Background: Dietary supplements of Carica papaya Linn fermented with yeast using a biotechnological process have well recognized positive effects on immunological, hematological, inflammatory, and oxidative stress parameters, utilized as biomarkers of chronic and degenerative diseases. Although many natural products fermented with lactic acid bacteria (LAB) have shown beneficial effects on the immune system and on antioxidant defenses, formulations of papaya fermented with LAB have not yet been studied. Aims: The aims of this study were to investigate the immunomodulatory activity linked to the type of papaya fermentation (yeast vs LAB) in macrophages and to evaluate whether the type of fermentation differently modulates oxidative stress both in cell free system and in a model of embryonic brain cells. Methods: Cytotoxicity was evaluated through cell proliferation kinetic and lactate dehydrogenase release assays; immunomodulatory activity through the transcriptional activation of inducible nitric oxide synthase (iNOS) and Tumor Necrosis Factor α (TNFα) by qRT-PCR in RAW 264.7 macrophages; antioxidant capacity was assessed, in cell free system and in pheochromocytoma cells embryonic brain cells, by measuring the intracellular ROS levels through a fluorescent dye. Results: Our data showed that all the formulations studied are safe at low concentrations (3-6 mg/ml); the LAB- fermented formulations promoted the expression of iNOS and TNFα more efficiently than yeast-fermented papaya preparation (p
