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Obesity is a significant risk factor for various metabolic diseases and is closely related to non-alcoholic fatty liver disease (NAFLD) characterized by inflammation and oxidative stress. Clusterin is a multi-functional protein that is up-regulated in the pathogenesis of various metabolic diseases, including obesity and NAFLD. Our previous studies indicated that hepatocyte-specific overexpression of clusterin alleviates methionine choline-deficient (MCD) diet-induced non-alcoholic steatohepatitis (NASH) by activating nuclear factor erythroid 2-related factor 2 (Nrf2). Here we generated transgenic mice with whole-body clusterin overexpression (wCLU-tg) and investigated the role of clusterin in Western diet-induced obesity and NAFLD. We confirmed that obesity parameters and the spectrum of NAFLD of wCLU-tg mice were improved compared to wild type mice. Contrarily, clusterin deficiency deteriorated metabolic disruptions. We also found that clusterin activates target molecules for obesity and NAFLD, namely Nrf2 and AMPK, suggesting that clusterin protects against Western diet-induced obesity and NAFLD by activating Nrf2 and AMPK.

Background Chemotherapy is a standard therapeutic regimen to treat triple-negative breast cancer (TNBC); however, chemotherapy alone does not result in significant improvement and often leads to drug resistance in patients. In contrast, combination therapy has proven to be an effective strategy for TNBC treatment. Whether metformin enhances the anticancer effects of cisplatin and prevents cisplatin resistance in TNBC cells has not been reported. Methods Cell viability, wounding healing, and invasion assays were performed on Hs 578T and MDA-MB-231 human TNBC cell lines to demonstrate the anticancer effects of combined cisplatin and metformin treatment compared to treatment with cisplatin alone. Western blotting and immunofluorescence were used to determine the expression of RAD51 and gamma-H2AX. In an in vivo 4T1 murine breast cancer model, a synergistic anticancer effect of metformin and cisplatin was observed. Results Cisplatin combined with metformin decreased cell viability and metastatic effect more than cisplatin alone. Metformin suppressed cisplatin-mediated RAD51 upregulation by decreasing RAD51 protein stability and increasing its ubiquitination. In contrast, cisplatin increased RAD51 expression in an ERK-dependent manner. In addition, metformin also increased cisplatin-induced phosphorylation of γ-H2AX. Overexpression of RAD51 blocked the metformin-induced inhibition of cell migration and invasion, while RAD51 knockdown enhanced cisplatin activity. Moreover, the combination of metformin and cisplatin exhibited a synergistic anticancer effect in an orthotopic murine model of 4T1 breast cancer in vivo. Conclusions Metformin enhances anticancer effect of cisplatin by downregulating RAD51 expression, which represents a novel therapeutic target in TNBC management.

Resistin, an adipocyte-secreted factor, is known to be elevated in breast cancer patients. However, the molecular mechanism by which resistin acts is not fully understood. The aim of this study was to investigate whether resistin could stimulate invasion and migration of breast cancer cells. Here, we report that resistin stimulated invasion and migration of breast cancer cells as well as phosphorylation of c-Src. Inhibition of c-Src blocked resistin-induced breast cancer cell invasion. Resistin increased intracellular calcium concentration and chelation of intracellular calcium blocked resistin-mediated activation of Src. Resistin also induced phosphorylation of protein phosphatase 2A (PP2A). Inhibition of c-Src blocked resistin-mediated PP2A phosphorylation. In addition, resistin increased phosphorylation of PKCα. Inhibition of PP2A enhanced resistin-induced PKCα phosphorylation, demonstrating that PP2A activity is critical for PKCα phosphorylation. Resistin also increased phosphorylation of ezrin, radixin and moesin (ERM). Additionally, ezrin interacted with PKCα and resistin promoted co-localization of ezrin and PKCα. Either inhibition of c-Src and PKCα or knock-down of ezrin blocked resistin-induced breast cancer cells invasion. Moreover, resistin increased expression of vimentin, a key molecule for cancer cell invasion. Knock-down of ezrin abrogated resistin-induced vimentin expression. These results suggest that resistin play as a critical regulator of breast cancer metastasis.

Co-treatment of astragalin and quercetin (AGQC) significantly suppressed the ultraviolet (UV)-induced keratinocyte damage. Administration of AGQC in UV-irradiated mice reduced the histological skin alterations and the levels of chemokine (C-X-C motif) ligand 1 (CXCL1) and CXCL2. These results suggest that AGQC has a potential use as a compound for protection against UV-irradiated skin damage.

Ultraviolet B (UVB) irradiation induces skin damage and inflammation. Persimmon leaf extract (PLE) has traditionally been used for the treatment of acute and chronic diseases in Asia, but there have been no reports on its UVB-protective effects. Thus, protective effects of PLE against UVB-induced inflammations in HaCaT keratinocytes and mice were investigated. In an in vitro study using HaCaT keratinocytes, UVB irradiation decreased cell viability and increased chemokine production. PLE recovered cell viability and suppressed UVB-induced production of monocyte chemotactic protein-1 (CCL2) and cutaneous T cell-attracting chemokine (CCL27). Moreover, oral administration of PLE to UVB-irradiated mice resulted in significant suppression of skin damage. Histological analyses revealed that infiltration of inflammatory cells, especially degranulated mast cells, thickening of the epidermis, and hyperplasia were significantly reduced. PLE treatment suppressed UVB-induced CCL2 and CCL27 expressions in the skin. These results suggest PLE has potential as an effective material for protection against UVB-induced skin inflammation.

Although the altered expression of integrin alpha4 is known to be associated with transformation or metastasis in several human cancers, the information on cholangiocarcinoma (CC) is still poor. In this study, we investigated the promoter methylation status of integrin alpha4 gene in CC.A total of 29 CC, 19 adjacent non-tumor-containing tissue and 15 normal liver specimens were used for identification of gene methylation status by methylation-specific polymerase chain reaction.The frequency of DNA methylation was 55.17% (16 of 29) in the CC specimens (P0.001). Also, transcripts of the integrin alpha4 gene were decreased in all CC tissues in which there was DNA methylation of the integrin alpha4 gene. In addition, the downregulated expression of integrin alpha4 in CC cells with hypermethylation of the integrin alpha4 gene was restored by treatment with 5-aza-2'-deoxycytidine, a DNA methyltransferase inhibitor. Moreover, we found that DNA methylation of integrin alpha4 was detected in all CC tissues obtained from patients with LN metastasis (7/7). Furthermore, phosphorylation of paxillin, cell migration-related molecule, was regulated by silencing of integrin alpha4.Taken together, these results suggest that loss of the integrin alpha4 gene is caused by aberrant DNA methylation of the 5'-CpG island site of the gene, and methylation of the integrin alpha4 gene can be a useful marker of metastasis of CC.

Interleukin (IL)-4 inhibits proliferation of several human cancer cell lines in vitro. Although IL-4 is known to regulate proliferation of lymphocytes by modulating p27KIP1 expression, the mechanism involved in the IL-4-induced growth inhibition of nonhematopoietic cancer cells has not been fully elucidated. Previously, we reported that IL-4 suppressed proliferation of human renal cell carcinoma (RCC) cell lines in vitro. Here, we show that IL-4 inhibits cell cycle progression at the G1 phase in Caki-1 cells by increasing the expression of p21WAF1 and interferon regulatory factor (IRF)-1, and decreasing the cyclin dependent kinase (CDK) 2 activity. Up-regulation of p21WAF1 and IRF-1 expression is transcriptional, but independent of p53. The levels of p21WAF1 and IRF-1 proteins were enhanced as early as 1 h after IL-4 treatment. CDK2 activity started to decline at 4 h after IL-4 treatment, and by 24 h, was approximately 50% of the control. Neither the protein expressions of p27KIP1 and p16INK4a, nor the phosphorylation level of pRb was changed. The importance of p21WAF1 and IRF-1 in the growth inhibition induced by IL-4 was confirmed by antisense oligonucleotide transfection. Both of p21WAF1 and IRF-1 antisense oligonucleotides prevented IL-4-mediated growth inhibition by approximately 30% compared to the respective sense oligonucleotides. In summary, our study indicated that p21WAF1 and IRF-1 mediate the growth inhibitory effect of IL-4 in human RCC cells.

Background: The hypermethylation of Alcohol dehydrogenase iron containing 1 (ADHFE1) was recently reported to be associated with colorectal cancer (CRC) differentiation. However, the effect of alcohol on ADHFE1 hypermethylation in CRC is still unclear. Methods: The methylation status and expression levels of ADHFE1 were investigated in primary tumor tissues and adjacent normal tissues of 73 patients with CRC, one normal colon cell line, and 4 CRC cell lines (HT-29, SW480, DLD-1, and LoVo) by quantitative methylation-specific polymerase chain reaction (QMSP) and real-time reverse transcription polymerase chain reaction (real time PCR), respectively. The effect of alcohol on the methylation status of ADHFE1 was analyzed in HT-29, SW480, DLD-1, and CCD18Co cells using QMSP, real-time PCR, immunoblot, and cell proliferation assay. Results: ADHFE1 was hypermethylated in 69 of 73 CRC tissues (95%) compared to adjacent normal tissues (p < 0.05). The mRNA expression of ADHFE1 was significantly reduced in CRC compared to adjacent normal tissues (p < 0.05) and its expression was decreased in the alcohol consumption group (p < 0.05). ADHFE1 was hypermethylated and its expression was decreased in 4 CRC cell lines compared with normal colon cell line. Alcohol induced hypermethylation of ADHFE1, decreased its expression, and stimulated cell proliferation of HT-29, SW480, and DLD-1cells. Conclusion: These results demonstrate that the promoter hypermethylation of ADHFE1 is frequently present in CRC and alcohol induces methylation-mediated down expression of ADHFE1 and proliferation of CRC cells.

Neutrons from a source are moderated by means of hydrogenous materials such as polyethylene (PE) or water to reduce the energy of fast neutrons and to increase the fluence rate of moderated neutrons. The rise-time and γ-ray pulse height spectrum from a PE moderated241Am-Be neutron-gamma (n-γ) mixed source were measured by using6Li-BC501 scintillation detector and pulse shape discriminator (PSD) system. The difference in rise-time between γ and neutron signals tumed out to be 18.5 ns for the6Li-BC501 (n-γ) spectrometer system. The figure of merit (FOM) for this separation was estimated to be 1.52, and this was compared with the published results. From this comparison, the6Li-BC501 system has much superior characteristics in (n-γ) separation to other detector systems. Two Compton edges at around 1.87 and 3.99 MeV which are produced by H(n,γ)D reaction and by the first excited state of12C* from Be(α, n)12C* reaction were also investigated.

In a previous study, our group showed that the effective microorganism substance (EM-S) produced by fermentation of medicinal plants with effective microorganisms has an antiinflammatory effect on atopic dermatitis-like lesions in NC/Nga mice. However, the possible antiinflammatory effect and skin barrier function of EM-S for inflammatory cell infiltration, Interleukin-4 (IL-4) production, C-C chemokine receptor 10 (CCR10), and filaggrin (FLG) expression were not reported. Therefore, effects of EM-S on the development of atopic dermatitislike skin lesions in NC/Nga mice were evaluated. Efficacy of EM-S was judged by measurement of scratching behavior, T-cell subset infiltration, cytokine production, and FLG expression. Topical application of EM-S significantly reduced scratching behavior in NC/Nga mice caused by house dust mite antigen (Dermatophagoides farinse extract, DfE) sensitization. IL-4 production and CD4+ and CD45+ cell infiltrations were significantly reduced by EM-S. CCR10 expression was also significantly inhibited by EM-S. EM-S treatment also increased the level of FLG reduced by DfE sensitization. These results demonstrate EM-S, when applied topically, may be an effective substance for management of atopic dermatitis patients.

Dry etching characteristics of GaN using reactive ion beam etching (RIBE) were studied. Etching profile, etching rate and etching selectivity to a photoresist (PR) mask were investigated as a function of various etching parameters. Characteristics of chemically assisted reactive ion beam etching (CARIBE) and RIBE were compared at varied mixtures of CH4 and Cl2. A highly anisotropie etching profile with a smooth surface was obtained for tilted RIBE with Ch at room temperature. Etching selectivity to a PR was dramatically improved in RIBE and CARIBE when a volume fraction of CH4 to the mixture of CH4 and Ch was larger than 0.83.

Rapid thermal annealing (RTA) was applied to anneal polycrystalline CdTe thin films evaporated on CdS/ITO substrate and the effects of rapid thermal annealing temperatures and gas environments were studied. X-ray diffractometer (XRD), X-ray photoelectron spectroscopy(XPS), energy dispersive X-ray spectroscopy(EDX), cross-sectional transmission microscopy(TEM), and micro-EDX in TEM were used to characterize physical and chemical properties of rapid thermal annealed CdTe thin films. Complete CdTe/CdS photovoltaic cells were fabricated and I-V characteristics of these cells were measured under the illumination. Results showed that the bulk composition of CdTe remained stoichiometric to 550°C in the air environment and surface composition became Cd-rich. Cross-sectional TEM and micro-EDX showed columnar grains and micro-twins remained even after RTA, however, sulfur content in rapid thermal annealed CdTe caused by sulfur diffusion from CdS during the annealing was much smaller than that by furnace annealing. Among the investigated RTA temperatures and gas environments, the cell made with CdTe annealed at 550°C in the air showed the best solar energy conversion efficiency.

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