Chang-Yup Shin

Perilla frutescens leaves extract ameliorates ultraviolet radiation-induced extracellular matrix damage in human dermal fibroblasts and hairless mice skin

ETHNOPHARMACOLOGICAL RELEVANCE Perilla frutescens (L.) Britt. (Lamiaceae) is a traditional herb that is consumed in East Asian countries as a traditional medicine. This traditional herb has been documented for centuries to treat various diseases such as depression, allergies, inflammation and asthma. However, the effect of Perilla frutescens on skin has not been characterized well. AIM OF THE STUDY The present study aimed to investigate the effect of Perilla frutescens leaves extract (PLE) on ultraviolet radiation-induced extracellular matrix damage in human dermal fibroblasts and hairless mice skin. MATERIALS AND METHODS Human dermal fibroblasts and Skh-1 hairless mice were irradiated with UV and treated with PLE. Protein and mRNA levels of various target molecules were analyzed by western blotting and quantitative RT-PCR, respectively. Histological changes of mouse skin were analyzed by H&E staining. To elucidate underlying mechanism of PLE, activator protein-1 (AP-1) DNA binding assay and the measurement of reactive oxygen species (ROS) were performed. RESULTS PLE significantly inhibited basal and UV-induced MMP-1 and MMP-3 expression dose-dependently, and also decreased UV-induced phosphorylation of extracellular signal-regulated kinases and c-Jun N-terminal kinases. This inhibitory effects of PLE on MMP-1 and MMP-3 were mediated by reduction of ROS generation and AP-1 DNA binding activity induced by UV. Furthermore, PLE promoted type I procollagen production irrespective of UV irradiation. In the UV-irradiated animal model, PLE significantly reduced epidermal skin thickness and MMP-13 expression induced by UV. CONCLUSION Our results demonstrate that PLE has the protective effect against UV-induced dermal matrix damage. Therefore, we suggest that PLE can be a potential agent for prevention of skin aging.

p21 upregulation in hair follicle stem cells is associated with telogen retention in aged mice.

doubly transfected with si-Mitf and a control siRNA, filled in a wounded area more readily than si-Mitf/si-Mcam doubly transfected cells. These results, confirmed in corresponding transwell assays (Fig. 2c,d), suggest that MITF and MCAM are linked in a direct linear pathway to affect cell migratory behaviours. Conclusions Here, we show that MITF inhibits melanoblast migration as a transcriptional repressor of a cell adhesion molecule, MCAM, which has originally been identified as a marker that distinguishes benign nevi from melanomas whose metastasis it promotes (6). MCAM is detected in several melanocytic cell lines (7, S20–S21), although its regulation and function are largely unexplored. Given the multiple target genes MITF regulates in melanocytes, it is not surprising that MITF is also involved in the regulation of MCAM. Nevertheless, most MITF target genes are stimulated by MITF, even though some, such as ZEB1 and SHC4, are apparently suppressed (8,9). Hence, our findings add MCAM to the list of MITF target genes that are negatively regulated by this multifunctional transcription factor. In sum, our results provide new evidence that MITF works as a transcriptional repressor to play a functional role in regulating melanoblast migration. This finding may have implications for our understanding of skin wound healing, melanocyte repopulation in vitiligo lesions and melanoma invasion and metastasis. Acknowledgements We thank for Drs. Dorothy Bennett, Ming Zhang and Zhihai Qin for reagents and Dr. Heinz Arnheiter for reagents and thoughtful comments on the manuscript. This work was supported by NSFC (30971467, 31171408), Zhejiang Provincial NSF (LZ12C12001, Q14C120004, LQ13H120004). Author contribution BR/SZ designed/performed experiments and analysed data. XM/XZ/YL performed experiments. FL/JQ contributed reagents. LH designed experiments, analysed data and wrote the manuscript. Conflict of interest The authors state no conflict of interest. Supporting Information

Endogenous Estrogen Exacerbates UV-Induced Inflammation and Photoaging in Mice

likely by extensive cross-linking. As a first effect of the depletion of non-desmosomal Dsg1, intercellular widening occurs. Then, when the desmosomes also become depleted of Dsg1, they shrink in size and number. When the amount of anti-Dsg1 IgG increases, the IgG will spread further upward into the higher layers, also leading to intercellular widening and desmosomal reduction there. Finally, when the IgG reaches the layers where Dsg3 is absent and cannot compensate for the loss of Dsg1, desmosomes will no longer be able to form stable structures and will melt away with subcorneal acantholysis as the final result. The effects of anti-Dsg3 antibodies on the epidermis differ from those of antiDsg1 antibodies. IgG directed against Dsg3 spreads through the epidermis and leads to clustering and depletion of Dsg3 throughout the Dsg3-expressing layers. This does not, however, lead to intercellular widening or a reduction in the size and number of the desmosomes. Apparently, loss of Dsg3 is less devastating than loss of Dsg1 to the desmosomes as they retain their normal shape. This fits with observations in patients with mdPV, who have blistering of the mucous membranes but a perfectly healthy and strong skin. Although their skin is loaded with anti–cell surface IgG deposits, it does not blister, even when it is firmly rubbed to elicit the Nikolsky sign. Next, when antibodies directed against Dsg1 are also present in addition to antibodies against Dsg3 (as in mcPV), the depletion of Dsg1 will affect the desmosomes, which then start to shrink. As the desmosomes can no longer compensate for the loss of both Dsg1 and Dsg3, they will melt away in the lower layers, which eventually leads to suprabasal acantholysis. We therefore conclude that Dsg1, but not Dgs3, is necessary for preserving the normal size and number of desmosomes in the human epidermis and that loss of Dsg1 is conditional for developing cutaneous acantholysis in pemphigus.

The effect of cilostazol, a phosphodiesterase 3 (PDE3) inhibitor, on human hair growth with the dual promoting mechanisms

BACKGROUND Cilostazol, a phosphodiesterase 3 (PDE3) inhibitor, increases the intracellular level of cyclic adenosine monophosphate to cause vasodilation. Topical application of cilostazol is reported to improve local blood flow and enhance wound healing; however, its effect on human hair follicles is unknown. OBJECTIVE The purpose of this study was to determine the effect of cilostazol on hair growth. METHODS We investigated the expression of PDE3 in human dermal papilla cells (DPCs), outer root sheath cells (ORSCs), and hair follicles. The effects of cilostazol on DPC and ORSC proliferation were evaluated using BrdU and WST-1 assays. The expression of various growth factors in DPCs was investigated by growth factor antibody array. Additionally, hair shaft elongation was measured using ex vivo hair follicle organ cultures, and anagen induction was evaluated in C57BL/6 mice. Finally, the effects of cilostazol on vessel formation and activation of the mitogen-activated protein kinase pathway were evaluated. RESULTS We confirmed high mRNA and protein expression of PDE3 in human DPCs. Cilostazol not only enhanced the proliferation of human DPCs but also regulated the secretion of several growth factors responsible for hair growth. Furthermore, it promoted hair shaft elongation ex vivo, with increased proliferation of matrix keratinocytes. Cilostazol also accelerated anagen induction by stimulating vessel formation and upregulating the levels of phosphorylated extracellular signal-regulated kinase, c-Jun N-terminal kinase, and P38 after its topical application in C57BL/6 mice. CONCLUSION Our results show that cilostazol promotes hair growth and may serve as a therapeutic agent for the treatment of alopecia.

A synthetic peptide blocking TRPV1 activation inhibits UV-induced skin responses

BACKGROUND Transient receptor potential type 1 (TRPV1) can be activated by ultraviolet (UV) irradiation, and mediates UV-induced matrix metalloproteinase (MMP)-1 and proinflammatory cytokines in keratinocytes. Various chemicals and compounds targeting TRPV1 activation have been developed, but are not in clinical use mostly due to their safety issues. OBJECTIVE We aimed to develop a novel TRPV1-targeting peptide to inhibit UV-induced responses in human skin. METHODS We designed and generated a novel TRPV1 inhibitory peptide (TIP) which mimics the specific site in TRPV1 (aa 701-709: Gln-Arg-Ala-Ile-Thr-Ile-Leu-Asp-Thr, QRAITILDT), Thr705, and tested its efficacy of blocking UV-induced responses in HaCaT, mouse, and human skin. RESULTS TIP effectively inhibited capsaicin-induced calcium influx and TRPV1 activation. Treatment of HaCaT with TIP prevented UV-induced increases of MMP-1 and pro-inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor-α. In mouse skin in vivo, TIP inhibited UV-induced skin thickening and prevented UV-induced expression of MMP-13 and MMP-9. Moreover, TIP attenuated UV-induced erythema and the expression of MMP-1, MMP-2, IL-6, and IL-8 in human skin in vivo. CONCLUSION The novel synthetic peptide targeting TRPV1 can ameliorate UV-induced skin responses in vitro and in vivo, providing a promising therapeutic approach against UV-induced inflammation and photoaging.

Activation of Peroxisome Proliferator-Activated Receptor Alpha Improves Aged and UV-Irradiated Skin by Catalase Induction

Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear hormone receptor involved in the transcriptional regulation of lipid metabolism, fatty acid oxidation, and glucose homeostasis. Its activation stimulates antioxidant enzymes such as catalase, whose expression is decreased in aged human skin. Here we investigated the expression of PPARα in aged and ultraviolet (UV)-irradiated skin, and whether PPARα activation can modulate expressions of matrix metalloproteinase (MMP)-1 and procollagen through catalase regulation. We found that PPARα mRNA level was significantly decreased in intrinsically aged and photoaged human skin as well as in UV-irradiated skin. A PPARα activator, Wy14643, inhibited UV-induced increase of MMP-1 and decrease of procollagen expression and caused marked increase in catalase expression. Furthermore, production of reactive oxygen species (ROS) was suppressed by Wy14643 in UV-irradiated and aged dermal fibroblasts, suggesting that the PPARα activation-induced upregulation of catalase leads to scavenging of ROS produced due to UV irradiation or aging. PPARα knockdown decreased catalase expression and abolished the beneficial effects of Wy14643. Topical application of Wy14643 on hairless mice restored catalase activity and prevented MMP-13 and inflammatory responses in skin. Our findings indicate that PPARα activation triggers catalase expression and ROS scavenging, thereby protecting skin from UV-induced damage and intrinsic aging.

Lycopersicon esculentum Extract Enhances Cognitive Function and Hippocampal Neurogenesis in Aged Mice

A decrease in adult neurogenesis is associated with the aging process, and this decrease is closely related to memory impairment. Tomato (Lycopersicon esculentum) is a fruit with diverse bioactive nutrients that is consumed worldwide. In this study, we investigated the cognition-enhancing effect of tomato ethanolic extracts (TEE) in aged mice. Six weeks of oral TEE administration in 12-month-old aged mice significantly increased their exploration time of novel objects when compared to vehicle-treated mice. The TEE supplement increased doublecortin (DCX)-positive cells and postsynaptic density-95 (PSD95) expression in mice hippocampus. Moreover, we found an increased expression of brain-derived neurotrophic factor (BDNF) and subsequently-activated extracellular-signal-regulated kinase (ERK)/cAMP response element binding (CREB) signaling pathway in the TEE-supplemented mice hippocampus. In conclusion, the oral administration of TEE exhibits a cognition-enhancing effect, and the putative underlying mechanism is the induction of BDNF signaling-mediated proliferation and synapse formation in the hippocampus. These findings indicate that TEE could be a candidate for treatment of age-related memory impairment and neurodegenerative disorders.

UV irradiation through skin or eye reduces hippocampal neurogenesis and synaptic protein expression

We are exposed to sunlight that contains ultraviolet (UV) rays that are absorbed through our skin and eyes. Sunlight is responsible for the synthesis of vitamin D and maintains the balance of serotonin and melatonin (1). However, exposure to excessive sunlight causes skin cancer, and eye diseases such as UV-induced keratitis and cortical cataract. Moreover, skin exposure to UV regulates systemic homeostasis. This article is protected by copyright. All rights reserved.

Topical or oral treatment of peach flower extract attenuates UV-induced epidermal thickening, matrix metalloproteinase-13 expression and pro-inflammatory cytokine production in hairless mice skin

BACKGROUND/OBJECTIVES Ultraviolet radiation (UV) is a major cause of skin photoaging. Previous studies reported that ethanol extract (PET) of Prunus persica (L.) Batsch flowers (PPF, peach flowers) and its subfractions, particularly the ethylacetate (PEA) and n-butanol extracts (PBT), have potent antioxidant activity and attenuate the UV-induced matrix metalloproteinase (MMP) expression in human skin cells. In this study, we investigated the protective activity of PPF extract against UV-induced photoaging in a mouse model. MATERIALS/METHODS Hairless mice were treated with PET or a mixture of PEA and PBT either topically or orally along with UV irradiation. Histological changes and biochemical alterations of mouse skin were examined. Major phenolic compounds in PPF extract were analyzed using an ACQUITY UPLC system. RESULTS The overall effects of topical and oral treatments with PPF extract on the UV-induced skin responses exhibited similar patterns. In both experiments, the mixture of PEA and PBT significantly inhibited the UV-induced skin and epidermal thickening, while PET inhibited only the UV-induced epidermal thickening. Treatment of PET or the mixture of PEA and PBT significantly inhibited the UV-induced MMP-13 expression, but not typeⅠ collagen expression. Topical treatment of the mixture of PEA and PBT with UV irradiation significantly elevated catalase, superoxide dismutase (SOD) and glutathione-peroxidase (GPx) activities in the skin compared to those in the UV irradiated control group, while oral treatment of the mixture of PEA and PBT or PET elevated only catalase and SOD activities, but not GPx. Thirteen phytochemical compounds including 4-O-caffeoylquinic acid, cimicifugic acid E and B, quercetin-3-O-rhamnoside and kaempferol glycoside derivatives were identified in the PPF extract. CONCLUSIONS These results demonstrate that treatment with PET or the mixture of PEA and PBT, both topically or orally, attenuates UV-induced photoaging via the cooperative interactions of phenolic components having anti-oxidative and collagen-protective activities.