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Dermatologic Application of Autophagy Regulator
( Sekyoo Jeong ),( Keedon Park ) 한국피부장벽학회 2017 한국피부장벽학회지 Vol.19 No.2
Autophagy can be defined as a self-digestive process, targeting internal or damaged organelles and misfolded proteins to lysosomal degradation. While its major role is a survival mechanism under stress conditions, such as nutrient restriction, it can also induce cell death under certain conditions. Changes in cellular energy status or inhibition of mTOR(mammalian target of rapamycin) are well-known activating signals of autophagy. In addition, sphingolipids metabolites, including sphingosine-1-phosphate and dihydroceramides, are also known to modulate the autophagy responses in various cells. Recently, increased attentions have been paid to the roles of autophagy process in skin(patho)physiology. Along with the potential involvement of autophagy in differentiation of epidermal keratinocytes, several studies also reported that autophagy activation alleviated local inflammation responses and skin aging. Previously, we have reported development of new autophagy activators in human epidermal keratinocytes. Significant anti-inflammatory activities and anti-aging effects were observed for those newly developed autophagy activators. In this talk, practical application of those developed compounds as cosmetic ingredients will be discussed.
Autophagy regulates lipid production in human sebocytes
( Seong Hoon Seo ),( Ju Yeon Jung ),( Keedon Park ),( Christos C ),( Zouboulis ),( Sang Eun Lee ) 대한피부과학회 2018 대한피부과학회 학술발표대회집 Vol.70 No.2
Background: Recently, lipids have been demonstrated to be targets for autophagosomal degradation in liver and adipose tissue. However, the function of autophagy in sebaceous glands is not yet fully understood. Objectives: To investigate the role of autophagy in sebaceous lipogenesis. Methods: SZ95 sebocytes were treated with either autophagy inhibitors or inducer, rapamycin with lipogenic stimuli. Intracellular lipids were assessed by BODIPY and fluorescent Nile Red staining. Autophagic activity was assessed by immunofluorescence and Western blot for autophagy markers. Autophagy markers expression in sebaceous gland was detected by immunohistochemistry. Results: In healthy human sebaceous glands, LC3B shows the strongest expression in the maturing sebocytes, but in acne lesional skin, LC3B expression is markedly reduced. IGF-1 or testosterone/linoleic acid inhibited starvationinduced sebocyte autophagy. Autophagy inhibitors led to increased lipid accumulation in sebocytes. Conversely, rapamycin inhibits the lipogenic actions of IGF-1 and testosterone/linoleic acid. All-trans retinoic acid (ATRA) increases autophagy markers in sebocytes, while autophagy inhibitors abolish the sebosuppressive effect of ATRA. Conclusion: Androgen and IGF-1 may contribute to reduce autophagic activity in sebocyte in acne. Autophagy plays an important role in the modulation of lipogenesis in human sebocytes and is responsible for the action of ATRA on sebostatic effect, thereby influencing the pathogenesis of acne
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.
AQUATIDE Plays a Role as Innovative Skin-Care Vaccine Through The Autophagy Induction
( Chaejin Lim ),( Myungho Kor ),( Seokjeong Yoon ),( Heungjae Kim ),( Kyungho Park ),( Keedon Park ) 한국피부장벽학회 2016 한국피부장벽학회지 Vol.18 No.2
Natural moisturizing factor (NMF) in the stratum corneum has a high moisture retaining efficacy, and plays a major role in the skin barrier function. Pyrrolidone carboxylic acid (PCA) is one of the major NMFs found in human skin. Aquatide, a PCA-mimetic peptide, improves the skin barrier function by stimulating filaggrin expression as well as reducing Trans-Epidermal Water Loss (TEWL) correlated with increased water retention and moisturization. Autophagy is the natural destructive mechanism that allows the orderly degradation and recycling of cellular damaged components. So, Increased autophagy delays ageing process and extends longevity. Sirtuin1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase functioning in the regulation of metabolism, cell survival and organismal lifespan. AQUATIDE alleviates ROS- and heavy metal-mediated senescence and cytotoxicity of cells by SIRT1-dependent autophagy. Furthermore, AQUATIDE reduces pollen-mediated PGE2 release and keeps the skin healthy during an allergic reaction against pollen treatment. In conclusion, AQUATIDE is considered as the first needle-free “skin-care vaccine” for various troubled skins including inflamed and irritated skin as well as aged skin.
Yoon, Seok Jeong,Lim, Chae Jin,Chung, Hwa-Jee,Kim, Joo-Hwan,Huh, Yang Hoon,Park, Keedon,Jeong, Sekyoo MDPI AG 2019 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.20 No.3
<P>Pollution-induced skin damage results in oxidative stress; cellular toxicity; inflammation; and, ultimately, premature skin aging. Previous studies suggest that the activation of autophagy can protect oxidation-induced cellular damage and aging-like changes in skin. In order to develop new anti-pollution ingredients, this study screened various kinds of natural extracts to measure their autophagy activation efficacy in cultured dermal fibroblast. The stimulation of autophagy flux by the selected extracts was further confirmed both by the expression of proteins associated with the autophagy signals and by electron microscope. <I>Crepidiastrum denticulatum</I> (CD) extract treated cells showed the highest autophagic vacuole formation in the non-cytotoxic range. The phosphorylation of adenosine monophosphate kinase (AMPK), but not the inhibition of mammalian target of rapamycin (mTOR), was observed by CD-extract treatment. Its anti-pollution effects were further evaluated with model compounds, benzo[a]pyrene (BaP) and cadmium chloride (CdCl<SUB>2</SUB>), and a CD extract treatment resulted in both the protection of cytotoxicity and a reduction of proinflammatory cytokines. These results suggest that the autophagy activators can be a new protection regimen for anti-pollution. Therefore, CD extract can be used for anti-inflammatory and anti-pollution cosmetic ingredients.</P>
( Ji Young Choi ),( Soon Hyo Kwon ),( Chae Jin Lim ),( Juyeon Jung ),( Heung Jae Kim ),( Keedon Park ),( Jung Won Shin ),( Chang Hun Huh ),( Kyoung Chan Park ),( Jung Im Na ) 대한피부과학회 2018 대한피부과학회 학술발표대회집 Vol.70 No.2
Background: The use of moisturizer is an essential part of atopic dermatitis (AD) treatment. Pentasodiumtetracarboxymethyl palmitoyl dipeptide-12 (PTPD-12), a newly-synthesized peptide, enhances autophagy activity, thereby modulating inflammation. Objectives: To determine the effect of new moisturizer containing PTPD-12 in the treatment of mild-to-moderate AD. Methods: In this double-blind, randomized, placebocontrolled trial, 43 patients with mild-to-moderate AD were randomly assigned to the moisturizer containing PTPD-12 or control product. Evaluations were performed at baseline, week 2 and week 4 including SCORAD index score, corneometry, trans-epidermal water loss (TEWL), visual analogue scale (VAS) for pruritus, 7-point investigator’s global assessment (IGA), and adverse events. Results: The PTPD-12 group showed significant improvement in terms of SCORAD score, skin hydration, TEWL and pruritus at week 2 and week 4 compared with baseline. Though the control group also showed significant improvement in the SCORAD score and skin hydration, no significant change in TEWL or pruritus was demonstrated. The mean changes in the SCORAD index score, skin hydration, TEWL, pruritus, and the number of patients with improvement in IGA were not statistically different between the two groups. Conclusion: The moisturizer with autophagy-stimulating property provides a good therapeutic option to mild-to-moderate atopic dermatitis by contributing to skin barrier restoration and control of inflammation.
( Chae Jin Lim ),( Jung Eun Jeon ),( Se Kyoo Jeong ),( Seok Jeong Yoon ),( Seon Deok Kwon ),( Jina Lim ),( Keedon Park ),( Dae Yong Kim ),( Jeong Keun Ahn ),( Bong Woo Kim ) 생화학분자생물학회(구 한국생화학분자생물학회) 2015 BMB Reports Vol.48 No.9
Based on the potential beneficial effects of growth hormone releasing peptide (GHRP)-6 on muscle functions, a newly synthesized GHRP-6-biotin conjugate was tested on cultured myoblast cells. Increased expression of myogenic marker proteins was observed in GHRP-6-biotin conjugate-treated cells. Additionally, increased expression levels of insulin-like growth factor-1 and collagen type I were observed. Furthermore, GHRP-6-biotin conjugate-treated cells showed increased metabolic activity, as indicated by increased concentrations of energy metabolites, such as ATP and lactate, and increased enzymatic activity of lactate dehydrogenase and creatine kinase. Finally, binding protein analysis suggested few candidate proteins, including desmin, actin, and zinc finger protein 691 as potential targets for GHRP6-biotin conjugate action. These results suggest that the newly synthesized GHRP-6-biotin conjugate has myogenic stimulating activity through, at least in part, by stimulating collagen type I synthesis and several key proteins. Practical applications of the GHRP-6-biotin conjugate could include improving muscle condition. [BMB Reports 2015; 48(9): 501-506]
Aquatide Activation of SIRT1 Reduces Cellular Senescence through a SIRT1-FOXO1-Autophagy Axis
Lim, Chae Jin,Lee, Yong-Moon,Kang, Seung Goo,Lim, Hyung W.,Shin, Kyong-Oh,Jeong, Se Kyoo,Huh, Yang Hoon,Choi, Suin,Kor, Myungho,Seo, Ho Seong,Park, Byeong Deog,Park, Keedon,Ahn, Jeong Keun,Uchida, Yos The Korean Society of Applied Pharmacology 2017 Biomolecules & Therapeutics(구 응용약물학회지) Vol.25 No.5
Ultraviolet (UV) irradiation is a relevant environment factor to induce cellular senescence and photoaging. Both autophagy- and silent information regulator T1 (SIRT1)-dependent pathways are critical cellular processes of not only maintaining normal cellular functions, but also protecting cellular senescence in skin exposed to UV irradiation. In the present studies, we investigated whether modulation of autophagy induction using a novel synthetic SIRT1 activator, heptasodium hexacarboxymethyl dipeptide-12 (named as Aquatide), suppresses the UVB irradiation-induced skin aging. Treatment with Aquatide directly activates SIRT1 and stimulates autophagy induction in cultured human dermal fibroblasts. Next, we found that Aquatide-mediated activation of SIRT1 increases autophagy induction via deacetylation of forkhead box class O (FOXO) 1. Finally, UVB irradiation-induced cellular senescence measured by $SA-{\beta}-gal$ staining was significantly decreased in cells treated with Aquatide in parallel to occurring SIRT1 activation-dependent autophagy. Together, Aquatide modulates autophagy through SIRT1 activation, contributing to suppression of skin aging caused by UV irradiation.