Hyun Yoo

Syndecan-2 Regulates the Migratory Potential of Melanoma Cells

Syndecan-2, a transmembrane heparan sulfate proteoglycan, is a critical mediator in the tumorigenesis of colon carcinoma cells. We explored the function of syndecan-2 in melanoma, one of the most invasive types of cancers, and found that the expression of this protein was elevated in tissue samples from both nevus and malignant human melanomas but not in melanocytes of the normal human skin tissues. Similarly, elevated syndecan-2 expression was observed in various melanoma cell lines. Overexpression of syndecan-2 enhanced migration and invasion of melanoma cells, whereas the opposite was observed when syndecan-2 levels were knocked down using small inhibitory RNAs. Syndecan-2 expression was enhanced by fibroblast growth factor-2, which is known to stimulate melanoma cell migration; however, α-melanocyte-stimulating hormone decreased syndecan-2 expression and melanoma cell migration and invasion in a melanin synthesis-independent manner. Furthermore, syndecan-2 overexpression rescued the migration defects induced by α-melanocyte-stimulating hormone treatment. Together, these data strongly suggest that syndecan-2 plays a crucial role in the migratory potential of melanoma cells.

Homoisoflavanone inhibits UVB-induced skin inflammation through reduced cyclooxygenase-2 expression and NF-κB nuclear localization

BACKGROUND Since the generation of reactive oxygen species (ROS) and release of inflammatory mediators play a major role in UVB-induced inflammation, vigorous attempts have been made for the pharmacological management of these molecules as well as for uncovering the molecular signaling pathways. Homoisoflavanone (5,7-dihydroxy-3-(3-hydroxy-4-methoxybenzyl)-chroman-4-one, HIF) extracted from Cremastra appendiculata has anti-angiogenic activities, but its effect on inflammation was unknown. OBJECTIVE To investigate the anti-inflammatory effects of HIF on the skin and the underlying molecular mechanisms. METHODS HaCaT cells were irradiated by UVB (10 mJ/cm(2)) with or without HIF. Prostaglandin E(2) (PGE(2)) level was measured by enzyme immunoassay. Activation of MAPK and production of cyclooxygenase-2 (COX-2) were determined by Western blot analysis. Localization of nuclear factor kappa B (NF-kappaB) was assessed by immunofluorescence microscopy. Hairless mice were stimulated with UVB or chemical stimulants to induce inflammatory responses in skin. RESULTS Pretreatment with HIF inhibited the production of intracellular ROS induced by UVB irradiation in HaCaT cells. Further analysis revealed a decrease in the level of MAPK activation and down-regulation of COX-2 expression. In addition, HIF attenuated the nuclear localization of NF-kappaB, resulting in the suppression of inflammatory molecules such as IL-6, IL-8, and TNF-alpha. Finally, topical treatment with HIF inhibited ear edema induced by UVB, 12-O-tetradecanoylphorbol-13-acetate (TPA), arachidonic acid (AA), or croton oil. CONCLUSION HIF has a strong protective effect against proinflammatory responses, implying the possibility of preventive application for inflammatory skin diseases.

Pachastrissamine from Pachastrissa sp. inhibits melanoma cell growth by dual inhibition of Cdk2 and ERK-mediated FOXO3 downregulation.

Melanoma cells are relatively resistant to apoptosis compared with other tumor cell types, and thus, chemotherapy, radiotherapy and immunotherapy are not effective in treating melanoma. Pachastrissamine (PA) exhibits cytotoxic activity and promotes apoptosis in several cancer cells. However, its specific molecular mechanisms have not been characterized fully. This study investigated the antimelanoma effect of PA, an anhydrophytosphingosine derived from marine sponge, and its underlying molecular mechanisms. The data demonstrated that treatment with PA inhibited the phosphorylation of ERK and subsequent ERK‐mediated FOXO3 phosphorylation in melanoma cells. Interestingly, PA did not inhibit AKT‐mediated FOXO3 phosphorylation. Therefore, it appears that PA‐induced apoptosis results from the inhibition of ERK. Furthermore, intravenous administration of PA was found to suppress melanoma cell growth in a C57BL6 mouse without causing side effects. Additionally, PA inhibited the production of Cdk2, which is involved in cell cycle regulation. Taken together, inhibition of melanoma cell growth by PA is a result of the inhibition of ERK‐mediated FOXO3 downregulation and decreased Cdk2 levels. The results of this study imply that dual inhibition of the ERK pathway and cell cycle progression could be an effective approach to control the growth of melanoma cells. Copyright

Reciprocal regulation of 12- and 15-lipoxygenases by UV-irradiation in human keratinocytes

The 12/15‐lipoxygenase (12/15‐LOX) pathways of arachidonate metabolism have been implicated in the pathogenesis of psoriasis. Since UV photo‐therapy is a commonly used technique for inhibiting cell proliferation and inflammation in skin diseases, we hypothesized that UV‐irradiation may affect 12/15‐LOX expression which might regulate cell proliferation. In this study, we showed that UV‐irradiation suppressed 12‐LOX expression, whereas up‐regulated 15‐LOX expression. Treatment with the 15‐LOX metabolites sufficiently suppressed insulin‐like growth factor II‐induced 12‐LOX expression and blocked cell cycle progression. On the basis of our findings, we think that the 15‐LOX metabolites may inhibit epidermal hyperplasia in psoriasis by regulating 12‐LOX expression.

Anti‐angiogenic activity of thienopyridine derivative LCB03‐0110 by targeting VEGFR‐2 and JAK/STAT3 Signalling

Vascular endothelial growth factor receptor‐2 (VEGFR‐2) and Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signalling are important for tumor angiogenesis and metastasis. In this study, we identified (3‐(2‐(3‐(morpholinomethyl)phenyl)thieno[3,2‐b]pyridin‐7‐ylamino)phenol (LCB03‐0110) as a potent angiogenesis inhibitor. LCB03‐0110 inhibited VEGFR‐2 and JAK/STAT3 signalling in primary cultured human endothelial cells and cancer cells. An in vitro kinase assay and molecular modelling revealed that LCB03‐0110 inhibited VEGFR‐2, c‐SRC and TIE‐2 kinase activity via preferential binding at the ATP‐binding site of their kinases. LCB03‐0110 successfully occupied the hydrophobic pocket of VEGFR‐2, c‐SRC and TIE‐2. LCB03‐0110 also inhibited hypoxia‐induced HIF/STAT3 and EGF‐ or angiopoietin‐induced signalling cascades. In addition, LCB03‐0110 inhibited VEGF‐induced proliferation, viability, migration and capillary‐like tube formation. LCB03‐0110 also suppressed the sprouting of endothelial cells in the rat aorta and the formation of new blood vessels in the mouse Matrigel plug assay, but also suppressed pulmonary metastasis and tumor xenograft in mice. Our results suggest that LCB03‐0110 is a potential candidate small molecule for blocking angiogenesis mediated by aberrant activation of VEGFR‐2 and JAK/STAT3 signalling.

EC-SOD induces apoptosis through COX-2 and galectin-7 in the epidermis

BACKGROUND Extracellular superoxide dismutase (EC-SOD) is an anti-oxidant enzyme found in the extracellular matrix of tissues, and plays an important role in the prevention of many diseases caused by oxidative stress. However, other functions of EC-SOD in epidermis are not well known. OBJECTIVE We investigated the functions of EC-SOD in epidermis using keratinocyte cell line and EC-SOD transgenic mice. METHODS Expression of galectin-7 in pEC-SOD transfected cells or skin of EC-SOD transgenic mice was detected by western blot analysis. The percentage of apoptotic cells was determined by propidium iodide staining and subsequent FACS analysis. COX-2 siRNA or scrambled siRNA was transfected into HaCaT cells and western blot analysis was performed to detect pro-apoptotic protein levels. RESULTS The epidermis of EC-SOD transgenic mice was thinner than wild type mice. In addition, we showed that the thin epidermis of EC-SOD transgenic mice results from the apoptosis of epidermal cells. To elucidate which molecules are involved in EC-SOD-induced apoptosis, we utilized two-dimensional electrophoresis; the results showed that the epidermis of EC-SOD transgenic mice produces more galectin-7, a pro-apoptotic factor, than the wild type. Furthermore, we showed that the transfection of EC-SOD-expressing plasmids induces the production of galectin-7, and pro-apoptotic proteins in keratinocytes. This suggests that EC-SOD induces apoptosis through increased galectin-7 expression. Finally, we demonstrated that EC-SOD-induced galectin-7 results from the production of COX-2. CONCLUSION Our results imply that EC-SOD plays a role not only as a reactive oxygen species scavenger, but also as a pro-apoptotic factor via COX-2/galectin-7 pathways in the epidermis.

Pain Nursing Intervention Supporting Method using Collaborative Filtering in Health Industry

AbstractIn modern society, the amount of information has been significantly increased according to the development of Internet and IT convergence technology and that leads to develop information obtaining and searching technologies from lots of data. Although the system integration for medicare has been largely established and that accumulates large amounts of information, there is a lack of providing and supporting information for nursing activities using such established database. In particular, the judgement for the intervention of pains depends on the experience of individual nurses and that leads to make subjective decisions in usual. In this paper, a pain nursing supporting method that uses the existing medical data and performs collaborative filtering is proposed. The proposed collaborative filtering is a method that extracts some items, which represent a high relativeness level, based on similar preferences. A preference estimation method using a user based collaborative filtering method calculates user similarities through Pearson correlation coefficients in which a neighbor selection method is used based on the user preference.