# Antimicrobial Peptides--Mechanisms of Action, Antimicrobial Effects and Clinical Applications
## 4 Clinical Application of AMPs
### Moving beyond Antimicrobial Usage  
Several AMPs that are already in advanced stages of clinical development are characterized by mechanisms of action that are not strictly related to their antimicrobial effect  
Figure 7: Approved AMPs for use in clinical settings. STD—sexually transmitted diseases.  
(e.g., re-epithelialization and angiogenesis). A salient and well-known example is PXL01, a lactoferrin derivative used to prevent post-surgical adhesions in patients undergoing surgery for flexor tendon repairment, confirmed in phase II trials (NCT01022242) [138]. Such treatment with PXL01, reinforced by important in vitro studies, demonstrated that not only there is no proof of cytotoxicity, but its retained antimicrobial action is also superior to that of lactoferrin [125; 138].  
Another example is the aforementioned LL-37, with previous preclinical evidence of its involvement in wound healing, although the results were not entirely consistent [125]. An earlier randomized, placebo-controlled trial demonstrated that the topical application of LL-37 can enhance the healing rate of chronic venous leg ulcers [139]. However, that was not corroborated in a newer trial, and it was still concluded that this human synthetic peptide could offer a certain treatment benefit in individuals with large ulcers [140]. Although the exact mechanism of wound repair is still elusive, there is a supposed effect of LL-37 in modulating the inflammatory response and driving angiogenesis together with re-epithelialization [125; 141]. Such a wide array of modulatory cell activities also led to the repurposing of LL-37 for cancer treatment [142]. Moreover, its role in oral homeostasis is also known, and it is not related merely to microbiota stabilization [143].  
Other clinical studies have evaluated the use of hybrid peptide C16G2 in dental caries in the form of mouth rimse or gel (NCT031962, NCT02044081) [144], porcine protegrin-1 known as iseganan in oral solution for complications in the mouth linked to radiation treatment of head/neck malignancies (NCT000223) [145], and indolicidin in intravenous infusion for oral mucositis that is seen after chemotherapy for squamous cell carcinoma (NCT020130) [146]. In addition, recent studies have shown that regulating the expression of AMPs in gynecological cancers may influence the sensitivity of malignant cells to chemotherapy [147].  
In addition to those AMPs administered directly, there are many efforts to boost endogenous AMP synthesis. For example, vitamin D3 has been associated with the upregulation of many AMPs, such as beta-defensins, cathelicidins, and neutrophil gelatinase-associated lipocalin from epithelial cells in the respiratory tract, as well as from macrophages and neutrophils [125; 148; 149; 150]. Furthermore, the increase in plasma levels of free 25-hydroxyvitamin D resulted in increased expression of circulating human cationic antimicrobial protein (hCAP18) mRNA in both healthy and gravely ill ventilator-dependent adult individuals [151; 152], with implications for the overall immune response.