Revolutionizing non-conventional wound healing using honey by simultaneously targeting multiple molecular mechanisms.

Hospital-acquired infections and treatment-related wound complications constitute a tremendous burden for the health care system, particularly given the serious increase in multidrug resistant pathogens. Imagine that a large part of nosocomial infections can be prevented using a simple treatment. In this respect, honey is used mainly in topical cutaneous wound care because of its potent broad-spectrum antibacterial and wound healing activities. However, therapeutic use outside this scope has been limited. The current review provides an in-depth view of studies using honey outside the conventional wound care indications. Non-conventional routes of honey application include subcutaneous, intra-socket, abdominal, and oral administration in novel indications, such as post colon surgery, mucositis, and tooth extraction. Honey consistently demonstrates beneficial therapeutic activities in these novel applications, orchestrating antimicrobial and prophylactic activity, reducing inflammation and wound dehiscence, and inducing healing, epithelialization, and analgesic activity. Several molecular mechanisms are responsible for these beneficial clinical effects of honey during the course of wound healing. Pro-inflammatory effects of honey, such as induction of iNOS, IL-1β, and COX-2, are mediated by TLR4 signaling. In contrast, honey's anti-inflammatory actions and flavonoids induce anti-inflammatory and antioxidant pathways by inducing NRF2 target genes, including HO-1 and PRDX1. The molecular and biochemical pathways activated by honey during the different phases of wound healing are also discussed in more detail in this review. Variation between different honey origins exists, and therefore standardized medical-grade honey may offer an optimized and safe treatment. Honey is a valuable alternative to conventional antimicrobial and anti-inflammatory therapies that can strongly reduce nosocomial infections.