PJ PALGO JOURNAL OF MEDICINE AND MEDICAL SCIENCES ISSN 2476-8340 DOI : https://doi.org/10.5281/zenodo.17370559 Volume 11 Issue 1, October 2025.Page 1-14 http://www.palgojournals.org/PJER/Index.htm Corresponding Author’s Email:sidiqat.shodehinde@aaua.edu.ng Alleviation of Oxidative Stress and Modulation of Insulin- Related Genes by Ficus exasperata Leaf Fractions in Sucrose-Induced Diabetic Drosophila melanogaster *S.A. Shodehinde 1,3 ., D. A. Omoboyowa 1 .,V.O. Awojulu 1,3 ., L. Bello 1,3 ., E.E. Nwanna 2 ., O. S. Bakare 1 ., S.O. Olubode 1,3 ., D.O. Nwankwo 1 ., O.V. Awelewa 1,3 ., A. Adeuti 1 ., T.K. Garuba 1 and O.J. Ernest 1 Department of Biochemistry, Faculty of Science, Adekunle Ajasin University, Akungba-Akoko, Ondo, Nigeria. 1 Department of Biochemistry, School of Life Sciences, Federal University of Technology, Akure, Ondo, Nigeria. 2 Phyto-Fakts Laboratory, Akungba-Akoko, Ondo, Nigeria. 3 Accepted 10, October, 2025 Oxidative stress plays a central role in the pathogenesis of diabetes mellitus and its complications. Ficus exasperata has been widely used in traditional medicine for its potential antioxidant and antidiabetic properties. This study aimed to evaluate and compare the antioxidant and therapeutic effects of n-hexane and n-butanol leaf fractions of F. exasperata in sucrose-induced diabetic Drosophila melanogaster. Fractions were analyzed for total phenol and flavonoid content, ferric reducing antioxidant power (FRAP), and DPPH radical scavenging activity. In vivo studies assessed survival rate, locomotor activity, glucose concentration, non-protein and total thiol levels, nitric oxide (NO), and hydrogen peroxide (H₂O₂) production. Gene expression analysis was carried out to determine the effects of both fractions on insulin-related genes (ILP-2, Imp-L2, and InR). The n-hexane fraction exhibited higher total phenolic content (152.12 ± 1.95 mg/g) and FRAP activity, whereas the n-butanol fraction showed superior DPPH radical scavenging (86.97 ± 0.92%) and α-amylase inhibition, leading to a greater reduction in glucose concentration. Both fractions enhanced thiol defense systems, reduced oxidative biomarkers (NO and H₂O₂), and improved locomotor activity in diabetic flies, with the n-butanol fraction showing the most pronounced effects. Gene expression analysis revealed dose-dependent upregulation of ILP-2, Imp-L2, and InR genes. The findings demonstrate that Ficus exasperata possesses significant antioxidant and antidiabetic activities, mediated through restoration of thiol defenses, reduction of oxidative stress, and modulation of insulin signaling genes. While the n-hexane fraction was richer in phenolic content, the n-butanol fraction exhibited superior antidiabetic potential, making it the recommended fraction for further therapeutic exploration. These results support the ethnomedicinal use of F. exasperata and highlight its promise as a natural therapeutic candidate for managing diabetes and oxidative stress- related complications. Keywords: Ficus exasperata, leaf fractions, oxidative stress, insulin signaling, Imp-L2, ILP-2, InR, Drosophila melanogaster, sucrose-induced diabetes. INTRODUCTION Diabetes mellitus (DM) is a metabolic disorder characterized by elevated blood glucose levels resulting from either insufficient or ineffective insulin. Numerous factors, including heredity and epigenetic propensity, lifestyle choices, and genetics, influence the release and function of insulin (Mobasseri et al., 2020). Diabetes was estimated to be the eighth most common cause of death and disability worldwide in 2019 by the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD), with over 460 million people of all ages and in all countries having the condition (Vos et al., 2020). Diabetes can lead to various complications such as cardiovascular disease, neuropathy, retinopathy, and nephropathy (Izzo et al., 2021). The development of these complications is often caused by oxidative stress triggered by high blood sugar levels (Akinnusi et al., 2023). It is acknowledged that type 2 diabetes is a major public health issue that significantly affects both human life expectancy and medical expenses. In many regions of the world, the prevalence of diabetes is on the rise due to rapid urbanization and economic growth (Onyango et al., 2018). Drosophila melanogaster, a fruit fly, is a useful model for examining the molecular causes of conditions like metabolic syndrome and type 2 diabetes (Bai et al., 2018; Graham and Pick, 2017). These disorders share genetic and environmental factors that have been retained throughout evolution, and they are typified by metabolic abnormalities (Graham and Pick, 2017). Insulin is essential for anabolism in mammals (Goldfine and Youngren, 1998) and has a major impact on fuel metabolism in Drosophila (Álvarez-Rendón et al., 2018). Important elements of the insulin signaling system in fruit flies include the ecdysone-inducible gene L2 (Imp-L2), insulin-like peptide-2 (ILP2), and the insulin-like receptor