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.

Antioxidative phytochemicals counteract the anticancer effect of oxaliplatin against colorectal cancer

Nayoung Moon,Chan Ho Jang,Janice Nullan Averilla,Jungeun Kim,Seungmin Park,Siyul Byeon,Soojung Jeong,Yoonsu Kim,Yunju Woo,Ji Sun Lim,Sunghee Kim,Jisun Oh,Jong-Sang Kim 한국식품영양과학회 2018 한국식품영양과학회 학술대회발표집 Vol.2018 No.10

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.

Prevalence and Risk Factors of Atrophic Gastritis and Intestinal Metaplasia in a Korean Population Without Significant Gastroduodenal Disease

Kim, Nayoung,Park, Young Soo,Cho, Sung-Il,Lee, Hye Seung,Choe, Gheeyoung,Kim, In Wook,Won, Yoo-Deok,Park, Ji Hyun,Kim, Joo Sung,Jung, Hyun Chae,Song, In Sung Wiley (Blackwell Publishing) 2008 Helicobacter Vol.13 No.4

<P>BACKGROUND AND AIM: The prevalence of gastric cancer and Helicobacter pylori infection is unacceptably high in Korea. This study was performed to evaluate the prevalence of atrophic gastritis (AG) and intestinal metaplasia (IM) and to identify their risk factors with respect to H. pylori virulence factors, and environmental and host factors, in Korean population without significant gastroduodenal disease. METHODS: The study cohort consisted of 389 subjects (> or = 16 years). AG and IM were scored histologically using the Sydney classification in the antrum and body, respectively. Prevalences and bacterial factors (i.e. cagA, vacA m1, and oipA), environmental factors (i.e. smoking and alcohol), and host factors (i.e. genetic polymorphisms of IL-1B-511, IL-1RN, TNF-A-308, IL-10-592, IL-10-819, IL-10-1082, IL-8-251, IL-6-572, GSTP1, p53 codon 72, and ALDH2) were evaluated. RESULTS: Prevalences of AG in the antrum and body were 42.5% and 20.1%, and those of IM were 28.6% and 21.2%, respectively. The presences of AG and IM were significantly higher in H. pylori-positive than in the H. pylori-negative subjects. Multivariate analysis showed that the risk factors for AG were H. pylori infection, age > or = 61 years, and cagA and vacA m1 positivity. For IM the risk factors were H. pylori infection, age > or = 61 years, a smoking history (rather than current smoking), strong spicy food, occupation (unemployed or nonprofessional vs. professional), and the presence of IL10-592 C/A as opposed to A/A. In addition, IL6-572 G carrier was found to have a protective effect against IM development as compared with C/C. CONCLUSION: H. pylori infection was most important risk factor of AG and IM. Bacterial factors were found to be important risk factor for AG but environmental and host factors were more important for IM.</P>

Differential disruption of autoinhibition and defect in assembly of cytoskeleton during cell division decide the fate of human <i>DIAPH1</i>-related cytoskeletopathy

Kim, Bong Jik,Ueyama, Takehiko,Miyoshi, Takushi,Lee, Seungmin,Han, Jin Hee,Park, Hye-Rim,Kim, Ah Reum,Oh, Jayoung,Kim, Min Young,Kang, Yong Seok,Oh, Doo Yi,Yun, Jiwon,Hwang, Sang Mee,Kim, Nayoung K D BMJ Publishing Group Ltd 2019 Journal of medical genetics Vol.56 No.12

<P><B>Background</B></P><P>Diaphanous-related formin 1 (DIA1), which assembles the unbranched actin microfilament and microtubule cytoskeleton, is encoded by <I>DIAPH1</I>. Constitutive activation by the disruption of autoinhibitory interactions between the N-terminal diaphanous inhibitory domain (DID) and C-terminal diaphanous autoregulatory domain (DAD) dysregulates DIA1, resulting in both hearing loss and blood cell abnormalities.</P><P><B>Methods and results</B></P><P>Here, we report the first constitutively active mutant in the DID (p.A265S) of humans with only hearing loss and not blood cell abnormality through whole exome sequencing. The previously reported DAD mutants and our DID mutant (p.A265S) shared the finding of diminished autoinhibitory interaction, abnormally upregulated actin polymerisation activity and increased localisations at the plasma membrane. However, the obvious defect in the DIA1-driven assembly of cytoskeleton ‘during cell division’ was only from the DAD mutants, not from p.A265S, which did not show any blood cell abnormality. We also evaluated the five DID mutants in the hydrophobic pocket since four of these five additional mutants were predicted to critically disrupt interaction between the DID and DAD. These additional pathogenic DID mutants revealed varying degrees of defect in the DIA1-driven cytoskeleton assembly, including nearly normal phenotype during cell division as well as obvious impaired autoinhibition, again coinciding with our key observation in DIA1 mutant (p.A265S) in the DID.</P><P><B>Conclusion</B></P><P>Here, we report the first mutant in the DID of humans with only hearing loss. The differential cell biological phenotypes of DIA1 during cell division appear to be potential determinants of the clinical severity of <I>DIAPH1-</I>related cytoskeletopathy in humans.</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>