Evaluation of Passiflora edulis Seed Extract and Piceatannol in Attenuating Hyperglycemia and Oxidative Stress Using Human and Nonhuman Antidiabetic Enzymes, Human Neutrophil Oxidative Burst, and Embryonic Zebrafish Hyperglycemia Model

Abstract Passiflora edulis seeds are frequently discarded as agro-industrial residues despite being a source of bioactive compounds such as piceatannol (PIC). Their valorization through ethanolic extraction aligns with circular economy principles and enables the investigation of antioxidant, anti-inflammatory, and antidiabetic potential relevant to metabolic disorders associated with oxidative stress, inflammation, and impaired glucose homeostasis. Therefore, this study compared the biological activities and toxicological profiles of P. edulis seed ethanol extract (PESE) and PIC using in vitro and in vivo assays, including human and nonhuman models, and hyperglycemia induced during embryogenesis. The zebrafish procedures were approved by the Animal Use Ethics Committee (CEUA; protocol No. 13/2022). LC–MS identified PIC among the main constituents of PESE, which exhibited a high total phenolic content and relevant antioxidant capacity. PIC showed greater antioxidant potency than PESE against DPPH•, HOCl, and O2•–. It also inhibited α-amylase and α-glucosidase, with IC50 values of 11.8 and 3.1 μg/mL, respectively, outperforming acarbose against α-glucosidase, and activated glucokinase. In contrast, PESE inhibited PTP1B (IC50 = 29.8 μg/mL), an effect not observed with PIC alone. Both samples reduced ROS production in human neutrophils, with PIC displaying high potency in the luminol assay (IC50 = 0.12 μg/mL). In zebrafish embryos, PESE was less embryotoxic than PIC, with LC50 values of 39.3 and 6.2 μg/mL, respectively. In the hyperglycemic zebrafish model, both samples significantly reduced total free glucose and oxidant activity (p ≤ 0.05) and induced distinct antioxidant gene-expression responses: PESE upregulated nfe2l2a, sod1, sod2, and cat, whereas PIC upregulated nfe2l2a, gpx1a, and cat. These findings demonstrate that PESE and PIC act through multiple complementary mechanisms to counteract hyperglycemia and oxidative stress, highlighting the therapeutic potential of an underutilized byproduct while emphasizing the importance of developmental toxicity assessment for the safe advancement of plant-derived agents.