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.