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Choi, Jang Hyun,Yang, Yong Ryoul,Lee, Seul Ki,Kim, Sun-Hee,Kim, Yun-Hee,Cha, Joo-Young,Oh, Se-Woong,Ha, Jong-Ryul,Ryu, Sung Ho,Suh, Pann-Ghill Wiley (New York Academy of Sciences) 2008 Annals of the New York Academy of Sciences Vol.1138 No.1
<P>3'-Phosphoinositide-dependent kinase-1 (PDK1) has been identified for its ability to phosphorylate and activate Akt. Accumulated studies have shown that the activation of the PDK1/Akt pathway plays a pivotal role in cell survival, proliferation, and tumorigenesis. Therefore, the PDK1/Akt pathway is believed to be a critical target for cancer intervention. In this paper, we report the discovery of a new function of phenothiazines, widely known as antipsychotics, inhibiting PDK1/Akt pathway. Upon epidermal growth factor (EGF) stimulation, phenothiazines specifically suppressed the kinase activity of PDK1 and the phosphorylation level of Akt. The inhibition of PDK1/Akt kinase resulted in suppression of EGF-induced cell growth and induction of apoptosis in human ovary cancer cells. In particular, phenothiazines were highly selective for downstream targets of PDK1/Akt and did not inhibit the activation of phosphatidylinositol 3-kinase (PI3K), EGFR, or extracellular signal-regulated kinase 1/2 (ERK1/2). In particular, phenothiazines effectively suppressed tumor growth in nude mice of human cancer cells. Taken together, these findings provide strong evidence for novel function of phenothiazines, pharmacologically targeting PDK1/Akt for anticancer drug discovery.</P>
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Lim, Minsu,Park, Leejin,Shin, Geewook,Hong, Hekyung,Kang, Incheol,Park, Yongsoo Wiley (New York Academy of Sciences) 2008 Annals of the New York Academy of Sciences Vol.1150 No.1
<P>We herein report cytotoxicity of advanced glycation end-products (AGEs) on pancreatic beta cells. AGEs stimulated reactive oxygen species (ROS) generation but did not arrest proliferation of the INS-1 cell line. Pancreatic beta cell lines or primary cultured islets possess a receptor for AGE (RAGE), and its expression increased after AGE treatment. TUNEL staining and FACS analysis using annexin V/PI antibodies showed that apoptosis increased in INS-1 cells or primary cultured islets when incubated with BSA conjugated with glyceraldehyde (AGE2) or glucoaldehyde (AGE3), compared with those conjugated with glucose (AGE1). Reaction of INS-1 cells to Ki67, which is a cellular marker for proliferation, was also increased after AGE treatment. The ability of primary cultured islets to secrete insulin was retained even after AGE treatment under either low or high glucose conditions. The antiserum against RAGE partially prevented AGE-induced cellular events. Treatment of beta cells with the antioxidant metallothionein results in a significant reduction in pathologic changes. AGEs might be able to induce apoptosis as well as proliferation of pancreatic beta cell lines or primary cultured islets. Moreover, antibody array showed that RAD51 and RAD52 were significantly decreased in AGE2-treated INS-1 cells. AGEs might inhibit homologous DNA recombination for repairing DNA of INS-1 cells damaged by ROS generation. It might be suggested that treatment of AGEs resulted in ROS production and apoptosis through their receptor on pancreatic beta cells. AGEs might deteriorate function of pancreatic beta cells in patients with long-term hyperglycemia.</P>
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Independent Association of Tumor Necrosis Factor Polymorphism with Type 1 Diabetes Susceptibility
Shin, Hyoung Doo,Yang, Sei Won,Kim, Duk Hee,Park, Yongsoo Wiley (New York Academy of Sciences) 2008 Annals of the New York Academy of Sciences Vol.1150 No.1
<P>The contribution of SNPs in TNF genes to type 1 diabetes (T1D) is not well established and may be confounded by the linkage disequilibrium within the HLA genes. Seven SNPs in the TNF genes (TNFA and TNFB) were genotyped in a Korean cohort (398 T1D patients and 1422 nondiabetic controls), along with HLA DRB1, DQB1, and MICA (MHC class I chain-related genes). Among them, three SNPs (TNFB+318, TNFA-857, and TNFA-308) and two common TNF haplotypes showed significant association with the risk of T1D (P= 5 x 10(-3)-10(-5)). T1D patients were more often heterozygous for the alleles at the TNFB+318 (OR = 1.7, P= 10(-3)) and TNFA-308 (OR = 1.7, P < 10(-5)) than were the controls. Genetic association analyses of the DRB1, DQB1, and MICA alleles with the risk of T1D revealed dramatic associations in several alleles as expected. Independent analyses to discern the genetic effects of TNF polymorphisms on the risk of T1D suggested that these genetic influences might be not totally dependent on the nearby HLA genes. Our results support the hypothesis that two susceptibility loci in the MHC (one in the HLA class II and another in the central MHC region) act epistatically to increase susceptibility to T1D.</P>
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TGFβ Plasmid Construction and Delivery for the Prevention of Type 1 Diabetes
Park, Leejin,Lee, Eunjig,Lee, Sangkyung,Lim, Minsu,Hong, Hekyung,Shin, Geewook,Park, Yongsoo Wiley (New York Academy of Sciences) 2008 Annals of the New York Academy of Sciences Vol.1150 No.1
<P>Studies of animals with spontaneous autoimmune diabetes have revealed that autoreactive T cells that mediate islet beta cell destruction can be manipulated by the administration of Th(2) cytokines. Using gene delivery to express the targeted protein, we can overcome the need for frequent administration of cytokines on account of their short half-lives. In this study, the effect of hTGFbeta gene delivery was evaluated both in vitro and in vivo using an adenovirus vector (Ad) constructed with an hTGFbeta cDNA. In vitro transfection assays of the construct in HepG2, beta cell lines, and islets showed good expression levels of hTGFbeta and activation of smad3. Ad-hTGFbeta enhanced differentiation and proliferation in the beta cell line or islets without causing apoptosis. Of interest, Ad-hTGFbeta transduction in CD4(+)CD25(-) T cells resulted in a significant enhanced expression of CD25 and a regulatory T cell-specific transcription factor, Foxp3. To evaluate in vivo efficacy, Ad-hTGFbeta was intravenously injected into 7-week-old NOD mice and compared to the transduction using the vector only. The Ad-hTGFbeta group had persistent gene expression for longer than 5 weeks, and high TGFbeta serum level was secreted. There was no difference in the degree of insulitis between the Ad-hTGFbeta group and controls. Although we found favorable in vitro results, such as decrease in islet apoptosis, enhanced proliferation and differentiation, and increase in the level of CD4(+)CD25(+) regulatory T cells, there was no difference in reduction of the development of T1D between controls and Ad-hTGFbeta-injected mice. Nevertheless, if we find the appropriate mode and timing of TGFbeta gene transduction, Ad-hTGFbeta gene therapy might be useful in therapeutic cytokine delivery for the treatment of T1D.</P>
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