Protein‐Induced Pluripotent Stem Cells Ameliorate Cognitive Dysfunction and Reduce Aβ Deposition in a Mouse Model of Alzheimer's Disease

Cha, Moon&#x2010,Yong,Kwon, Yoo&#x2010,Wook,Ahn, Hyo&#x2010,Suk,Jeong, Hyobin,Lee, Yong Yook,Moon, Minho,Baik, Sung Hoon,Kim, Dong Kyu,Song, Hyundong,Yi, Eugene C.,Hwang, Daehee,Kim, Hyo&#x2010,Soo,Mo John Wiley and Sons Inc. 2017 Stem cells translational medicine Vol.6 No.1

<P><B>Abstract</B></P><P>Transplantation of stem cells into the brain attenuates functional deficits in the central nervous system via cell replacement, the release of specific neurotransmitters, and the production of neurotrophic factors. To identify patient‐specific and safe stem cells for treating Alzheimer's disease (AD), we generated induced pluripotent stem cells (iPSCs) derived from mouse skin fibroblasts by treating protein extracts of embryonic stem cells. These reprogrammed cells were pluripotent but nontumorigenic. Here, we report that protein‐iPSCs differentiated into glial cells and decreased plaque depositions in the 5XFAD transgenic AD mouse model. We also found that transplanted protein‐iPSCs mitigated the cognitive dysfunction observed in these mice. Proteomic analysis revealed that oligodendrocyte‐related genes were upregulated in brains injected with protein‐iPSCs, providing new insights into the potential function of protein‐iPSCs. Taken together, our data indicate that protein‐iPSCs might be a promising therapeutic approach for AD. S<SMALL>TEM</SMALL> C<SMALL>ELLS</SMALL> T<SMALL>RANSLATIONAL</SMALL> M<SMALL>EDICINE</SMALL><I>2017;6:293–305</I></P>

Amyloid β‐induced elevation of O‐GlcNAcylated c‐Fos promotes neuronal cell death

Choi, Heesun,Kim, Chaeyoung,Song, Hyundong,Cha, Moon&#x2010,Yong,Cho, Hyun Jin,Son, Sung Min,Kim, Haeng Jun,Mook&#x2010,Jung, Inhee BLACKWELL PUBLISHING 2019 Aging Cell Vol.18 No.1

<P><B>Abstract</B></P><P>Alzheimer's disease (AD) is an age‐related neurodegenerative disease characterized by progressive memory loss resulting from cumulative neuronal cell death. O‐linked β‐N‐acetyl glucosamine (O‐GlcNAc) modification of the proteins reflecting glucose metabolism is altered in the brains of patients with AD. However, the link between altered O‐GlcNAc modification and neuronal cell death in AD is poorly understood. Here, we examined the regulation of O‐GlcNAcylation of c‐Fos and the effects of O‐GlcNAcylated c‐Fos on neuronal cell death during AD pathogenesis. We found that amyloid beta (Aβ)‐induced O‐GlcNAcylation on serine‐56 and 57 of c‐Fos was resulted from decreased interaction between c‐Fos and O‐GlcNAcase and promoted neuronal cell death. O‐GlcNAcylated c‐Fos increased its stability and potentiated the transcriptional activity through higher interaction with c‐Jun, resulting in induction of Bim expression leading to neuronal cell death. Taken together, Aβ‐induced O‐GlcNAcylation of c‐Fos plays an important role in neuronal cell death during the pathogenesis of AD.</P>

Association of 5‐hydroxytryptamine (serotonin) receptor 4 (5‐HTR4) gene polymorphisms with asthma

KIM, TAE&#x2010,HOON,AN, SUNG&#x2010,HYE,CHA, JI&#x2010,YEON,SHIN, EUN&#x2010,KYONG,LEE, JI&#x2010,YEON,YOON, SANG&#x2010,HYUK,LEE, YOUNG&#x2010,MOK,UH, SOO&#x2010,TAEK,PARK, SUNG&#x2010,WOO,PARK, JON Blackwell Publishing Asia 2011 RESPIROLOGY Vol.16 No.4

<P><B>ABSTRACT</B></P><P><B>Background and objective: </B> The neurotransmitter, 5‐hydroxytryptamine, acts as an immunomodulator by stimulating the release of inflammatory cytokines and regulating the function of dendritic cells and monocytes. The 5‐hydroxytryptamine receptor 4 (<I>HTR4</I>) gene is located in a region previously linked to an increased risk of asthma and atopy. The aim of this study was to investigate the association between <I>HTR4</I> and asthma.</P><P><B>Methods: </B> Thirty‐two single nucleotide polymorphisms (SNP) in <I>HTR4</I> were investigated by direct sequencing of 24 DNA samples from unrelated Korean subjects.</P><P><B>Results: </B> The 32 genetic variants comprised 22 intronic SNP, two SNP in the 3′‐untranslated region (exon 7) and eight SNP in the 3′‐downstream region. Logistic regression analysis showed that two intronic polymorphisms were significantly associated with the risk of asthma. Two minor <I>HTR4</I> alleles, +<I>142828G</I> > <I>A</I> and +<I>122769G</I> > <I>A</I>, occurred at significantly higher frequencies in the asthmatic group than in the healthy control group (49.59% vs 42.29%, <I>P</I> = 0.003, and 47.99% vs 40.35%, <I>P</I> = 0.008, respectively), and these differences remained significant after correction for multiple testing (<I>P</I> = 0.05, dominant mode of inheritance; and <I>P</I> = 0.03, dominant mode, respectively). Haplotype analysis revealed three haplotype blocks. The frequency of haplotype 1 in block 2 was significantly higher in asthmatics (<I>P</I> = 0.003, dominant mode), whereas the frequency of haplotype 4 in block 3 was significantly lower in asthmatics (<I>P</I> = 0.0009, dominant mode).</P><P><B>Conclusions: </B> SNP and haplotypes of the <I>HTR4</I> gene were associated with the asthma phenotype and genetic variation of <I>HTR4</I> may affect susceptibility to the development of asthma.</P>

Efficacy and safety of ipragliflozin as an add‐on therapy to sitagliptin and metformin in Korean patients with inadequately controlled type 2 diabetes mellitus: A randomized controlled trial

Han, Kyung&#x2010,Ah,Chon, Suk,Chung, Choon Hee,Lim, Soo,Lee, Kwan&#x2010,Woo,Baik, SeiHyun,Jung, Chang Hee,Kim, Dong&#x2010,Sun,Park, Kyong Soo,Yoon, Kun&#x2010,Ho,Lee, In&#x2010,Kyu,Cha, Bong&#x2010 Blackwell Publishing Ltd 2018 DIABETES OBESITY AND METABOLISM Vol.20 No.10

<P><B>Aim</B></P><P>To evaluate the efficacy and safety of ipragliflozin vs placebo as add‐on therapy to metformin and sitagliptin in Korean patients with type 2 diabetes mellitus (T2DM).</P><P><B>Methods</B></P><P>This double‐blind, placebo‐controlled, multi‐centre, phase III study was conducted in Korea in 2015 to 2017. Patients were randomized to receive either ipragliflozin 50 mg/day or placebo once daily for 24 weeks in addition to metformin and sitagliptin. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to end of treatment (EOT).</P><P><B>Results</B></P><P>In total, 143 patients were randomized and 139 were included in efficacy analyses (ipragliflozin: 73, placebo: 66). Baseline mean (SD) HbA1c levels were 7.90 (0.69)% for ipragliflozin add‐on and 7.92 (0.79)% for placebo. The corresponding mean (SD) changes from baseline to EOT were −0.79 (0.59)% and 0.03 (0.84)%, respectively, in favour of ipragliflozin (adjusted mean difference −0.83% [95% CI −1.07 to −0.59]; <I>P</I> < .0001). More ipragliflozin‐treated patients than placebo‐treated patients achieved HbA1c target levels of <7.0% (44.4% vs 12.1%) and < 6.5% (12.5% vs 1.5%) at EOT (<I>P</I> < .05 for both). Fasting plasma glucose, fasting serum insulin, body weight and homeostatic model assessment of insulin resistance decreased significantly at EOT, in favour of ipragliflozin (adjusted mean difference −1.64 mmol/L, −1.50 μU/mL, −1.72 kg, and −0.99, respectively; <I>P</I> < .05 for all). Adverse event rates were similar between groups (ipragliflozin: 51.4%; placebo: 50.0%). No previously unreported safety concerns were noted.</P><P><B>Conclusions</B></P><P>Ipragliflozin as add‐on to metformin and sitagliptin significantly improved glycaemic variables and demonstrated a good safety profile in Korean patients with inadequately controlled T2DM.</P>

Combination of a peroxisome proliferator‐activated receptor‐gamma agonist and an angiotensin  II receptor blocker attenuates myocardial fibrosis and dysfunction in type 2 diabetic rats

Shim, Chi Young,Song, Byeong&#x2010,Wook,Cha, Min&#x2010,Ji,Hwang, Ki&#x2010,Chul,Park, Sungha,Hong, Geu&#x2010,Ru,Kang, Seok&#x2010,Min,Lee, Jong Eun,Ha, Jong&#x2010,Won,Chung, Namsik John Wiley & Sons Ltd 2014 Journal of diabetes investigation Vol.5 No.4

<P><B>Abstract</B></P><P><B>Aims/Introduction</B></P><P>We aimed to examine the effect of an angiotensin II receptor blocker (ARB), a peroxisome proliferator‐activated receptor (PPAR)‐gamma agonist, and their combination on myocardial fibrosis and function in type 2 diabetic rats.</P><P><B>Materials and Methods</B></P><P>Five male Long‐Evans Tokushima Otsuka (LETO) rats and 20 male Otsuka Long‐Evans Tokushima Fatty (OLETF) rats were used. OLETF rats were assigned to four groups (<I>n</I> = 5 per group) at 28 weeks‐of‐age: untreated, losartan‐treated, rosiglitazone‐treated and combination‐treated. The ARB, losartan, was administered at a dose of 5 mg/kg/day, and the PPAR‐gamma agonist, rosiglitazone, was administered at a dose of 3 mg/kg/day by oral gavage for 12 weeks. Urine and blood samples were collected, and two‐dimensional echocardiograms and strain rate imaging were obtained at 28 and 40 weeks. Cytokines were evaluated by reverse transcriptase polymerase chain reaction, and histological analysis was carried out at 40 weeks.</P><P><B>Results</B></P><P>At 40 weeks, the global radial strains of the losartan‐treated (55.7 ± 4.5%, <I>P</I> = 0.021) and combination‐treated groups (59.3 ± 6.7%, <I>P</I> = 0.001) were significantly higher compared with the untreated OLETFs (44.3 ± 10.5%). No difference was observed when compared with LETO rats. Although the rosiglitazone‐treated group showed a better metabolic profile than the untreated OLETF group, there was no difference in the global radial strain (49.8 ± 6.0 vs 44.3 ± 10.5, <I>P</I> = 0.402). The expression of pro‐inflammatory cytokines, and collagen type I and III were consistently attenuated in the losartan‐treated and combination‐treated OLETF groups, but not in the rosiglitazone‐treated group.</P><P><B>Conclusions</B></P><P>A combination of rosiglitazone and losartan attenuates myocardial fibrosis and dysfunction in type 2 diabetic rats.</P>

Functional intronic variant of <i>SLC5A10</i> affects <i>DRG2</i> expression and survival outcomes of early‐stage non‐small‐cell lung cancer

Hong, Mi Jeong,Yoo, Seung Soo,Choi, Jin Eun,Kang, Hyo&#x2010,Gyoung,Do, Sook Kyung,Lee, Jang Hyuck,Lee, Won Kee,Lee, Jaehee,Lee, Shin Yup,Cha, Seung Ick,Kim, Chang Ho,Lee, Eung Bae,Cho, Sukki,Jheon, S John Wiley and Sons Inc. 2018 Cancer Science Vol.109 No.12

<P>RegulomeDB is a new tool that can predict the regulatory function of genetic variants. We applied RegulomeDB in selecting putative functional variants and evaluated the relationship between these variants and survival outcomes of surgically resected non‐small‐cell lung cancer. Among the 244 variants studied, 14 were associated with overall survival (<I>P </I><<I> </I>0.05) in the discovery cohort and one variant (rs2257609 C>T) was replicated in the validation cohort. In the combined analysis, rs2257609 C>T was significantly associated with worse overall and disease‐free survival under a dominant model (<I>P </I>=<I> </I>2 × 10<SUP>−5</SUP> and <I>P </I>=<I> </I>0.001, respectively). rs2257609 is located in the <I>SLC5A10</I> intron, but RegulomeDB predicted that this variant affected <I>DRG2</I>, not <I>SLC5A10</I> expression. The expression level of <I>SLC5A10</I> was not different with the rs2257609 genotype. However, <I>DRG2</I> expression was different according to the rs2257609 genotype (<I>P</I><SUB>trend</SUB><SUP> </SUP>= 0.03) and was significantly higher in tumor than in non‐malignant lung tissues (<I>P </I>=<I> </I>1 × 10<SUP>−5</SUP>). Luciferase assay also showed higher promoter activity of <I>DRG2</I> in samples with the rs2257609 T allele (<I>P </I><<I> </I>0.0001). rs2257609 C>T affected <I>DRG2</I> expression and, thus, influenced the prognosis of early‐stage non‐small‐cell lung cancer. This study was approved by the Institutional Review Broad of Kyungpook National University of Hospital (Approval No. KNUMC 2014‐04‐210‐003).</P>

Tolerability, effectiveness and predictive parameters for the therapeutic usefulness of exenatide in obese, K orean patients with type 2 diabetes

Song, Sun Ok,Kim, Kwang Joon,Lee, Byung&#x2010,Wan,Kang, Eun Seok,Cha, Bong Soo,Lee, Hyun Chul Wiley-Blackwell 2014 Journal of diabetes investigation Vol.5 No.5

<P><B>Abstract</B></P><P><B>Aims/Introduction</B></P><P>We assessed the tolerability, effectiveness and predictive parameters for the therapeutic usefulness of exenatide in obese Korean participants with type 2 diabetes. We also evaluated the characteristics of participants who respond adequately to glucagon‐like peptide‐1 (GLP‐1) analog therapy in terms of glycated hemoglobin (HbA1c) level reductions and weight loss.</P><P><B>Materials and Methods</B></P><P>This prospective, observational, single‐arm (exenatide b.i.d. in combination with both metformin and sulphonylurea), open‐label study of GLP‐1 analog treatment with close monitoring of metabolic parameters and weight changes was carried out for up to 22 weeks.</P><P><B>Results</B></P><P>Of the 110 enrolled obese participants, 37 participants dropped out during the 22‐week treatment period. A total of 73 participants completed the study (median age 55.0 years, interquartile range 44.0–65.0). The median duration of diabetes was 8.0 years (interquartile range 3.5–12.5) with a mean HbA1c value of 7.6% (interquartile range 7.00–8.55). The median body mass index was 30.78 kg/m<SUP>2</SUP> (interquartile range 27.89–33.92). After 22 weeks, median changes from baseline for HbA1c levels and weight were −0.7% and −3.0 kg, respectively, which were significant. No severe hypoglycemic events were observed. Multivariate regression analysis showed that C‐peptide values were a significant independent predictor for a reduction in HbA1c levels (β = 0.865, <I>P</I> = 0.018) with exenatide BID in combination with both sulphonylurea and metformin in obese Korean participants with type 2 diabetes and insulin naïveté.</P><P><B>Conclusions</B></P><P>Clinical and laboratory parameters, such as insulin naïveté and preserved β‐cell function, should be taken into consideration as important factors in the choice of GLP‐1 analog when predicting GLP‐1 analog responsiveness. This trial was registered with the local committee at Yonsei University in Korea (4‐2011‐0032).</P>

<i>MICB</i> polymorphisms and haplotypes with <i>MICA</i> and HLA alleles in Koreans

Cha, C.&#x2010,H.,Sohn, Y.&#x2010,H.,Oh, H.&#x2010,B.,Ko, S.&#x2010,Y.,Cho, M.&#x2010,C.,Kwon, O.&#x2010,J. Blackwell Publishing Ltd 2011 Tissue antigens Vol.78 No.1

<P>Major histocompatibility complex (MHC) class I chain‐related gene B (<I>MICB</I>) is located within the human MHC class I region. The location of <I>MICB</I> in the MHC region may imply the presence of linkage disequilibrium with polymorphic <I>MICA</I> and human leukocyte antigen (HLA) loci. <I>MICB</I> is also polymorphic; however, <I>MICB</I> polymorphisms have not been investigated in Koreans. Using sequence‐based typing (SBT), we estimated the allelic frequencies of <I>MICB</I> and haplotypes with <I>MICA</I>, <I>HLA‐B</I>, and <I>HLA‐DRB1</I> at high resolution in a population of 139 unrelated Korean individuals. Eight <I>MICB</I> alleles were identified. The most frequent allele was <I>MICB*005:02/*010</I> (57.2%), followed by <I>*002</I> (11.5%), <I>*004</I> (8.3%), <I>*005:03</I> (8.3%), and <I>*008</I> (6.8%). The most common two‐locus haplotypes were <I>MICB*005:02/*010‐MICA*010</I> (19.4%), <I>MICB*005:02/*010‐DRB1*15:01</I> (6.5%), and <I>MICB*005:02/*010‐B*15:01</I> (10.4%); the most common three‐locus haplotypes were <I>B*15:01‐MICA*010‐MICB*005:02/*010</I> (5.8%) and <I>MICA*010‐MICB*005:02/*010‐DRB1*04:06</I> (10.4%); and the most common four‐locus haplotype was <I>B*15:01‐MICA*010‐MICB*005:02/*010‐DRB1*04:06</I> (5.8%). This is the first study to provide information about <I>MICB</I> allele frequencies and haplotypes with HLA in Koreans. These study results should help understand mechanisms of disease association between the <I>MICB</I> locus and neighboring loci in Koreans.</P>

E1A physically interacts with RUNX3 and inhibits its transactivation activity

Cha, Eun&#x2010,Jeong,Oh, Byung&#x2010,Chul,Wee, Hee&#x2010,Jun,Chi, Xin&#x2010,Zi,Goh, Yun&#x2010,Mi,Lee, Kyeong&#x2010,Sook,Ito, Yoshiaki,Bae, Suk&#x2010,Chul Wiley Subscription Services, Inc., A Wiley Company 2008 Journal of cellular biochemistry Vol.105 No.1

<P><B>Abstract</B></P><P>The adenoviral gene, termed <I>early region 1A</I> (<I>E1A</I>), is crucial for transformation and has been used very effectively as a tool to determine the molecular mechanisms that underlie the basis of cellular transformation. pRb, p107, p130, p300/CBP, p400, TRRAP, and CtBP were identified to be E1A‐binding proteins and their roles in cellular transformation have been established. Although the major function of E1A is considered to be the regulation of gene expression that is critical for differentiation and cell cycle exit, one of the most significant questions relating to E1A transformation is how E1A mediates this regulation. RUNX3 is a transcription factor that was first described as a gastric cancer tumor suppressor but is now known to be involved in many different cancers. Exogenous expression of <I>RUNX3</I> strongly inhibits the growth of cells. Here, we show that the adenovirus oncoprotein E1A interacts with RUNX3 in vitro and in vivo. RUNX3 interacts with the N‐terminus (amino acids 2‐29) of E1A, which is known to interact with p300/CBP, p400, and TRRAP. E1A interacts directly with the Runt domain of RUNX3 but does not interfere with CBFβ‐RUNX3 interactions. In addition, E1A inhibits the transactivation activity of RUNX3 on the <I>p21</I><SUP><I>WAF1/CIP1</I></SUP> promoter. Consistent with these observations, the growth inhibition induced by RUNX3 is reduced by E1A. These results demonstrate that E1A specifically binds to RUNX3 and inactivates its transactivation activity. We propose that one of the mechanisms for the oncogenic activity of E1A is the inhibition of RUNX3, similar to that of RB and p300/CBP. J. Cell. Biochem. 105: 236–244, 2008. © 2008 Wiley‐Liss, Inc.</P>

Hypoxia‐induced downregulation of XIAP in trophoblasts mediates apoptosis via interaction with IMUP‐2: Implications for placental development during pre‐eclampsia

Jeon, Su Yeon,Lee, Hyun&#x2010,Jung,Na, Kyu&#x2010,Hwan,Cha, Dong&#x2010,Hyun,Kim, Jin Kyeoung,Park, Jong&#x2010,Wan,Yoon, Tae Ki,Kim, Gi Jin Wiley Subscription Services, Inc., A Wiley Company 2013 Journal of cellular biochemistry Vol.114 No.1

<P><B>Abstract</B></P><P>The regulation of trophoblast apoptosis is essential for normal placentation, and increased placental trophoblast cell apoptosis is the cause of pathologies such as intrauterine growth retardation (IUGR) and pre‐eclampsia. X‐linked inhibitor of apoptosis (XIAP) is expressed in trophoblasts, but little is known about the role of XIAP in placental development. In the present study, the function of XIAP in the placenta and in HTR‐8/SVneo trophoblasts under hypoxic conditions was examined. In addition, the correlation between XIAP and immortalization‐upregulated protein‐2 (IMUP‐2) was demonstrated in HTR‐8/SVneo trophoblasts under hypoxia, based on a previous study showing that increased IMUP‐2 induces trophoblast apoptosis and pre‐eclampsia. XIAP was downregulated in pre‐eclamptic placentas (<I>P</I> < 0.05). In HTR‐8/SVneo trophoblasts, XIAP expression was decreased and the expression of apoptosis‐related genes was increased in response to hypoxia. Ectopic expression of hypoxia inducible factor (HIF)‐1α in HRT‐8 SV/neo cells induced the nuclear translocation of XIAP and alterations of XIAP protein stability. Furthermore, hypoxia induced nuclear translocated XIAP co‐localized with upregulated IMUP‐2 in trophoblast nuclei, and the interaction between XIAP and IMUP‐2 induced apoptosis in HRT‐8 SV/neo cells. The present results suggest that hypoxia‐induced down‐regulation of XIAP mediates apoptosis in trophoblasts through interaction with increased IMUP‐2, and that this mechanism underlies the pathogenesis of pre‐eclampsia. J. Cell. Biochem. 114: 89–98, 2012. © 2012 Wiley Periodicals, Inc.</P>