Contents lists available at ScienceDirect Pesticide Biochemistry and Physiology journal homepage: www.elsevier.com/locate/pest Possible involvement of transcriptional activation of nuclear factor erythroid 2-related factor 2 (Nrf2) in the protective effect of caffeic acid on paraquat-induced oxidative damage in Drosophila melanogaster Ricardo Gomes dos Santos Nunes a , Pedro Silvino Pereira b , Olusola Olalekan Elekofehinti c , Kleber Ribeiro Fidelis a , Cícera Simoni da Silva a , Mohammad Ibrahim d , Luiz Marivando Barros a , Francisco Assis Bezerra da Cunha a , Kiven Erique Lukong e , Irwin Rose Alencar de Menezes a , Apollinaire Tsopmo f , Antonia Eliene Duarte a , Jean Paul Kamdem a, ⁎ a Departamento de Ciências Biológicas, Universidade Regional do Cariri, URCA, Rua Cel. Antônio Luis, 1161, Campus Pimenta CEP: 63105-000, Crato, Ceará, Brazil b Laboratory of Farmatoxicological Prospecting of Bioactive Products (BIOFARMATOX), Department of Antibiotics, Federal University of Pernambuco (UFPE), Recife, Brazil c Bioinformatics and Molecular Biology Unit, Department of Biochemistry, Federal University of Technology, Akure 340252, Ondo State, Nigeria d Department of Chemistry, Abdul Wali Khan University, Mardan 23200, Khyber Pakhtunkhwa, Pakistan e Department of Biochemistry, Microbiology and Immunology, College of Medicine, University of Saskatchewan, 107 Wiggins Road, Saskatoon, SK S7N 5E5, Canada f Food Science and Nutrition Program, Institute of Biochemistry, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario K1S 5B6, Canada ARTICLE INFO Keywords: Caffeic acid Paraquat poisoning Drosophila melanogaster Oxidative stress ABSTRACT Paraquat (PQ) is a widely used herbicide with no antidote which is implicated in the pathogenesis of the Parkinson's disease. The present study then investigated the potential of caffeic acid (CA), a known antioxidant, cardioprotective and neuroprotective molecule to counteract oxidative stress mediated by PQ. In addition, molecular docking was performed to understand the mechanism underlying the inhibitory effect of CA against PQ poisoning. The fruit fly, Drosophila melanogaster, was exposed to PQ (0.44 mg/g of diet) in the absence or presence of CA (0.25, 0.5, 1 and 2 mg/g of died) for 7 days. Data showed that PQ-fed flies had higher incidence of mortality which was associated with mitochondrial dysfunction, increased free Fe(II) content and lipid perox- idation when compared to the control. Co-exposure with CA reduced mortality and markedly attenuated bio- chemical changes induced by PQ. The mechanism investigated using molecular docking revealed a strong in- teraction (-6.2 Kcal/mol) of CA with D. melanogaster transcriptional activation of nuclear factor erythroid 2- related factor 2 (Nrf2). This was characterized by the binding of CA to keap-1 domain of Nrf2. Taking together these results indicate the protective effect of CA against PQ-induced oxidative damage in D. melanogaster was likely through its coordination which hinders Nrf2-keap-1 binding leading to an increase of the antioxidant defense system. 1. Introduction Paraquat (PQ) (1,1′-dimethyl-4,4′-bipyridinium dichloride), is a non-selective contact herbicide, acting directly and rapidly on green tissue from a wide range of plants (Lock and Wilks, 2001), and it is very toxic to mammals, including humans. For instance, PQ can induce pulmonary fibrosis in humans, monkeys, dogs and rats, and can accu- mulate in the human lungs (Murray and Gibson, 1972; Mainwaring et al., 2006; Tomita et al., 2007). Most importantly, PQ is known as an environmental risk factor for Parkinson's disease (PD) due to its similarity with MPP + , the active form of the inducer agent of PD, 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Berry et al., 2010). For this reason, PQ is extensively used in the literature to mimic PD, since it has been reported to cross the blood brain barrier (Moretto and Colosio, 2011) and cause reduction in the number of dopaminergic neurons (Shimizu et al., 2003; Moretto and Colosio, 2011; Michel et al., 2016) similarly to that observed in patients with PD. Cumulative evidence from the literature indicate that PQ exerts its toxicity mainly by generating excess superoxide anion radical, leading to the alteration of biochemical processes (e.g., depletion of antioxidant https://doi.org/10.1016/j.pestbp.2019.03.017 Received 5 February 2019; Received in revised form 16 March 2019; Accepted 27 March 2019 ⁎ Corresponding author. E-mail addresses: kamdemjeanpaul2005@yahoo.fr, jpkamdem@gmail.com (J.P. Kamdem). Pesticide Biochemistry and Physiology xxx (xxxx) xxx–xxx 0048-3575/ © 2019 Elsevier Inc. All rights reserved. Please cite this article as: Ricardo Gomes dos Santos Nunes, et al., Pesticide Biochemistry and Physiology, https://doi.org/10.1016/j.pestbp.2019.03.017