Citrus by-products, especially orange peels, are a significant global waste issue, driving research into management solutions. Solid-substrate fermentation is a promising method to convert this waste into valuable resources, enhancing its medicinal and nutritional potential while addressing environmental and economic concerns in food waste management. Therefore, this study was carried out to evaluate the impact of solid-substrate fermentation (SSF) with Penicillium camemberti on the nutrient profile, antioxidative properties, and potential neuroprotective effects of orange peels in AlCl3 (Al)-induced neurotoxicity in fruit fly (Drosophila melanogaster) model. Orange peels were collected, air-dried to a constant weight, and subjected to a 10-day SSF process with Penicillium camemberti. Post-fermentation, in vitro nutritional profiling, and antioxidant assays were conducted, alongside in vivo assessments of the neuroprotective effects on survival rate, memory index, monoamine oxidase (MAO) activity, and endogenous antioxidant markers on Al-induced fruit flies were determined. The results showed that fermentation with Penicillium camemberti significantly enhanced the nutritional composition of the orange peels compared to their unfermented counterparts. The antioxidant properties of fermented orange peels were significantly (p < 0.05) increased, as evidenced by increased DPPH scavenging activity (81.68 ± 0.18) and ferric reducing antioxidant power (10.77 ± 0.27). Additionally, biochemical assays in vivo revealed a significant improvement in survival rates and memory indices in Al-induced flies. Also, monoamine oxidase (MAO) levels were significantly reduced, while glutathione S-transferase (GST) levels were significantly (p < 0.05) elevated in the induced flies fed with the fermented samples. Conclusively, this study highlights the capability of Penicillium camemberti fermentation in converting waste into valuable resources, enhancing the nutrient profile of citrus peels for applications in livestock feed and potential therapeutic interventions for degenerative disorders.
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