## 3 Impact of EDPs on ROS Production  
As described above, ROS can take part in elastin degradation directly, resulting in increased amounts of EDP protein in the organism. To date, EDPs have been well-described to cause biological effects mainly through activation of the cell receptor present naturally in the cell membrane [18; 38]. EDP binds to 67-kDa elastin-binding protein (EBP), which is a catalytically inactive form of beta-galactosidase produced by alternative splicing of the GLB1 gene (Figure 2) [39; 40]. The presence of EDPs in the extracellular matrix is able to have an impact on many metabolic parameters in cells, e.g., proliferation, metabolic activity, expression of such proteolytic enzymes as MMPs, and even cell death [41; 42; 43]. Moreover, the ability of these peptides to induce ROS production has been also described in the literature [9; 44; 45]. The increase in the level of ROS in the cell is believed to be caused by at least two main processes, i.e., Ca\({}^{2+}\) influx and disruption of the expression and/or activity of antioxidant enzymes mediated through the peroxisome proliferatorator-activated receptor gamma (PPAR\(\gamma\)) pathway (Figure 2) [9]. A number of studies have reported that tropoelastin, \(\kappa\)-elastin, EDPs, and the VGVAPG peptide increase Ca\({}^{2+}\) influx in human monocytes, fibroblasts, human umbilical venous endothelial cells (HUVEC), different glioma cell lines (C6, CB74, CB109, and CB191), and smooth muscle cells from pig aorta or mouse astrocytes [10; 46; 47; 48; 49]. It is well known that different Ca\({}^{2+}\) signaling pathways can increase the level of cell ROS [50]. To date, depending on the model, EDPs have been shown to decrease or increase the cell ROS level [51]. However, the vast majority of studies show that EDPs induce ROS production in human fibroblasts and neuroblastoma (SH-SY5Y) as well as and murine monocytes and astrocytes [9; 12; 44; 45; 52]. In addition to the impact on ROS, various authors have shown that EDPs affect the expression and/or activity of antioxidant enzymes. As reported by [PERSON] et al., EDPs enhance the activities of superoxide dismutase (SOD), CAT, or glutathione peroxidase (GPx) and increase lipid peroxidation in human fibroblasts [53]. Similarly, [PERSON] et al. have described that the VGVAPG peptide increases GPx activity and slightly (but not statistically significantly) influenced the activity of SOD and CAT [9]. [PERSON] et al., have also described PPAR\(\gamma\) as a key receptor involved in the VGVAPG peptide mechanism of action in mouse astrocytes and the human SH-SY5Y neuroblastoma cell line [9; 43]. Furthermore, it is generally accepted that PPAR\(\gamma\) together with ROS are crucial in the inflammation process [54; 55], which is in line with data on the proinflammatory mechanism of action of EDPs. To date, EDPs have been reported to increase inflammatory markers in various cell types such as human malignant melanoma (M3 Da), human monocytes, and human ligamentum flavum cells [56; 57; 58]. Moreover, EDPs have also been shown to be chemotactic agents for monocytes, which are responsible for development of inflammation [58; 59; 60]. Interestingly, the VGVAPG peptide does not activate the inflammatory process in mouse astrocytes, probably due to the special role of the nervous system [61]. Figure 2: Scheme of the positive feedback of reactive oxygen species (ROS) and elastin degradation yielding elastin-derived peptides (EDPs), which induce ROS production. EBP—elastin-binding protein; Neu1—neuraminidase; PPAR\(\gamma\)—peroxosome proliferatorator-activated receptor gamma; PPCA—protective protein/cathepsin A; ERC—elastin receptor complex; CAT—catalase; SOD—superoxide dismutase. PPARy is also involved in the control of the expression of MMPs [62]. To date, it has been well described that EDPs increase the expression of various MMPs and degradation of ECM [63; 64; 65].