Tomato and Olive Bioactive Compounds (TOBC) Promote Regeneration by Modulating Inflammation in Zebrafish and Human Epithelial Cells

Inflammation is a key determinant of tissue regeneration, where its timing and resolution dictate the success of repair. Tomato and Olive Bioactive Compounds (TOBC) is a patented nutraceutical derived from tomato and olive mill wastewater, rich in polyphenols such as lycopene and hydroxytyrosol. Here, we demonstrate for the first time that TOBC enhances tissue regeneration by fine-tuning inflammatory responses in both zebrafish and human epithelial cells. Using the zebrafish caudal fin amputation model at 72 hours post-fertilization (hpf), larvae were treated with TOBC (1 or 2 mg/mL). In Tg(mpx:GFP) transgenic fish, 1 mg/mL TOBC promoted early neutrophil recruitment at 6 hours post amputation (hpa) and significantly upregulated il1β and irf8, while the higher dose showed no effect. Western blotting revealed early activation of cleaved Il1β at 2 hpa, suggesting inflammasome involvement. At 24 hpa, TOBC increased macrophage infiltration and tnfα expression, followed by enhanced proliferation at 48 hpa, as shown by elevated Pcna and Tgfβ1 protein levels and EdU incorporation. Fin outgrowth was markedly greater in TOBC-treated larvae compared to controls. Notably, co-treatment with the caspase-1 inhibitor AC-YVAD-CMK abolished these effects, confirming that TOBC acts through inflammasome-dependent Il1β activation. Parallel in vitro experiments using human bronchial epithelial BEAS-2B cells confirmed the pro-regenerative role of TOBC. Treatment with 1 mg/mL TOBC increased cell viability and accelerated the cell cycle (S/G₂ phases), elevated IL-1β and EGF secretion, and induced cytoskeletal remodeling through vimentin disassembly. Moreover, TOBC-treated cells displayed faster wound closure in scratch assays, demonstrating enhanced proliferative and migratory capacities. Collectively, these results indicate that TOBC establishes a regeneration-permissive microenvironment by coordinating inflammatory and proliferative cues. By triggering a transient, well-orchestrated inflammatory phase through Il1β and Tnfα modulation, followed by Tgfβ1 and EGF-driven proliferation, TOBC supports effective tissue repair. Given its safety as a dietary supplement and its efficacy in both in vivo and in vitro systems, TOBC represents a promising candidate for therapeutic applications in wound healing and regenerative medicine. Acknowledgements: This project was funded by the European Union – Next Generation EU. Codice Progetto: ECS00000041; CUP Progetto: C43C22000380007; Titolo Progetto: Innovation, digitalization and sustainability for the diffused economy in Central Italy – VITALITY.