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Autophagy activation decreases AGEs in skin cells in vitro and ex vivo
( Kayoung Shin ),( Yeonjae Kim ),( Sungwoo Kim ),( Sekyoo Jeong ),( Hwa-jee Chung ),( Keedon Park ),( Sungha Hwang ),( Dayeon Song ),( Minkyung Shin ),( Dabin Jeong ),( Jeong Ho Park ) 한국피부장벽학회 2023 한국피부장벽학회지 Vol.25 No.2
While the initial generation of AGEs (advanced glycation end products) usually takes place in a time-lapse of hours, it is reported that the complete formation of AGEs after the rearrangement and cross-liking with other proteins requires weeks to years under physiological conditions. However, in pathological conditions such as hyperglycemia, oxidative stress, and higher temperature, it can be accelerated up to hour-scale reaction. While AGEs can mechanically and/or biochemically alters the protein and tissue structures and functions, AGEs can also elicit downstream cellular signaling through binding to the RAGE (receptor for advanced glycation end products). Activation of RAGE induces NF-κB and MAPK pathways and results in the release of various cytokines and matrix metalloproteinases (MMPs). In skin, along with the direct ultraviolet irradiation, exposure to particulate matters (PMs) or smoking can also accelerate the formation of AGEs, which subsequently induces irregular pigmentation, wrinkle formation, and skin barrier dysfunction. Based on the deleterious effects of AGEs on skin aging, significant efforts have been exerted to develop anti-AGE molecules. Most of the currently available anti-AGE molecules, however, focus on the prevention of AGEs through the anti-oxidant property of molecules. Autophagy is a cellular mechanism to maintain cellular homeostasis role by removing dysfunctional cellular organelles and proteins. Recently, it was reported that AGEs removal can be stimulated by autophagy activator treatment in human epidermal keratinocytes. In this study, using a newly developed compound derivative with autophagy stimulating activity and anti-oxidant capacity, we investigated the modulation of AGEs formation and elimination by autophagy activator in vitro and ex vivo. In cultured human epidermal keratinocytes, high glucose- or glyoxal-induced AGEs formation was attenuated by autophagy activator treatment. Removal of BSA-AGE by keratinocytes was also accelerated by autophagy activator. Similar activities were also observed in ex vivo human skin explant model. Interestingly, epidermal expression of RAGE was also down-regulated by autophagy activator treatment. These results suggest that autophagy signaling is closely related to AGEs formation and elimination, and stimulation of autophagic flux can be a new regimen for anti-AGEs therapeutics.