PROTECTIVE INFLUENCE OF FISETIN ON COGNITIVE AND BIOCHEMICAL INDICES IN N-NITROSODIETYHLAMINE TREATED DROSOPHILA MELANOGASTER
Keywords:Cancer, Drosophila melanogaster, Fisetin, Behavioural assays, Free radical
Objective: The current investigation is intended to investigate the protecting influence of fisetin on cognitive, as well as biochemical indices in N-Nitrosodiethylamine (NDEA, a potent carcinogen), treated Drosophila melanogaster.
Methods: D. melanogaster is used as a model organism for this investigation. Experimental flies are divided into four groups. Group 1–control, group 2-flies were treated with 0.01% NDEA in food medium, group 3–flies treated with 0.01% NDEA and 0.01% fisetin and group 4-flies were treated with 0.01% fisetin alone. Behavioural abnormalities (negative geotaxis, phototaxis, smell and taste chemotaxis, hygrotaxis and thermotaxis) were quantitatively observed to be deviated in NDEA treated flies compared to control but were tend to be normalized in fisetin treated flies.
Results: The contents of protein carbonyl, thiobarbituric acid reactive substance (TBARS), protein thiol and lipid peroxides were noticeably augmented in NDEA treated flies than control flies and correspondingly tend to normalize in fisetin treated groups. Further, superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), glutathione peroxidise (GPX) and reduced glutathione (GSH) were decreased in NDEA treated group and were significantly increased (p<0.05) in fisetin treated groups.
Conclusion: Fisetin, a bioactive phytochemical could act as a potent antioxidant and as well exhibit antiproliferative characteristics. Our investigation indicates that this could prevent the abnormalities in behaviour and redox homeostasis during carcinogenesis in D. melanogaster.
2. Illburn GH, Grosby MA, Gramates LS, Tweedie S, FlyBase C. Fly base portals to human disease research using Drosophila models. Dis Models Mechan 2016;9:245-52.
3. Sonoshita M, Cagan RL. Modelling human cancers in Drosophila. Curr Topics Dev Biol 2017;121:287-309.
4. Adnan H, Adnan SM, Deng K, Yang C, Zhao W, Li K. Variation in insurance-mortality relationship amid macroeconomic shifts: a study of SEER female-specific cancer patients in USA. Public Health 2020;185:130-8.
5. Hoskins RA. Drosophila genome sequence, a model for the human. Biomed Pharmacother 2000;54:415-6.
6. Hussain M, Jabeen N, Shabbir S. Dataset for homologous proteins in Drosophila melanogaster for SARS-CoV-2/human interactome. Data Brief 2020;32:106082
7. Mirozoyan Z, Sollazzo M, Allocca M, Valenza AM, Grifoni D, Bellosta P. Drosophila melanogaster: a model organism to study cancer. Front Genet 2014;10:51.
8. Vang LL, Medvedev AV, Adler J. Simple ways to measure behavioral responses of Drosophila to stimuli and use of these methods to characterize a novel mutant. PLOS One 2012;7:e37495.
9. Antoni MH, Lutgendorf SK, Cole SW. The influence of bio behavioural factors in tumor biology: pathways and mechanisms. Nat Rev Cancer 2006;6:240-8.
10. Bonilla E, Contreras R, Medina Leendertz S, Mora M, Villalobos V, Bravo Y. Minocycline increases the life span and motor activity and decreases lipid peroxidation in manganese treated Drosophila melanogaster. Toxicology 2012;294:50-3.
11. Subramanian P, Prasanna V, Jayapalan JJ, Adbul Rahman PS, Hashim OH. Role of Bacopa monnieri in the temporal regulation of oxidative stress in clock mutant (cryb) of Drosophila melanogaster. J Insect Physiol 2014;65:37-44.
12. Hebels DGAJ, Jennen DGJ, Kleinjans JCS, de Kok TMCM. Molecular signatures of N-nitroso compounds in caco-2 cells: implications for colon carcinogenesis. Toxicol Sci 2009;108:290-300.
13. El-Din NKB, Ali DA, Othman R, French SW, Ghoneum M. Chemopreventive role of arabinoxylan rice-bran, MGN-3/Biobran, on liver carcinogenesis in rats. Biomed Pharmacother 2020;126:110064.
14. Lu S, Li G, Lv Z. Facile and sensitive determination of N-nitrosoamines in food samples by high-performance liquid chromatography via combining fluorescent labelling with dispersive liquid-liquid microextraction. Food Chem 2017;234:408-15.
15. Stuff JE, Goh ET, Barrera SL, Bondy ML, Forman MR. Construction of an N-nitroso database for assessing dietary intake. J Food Comp Anal 2009;225:542-77.
16. Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chemico-Biol Interact 2006;160:1-40.
17. Claudia AF, Aiuba GG, Izaura O. N-Nitrosodiethylamine genotoxicity in primary rat hepatocytes: Effects of cytochrome P450 induction by phenobarbital. Toxicol Lett 2011;206:139-43.
18. Pinto, RLF. Differences between isoamylalcohol and ethanol on the metabolism and DNA ethylation of N-nitrosodiethylamine in the rat. Toxicology 2000;151:73–9.
19. Muller FL, Lustgarten MS, Jang Y, Richardson A, Remmen VH. Trends in oxidative aging theories. Free Radical Biol Med 2007;43:477-503.
20. Lin Y, Jiang M, Chen W, Zhao T, Wei Y. Cancer and ER stress: mutual crosstalk between autophagy, oxidative stress and inflammatory response. Biomed Pharmacother 2019;118:109249.
21. Wong KC, Sankaran S, Jayapalan JJ, Subramanian P, Abdul Rahman PS. Melatonin improves cognitive behaviour, oxidative stress and metabolism in tumor-prone lethal giant larvae mutant of Drosophila melanogaster. Arch Insect Biochem Physiol 2021;107:e21785.
22. Donohoe C, Senge MO, Arnaut LG, Gomes-da-Silva LC. Cell death in photodynamic therapy: from oxidative stress to anti-tumor immunity. Biochim Biophys Acta Rev Cancer 2019;1872:188308.
23. Nimse SB, Pal D. Free radicals, natural antioxidants, and their reaction mechanisms. Royal Soc Chem Adv 2015;5:27986–8006.
24. Barreca D, Trombretta D, Smeriglio A. Food flavonols: nutraceuticals with complex health benefits and functionalities. Trends Food Sci Technol 2021. DOI:10.1016/j. tifs.2021.03.030
25. Grynkiewicz G, Demchuk V. New perspective for fisetin. Front Chem 2019;7:697.
26. Hostetler GL, Ralston RA, Schwartz SJ. Flavones: food sources, bioavailability, metabolism and bioactivity. Nat Prod Res 2017;24:995-1003.
27. AITamimi JZ, BioMowyna MN, Alfaris NA, Alagal RI, El-kott AF, Al-farga AM. Fisetin protects against streptozotocin-induced diabetic cardiomyopathy in rats by suppressing fatty acid oxidation and inhibiting protein kinase. Saudi Pharm J 2021;29:27-42.
28. Sung B, Pandey MK, Aggarwal BB. Fisetin, an inhibitor of cyclin-dependent kinase 6, down-regulates nuclear factor-kappaB regulated cell proliferation, anti-apoptotic and metastatic gene products through the suppression of TAK-1 and receptor interacting protein-regulated IkappaBalpha kinase activation. Mol Pharmacol 2007;71:1703-14.
29. Henneken A, Lin FF, Johnson J, Maher P. Flavonoids protect human retinal pigment epithelial cells from oxidative-stress-induced death. Retinal Cell Biol 2006;47:3164-77.
30. Biela M, Rimarckik J, Senajova E, Kleinova A, Klein E. Antioxidant action of deprotonated flavonoids: thermodynamics of sequential proton-loss electron transfer. Phytochemistry 2020;180:112528.
31. Touil YS, Seguin J, Scherman D, Chabot GG. Improved antiangiogenic and antitumour activity of the combination of the natural flavonoid fisetin and cyclophosphamide in lewis lung carcinoma-bearing mice. Cancer Chemother Pharmacol 2011;68:445–55.
32. Garza Lombo C, Pappa A, Panayiotidis MI, Franco R. Redox homeostasis, oxidative stress and mitophagy. Mitochondrion 2020;51:105-17.
33. Tsai CF, Chen JH, Chang CN. Fisetin inhibits cell migration via inducing HO-1 and reducing MMPs expression in breast cancer cell lines. Food Chem Toxicol 2018;120:528-35.
34. Moolakkaddath T, Aquil M, Ahad A. Fisetin loaded binary ethosomes for management of skin cancer by dermal application on UV exposed mice. Int J Pharm 2015;560:78-91.
35. Coll Tane M, Krebbers A, Castells Nobau A, Zweier C, Schencka A. Intellectual disability and autism spectrum disorders ‘on the fly’: insights from Drosophila. Disease Mod Mechan 2019;12. DOI:10.1242/dmm.039180
36. Pendergrass JC, Targum SD, Harrison JE. Cognitive impairment associated with cancer: a brief review. Inn Clin Neurosci 2018;15:36-44.
37. Haddadi M, Jahromi SR, Sagar BK, Patil RK, Shivanandappa T, Ramesh SR. Brain aging, memory impairment and oxidative stress: a study in Drosophila melanogaster. Behav Brain Res 2014;259:60-9.
38. Subramanian P, Jayapalan JJ, Abdul Rahman PS, Manjula A, Hashim OH. Temporal regulation of proteome profile in the fruit fly, Drosophila melanogaster. Peer J 2016;4:102-31.
39. Macmillan HA, Hughson BN. A high-throughput method of hemolymph collection from adult Drosophila without anesthesia. J Insect Physiol 2014;63:27-31.
40. Neckameyer WS, Bhatt P. Protocols to study behavior in drosophila. In: Dahmann C. Ed. Drosophila: methods and protocols: Springer, New York; 2016. p. 303-20.
41. Feany MB, Bender WW. A Drosophila model of Parkinson’s disease. Nature 2000;404:394-8.
42. Levine RL, Garland D, Oliver CN. Determination of carbonyl content in oxidatively modified proteins. Met Enzymol 1990;186:464-78.
43. Niehaus WG, Samuelsson B. Formation of malondialdehyde from phospholipid arachidonate during microsomal lipid peroxidation. Eur J Biochem 1968;6:126-30.
44. Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys 1959;82:70-7.
45. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979;95:351-8.
46. Habig WH, Palst MJ, Jakpoly WB. Glutathione transferase: a first enzymatic step in mercapturic acid and formation. J Biol Chem 1974;249:7130-9.
47. Kakkar P, Das B, Viswanathan PN. A modified spectrophotometric assay of superoxide dismutase (SOD). Ind J Biochem Biophys 1984;21:130-2.
48. Sinha KA. Colorimetric assay of catalase. Anal Biochem 1972;7:389-94.
49. Rotruck JT, Pope A, Ganther HE, Swanson AB, Hafeman DG, Hoekstra WG. Selenium: biochemical roles as components of glutathione peroxidase. Science 1973;179:588–90.
50. Takahashi E, Marczylo TH, Watanabe T, Nagai S, Hayatsu H, Negishi T. Preventive effects of anthraquinone food pigments on the DNA damage induced by carcinogens in Drosophila. Mut Res 2001;1:139-45.
51. Hosamani R, Muralidhara. Neuroprotective efficacy of Bacopa monnieri against rotenone-induced oxidative stress and neurotoxicity in Drosophila melanogaster. Neurotoxicol 2009;30:977-85.
52. Hill VM, O'Connor RM, Sissoko GB. A bidirectional relationship between sleep and oxidative stress in Drosophila. PLoS Biol 2018;16:e2005206.
53. Ding G, Xu X, Li D. Fisetin inhibits proliferation of pancreatic adenocarcinoma by inducing DNA damage via PFXAP/KDM4A-dependent histone H3K36 demethylation. Cell Death Dis 2020;1:893.
54. Agioutantis PC, Kotsikoris V, Kolisis N, Loutari H. RNA-sequence data analysis of stimulated hepatocellular carcinoma cells treated with epigallocatechin gallate and fisetin reveals target genes and action mechanisms. Comput Structural Biotech J 2020;18:686-95.
55. Fan Q, Wang X, Chinnathambi A, Alharbi SA, Wang Q. Fisetin suppresses 1,2-diemthylhydrazine-induced colon tumorigenesis in wistar rats via enhancing the apoptotic signaling pathway. J King Saud Univ Sci 2020;32:1959-64.
56. Ishii N, Homma T, Guo X, Yamada KI, Yamada S, Fujii J. Ascorbic acid prevents N-nitrosodiethylamine induced hepatic injury and hepatocarcinogenesis in akr1a-knockout mice. Toxicol Lett 2020;333:192-201.
57. Yang Y, Zhang G, Guo F. Mitochondrial UQCC3 modulates hypoxia adaptation by orchestrating OXPHOS and glycolysis in hepatocellular carcinoma. Cell Rep 2020;33:108340.
58. Imai K, Nakanishi I, Ohkubo K. Synthesis and radical-scavenging activity of C-methylated fisetin analogs. Bioorg Med Chem 2019;27:1720-7.
59. Weinberg F, Ramnath N, Nagrath D. Reactive oxygen species in the tumor microenvironment: an overview. Cancers 2019;11:1191.
60. Kasapoglu M, Ozben T. Alterations of antioxidant enzymes and oxidative stress markers in aging. Exp Gerontol 2001;36:209-20.
61. Aguiar LM, Figueira FH, Gottschalk MS, Rosa CE. Glyphosphate-based herbicide exposure causes antioxidant defense responses in the fruit fly Drosophila melanogaster. Comp Biochem Physiol C: Toxicol Pharmacol 2016;185-186:94-101.
62. Subramanian P, Jayakumar M, Singaravel M. Fisetin, a dietary flavonoid attenuates hyperammonemia and improves circadian locomotor deficits, redox balance and astrocytic markers in rats. J Func Foods 2015;12:405-19.
63. Kuo CL, Chou HY Chiu YC. Mitochondrial oxidative stress by Lon-PYCR1 maintains an immunosuppressive tumor microenvironment that promotes cancer progression and metastasis. Cancer Lett 2020;474:138-50.
64. Gaya Bover A, Hernandez Lopez R, Alorda Clara M. Antioxidant enzymes change in different non-metastatic changes in tumoral and peritumoral tissues of colorectal cancer. Int J Biochem Cell Biol 2020;120:105698.
65. Li Z, Wang Y, Zhang Y. Protective effects of fisetin on hepatic ischemia-repurfusion injury through alleviation of apoptosis and oxidative stress. Ach Med Res 2021;52:167-73.
66. Koneru M, Sahu BD, Kumar JM. Fisetin protects the liver from binge alcohol-induced toxicity by mechanisms including inhibition of matrix metalloproteinases (MMPs) and oxidative stress. J Funct Foods 2016;22:588-601.