| Summary: | In this study, a surfactant-mediated ultrasonic-assisted process was used for the first time to produce an antioxidant-enriched extract from <i>Chaenomeles speciosa</i> (Sweet) Nakai (<i>C. speciosa</i>, a popular fruit grown widely in the temperate regions of China). Ultrasonic treatment at 51 °C and 200 W for 30 min with sodium dodecyl sulfate as the surfactant led to a phenolic yield of 32.42 mg/g from dried <i>C. speciosa</i> powder, based on single-factor experiments, the Plackett–Burman design and the Box–Behnken design. The phenolic content increased from 6.5% (the crude extract) to 57% (the purified extract) after the purification, using LSA-900C macroporous resin. Both the crude and purified extracts exhibited a significant total reducing power and DPPH/ABTS scavenging abilities, with the purified extract being more potent. The purified extract exerted significant antioxidant actions in the tert-butyl hydroperoxide-stimulated HepG2 cells, e.g., increasing the activities of superoxide dismutase and catalase, while decreasing the reactive oxygen species and malondialdehyde levels, through the regulation of the genes and proteins of the Nrf2/Keap1 signaling pathway. Therefore, the extract from <i>C. speciosa</i> is a desirable antioxidant agent for the oxidative damage of the body to meet the rising demand for natural therapeutics.
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