Honey-mediated wound healing: H ₂ O ₂ entry through AQP3 determines extracellular Ca ²⁺ influx

Since Biblical times, honey has been utilized in “folk medicine”, and in recent decades the positive qualities of honey have been re-discovered and are gaining acceptance. Scientific literature states that honey has been successfully utilized on infections not responding to classic antiseptic and antibiotic therapy, because of its intrinsic H ₂ O ₂ production. In our study, we demonstrated the involvement of H ₂ O ₂ as a main mediator of honey regenerative effects on an immortalized human keratinocyte cell line. We observed that this extracellularly released H ₂ O ₂ could pass across the plasma membrane through a specific aquaporin (i.e., AQP3). Once in the cytoplasm H ₂ O ₂ , in turn, induces the entry of extracellular Ca ²⁺ through Melastatin Transient Receptor Potential 2 (TRPM2) and Orai1 channels. Honey-induced extracellular Ca ²⁺ entry results in wound healing, which is consistent with the role played by Ca ²⁺ signaling in tissue regeneration. This is the first report showing that honey exposure increases intracellular Ca ²⁺ concentration ([Ca ²⁺ ] _i ), due to H ₂ O ₂ production and redox regulation of Ca ²⁺ -permeable ion channels, opening up a new horizon for the utilization of the honey as a beneficial tool.