The Anti-Inflammatory and Antibacterial Action of Nanocrystalline Silver and Manuka Honey on the Molecular Alternation of Diabetic Foot Ulcer: A Comprehensive Literature Review

Table 1

The molecular alternations of DFU.

Number	Author	Nature of study	Cellular abnormalities
[30]	Loots et al., 1999	In vitro	Fibroblasts decrease proliferative capacity and abnormal morphology
[31]	Galkowska et al., 2005	In vivo	Leukocytes decrease accumulation
[32]	Waltenberger et al., 2000	In vitro	Monocytes in diabetic patient are less reactive to VEGF
[33]	Usui et al., 2008	In vivo	Impaired migration and differentiation of keratinocytes
[34]	Albiero et al., 2011	Animal study	Reduced in the recruitment, survival, and proliferation of endothelial progenitors at the site of the injury
[35]	Kanter et al., 2012	Animal study	Decreased in the polarization and activation of macrophages
Number	Author	Nature of study	Poor ECM formation
[29]	Blakytny and Jude, 2006	Review	AGEs cause the upregulation of MMPs and cytokines that degrades ECM through the production of ROS
[40]	Sibbald and Woo, 2008	Review	The overexpression of MMPs and elastase breaks down the components of ECM and inhibits growth factors
Number	Author	Nature of study	High levels of MMPs
[41]	Lobmann et al., 2002	In vivo	MMP-1 and MMP-9 increased 65-fold and 14-fold, respectively, in diabetic ulcer biopsies
[42]	Muller et al., 2008	In vivo	MMP-8 and MMP-9 remained stable in the poor healer group but decreased in the good healer group
Number	Author	Nature of study	High proinflammatory cytokines
[27]	Lobmann et al., 2005	Review	The upregulation of TNF-α and IL-1 stimulated the synthesis of MMP-1 and inhibited the synthesis of collagen
[39]	McLennan et al., 2008	Review	Hyperglycaemia activates the pathways of mitogen-activated protein kinase to stimulate cytokine production and promote inflammation
[44]	Trengove et al., 2000	In vivo	IL-1, IL-6, and TNF-α are upregulated in chronic nonhealing ulcers
[45]	Chan et al., 2012	In vitro	Neutralization of TNF improves the angiogenesis
Number	Author	Nature of study	High oxidative stress
[47]	van den Berg et al., 2008	In vitro	Free radicals (superoxide anion and hydroxyl radicals) are formed by the oxidative degradation of glycated proteins, which subsequently form AGEs
[49]	Soneja et al., 2005	Review	The production of peroxynitrite anion and peroxynitrous acid can lead to biological damage