Honey-Mediated Wound Healing: H₂O₂ Entry through AQP3 Determines Extracellular Ca²⁺ 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 H₂O₂ production. In our study, we demonstrated the involvement of H₂O₂ as a main mediator of honey regenerative effects on an immortalized human keratinocyte cell line. We observed that this extracellularly released H₂O₂ could pass across the plasma membrane through a specific aquaporin (i.e., AQP3). Once in the cytoplasm H₂O₂, in turn, induces the entry of extracellular Ca²⁺ through Melastatin Transient Receptor Potential 2 (TRPM2) and Orai1 channels. Honey-induced extracellular Ca²⁺ entry results in wound healing, which is consistent with the role played by Ca²⁺ signaling in tissue regeneration. This is the first report showing that honey exposure increases intracellular Ca²⁺ concentration ([Ca²⁺]_i), due to H₂O₂ production and redox regulation of Ca²⁺-permeable ion channels, opening up a new horizon for the utilization of the honey as a beneficial tool.