Palmitoyl­RGD promotes the expression of dermal­epidermal junction components in HaCaT cells.

With age, the dermal­epidermal junction (DEJ) becomes thinner and production of its protein components decreases; this may be associated with increased fragility and wrinkling of skin. Topical treatment with palmitoyl­Arg­Gly­Asp (PAL­RGD) improves facial wrinkles, skin elasticity and dermal density in humans. In the present study, the effect of PAL­RGD on expression of DEJ components, such as laminin and collagen, was assessed. Human HaCaT keratinocytes were treated with PAL­RGD. The protein expression levels of laminin­332, collagen IV and collagen XVII were examined by western blotting. Reverse transcription-quantitative PCR was used to analyze laminin subunit (LAM)A3, LAMB3, LAMC2, collagen type IV α 1 chain (COL4A1) and COL17A1 mRNA expression levels. Western blot analysis showed that the expression levels of proteins comprising the DEJ, including laminin α3, ß3 and γ2 and collagen IV and XVII demonstrated a significant dose­dependent increase following PAL­RGD treatment. Furthermore, PAL­RGD treatment significantly enhanced LAMA3, LAMB3, LAMC2, COL4A1 and COL17A1 mRNA expression levels. PAL­RGD may enhance the DEJ by inducing the expression of laminin­332, collagen IV and collagen XVII.

Comparison of the Gut Microbiota of Centenarians in Longevity Villages of South Korea with Those of Other Age Groups.

Several studies have attempted to identify factors associated with longevity and maintenance of health in centenarians. In this study, we analyzed and compared the gut microbiota of centenarians in longevity villages with the elderly and adults in the same region and urbanized towns. Fecal samples were collected from centenarians, elderly, and young adults in longevity villages, and the gut microbiota sequences of elderly and young adults in urbanized towns of Korea were obtained from public databases. The relative abundance of Firmicutes was found to be considerably higher in subjects from longevity villages than those from urbanized towns, whereas Bacteroidetes was lower. Age-related rearrangement of gut microbiota was observed in centenarians, such as reduced proportions of Faecalibacterium and Prevotella, and increased proportion of Escherichia, along with higher abundances of Akkermansia, Clostridium, Collinsella, and uncultured Christensenellaceae. Gut microbiota of centenarians in rehabilitation hospital were also different to those residing at home. These differences could be due to differences in diet patterns and living environments. In addition, phosphatidylinositol signaling system, glycosphingolipid biosynthesis, and various types of N-glycan biosynthesis were predicted to be higher in the gut microbiota of centenarians (corrected p < 0.05). These three metabolic pathways of gut microbiota can be associated with the immune status and healthy gut environment of centenarians. Although further studies are necessary to validate the function of microbiota between groups, this study provides valuable information on centenarians' gut microbiota.

Black rice (Oryza sativa L.) extract modulates ultraviolet-induced expression of matrix metalloproteinases and procollagen in a skin cell model.

Exposure of the skin to ultraviolet (UV) radiation causes extracellular matrix (ECM) collapse in the dermis, owing to an increase in matrix metalloproteinase (MMP) production in both the epidermis and dermis, and a decrease in type I collagen expression in the dermis. Recently, black rice (Oryza sativa L.) was reported to have a wide range of pharmacological effects in various settings. However, the effects of black rice extract (BRE) on UV­irradiated skin cells have not yet been characterized. BRE treatment did not affect cell morphology and viability of HaCaT and human dermal fibroblasts (HDF). We demonstrated that BRE downregulated basal and UV­induced MMP­1 expression in HaCaT cells. Furthermore, BRE significantly increased type I procollagen expression, and decreased MMP­1 and MMP­3 expression in UV­irradiated HDF. The underlying mechanisms of these results involve a decrease in p38 and c­Jun N­terminal kinase activity, and suppression of UV­induced activation of activator protein­1 (AP­1). BRE reduced UV­induced reactive oxygen species production in HaCaT cells in a dose­dependent manner. Indeed, mass spectrometry revealed that BRE contained antioxidative flavonoid components such as cyanidin­3­O­ß­D­glycoside and taxifolin­7­O­glucoside. These findings suggest that BRE attenuates UV­induced ECM damage by modulating mitogen­activated protein kinase and AP­1 signaling, and could be used as an active ingredient for preventing photoaging of the skin.

UV irradiation to mouse skin decreases hippocampal neurogenesis and synaptic protein expression via HPA axis activation.

The skin senses external environment, including ultraviolet light (UV). Hippocampus is a brain region that is responsible for memory and emotion. However, changes in hippocampus by UV irradiation to the skin have not been studied. In this study, after 2 weeks of UV irradiation to the mouse skin, we examined molecular changes related to cognitive functions in the hippocampus and activation of the hypothalamic-pituitary-adrenal (HPA) axis. UV exposure to the skin decreased doublecortin-positive immature neurons and synaptic proteins, including N-methyl-D-aspartate receptor 2 A and postsynaptic density protein-95, in the hippocampus. Moreover, we observed that UV irradiation to the skin down-regulated brain-derived neurotrophic factor expression and ERK signaling in the hippocampus, which are known to modulate neurogenesis and synaptic plasticity. The cutaneous and central HPA axes were activated by UV, which resulted in significant increases in serum levels of corticosterone. Subsequently, UV irradiation to the skin activated the glucocorticoid-signaling pathway in the hippocampal dentate gyrus. Interestingly, after 6 weeks of UV irradiation, mice showed depression-like behavior in the tail suspension test. Taken together, our data suggest that repeated UV exposure through the skin may negatively affect hippocampal neurogenesis and synaptic plasticity along with HPA axis activation.

Topical application of palmitoyl-RGD reduces human facial wrinkle formation in Korean women.

Maintaining a youthful appearance is a common desire among the aging population. Loss of elasticity and dermal density constitutes major causes of wrinkle formation during skin aging. In particular, periorbital wrinkles comprise the critical assessment point of skin aging. To address these issues, cosmetic industries have been making increasing efforts to develop efficient agents against wrinkle formation. Arg-Gly-Asp (RGD) is a tripeptide sequence used for surface coating because of its integrin-binding property. However, its pharmacological properties on skin have not yet been studied. Here, we synthesize the novel palmitoyl-Arg-Gly-Asp (Palm-RGD) and investigate its effects on periorbital wrinkle formation by clinical and in vitro studies. We observed that Palm-RGD cream application for 12 weeks decreased global photodamage and skin roughness (R1, R2, R3, and Ra) scores without causing skin irritation. In addition, topical application of Palm-RGD cream time-dependently increased skin elasticity and dermal density. An in vitro study using human dermal fibroblasts (HDFs) demonstrated increased type I procollagen production by Palm-RGD treatment. Furthermore, Palm-RGD suppressed MMP-1 expression in HDFs. Our results demonstrate that Palm-RGD has protective effects against wrinkle formation, likely through the activation of collagen expression and the protection against collagen degradation. Therefore, Palm-RGD could be used as a potential agent for the prevention of wrinkle formation consequent to aging.

Effects of palmitoyl-KVK-L-ascorbic acid on skin wrinkles and pigmentation.

Wrinkle formation and abnormal pigmentation are major clinical alterations associated with skin aging. As the aim of our study was to investigate the effects of palmitoyl-KVK-L-ascorbic acid on skin aging, the anti-wrinkle and depigmentation effects of palmitoyl-KVK-L-ascorbic acid were evaluated by measuring collagen expression in dermal fibroblast cells and inhibition of melanogenesis in B16F1 cells, respectively. The anti-aging effect of palmitoyl-KVK-L-ascorbic acid cream was also evaluated against a placebo cream in a clinical trial. Our results confirmed that the expression of type Ι collagen in dermal fibroblast cells treated with palmitoyl-KVK-L-ascorbic acid (0.1-4 µg/mL) increased in a dose-dependent manner. In B16F1 cells, treatment with 20 µg/mL palmitoyl-KVK-L-ascorbic acid reduced the melanin content by approximately 20% compared to alpha-melanocyte stimulating hormone treatment. In the clinical trial, application of palmitoyl-KVK-L-ascorbic acid cream led to an improvement in skin roughness and lightness in 12 and 8 weeks, respectively. Our data show that palmitoyl-KVK-L-ascorbic acid is an effective anti-aging agent that reduces wrinkles and abnormal skin pigmentation.

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.

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.

Oral Supplementation with Cocoa Extract Reduces UVB-Induced Wrinkles in Hairless Mouse Skin.

Cacao beans contain various bioactive phytochemicals that could modify the pathogeneses of certain diseases. Here, we report that oral administration of cacao powder (CP) attenuates UVB-induced skin wrinkling by the regulation of genes involved in dermal matrix production and maintenance. Transcriptome analysis revealed that 788 genes are down- or upregulated in the CP supplemented group, compared with the UVB-irradiated mouse skin controls. Among the differentially expressed genes, cathepsin G and serpin B6c play important roles in UVB-induced skin wrinkle formation. Gene regulatory network analysis also identified several candidate regulators responsible for the protective effects of CP supplementation against UVB-induced skin damage. CP also elicited antiwrinkle effects via inhibition of UVB-induced matrix metalloproteinases-1 expression in both the human skin equivalent model and human dermal fibroblasts. Inhibition of UVB-induced activator protein-1 via CP supplementation is likely to affect the expression of matrix metalloproteinases-1. CP supplementation also downregulates the expression of cathepsin G in human dermal fibroblasts. 5-(3',4'-Dihydroxyphenyl)-γ-valerolactone, a major in vivo metabolite of CP, showed effects similar to CP supplementation. These results suggest that cacao extract may offer a protective effect against photoaging by inhibiting the breakdown of dermal matrix, which leads to an overall reduction in wrinkle formation.

Chaetocin inhibits IBMX-induced melanogenesis in B16F10 mouse melanoma cells through activation of ERK.

Chaetocin is a natural product isolated from Chaetomium species that has anti-bacterial and anti-myeloma activities. In this study, we investigated the inhibitory effect of chaetocin on melanogenesis and the underlying mechanisms in B16F10 mouse melanoma cells. In the present study, chaetocin significantly inhibited IBMX-induced melanin production and tyrosinase activity without any cytotoxicity. Furthermore, chaetocin down-regulated both the protein and mRNA levels of tyrosinase, which is a specific enzyme that catalyzes the conversion of tyrosine to melanin. We also observed that the protein level of MITF was significantly reduced by chaetocin treatment. In addition, we found that the anti-melanogenic effect of chaetocin was suppressed by treatment with the specific ERK inhibitor (PD98059). Accordingly, chaetocin inhibited melanogenesis via suppressing the protein level of MITF followed by activation of the ERK signaling pathway. These data suggest that chaetocin may be a potential anti-melanogenic agent for use in skin-whitening cosmetics and a topical agent for treatment of hyperpigmentation disorders.

Toll-like receptor family members in skin fibroblasts are functional and have a higher expression compared to skin keratinocytes.

Toll-like receptors (TLRs) are known to recognize not only pathogen-associated molecular patterns but also danger-associated molecular patterns. Recent studies have characterized the expression levels and functions of TLRs in human epidermal cells. However, the characteristics of TLR family members in human dermal fibroblasts have not been thoroughly studied. Therefore, the present study systematically investigated the expression levels of TLRs and their functional responses to each ligand in skin fibroblasts. All 10 TLRs are expressed in skin fibroblasts. Stimulation of skin fibroblasts with each TLR ligand resulted in an increase of the interleukin-6 (IL-6), IL-8 and matrix metalloproteinase-1 proteins, indicating that ≥ 9 TLRs in skin fibroblasts are functionally active. Furthermore, stimulating skin fibroblasts with TLR1/2, 3 and 4 ligands induced the phosphorylation of inhibitor of nuclear factor κBα and the active phosphorylation of extracellular-signal regulated kinase 1/2. The expression level of each TLR was much higher in fibroblasts compared to keratinocytes. In particular, the fold-increase in IL-6 and IL-8 mRNA levels upon exposure to a TLR1/2 ligand was much higher in fibroblasts compared to keratinocytes, which appears to reflect the difference in expression levels of TLR1 and 2 between fibroblasts and keratinocytes. Taken together, these results show that all 10 TLRs are constitutively expressed and functional (except TLR10) in skin fibroblasts and suggest that TLRs in skin fibroblasts may play an important role in the detection of and response to different classes of pathogens and danger signals.

A layered polymorph of rare earth hydroxides.

A layered polymorph series of rare earth hydroxides has been developed by the conversion of RE2(OH)5Cl·mH2O to RE(OH)3·nH2O (RE = rare earths) with a typical layered structure with interlayer water molecules. A temperature-induced phase transition from the layered polymorph to its hexagonal form is completed at approximately 300 °C.

Red ginseng and 20(S)-Rg3 control testosterone-induced prostate hyperplasia by deregulating androgen receptor signaling.

Since prostate growth is governed by the androgen signaling pathway, blockade of the pathway is regarded as an appropriate strategy for the treatment of benign prostatic hyperplasia (BPH). Panax ginseng is known to have various pharmacological activities. Of several products of its root, red ginseng, having many bioactive ginsenosides, is most popularly used in Korea, and recently has been reported to control the proliferation of cancer cells. We here tested the effect of a water extract of Korean red ginseng (WKRG) on testosterone-induced prostate hyperplasia. WKRG (daily intraperitoneal injection) prevented prostate overgrowth and epithelial thickening induced by testosterone in rats, and suppressed a rat prostate kallikrein-S3. In human prostate cells, WKRG inhibited testosterone-induced cell proliferation, arrested cell cycle by inducing p21 and p27, and induced apoptosis. Testosterone-induced expression of human kallikrein-3 mRNA and activation of androgen receptor (AR) were effectively inhibited by WKRG. Of the major ginsenosides included in WKRG, 20(S)-Rg3 was identified to repress AR activity and to attenuate prostate cell growth during testosterone stimulation. Moreover, 20(S)-Rg3 downregulated AR by facilitating the degradation of AR protein. WKRG and 20(S)-Rg3 were found to have new pharmacological activities against testosterone-induced prostate overgrowth. Given that red ginseng has been used safely in Asia for 1000 years, red ginseng and 20(S)-Rg3 could be potential therapeutic regimens for treating BPH.