**4. AGEs and wound healing**

an important role in the pathogenesis of various pathologic conditions and their complications, such as type 1 diabetes mellitus in non-obese diabetic mice [21], atherosclerosis in apoEdeficient mice [22], type 2 diabetes, and impaired wound healing in db/db (+/+) mice [23]. It should be emphasized that a large portion of AGEs in the human body is derived from exogenous sources, e.g. from regular food, smoking, etc. [24]. Much attention has been paid to the so-called exogenous AGEs, harmful products of "browning" (or the Maillard reaction) in various foods. Together with endogenous AGEs, these compounds form the majority of glycation-free adducts. Among the various food processing methods, heating, sterilizing, and microwaves contribute to the generation of exogenous AGEs, all of which tend to accelerate the non-enzymatic addition of non-reducing sugars to free NH2 groups of proteins and lipids

AGEs could exert their actions not only directly but also through a receptor system, which includes two types of cell surface AGEs receptors: first type is that binds AGEs and initiates cell activation and second type is that binds and degrades AGEs. Receptor for AGEs (RAGE) is one receptor of the first type; it recognizes AGEs and initiates oxidative stress. The second type of receptors consists of AGER1, AGER3, and CD36 [26, 27]. However, it is noteworthy that there are other AGE receptors, such as the macrophage scavenger receptor and the galectin-3 receptor, which might have similar deleterious effects to RAGE when they interact

RAGE is a multi-ligand receptor of the immunoglobulin superfamily of cell surface molecules acting as a receptor not only for several molecules including AGEs but also for S100/calgranulins and amyloid. Circulating isoforms of RAGE include soluble RAGE (sRAGE) that has been cleaved from the cell surface by matrix metalloproteinases and endogenous secretory RAGE (esRAGE), and a splice variant of RAGE that is secreted into blood. Both sRAGE and esRAGE protect body against the AGEs-elicited tissue damage by acting as a decoy receptor for AGEs [29, 30]. The ligands of RAGE have a common feature that they accumulate in tissues during aging, inflammation, and degenerative diseases. Engagement of RAGE results in intracellular signaling that leads to the activation of NF-kB, a pro-inflammatory transcription factor, which is then translocated to the nucleus and subsequently activates the transcription of target genes [31]. These include genes of cytokines, adhesion molecules, and prothrombotic and vasoconstrictive products. The activation of NF-kB results in upregulation of the receptors in return. In addition, cellular-signaling cascades such as the ERK signaling pathway and PI-3

In the skin, RAGE expression was observed in both epidermis and dermis, and it was increased in sun-exposed compared with UV irradiation-protected areas [33]. Not only in vivo, but also in vitro, various skin cells types have been shown to express RAGE [34–36], such as keratinocytes, fibroblasts, dendritic cells, and to a lesser extent endothelial cells and lymphocytes. Patients with diabetes also exhibit increased immunoreactivity for RAGE and AGEs. For

kinases are activated by the binding of ligands with RAGE [32].

[25].

**3. RAGE**

226 Wound Healing - New insights into Ancient Challenges

with AGEs [28].

It is generally believed that wound healing is impaired in diabetes. Wound healing is a complex process in which several pathophysiological processes are involved. They include inflammation, repair, and regeneration. Until now, there is evidence from experimental studies that glycation is involved in wound healing in diabetes.
