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HSP47, a collagen-specific chaperone protein, is a limiting factor for type I collagen secretion in aged skin
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Abstracts from the 41st Annual Meeting / Journal of Dermatological Science 86 (2017) e1–e95
immunohistochemistry and serum analysis using blood sample. We tested cell viability and melanin contents in Mel-ab cells and normal human melanocytes cultured with adiponectin and AICAR. The expression level of melanogenesis associated genes and protein was determined using qRT-PCR and western blot. To identify adiponectin and AICAR signal pathway, western blot and MITF promoter assay was performed. Results: We showed that adiponectin and AICAR reduced melanin content in normal human and mouse melanocytes by inducing the inhibitory phosphorylation of CREB regulated transcription coactivators (CRTCs) via enhancing AMPK activity. This anti-melanogenic effect of adiponectin correlated with downregulation of MITF, tyrosinase, tyrosinase-related protein-1 (TRP-1) and dopachrometautomerase (DCT) expression, which was resulted from decreased transcriptional activity of CREB. Conclusion: These data emphasize the depigmenting effect of adiponectin is mediated through the activation of AMPK and subsequently suppressing a novel CRTC/CREB pathway in melanocytes and suggest a clinical strategy for using adiponectin and analogues in the treatment of hyperpigmentation disorders. http://dx.doi.org/10.1016/j.jdermsci.2017.02.268 L-11[O2-58] Effects of a novel PPAR␦ agonist NCP-1046 on the wound healing in animal models Toshitake Hirai ∗ , Takaichi Hamano, Tomio Yamakawa Nippon Chemiphar Co., Ltd, Japan Chronic wounds, also known as ulcers, are difficult to heal and have various causes, including venous insufficiency, neuropathy, pressure, and burns. Non-healing chronic wound is an important clinical problem and it requires immediate attention to develop new effective therapies. Peroxisome proliferator-activated receptors (PPARs) control many cellular and metabolic processes, and three subtypes called PPAR␣, PPAR/␦ and PPAR␥ have been identified. Recent reports demonstrated that PPAR␦ plays an important role in the keratinocyte responses to inflammation produced immediately after a skin injury and in skin wound healing. In this study, we investigated whether NCP-1046, a novel PPAR␦ agonist discovered by us, shows an effect of the recovery promotion on invivo wound models. NCP-1046 showed selectivity of approximately 1000-fold for human PPAR␦ over the other subtypes and exerted its activity on the nanomolar order in cell-based reporter gene assays. Topical treatment of 0.05% NCP-1046 ointment accelerated wound healing in db/db mice, a mice model of type 2 diabetes mellitus. In the rat pressure ulcer model, time to complete wound closure was significantly reduced by nearly 5 days in 0.005% NCP-1046-treated group as compared with their vehicle-treated counterparts. These results suggested that NCP-1046 is expected to be clinically effective for chronic wounds at low doses. http://dx.doi.org/10.1016/j.jdermsci.2017.02.269
L-12[O1-51] HSP47, a collagen-specific chaperone protein, is a limiting factor for type I collagen secretion in aged skin MinJu Pyo 1,∗ , Jun Sang Park 1 , Young Hun Lee 1 , Dong Hun Lee 2 , Jin Ho Chung 2 , Seung-Taek Lee 1 1 Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea 2 Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea Transcriptome analysis of dorsal skin tissues from young and old mice showed that expression of Hsp47 (heat shock protein 47; also known as Serpinh1) gene as well as Col1a1 and Col1a2 genes is significantly down-regulated during aging. HSP47 is a collagenspecific molecular chaperone protein which plays an important role in collagen triple helix formation and stabilization. Type I collagen which is the most abundant protein in dermis is composed of two chains of collagen ␣1 (I) and one chain of collagen ␣2 (I), encoded by Col1a1 and Col1a2 genes, respectively. RT-qPCR, western blot, and immunohistochemistry analyses of mouse skin tissues showed that transcripts and translational products of Hsp47, Col1a1, and Col1a2 genes were lower in old groups than those in young groups. In addition, expression of HSP47, COL1A1, and COL1 A2 genes is down-regulated in human dermal fibroblasts derived from buttock skin tissues of old volunteers compared with those of young volunteers. Overexpression of HSP47 induced secretion of type I collagen in foreskin fibroblasts. We thus assume that down-regulation of HSP47 gene in aged skin hampers secretion of type I collagen secretion in dermis and contributes to skin aging. Hence, induction of HSP47 expression would retard skin aging by restored collagen secretion and deposition in dermis.
http://dx.doi.org/10.1016/j.jdermsci.2017.02.270 L-13[O1-52] Expression of Tenascin-C is down-regulated during intrinsic skin aging Jun Sang Park 1,∗ , Young Hun Lee 1 , Dong Hun Lee 2 , Jin Ho Chung 2 , Seung-Taek Lee 1 1
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea 2 Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea The skin aging process can be divided into intrinsic aging and photoaging. Photo-aging has been extensively studied but intrinsic aging is poorly understood so far. In an attempt to identify genes involved in intrinsic skin aging, we performed RNA-sequencing analysis of dorsal skin tissues in 3-month-old (young) and 24month-old (old) SKH1 hairless mice. Transcriptome data indicated that over 1500 genes are up-regulated or down-regulated (log2 value is above 1 or below −1) during skin aging. Top five gene ontology terms for the differentially expressed genes (DEGs) were cell differentiation, extracellular matrix, neurogenesis, immune response, and cell migration. The TnC (Tenascin-C) gene was found to be significantly decreased in aged mouse skin tissues and to be involved in all of the above gene ontology terms. TNC (also known as a hexabrachion) forms homohexamer as its name suggests and has multiple epidermal growth factor (EGF)-like domains
Abstracts from the 41st Annual Meeting / Journal of Dermatological Science 86 (2017) e1–e95
immunohistochemistry and serum analysis using blood sample. We tested cell viability and melanin contents in Mel-ab cells and normal human melanocytes cultured with adiponectin and AICAR. The expression level of melanogenesis associated genes and protein was determined using qRT-PCR and western blot. To identify adiponectin and AICAR signal pathway, western blot and MITF promoter assay was performed. Results: We showed that adiponectin and AICAR reduced melanin content in normal human and mouse melanocytes by inducing the inhibitory phosphorylation of CREB regulated transcription coactivators (CRTCs) via enhancing AMPK activity. This anti-melanogenic effect of adiponectin correlated with downregulation of MITF, tyrosinase, tyrosinase-related protein-1 (TRP-1) and dopachrometautomerase (DCT) expression, which was resulted from decreased transcriptional activity of CREB. Conclusion: These data emphasize the depigmenting effect of adiponectin is mediated through the activation of AMPK and subsequently suppressing a novel CRTC/CREB pathway in melanocytes and suggest a clinical strategy for using adiponectin and analogues in the treatment of hyperpigmentation disorders. http://dx.doi.org/10.1016/j.jdermsci.2017.02.268 L-11[O2-58] Effects of a novel PPAR␦ agonist NCP-1046 on the wound healing in animal models Toshitake Hirai ∗ , Takaichi Hamano, Tomio Yamakawa Nippon Chemiphar Co., Ltd, Japan Chronic wounds, also known as ulcers, are difficult to heal and have various causes, including venous insufficiency, neuropathy, pressure, and burns. Non-healing chronic wound is an important clinical problem and it requires immediate attention to develop new effective therapies. Peroxisome proliferator-activated receptors (PPARs) control many cellular and metabolic processes, and three subtypes called PPAR␣, PPAR/␦ and PPAR␥ have been identified. Recent reports demonstrated that PPAR␦ plays an important role in the keratinocyte responses to inflammation produced immediately after a skin injury and in skin wound healing. In this study, we investigated whether NCP-1046, a novel PPAR␦ agonist discovered by us, shows an effect of the recovery promotion on invivo wound models. NCP-1046 showed selectivity of approximately 1000-fold for human PPAR␦ over the other subtypes and exerted its activity on the nanomolar order in cell-based reporter gene assays. Topical treatment of 0.05% NCP-1046 ointment accelerated wound healing in db/db mice, a mice model of type 2 diabetes mellitus. In the rat pressure ulcer model, time to complete wound closure was significantly reduced by nearly 5 days in 0.005% NCP-1046-treated group as compared with their vehicle-treated counterparts. These results suggested that NCP-1046 is expected to be clinically effective for chronic wounds at low doses. http://dx.doi.org/10.1016/j.jdermsci.2017.02.269
L-12[O1-51] HSP47, a collagen-specific chaperone protein, is a limiting factor for type I collagen secretion in aged skin MinJu Pyo 1,∗ , Jun Sang Park 1 , Young Hun Lee 1 , Dong Hun Lee 2 , Jin Ho Chung 2 , Seung-Taek Lee 1 1 Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea 2 Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea Transcriptome analysis of dorsal skin tissues from young and old mice showed that expression of Hsp47 (heat shock protein 47; also known as Serpinh1) gene as well as Col1a1 and Col1a2 genes is significantly down-regulated during aging. HSP47 is a collagenspecific molecular chaperone protein which plays an important role in collagen triple helix formation and stabilization. Type I collagen which is the most abundant protein in dermis is composed of two chains of collagen ␣1 (I) and one chain of collagen ␣2 (I), encoded by Col1a1 and Col1a2 genes, respectively. RT-qPCR, western blot, and immunohistochemistry analyses of mouse skin tissues showed that transcripts and translational products of Hsp47, Col1a1, and Col1a2 genes were lower in old groups than those in young groups. In addition, expression of HSP47, COL1A1, and COL1 A2 genes is down-regulated in human dermal fibroblasts derived from buttock skin tissues of old volunteers compared with those of young volunteers. Overexpression of HSP47 induced secretion of type I collagen in foreskin fibroblasts. We thus assume that down-regulation of HSP47 gene in aged skin hampers secretion of type I collagen secretion in dermis and contributes to skin aging. Hence, induction of HSP47 expression would retard skin aging by restored collagen secretion and deposition in dermis.
http://dx.doi.org/10.1016/j.jdermsci.2017.02.270 L-13[O1-52] Expression of Tenascin-C is down-regulated during intrinsic skin aging Jun Sang Park 1,∗ , Young Hun Lee 1 , Dong Hun Lee 2 , Jin Ho Chung 2 , Seung-Taek Lee 1 1
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea 2 Department of Dermatology, Seoul National University College of Medicine, Seoul, Republic of Korea The skin aging process can be divided into intrinsic aging and photoaging. Photo-aging has been extensively studied but intrinsic aging is poorly understood so far. In an attempt to identify genes involved in intrinsic skin aging, we performed RNA-sequencing analysis of dorsal skin tissues in 3-month-old (young) and 24month-old (old) SKH1 hairless mice. Transcriptome data indicated that over 1500 genes are up-regulated or down-regulated (log2 value is above 1 or below −1) during skin aging. Top five gene ontology terms for the differentially expressed genes (DEGs) were cell differentiation, extracellular matrix, neurogenesis, immune response, and cell migration. The TnC (Tenascin-C) gene was found to be significantly decreased in aged mouse skin tissues and to be involved in all of the above gene ontology terms. TNC (also known as a hexabrachion) forms homohexamer as its name suggests and has multiple epidermal growth factor (EGF)-like domains