuk GS, Khlebtsov BN, Bogatyrev VA, Dykman LA et al (2014) Penetration of pegylated gold nanoparticles through rat placental barrier. Bull Exp Biol Med 157(3):383–385
Vongsak B, Sithisarn P, Mangmool S, Thongpraditchote S, Wongkrajang Y, Gritsanapan W (2013) Maximizing total phenolics, total flavonoids contents and antioxidant activity of Moringa oleifera leaf extract by the appropriate extraction method. Ind Crop Prod 44:566–571
Wang JX, Zhou GQ, Chen CY, Yu HW, Wang TC, Ma YM, Jia G et al (2007) Acute toxicity and biodistribution of different sized titanium dioxide particles in mice after oral administration. Toxicol Lett 168:176–185
Wang J, Chen C, Liu Y, Jiao F, Li W, Lao F et al (2008) Potential neurological lesion after nasal instillation of TiO2 nanoparticles in the anatase and rutile crystal phases. Toxicol Lett 183(1–3):72–80
Warheit RA, Hoke DB, Finlay C, Donner EM, Reed KL, Sayes CM (2007) Development of a base set of toxicity tests using ultrafine TiO2 particles as a component of nanoparticle risk management. Toxicol Lett 171:99–110
Wild AC, Moinova HR, Mulcahy RT (1999) Regulation of gamma- glutamyl cysteine synthetase subunit gene expression by the transcription factor Nrf2. J Biol Chem 274:33627–33636
Wolf R, Matz H, Orion EJ (2003) Lipozencic, sunscreens—the ultimate cosmetic. Acta Dermatovenerol Croat 11(3):158–162
Worek F, Reiter G, Eyer P, Szinicz L (2002) Reactivation kinetics of acetylcholinesterase from different species inhibited by highly toxic organophosphates. Arch Toxicol 76:523–529
Wu KC, Cui JY, Klaassen CD (2011) Beneficial role of Nrf2 in regulating NADPH generation and consumption. Toxicol Sci 123:590–600
Wu Y, Wang D, Peng X, Chen Y, Zheng D, Chen W et al (2013) Epigenetic silencing of NAD(P)H: quinone oxidoreductase 1 by hepatitis B virus X protein increases mitochondrial injury and cellular susceptibility to oxidative stress in hepatoma cells. Free Radic Biol Med 65:632–664
Xia T, Kovochich M, Liong M, Mädler L, Gilbert B, Shi H, Yeh JI, Zink JI, Nel AE (2008) Comparison of the mechanism of toxicity of zinc oxide and cerium oxide nanoparticles based on dissolution and oxidative stress properties. ACS Nano 2:2121–2134
Yogalakshmi B, Viswanathan P, Anuradha CV (2010) Investigation of antioxidant, anti-inflammatory and DNA-protective properties of eugenol in thioacetamide-induced liver injury in rats. Toxicology 168:204–212
Yoo KC, Yoon CH, Kwon D, Hyun KH, Woo SJ, Kim RK, Lim EJ, Suh Y, Kim MJ, Yoon TH, Lee SJ (2012) Titanium dioxide induces apoptotic cell death through reactive oxygen species-mediated Fas upregulation and Bax activation. Int J Nanomedicine 7:1203–1214
Youdim KA, Joseph JA (2001) A possible emerging role of phytochemicals in improving age-related neurological dysfunctions: a multiplicity of effects. Free Radic Biol Med 30(6):583–594
Zahin N, Anwar R, Tewari D et al (2019) Nanoparticles and its biomedical applications in health and diseases: special focus on drug delivery. Environ Sci Pollut Res. https://doi.org/10.1007/s11356-019-05211-0
Zhu H, Jia Z, Mahaney JE, Ross D, Misra HP, Trush MA, Li Y (2007) The highly expressed and inducible endogenous NAD(P)H:quinone oxidoreductase 1 in cardiovascular cells acts as a potential superoxide scavenger. Cardiovasc Toxicol 7:202–211
Acknowledgments
We thank Dr. Rawya G. Abd El-Wahab, Department of Biochemistry, Beni-Suef University, Egypt, for helping in rearing of animals and sampling. The authors thank all staff members in the Biochemistry and Pathology Departments, Beni-Suef University, Egypt, for their help and advices.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no competing interests.
Additional information
Responsible editor: Philippe Garrigues
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
The original article was revised: The original publication of this paper contains a mistake. The correct title is shown in this paper.
Electronic supplementary material
ESM 1
(DOCX 19 kb)
Rights and permissions
About this article
Cite this article
Kandeil, M.A., Mohammed, E.T., Hashem, K.S. et al. Moringa seed extract alleviates titanium oxide nanoparticles (TiO2-NPs)-induced cerebral oxidative damage, and increases cerebral mitochondrial viability. Environ Sci Pollut Res 27, 19169–19184 (2020). https://doi.org/10.1007/s11356-019-05514-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11356-019-05514-2