당뇨병 치료를 위한 SGLT2 억제제의 심혈관계 안전성 관련 최근 임상시험 결과고찰

김혜럼, 한나영, 유미선, 권광일, 윤휘열 충남대학교 약학대학 의약품개발연구소 2017 藥學論文集 Vol.32 No.-

Patients with type 2 diabetes have a two-to three-times greater risk of developing car-diovascular disease than people without diabetes, and the mortality rate from cardiovascular disease is also reported to increase. The reason why cardiovascular disease is more common in type 2 diabetic patients is not only that cardiovascular risk factors are more common than non-diabetic patients, but also that diabetes itself is an independent risk factor for cardiovascular disease. Since rosiglitazone. which was introduced as a treatment for type 2 diabetes in 2000, has been argued to increase cardiovascular disease sluch as myocardial infarction. there were clinical trials of cardiovascular safety of it such as DREAM. ADOPT and RECORD. As a result. rosiglitazone has been banned due to the risk of cardiovascular disease. The US FDA and other regulatory agencies have required clinical trials for type 2 diabetes treatments afterward. 1n this study. it is reviewed that recently developed SGL T2 inhibitors has cardiovascular benefits as a novel mechanism of type 2 diabetes treatment. SGL T2 inhibitors inhibit the renal sodium glucose co-transporter(SGLT2), thereby reducing glucose reabsorption and increasing excretion of it. and consequently lowering blood glucose levels. Recent papers on ongoing cardiovascular-related clinical trials of SGL T2 in-hibitors such as CANVAS. CANVAS-R. CREDENCE of canagliflozin, DECLARE-TIMI 58 of dapagliflozin. and EMPA -REG outcomes of empagliflozin were examined thoroughly as well.

Loss-of-function screens of druggable targetome against cancer stem–like cells

Song, Mee,Lee, Hani,Nam, Myung-Hee,Jeong, Euna,Kim, Somin,Hong, Yourae,Kim, Nayoung,Yim, Hwa Young,Yoo, Young-Ji,Kim, Jung Seok,Kim, Jin-Seok,Cho, Yong-Yeon,Mills, Gordon B.,Kim, Woo-Young,Yoon, Sukjo Federation of American Societies for Experimental 2017 The FASEB Journal Vol.31 No.2

<P>Cancer stem–like cells (CSLCs) contribute to the initiation and recurrence of tumors and to their resistance to conventional therapies. In this study, small interfering RNA (siRNA)-based screening of ∼4800 druggable genes in 3-dimensional CSLC cultures in comparison to 2-dimensional bulk cultures of U87 glioma cells revealed 3 groups of genes essential for the following: survival of the CSLC population only, bulk-cultured population only, or both populations. While diverse biologic processes were associated with siRNAs reducing the bulk-cultured population, CSLC-eliminating siRNAs were enriched in a few functional categories, such as lipid metabolism, protein metabolism, and gene expression. Interestingly, siRNAs that selectively reduced CSLC only were found to target genes for cholesterol and unsaturated fatty acid synthesis. The lipidomic profile of CSLCs revealed increased levels of monounsaturated lipids. Pharmacologic blockage of these target pathways reduced CSLCs, and this effect was eliminated by addition of downstream metabolite products. The present CSLC-sensitive target categories provide a useful resource that can be exploited for the selective elimination of CSLCs.—Song, M., Lee, H., Nam, M.-H., Jeong, E., Kim, S., Hong, Y., Kim, N., Yim, H. Y., Yoo, Y.-J., Kim, J. S., Kim, J.-S., Cho, Y.-Y., Mills, G. B., Kim, W.-Y., Yoon, S. Loss-of-function screens of druggable targetome against cancer stem–like cells.</P>

In Situ Sensing of Copper-plating Thickness Using OPD-regulated Optical Fourier-domain Reflectometry

Nayoung Kim,Do Won Kim,Nam Su Park,Gyeong Hun Kim,Yang Do Kim,Chang-Seok Kim 한국광학회 2023 Current Optics and Photonics Vol.7 No.1

Changing prevalence of upper gastrointestinal disease in 28 893 Koreans from 1995 to 2005

Kim, Jin Il,Kim, Sang Gyun,Kim, Nayoung,Kim, Jae Gyu,Shin, Sung Jae,Kim, Sang Woo,Kim, Hyun Soo,Sung, Jae Kyu,Yang, Chang Heon,Shim, Ki-Nam,Park, Seun Ja,Park, Joon Yong,Baik, Gwang Ho,Lee, Sang Woo,P Lippincott Williams Wilkins, Inc. 2009 European journal of gastroenterology & hepatology Vol.21 No.7

OBJECTIVES: Changes in the pattern of gastrointestinal diseases in a population tend to be influenced by changes in diet and lifestyle. Shifts in gastrointestinal disease from 1995 to 2005 in Korea were evaluated, retrospectively. METHODS: Seventeen nationwide medical centers participated in this study. The cross-sectional review of endoscopic findings in 28 893 patients included 8441 patients from 1995, 10 350 patients from 2000, and 10 102 patients from 2005. RESULTS: The prevalence of reflux esophagitis increased from 1.8% in 1995 to 5.9% in 2000 and 9.1% in 2005 (P<0.001, the P value was only for the comparison between 1995 and 2005, the followings were as same). The prevalence of peptic ulcer diseases was 18.0% in 1995, 19.1% in 2000, and 20.2% in 2005 (P<0.001). Although no significant differences were noted in duodenal ulcers (8.4, 8.7, and 8.2%, P=0.449), gastric ulcers showed an increasing trend (9.6, 10.5, and 12.0%, P<0.001). The prevalence of gastric cancer increased from 3.4% in 1995 to 4.5% in 2000 (P<0.001), but then decreased to 2.4% in 2005 (P<0.001). The incidence of advanced gastric cancer was 2.5, 3.2, and 1.3%, respectively (P<0.001), and that of early gastric cancer remained constant with rates of 0.8%, 1.3, and 1.1%, respectively (P=0.056). CONCLUSION: The cross-sectional review of data collected in 1995, 2000, and 2005 showed an increase in reflux esophagitis and peptic ulcer diseases. Meanwhile, the prevalence of gastric cancer increased until 2000, but decreased in 2005.

Novel KCNQ4 variants in different functional domains confer genotype- and mechanism-based therapeutics in patients with nonsyndromic hearing loss

Sang-Yeon Lee,Hyun Been Choi,Mina Park,Il Soon Choi,Jieun An,Ami Kim,Eunku Kim,Nahyun Kim,Jin Hee Han,Min young Kim,Seung min Lee,Doo-Yi Oh,Bong Jik Kim,Nayoung Yi,Nayoung, K. D. Kim,Chung Lee,Woong-Y 생화학분자생물학회 2021 Experimental and molecular medicine Vol.53 No.-

Loss-of-function variant in the gene encoding the KCNQ4 potassium channel causes autosomal dominant nonsyndromic hearing loss (DFNA2), and no effective pharmacotherapeutics have been developed to reverse channel activity impairment. Phosphatidylinositol 4,5-bisphosphate (PIP2), an obligatory phospholipid for maintaining KCNQ channel activity, confers differentialpharmacological sensitivity of channels to KCNQ openers. Through whole-exome sequencing of DFNA2 families, we identified three novel KCNQ4 variants related to diverse auditory phenotypes in the proximal C-terminus (p.Arg331Gln), the C-terminus of the S6 segment (p.Gly319Asp), and the pore region (p.Ala271_Asp272del). Potassium currents in HEK293T cells expressing each KCNQ4 variant were recorded by patch-clamp, and functional recovery by PIP2 expression or KCNQ openers was examined. In the homomeric expression setting, the three novel KCNQ4 mutant proteins lost conductance and were unresponsive to KCNQ openers or PIP2 expression. Loss of p.Arg331Gln conductance was slightly restored by a tandem concatemer channel (WT-p.R331Q), and increased PIP2 expression further increased the concatemer current to the level of the WT channel. Strikingly, an impaired homomeric p.Gly319Asp channel exhibited hyperactivity when a concatemer (WT-p.G319D), with a negative shift in the voltage dependence of activation. Correspondingly, a KCNQ inhibitor and chelation of PIP2 effectively downregulated the hyperactive WTp. G319D concatemer channel. Conversely, the pore-region variant (p.Ala271_Asp272del) was nonrescuable under any condition. Collectively, these novel KCNQ4 variants may constitute therapeutic targets that can be manipulated by the PIP2 level and KCNQregulating drugs under the physiological context of heterozygous expression. Our research contributes to the establishment of a genotype/mechanism-based therapeutic portfolio for DFNA2.

Unraveling of Enigmatic Hearing-Impaired <i>GJB2</i> Single Heterozygotes by Massive Parallel Sequencing: DFNB1 or Not?

Kim, So Young,Kim, Ah Reum,Kim, Nayoung K. D.,Lee, Chung,Kim, Min Young,Jeon, Eun-Hee,Park, Woong-Yang,Choi, Byung Yoon,Xie., Maohua Williams & Wilkins Co 2016 Medicine Vol.95 No.14

<▼1><P>Supplemental Digital Content is available in the text</P></▼1><▼2><P><B>Abstract</B></P><P>The molecular etiology of nonsyndromic sensorineural hearing loss (SNHL) in subjects with only one detectable autosomal recessive <I>GJB2</I> mutation is unclear. Here, we report <I>GJB2</I> single heterozygotes with various final genetic diagnoses and suggest appropriate diagnostic strategies. A total of 160 subjects with SNHL without phenotypic markers were screened for <I>GJB2</I> mutations. Single-nucleotide variants or structural variations within the DFNB1 locus or in other deafness genes were examined by Sanger sequencing, breakpoint PCR, and targeted exome sequencing (TES) of 129 deafness genes. We identified 27 subjects with two mutations and 10 subjects with only one detectable mutation in <I>GJB2.</I> The detection rate of the single <I>GJB2</I> mutation among the 160 SNHL subjects in the present study (6.25%) was higher than 2.58% in normal hearing controls in Korean. The DFNB1 was clearly excluded as a molecular etiology in four (40%) subjects: other recessive deafness genes (N = 3) accounted for SNHL and the causative gene for the other non-DFNB1 subject (N = 1) was not identified. The etiology of additional two subjects was potentially explained by digenic etiology (N = 2) of <I>GJB2</I> with <I>MITF</I> and <I>GJB3</I>, respectively. The contribution of the single <I>GJB2</I> mutation in the four remaining subjects is unclear. Comprehensive diagnostic testing including TES is prerequisite for understanding <I>GJB2</I> single heterozygotes.</P></▼2>

Gene expression of AGS cells stimulated with released proteins by <i>Helicobacter pylori</i>

Kim, Nayoung,Park, Woong-Yang,Kim, Jung Mogg,Park, Ji Hyun,Kim, Joo Sung,Jung, Hyun Chae,Song, In Sung Blackwell Publishing Asia 2008 Journal of gastroenterology and hepatology Vol.23 No.4

<P>Abstract</P><P>Background and Aim: </P><P>Interactions between released proteins by <I>Helicobacter pylori</I> (<I>H. pylori</I>) and the cells of gastric epithelium to which it adheres may contribute to gastric inflammation and epithelial damage. The present study was performed to evaluate the gene expression of AGS gastric cancer cells stimulated with released proteins by <I>H. pylori</I>.</P><P>Methods: </P><P>Gene expression of AGS cells to the stimulation by <I>H. pylori</I>-released proteins (G27 strain) were monitored using oligonucleotide microarrays.</P><P>Results: </P><P>Eighty-eight genes (0.88%) and eight genes (0.08%) were up- or downregulated, respectively, by treating AGS cells with <I>H. pylori</I>-released proteins but not by <I>H. pylori</I> adhesion after 12 h of coculture. Out of the selected 40 up- and five downregulated genes, 29 upregulated genes classified as general RNA polymerase II transcription factor activity (<I>GTF2B</I>, <I>PPARGC1A</I>), <I>SH3</I>/<I>SH2</I> adaptor activity (<I>CRKL</I>), transferase activity (<I>ACLY</I>, <I>CRKL</I>, <I>PIGC</I>, <I>PLK4</I>), and oxidoreductase activity (<I>IDH1</I>) were confirmed to be upregulated by released proteins and not by <I>H. pylori</I> adhesion by real-time reverse transcription–polymerase chain reaction. When the concentrated <I>H. pylori</I>-cultured supernatant prepared by our protocol was treated by boiling, the upregulations of 26 of these 29 genes (89.7%) except for <I>CD160</I>, <I>ZNF268</I>, and <I>PSAT1</I> disappeared. This confirmed that most of these upregulations were caused by released proteins.</P><P>Conclusion: </P><P>Host genes involving transcription, signaling and stress are significantly modulated by the proteins released by <I>H. pylori</I>. This might strengthen the gastroduodenal pathogenesis induced by <I>H. pylori</I>.</P>

Colorectal adenocarcinoma‐derived EGFR mutants are oncogenic and sensitive to EGFR‐targeted monoclonal antibodies, cetuximab and panitumumab

Kim, Nayoung,Cho, Daseul,Kim, Hyunjin,Kim, Sujin,Cha, Young‐,je,Greulich, Heidi,Bass, Adam,Cho, Hyun‐,Soo,Cho, Jeonghee Alan R. Liss, Inc 2020 International journal of cancer Vol.146 No.8

<P>Somatic mutations of epidermal growth factor receptor (EGFR) occur in ~3% of colorectal cancer (CRC) patients. Here, through systematic functional screening of 21 recurrent EGFR mutations selected from public data sets, we show that 11 colon cancer‐derived EGFR mutants (G63R, E114K, R165Q, R222C, S492R, P596L, K708R, E709K, G719S, G724S and L858R) are oncogenic and able to transform cells in a ligand‐independent manner. We demonstrate that cellular transformation by these mutants requires receptor dimerization. Importantly, the EGF‐induced and constitutive oncogenic potential of these EGFR mutants are inhibited by cetuximab or panitumumab <I>in vivo</I> and <I>in vitro</I>. Taken together, we propose that a subset of EGFR mutations can serve as genomic predictors for response to anti‐EGFR antibodies and that metastatic CRC patients with such mutations may benefit from these drugs as part of the first‐line therapy.</P>

Raloxifene Induces Autophagy-Dependent Cell Death in Breast Cancer Cells via the Activation of AMP-Activated Protein Kinase

Kim, Dong Eun,Kim, Yunha,Cho, Dong-Hyung,Jeong, Seong-Yun,Kim, Sung-Bae,Suh, Nayoung,Lee, Jung Shin,Choi, Eun Kyung,Koh, Jae-Young,Hwang, Jung Jin,Kim, Choung-Soo Korean Society for Molecular and Cellular Biology 2015 Molecules and cells Vol.38 No.2

Raloxifene is a selective estrogen receptor modulator (SERM) that binds to the estrogen receptor (ER), and exhibits potent anti-tumor and autophagy-inducing effects in breast cancer cells. However, the mechanism of raloxifene-induced cell death and autophagy is not well-established. So, we analyzed mechanism underlying death and autophagy induced by raloxifene in MCF-7 breast cancer cells. Treatment with raloxifene significantly induced death in MCF-7 cells. Raloxifene accumulated GFP-LC3 puncta and increased the level of autophagic marker proteins, such as LC3-II, BECN1, and ATG12-ATG5 conjugates, indicating activated autophagy. Raloxifene also increased autophagic flux indicators, the cleavage of GFP from GFP-LC3 and only red fluorescence-positive puncta in mRFP-GFP-LC3-expressing cells. An autophagy inhibitor, 3-methyladenine (3-MA), suppressed the level of LC3-II and blocked the formation of GFP-LC3 puncta. Moreover, siRNA targeting BECN1 markedly reversed cell death and the level of LC3-II increased by raloxifene. Besides, raloxifene-induced cell death was not related to cleavage of caspases-7, -9, and PARP. These results indicate that raloxifene activates autophagy-dependent cell death but not apoptosis. Interestingly, raloxifene decreased the level of intracellular adenosine triphosphate (ATP) and activated the AMPK/ULK1 pathway. However it was not suppressed the AKT/mTOR pathway. Addition of ATP decreased the phosphorylation of AMPK as well as the accumulation of LC3-II, finally attenuating raloxifene-induced cell death. Our current study demonstrates that raloxifene induces autophagy via the activation of AMPK by sensing decreases in ATP, and that the overactivation of autophagy promotes cell death and thereby mediates the anti-cancer effects of raloxifene in breast cancer cells.

Direct potentiation of NK cell cytotoxicity by 8-azaguanine with potential antineoplastic activity

Kim, Nayoung,Choi, Ji-Wan,Song, Ah Young,Choi, Woo Seon,Park, Hye-Ran,Park, Sojung,Kim, Inki,Kim, Hun Sik Elsevier 2019 INTERNATIONAL IMMUNOPHARMACOLOGY Vol.67 No.-

<P><B>Abstract</B></P> <P>This study identified 8-azaguanine (8-AG) as a novel immunomodulatory drug (IMiD) through a high-throughput screen of the Preswick Chemical Library in a model of human NK cell cytotoxicity against blood cancer cells. 8-AG, originally developed as an antineoplastic agent, significantly increased the cytotoxicity of NK cells and was superior in this activity to previously known IMiDs, such as fluoxetine and amphotericin B, identified from the same library. IFN-γ expression was also slightly increased by 8-AG. Mechanistically, 8-AG increased conjugate formation between NK and target cells and subsequent cytolytic granule polarization, but not calcium mobilization, regulation of activating receptors, or expression of perforin or granzyme B. Thus, the antineoplastic activity of 8-AG should be re-evaluated in light of this novel potentiating effect on NK cells.</P> <P><B>Highlights</B></P> <P> <UL> <LI> 8-azaguanine (8-AG) was originally developed as an antineoplastic agent. </LI> <LI> 8-AG was identified by high-throughput screen to increase the cytotoxicity of NK cells. </LI> <LI> 8-AG increased the formation of NK-target conjugates and cytolytic granule polarization. </LI> <LI> 8-AG serves a dual function as antineoplastic and immunomodulatory drug. </LI> </UL> </P>