## 4 Therapeutic Effects of Honey
### Antibacterial Effects  
Another popular and complex biological property of honey with high therapeutic value (as manifest in in-vivo and in-vitro studies) is its antibacterial ability. Factors influencing this derive mainly from the botanical source of the plants, bee metabolism [111], bee species [143] and the climatic, processing and storage conditions that honey is submitted to [51; 58]. All of these factors have a critical importance for the inhibition of the structure and growth of microorganisms, influencing the physicochemical composition of honey and the mechanism of action of different bioactive compounds. In general, the antibacterial and antimicrobial activity of honey is related to the inhibition of microbial growth throughout different processes [39]. One process is associated to the enzymatic action, namely hydrogen peroxide (H\({}_{2}\)O\({}_{2}\)), and the other is related to the action of different compounds, such as the high content of sugars, viscosity, osmotic pressure and low pH [26], water activity or protein content [106; 144]. In addition, polyphenols, phenolic acids, flavonoids, together with antioxidants, lysozyme, methylglyoxal, and bee peptides (especially the peptide Defensin-1) [134; 145] are other vital components of this property. The H\({}_{2}\)O\({}_{2}\) is shaped by the oxidation of glucose throughout the action of the enzyme glucose oxidase during honey maturation [42] and then hydrolysed by catalase to water and oxygen [146]. Its main function is to prevent the spoilage of honey caused by microorganism's action [53] by producing minimum inhibitory concentrations in bacteria (10-1000 ug/mL) [51; 146] and thus damaging the bacterial cell walls [147]. Conversely, methylglyoxal is formed non-enzymatically from nectar dihydroxyacetone [39; 51] and it is found mainly in Manuka honey, where it is predominantly responsible for Manuka honey's antibacterial properties [148; 149]. This is achieved through its mechanism of action: inducing alterations in the structure of bacteria, and therefore preventing it to damage the cell membranes [150]. The bee Defensin-1 is an antibacterial peptide secreted by the bees [151], added into honey at the beginning of its processing [51]. It has been reported to be effective against both Gram-positive and Gram-negative bacteria [152], especially in wound healing [153], while also exhibiting a large spectrum of anti-biofilm activity [154; 155]. Studies that have evaluated the antibacterial potential of honey showed that the bioactive compounds found in honey's composition manifest in a direct correlation with the antimicrobial effects of honey [73; 156; 157]. Therefore, the antibacterial activity of honey may vary according to the geographical and botanical origin of the raw material [158; 159; 160], as the content of polyphenols can influence its beneficial health effects [144]. Literature reports that phenolic compounds have a well-structured antibacterial mechanism [28], as they are capable to diminish antibiotic resistance of infective bacteria and to prevent biofilm formation [161]. The outcomes indicated that the antimicrobial potential of several phenolic compounds present in various honey samples had a significant impact against microorganism inhibition. [PERSON] et al. (2018) [162] reported through in-vitro and in-vivo analyses that quercetin has bacteriostatic effects against Gram-positive bacteria (_Staphylococcus aureus_ in particular). Similar results were reported by [PERSON] et al. (2019) [163], who demonstrated that the same kind of bacteria was susceptible to all analysed honey samples (concentrations ranging from 3.12 to 25% \(w/v\)) that contained a high amount of phenyl lactic acid and 4-hydroxybenzoic acid. Interestingly, the study of [PERSON] and al.