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>

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.

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

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.

Helicobacter pylori genotyping findings from multiple cultured isolates and mucosal biopsy specimens: strain diversities of Helicobacter pylori isolates in individual hosts

Kim, Young Sun,Kim, Nayoung,Kim, Jung Mogg,Kim, Mi Soon,Park, Ji Hyun,Lee, Mi Kyoung,Lee, Dong Ho,Kim, Joo Sung,Jung, Hyun Chae,Song, In Sung Lippincott Williams Wilkins, Inc. 2009 European journal of gastroenterology & hepatology Vol.21 No.5

OBJECTIVES: To determine whether the genotypes of virulent genes in Helicobacter pylori isolates and mucosal biopsy specimens differ in individuals, and to investigate whether different isolates from single hosts show strain differences. METHODS: Sixty-one Korean patients with H. pylori infection were enrolled. PCR and DNA sequencing for cagA, vacA, iceA, and oipA were performed using DNA extracted from H. pylori isolates cultured (2.6 H. pylori isolates per host) directly from antral mucosal biopsy specimens. Strain diversities were analyzed in 234 H. pylori isolates obtained from 43 hosts with at least two H. pylori isolates from antrum and body, respectively, and random amplified polymorphic DNA fingerprinting was carried out on isolates obtained from patients who showed genotype diversity. RESULTS: The patients with inconsistent genotyping results between H. pylori isolates and mucosal biopsies were as follows: 16.4% for cagA, 19.7% for vacA m, 47.5% for vacA s1, 6.6% for vacA i-region, 34.4% for iceA, and 21.3% for oipA. Genotyping of H. pylori isolates from same hosts showed diversity in 58.1% (25/43 patients). When random amplified polymorphic DNA -PCR fingerprinting was carried out on 104 H. pylori isolates from 19 patients who showed genotype diversity among their isolates, 68.4% (13 of 19 patients) of patients were found to be colonized by multiple H. pylori strains. CONCLUSION: This study shows that the genotypes of virulent genes from biopsy samples produced different results when compared with those obtained from H. pylori isolates, especially for vacA s1, and iceA. In addition, about 60% of our patients were infected by multiple H. pylori strains.

Structural Insights into Modulation of Neurexin-Neuroligin <i>Trans</i>-synaptic Adhesion by MDGA1/Neuroligin-2 Complex

Kim, Jung A,Kim, Doyoun,Won, Seoung Youn,Han, Kyung Ah,Park, Dongseok,Cho, Eunju,Yun, Nayoung,An, Hyun Joo,Um, Ji Won,Kim, Eunjoon,Lee, Jie-Oh,Ko, Jaewon,Kim, Ho Min Elsevier 2017 Neuron Vol.94 No.6

<P><B>Summary</B></P> <P>Membrane-associated mucin domain-containing glycosylphosphatidylinositol anchor proteins (MDGAs) bind directly to neuroligin-1 (NL1) and neuroligin-2 (NL2), thereby respectively regulating excitatory and inhibitory synapse development. However, the mechanisms by which MDGAs modulate NL activity to specify development of the two synapse types remain unclear. Here, we determined the crystal structures of human NL2/MDGA1 Ig1-3 complex, revealing their stable 2:2 arrangement with three interaction interfaces. Cell-based assays using structure-guided, site-directed MDGA1 mutants showed that all three contact patches were required for the MDGA’s negative regulation of NL2-mediated synaptogenic activity. Furthermore, MDGA1 competed with neurexins for NL2 via its Ig1 domain. The binding affinities of both MDGA1 and MDGA2 for NL1 and NL2 were similar, consistent with the structural prediction of similar binding interfaces. However, MDGA1 selectively associated with NL2, but not NL1, in vivo. These findings collectively provide structural insights into the mechanism by which MDGAs negatively modulate synapse development governed by NLs/neurexins.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Crystal structure of neuroligin-2 (NL2) in complex with MDGA1 Ig1-Ig3 domains </LI> <LI> MDGA1 Ig1-Ig2 domains interact with NL2 dimer with 2:2 stoichiometry </LI> <LI> MDGA1 competes with Nrx1β for NL2 binding via their overlapping binding site on NL2 </LI> <LI> MDGA1 selectively forms complexes with NL2, but not NL1, in vivo </LI> </UL> </P>

Anti-gastric cancer effects of celecoxib, a selective COX-2 inhibitor, through inhibition of Akt signaling

Kim, Nayoung,Kim, Chung Hyun,Ahn, Dong-Won,Lee, Kyoung Soo,Cho, Soo-Jeong,Park, Ji Hyun,Lee, Mi Kyoung,Kim, Joo Sung,Jung, Hyun Chae,Song, In Sung Blackwell Publishing Asia 2009 Journal of Gastroenterology and Hepatology Vol.24 No.3

<P>Abstract</P><P>Background and Aim: </P><P>Previously, we showed that treatment with celecoxib significantly reduced the number of viable gastric cancer cells, in a dose- and time-dependent manner. However, the specific anti-cancer effects of celecoxib on gastric cancer cells have not been clarified. The present <I>in vitro</I> study was carried out to investigate the mechanism involved in the anti-gastric cancer effects of celecoxib.</P><P>Methods: </P><P>3-(4,5-Dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was carried out after treating AGS cells (human gastric cancer cell line, ATCC CRL 1739) with celecoxib or indomethacin, and the effect of prostaglandin E<SUB>2</SUB> or LY294002 (PI3K inhibitor) was evaluated. Western blot analysis of tAkt (total Akt), pAkt (phosphorylated Akt), pGSK3&bgr; (phosphorylated glycogen synthase kinase-3&bgr;), pFKHR (phosphorylated forkhead transcriptional factor), and caspase-9 was carried out at various concentrations (0, 5, 10, 25, or 50 µmol/L) of celecoxib or indomethacin-treatment for 24 or 48 h in AGS cells.</P><P>Results: </P><P>Celecoxib- or LY294002-induced cell death was found to occur in a dose-dependent manner in AGS cells, and these decreases were slightly recovered by the addition of PGE<SUB>2</SUB> (25 or 50 µmol/L). The expression of pAkt but not tAkt was lower in the celecoxib treated-AGS cells and the response was dose dependent (<I>P</I> < 0.05). The expression of pGSK3&bgr; and pFKHR was also significantly decreased in the celecoxib treated-AGS cells. Procaspase 9 (47 kDa) was frequently cleaved into 37, 35 and 17 kDa fragments in the celecoxib-treatment group. However, these changes in cell signal transduction were not observed in the indomethacin treated-AGS cells.</P><P>Conclusion: </P><P>The anti-cancer effects of celecoxib on gastric cancer cells might be partly mediated by downregulation of Akt, GSK3&bgr;, FKHR, and upregulation of caspase-9, in the mitochondrial apoptotic pathway.</P>

The Discrepancy Between Genetic Polymorphism of p53 Codon 72 and the Expression of p53 Protein in Helicobacter pylori-Associated Gastric Cancer in Korea

Kim, Nayoung,Cho, Sung-Il,Lee, Hye Seung,Park, Ji Hyun,Kim, Jee Hyun,Kim, Joo Sung,Jung, Hyun Chae,Song, In Sung Springer-Verlag 2010 Digestive diseases and sciences Vol.55 No.1

Clinical meaning of pepsinogen test and Helicobacter pylori serology in the health check-up population in Korea

Kim, Hyun Young,Kim, Nayoung,Kang, Jung Mook,Park, Young Soo,Lee, Dong Ho,Kim, Yu Rim,Kim, Joo Sung,Jung, Hyun Chae,Song, In Sung Lippincott Williams Wilkins, Inc. 2009 European journal of gastroenterology & hepatology Vol.21 No.6

OBJECTIVE: This study was performed to assess the affects of age, sex, and Helicobacter pylori status on pepsinogen testing for atrophic gastritis and to establish the clinical implications of pepsinogen test results and H. pylori serology in a Korean population presenting for a health check-up. METHODS: Serum pepsinogen (PG) I and PG II, and H. pylori IgG were measured in 1485 adults. The PG values were analyzed based on age, sex, and H. pylori status, and the cutoff value for atrophic gastritis was determined. RESULTS: Serum PG I (sPGI) and sPGII were higher in H. pylori positive than in H. pylori negative individuals (sPGI, 56.3 vs. 42.2 μg/l, P<0.001; sPGII, 17.5 vs. 8.0 μg/l, P<0.001). The PG I/II ratio was lower in H. pylori positive than in H. pylori negative individuals (3.7 vs. 6.0, P<0.001). The sPGII and PG I/II ratio had a positive (r=0.132, P<0.001) and negative correlation with age (r=−0.229, P<0.001), respectively. Men had a higher sPGI (54.7 μg/l) than did women (48.4 μg/l) (P<0.001) but the PG I/II ratio was not statistically different and neither the atrophic gastritis. The PG I/II cutoff value for atrophic gastritis was 6.0 for H. pylori negative and 3.0 for H. pylori positive individuals. sPGI and sPGII were, however, not specific for atrophic gastritis. CONCLUSION: The H. pylori IgG status, age, and sex were associated with the serum PG levels. To increase the efficacy of the PG I/II ratio for the detection of atrophic gastritis, the cutoff value of the PG I/II ratio should be stratified according to the H. pylori IgG status in the Korean population presenting for a health check-up.