간세포암종 조직의 Ribonuclease Inhibitor에 관한 연구

김용석,이성록,고재경 한양대학교 의과대학 1994 한양의대 학술지 Vol.14 No.1

In order to understand the interaction between ribonuclease(RNase) and RNase inhibitor in hepatocellular carcinoma, activities of RNase and RNase inhibitor were determined in the cancer tissue and ascitic fluid of patients with the liver cancer. Fractionated were the RNases and RNase inhibitors of the cancer tissue and the ascitic fluid to find out the enyme and the enzyme inhibitor specific to the liver cancer. RNase and RNase inhibitor activities in the peripheral area of liver cancer tissue were increased by 72% each and the positive rates of the enzyme and the enzyme inhibitor activities as markers for the liver cancer were high. RNase activity in the central area of liver cancer tissue was decreased significantly, while RNase inhibitor activity was unchanged. RNase activity in the ascitic fluid from patients with hepatocellular carcinoma was increased by 52%, while RNase inhibitor activity was unchanged. RNases in both contral and peripheral area of hepatocellular carcinoma tissue were separated by a DEAE-cellulose column chromatography into 7 isozymes(RNase isozyme Ⅰ-Ⅶ) each. No RNase specific to the cancer was isolated, but RNase isozyme V isolated from peripheral area of the liver cancer tissue was activated. Activity of RNase inhibitor associated with the RNase isozyme Ⅴ was also increased greatly as compared with that of the control tissue. Of the RNase isozymes isolated from both control and liver cancer tissues, RNase isozyme I was nonsecretory type of RNase active against RNA as substrate and RNase isozymes Ⅳ,Ⅴ,Ⅵ and Ⅶ were secretory type of RNase active against poly C. RNases in ascitic fluid from patient with hepatocellular carcinoma were separated into 4 isozymes(RNases isozymes Ⅰ-Ⅳ). No RNase specific to the cancer was isolated, but RNase isozyme I was markedly activated. RNase isozyme Ⅴ activated greatly in the peripheral area of the liver cancer tissue was, however, not found in the ascitic fluid. All RNase isozymes isolated from the ascitic fluid of patients with hepatocellular carcinoma were detected to be complexed with RNase inhibitor, of which RNase isozyme Ⅳ exhibited greater inhibitor activity. Observations that RNase isozyme Ⅴ isolated from peripheral area of hepatocellular carcinoma tissue (1)was activated. (2)was not released into the ascitic fluid confining the isozyme inside the liver cancer tissue, (3)was secretory type of RNase active against poly C as substrate and (4)exhibited higher RNase inhibitor activity suggested that regulatory action of the RNase isozyme Ⅴ and the RNase inhibitor might play an important role in carcinogenesis and suppression processes of the liver cancer.

제2형 당뇨병 환자에서 Metformin과 병용한 Sodium-Glucose Cotransporter 2 Inhibitors와 Dipeptidyl Peptidase 4 Inhibitors의 효능 비교

박소연,유다혜,권지은,윤정이,권은영,황보신이 한국병원약사회 2020 병원약사회지 Vol.37 No.3

Background : Type 2 diabetes has a high risk of complications such as cardiovascular and chronic kidney disease. In Korea, the combination therapy of the metformin and dipeptidyl peptidase 4 (DPP4) inhibitors is preferred to the sodium-glucose cotransporter 2 (SGLT2) inhibitors. The American Diabetes Association (ADA) has stated that the SGLT2 inhibitors can be used in combination with the metformin in parallel with the DPP4 inhibitors. But, there is a lack of direct comparative studies of the SGLT2 inhibitors and the DPP4 inhibitors in Korea. The purpose of this study was to compare the efficacy of the SGLT2 and the DPP4 inhibitors add-on to metformin therapy. Methods : This was a retrospective study conducted June 2018-May 2019. This study investigated the medical records of patients administered with metformin and SGLT2 or DPP4 inhibitors. Results : Of the total of 155 patients, 46 were administered with the metformin and the SGLT2 inhibitors (SGLT2-I group) and the remaining patients were administered with the DPP4 inhibitors (DPP4-I group). There was no significant difference in the average change in HbA1c and fasting blood sugar (FBS) in both groups (p=0.102, p=0.512). However, the average change in body weight decreased by 8.7±17.7 kg in the SGLT2-I group and increased by 0.3±3.9 kg in the DPP4-I group (P<0.001). The average change in the mean arterial pressure (MAP) decreased by 6.6±8.0 mmHg in the SGLT2-I group and 0.2±13.3 mmHg in the DPP4-I group (p=0.001). The average creatinine clearance (CrCl) change increased by 5.5±24.3 mL/min in the SGLT2-I group and 0.4±10.3 mL/min in the DPP4-I group (P=0.001). There was no significant difference in the incidence of hypoglycemia and urinary tract infections between the two groups (p=0.507, p=0.079, respectively). Conclusion : In summary, the SGLT2-I group was more effective in reducing body weight and the MAP and improving the CrCl than the DPP4-I group. So, we suggest that the SGLT2 inhibitors may be considered as the first choice in combination with the metformin in patients with a high risk of diabetic complications.

Comparative Renal Effects of Dipeptidyl Peptidase-4 Inhibitors and Sodium-Glucose Cotransporter 2 Inhibitors on Individual Outcomes in Patients with Type 2 Diabetes: A Systematic Review and Network Meta-Analysis

배재현,박은지,김선희,김신곤,한서경,김남훈 대한내분비학회 2021 Endocrinology and metabolism Vol.36 No.2

Background: To compare the renal effects of dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose cotransporter 2(SGLT2) inhibitors on individual outcomes in patients with type 2 diabetes. Methods: We searched electronic databases (MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials) from inception to June 2019 to identity eligible randomized controlled trials of DPP-4 inhibitors or SGLT2 inhibitors that reported at leastone kidney outcome in patients with type 2 diabetes. Outcomes of interest were microalbuminuria, macroalbuminuria, worseningnephropathy, and end-stage kidney disease (ESKD). We performed an arm-based network meta-analysis using Bayesian methodsand calculated absolute risks and rank probabilities of each treatment for the outcomes. Results: Seventeen studies with 87,263 patients were included. SGLT2 inhibitors significantly lowered the risks of individual kidney outcomes, including microalbuminuria (odds ratio [OR], 0.64; 95% credible interval [CrI], 0.41 to 0.93), macroalbuminuria(OR, 0.48; 95% CrI, 0.24 to 0.72), worsening nephropathy (OR, 0.65; 95% CrI, 0.44 to 0.91), and ESKD (OR, 0.65; 95% CrI, 0.46to 0.98) as compared with placebo. However, DPP-4 inhibitors did not lower the risks. SGLT2 inhibitors were considerably associated with higher absolute risk reductions in all kidney outcomes than DPP-4 inhibitors, although the benefits were statistically insignificant. The rank probabilities showed that SGLT2 inhibitors were better treatments for lowering the risk of albuminuria and ESKDthan placebo or DPP-4 inhibitors. Conclusion: SGLT2 inhibitors were superior to DPP-4 inhibitors in reducing the risk of albuminuria and ESKD in patients with type2 diabetes.

SIRT1 Inhibitor Enhances Hsp90 Inhibitor-mediated Abrogation of Hsp90 Chaperone Function and Potentiates the Cytotoxicity of Hsp90 Inhibitor in Chemo-resistant Human Cancer Cells

Hyun-Jung Moon(문현정),Su-Hoon Lee(이수훈),Hak-Bong Kim(김학봉),Kyoung-A Lee(이경아),Chi-Dug Kang(강치덕),Sun-Hee Kim(김선희) 한국생명과학회 2016 생명과학회지 Vol.26 No.7

본 연구는 Hsp90 inhibitor 및 SIRT1 inhibitor의 병용처리가 항암제 다제내성(MDR) 인간 암세포의 증식 억제에 효과적임을 밝혔다. SIRT1 활성 억제가 Hsp90 inhibitor인 17-AAG의 세포 독성의 효과를 증강시켰으며, 이로 인해 Hsp90 inhibitors에 대한 내성을 극복시킬 수 있음을 인간 자궁암세포인 HeyA8의 MDR 변이주인 HeyA8-MDR 세포에서 확인하였다. SIRT1 inhibitor는 Hsp90 inhibitor에 의한 Hsp90 샤페론 기능 억제를 증강시키며, ubiquitin ligase CHIP의 발현 증강을 유발하여, Hsp90 client protein 인 mutant p53 (mut p53)의 분해를 촉진시킨다. Mut p53 의 발현 감소는 암세포의 Hsp90 inhibitor 내성 획득의 가장 중요한 원인으로 지적되는 heat shock factor 1 (HSF1)/heat shock proteins (Hsps)의 발현 억제와 관련됨을 알 수 있었으며, 이는 항암제 다제내성 세포에서 SIRT1 inhibitor에 의하여 Hsp90 inhibitor에 대한 감수성이 증강되는 분자적 기전임을 밝혔다. 그러므로, SIRT1 억제에 의한 mut p53/HSF1 발현 감소가 MDR 암세포의 Hsp90 inhibitors 내성 극복에 매우 유효함을 시사하는 결과를 얻었다. The present investigation was undertaken to examine the effectiveness of the combination treatment of an Hsp90 inhibitor and a SIRT1 inhibitor on suppressing the growth of chemo-resistant human cancer cells. We showed that inhibition of SIRT1 effectively potentiated the cytotoxicity of 17-allylamino-17-demethoxygeldanamycin (17-AAG) and reversed Hsp90 inhibitor resistance in multidrug-resistant (MDR) human ovarian HeyA8-MDR cells. Amurensin G, a potent natural SIRT1 inhibitor, enhanced Hsp90 inhibitor-mediated abrogation of the Hsp90 chaperone function and accelerated degradation of mutated p53 (mut p53), an Hsp90 client protein, by up-regulation of ubiquitin ligase CHIP. Knockdown of CHIP significantly attenuated amurensin G-induced mut p53 degradation. Down-regulation of mut p53 reduced the expression of heat shock factor1 (HSF1)/heat shock proteins (Hsps), a major cause of Hsp90 inhibitor resistance, which led to sensitization of the MDR cells to the Hsp90 inhibitor by the SIRT1 inhibitor. Amurensin G potentiated cytotoxicity of the Hsp90 inhibitor in HeyA8-MDR cells through suppression of 17-AAG-induced Hsp70 and Hsp27 induction via down-regulation of mut p53/HSF1, and it caused activation of PARP and inhibition of Bcl-2. Our data suggests that SIRT1 inhibitors could be used to sensitize MDR cells to Hsp90 inhibitors, possibly through suppression of the mut p53/HSF1-dependent pathway, and a novel mut p53-directed action of SIRT1 inhibition could effectively prevent mut p53 accumulation in MDR cells.

Corrosion mitigation of steel rebars in chloride contaminated concrete pore solution using inhibitor: An electrochemical investigation

Lee, Han-Seung,Yang, Hyun-Min,Singh, Jitendra Kumar,Prasad, Shailesh Kumar,Yoo, Bongyoung Elsevier 2018 Construction and Building Materials Vol.173 No.-

<P><B>Abstract</B></P> <P>Inhibitor is one of the most accepted method to reduce, prolong the initiation of steel corrosion and increase the threshold value of Cl<SUP>−</SUP> and CO<SUB>3</SUB> <SUP>2−</SUP> ions. In present study, we have mixed sodium salt of phosphate and benzoate along with benzo triazole in water to prepare the inhibitor. Open circuit potential (OCP) results show that 5 v/v% inhibitor was exhibited most positive (nobler) potential than others at its prolonged exposure in simulated concrete pore (SCP) + 3.5 wt% NaCl solution. The OCP of 3 and 5% inhibitor containing solution proved that these concentrations are away from under corrosion region of steel rebar even after 192 h of exposure in SCP + 3.5 wt% NaCl solution. Electrochemical impedance spectroscopy (EIS) results show that the charge transfers resistance (R<SUB>ct</SUB>) to be highest for 5% inhibitor and gradually decreased once the concentration was reduced with exposure periods. Potentiodynamic studies reveal that inhibitor shows passive properties due to adsorption of inhibitor molecules on steel surface and enhance the corrosion resistance properties. The efficiency was calculated using R<SUB>ct</SUB> and corrosion current density (I<SUB>corr</SUB>) process and found that 3 and 5% inhibitor exhibit around 89 and 96%, respectively after 1 h of exposure in SCP + 3.5 wt% NaCl solution.</P> <P><B>Highlights</B></P> <P> <UL> <LI> The prepared inhibitor has worked effectively to reduce the corrosion of steel. </LI> <LI> Synthesized inhibitor work as anodic inhibitor. </LI> <LI> High concentration of inhibitor is required to mitigate the corrosion of steel. </LI> <LI> 96% efficiency was found for 5 v/v% inhibitor after 1 h of exposure. </LI> </UL> </P>

Review : The Therapeutic Approaches for Hepatitis C Virus: Protease Inhibitors and Polymerase Inhibitors

( Paul Y. Kwo ),( Rakesh Vinayek ) 대한간학회 2011 Gut and Liver Vol.5 No.4

The current standard of care for hepatitis C infection is peginterferon/ ribavirin (PegIFN/RBV). We are entering the era where direct-acting antiviral agents (DAAs) will be added to PegIFN/RBV, leading to higher sustained response rates in genotype 1 infected individuals. Currently DAAs are directed toward specific proteins involved in hepatitis C replication with NS3/NS4A protease inhibitors furthest in development. Telaprevir and boceprevir are both NS3/NS4a inhibitors that significantly improve sustained response when added to PegIFN and RBV. The hepatitis C virus (HCV) polymerase inhibitors are another promising DAA class. These molecules are divided into nucleoside/nucleotide polymerase inhibitors and nonnucleotide/nucleoside polymerase inhibitors. Nucleoside/ nucleotide polymerase inhibitors have a high barrier to resistance and appear to be effective across a broad range of genotypes. Nonnucleoside polymerase inhibitors have a lower barrier of resistance and appear to be genotype specifi c. Preliminary data with these compounds are also promising. A third class, NS5A inhibitors, has also shown potent HCV RNA suppression in preliminary studies as monotherapy and with PegIFN and RBV. Combinations of these agents are also entering clinical trials and indeed a preliminary report has demonstrated that the combination of an NS3/4A protease inhibitor and NS5B polymerase inhibitor can effectively suppress virus in genotype 1 individuals. Future studies will concentrate on combinations of direct-acting antiviral agents without and with PegIFN and RBV. Clinicians will need to be familiar with managing side effects as well as resistance as we enter this new era. (Gut Liver 2011;5:406-417)

The Effect of Corrosion Inhibitor on Corrosion Control of Copper Pipe and Green Water Problem

Ji Eun Lee,Hyun Dong Lee,Gi Eun Kim 대한환경공학회 2012 Environmental Engineering Research Vol.17 No.1

Concern about green water problem has surfaced as a serious issue in Korea. In order to solve this problem, it is necessary to research inhibition of green water and corrosion control of copper pipe in water service. This paper discovered that moderate corrosion inhibitors can solve the green water problem and copper corrosion in water service by adding the optimal concentration of corrosion inhibitors based on regulation. Firstly, in the case of phosphate based corrosion inhibitors, as dosage of the corrosion inhibitor increases from 1 mg/L to 5 mg/L, the relative effect of corrosion inhibitor declines rapidly. Secondly, except for 1 mg/L dosage of silicate based inhibitor, relative effects of the inhibitor displays a positive number depending on inhibitor concentration. The most significant result is that the amount of copper release shows a downward trend, whereas the phosphate based inhibitor accelerates copper ion release as the inhibitor dosage increases. Thirdly, as the dosage of mixed inhibitors increases to 10 mg/L, the copper release change shows a similar trend of phosphate based inhibitor. Lastly, according to the Langelier saturation index (LI), silicate based inhibitors have the most non corrosive value. Larson ratio (LR) indicates that phosphate based inhibitors are the least corrosive. Korea water index (KWI) represents that silicate based inhibitors are most effective in controlling copper pipe corrosion.

The Effect of Corrosion Inhibitor on Corrosion Control of Copper Pipe and Green Water Problem

Lee, Ji-Eun,Lee, Hyun-Dong,Kim, Gi-Eun Korean Society of Environmental Engineering 2012 Environmental Engineering Research Vol.17 No.1

Concern about green water problem has surfaced as a serious issue in Korea. In order to solve this problem, it is necessary to research inhibition of green water and corrosion control of copper pipe in water service. This paper discovered that moderate corrosion inhibitors can solve the green water problem and copper corrosion in water service by adding the optimal concentration of corrosion inhibitors based on regulation. Firstly, in the case of phosphate based corrosion inhibitors, as dosage of the corrosion inhibitor increases from 1 mg/L to 5 mg/L, the relative effect of corrosion inhibitor declines rapidly. Secondly, except for 1 mg/L dosage of silicate based inhibitor, relative effects of the inhibitor displays a positive number depending on inhibitor concentration. The most significant result is that the amount of copper release shows a downward trend, whereas the phosphate based inhibitor accelerates copper ion release as the inhibitor dosage increases. Thirdly, as the dosage of mixed inhibitors increases to 10 mg/L, the copper release change shows a similar trend of phosphate based inhibitor. Lastly, according to the Langelier saturation index (LI), silicate based inhibitors have the most non corrosive value. Larson ratio (LR) indicates that phosphate based inhibitors are the least corrosive. Korea water index (KWI) represents that silicate based inhibitors are most effective in controlling copper pipe corrosion.

Production of α-Glucosidase Inhibitor by β-Glucosidase Inhibitor-Producing Bacillus lentimorbus B-6

( Kyoung Ja Kim ),( Yong Joon Yang ),( Jong Kee Kim ) 한국미생물생명공학회 2002 Journal of microbiology and biotechnology Vol.12 No.6

Histone Deacetylase as a Valuable Predictive Biomarker and Therapeutic Target in Immunotherapy for Non-Small Cell Lung Cancer

신현석,최주환,이진환,이승룡 대한암학회 2022 Cancer Research and Treatment Vol.54 No.2

Purpose Histone deacetylase inhibitors (HDACis) are epigenetic regulators and used clinically for hematopoietic malignancies. Recently, HDACis have received attention as a factor that modulates the immune system. In this study, the role of histone deacetylase (HDAC) expression as a predictive marker in lung cancer patients who were treated with immune checkpoint inhibitors (ICIs) and the role of HDACi and ICI combination treatment in the mouse tumor model were analyzed. Materials and Methods The overall response rate (ORR) and progression-free survival (PFS) were analyzed by the expression of HDAC. In vitro assay, the mRNA and protein expression levels of cytokines and programmed death-ligand 1 (PD-L1) were analyzed after HDACi treatment. In vivo assay, TC-1 tumor-bearing mice were treated with HDACi and mouse programmed cell death 1 (PD-1) inhibitor. Results The HDAC6 low expression group showed high ORR and prolonged PFS. When the selective HDAC6 inhibitor was administered to the A549 cell line, the levels of interleukin-1β and interleukin-6 decreased and the expression of PD-L1 was reduced. Mice that received both the mouse PD-1 inhibitor and pan-HDACi had a smaller tumor size than that of the mice from the control group. Moreover, mice treated with the mouse PD-1 inhibitor and pan-HDACi generated greater numbers of E7-specific CD8+ T cells. Conclusion HDAC6 expression can predict the prognosis of non–small cell lung cancerpatients who were treated with ICIs. Furthermore, co-treatment with HDACi and PD-1 inhibitor was shown to decrease the tumor growth rate and create a favorable tumor microenvironment for cytotoxic T lymphocytes in the TC-1 mouse model. Purpose Histone deacetylase inhibitors (HDACis) are epigenetic regulators and used clinically for hematopoietic malignancies. Recently, HDACis have received attention as a factor that modulates the immune system. In this study, the role of histone deacetylase (HDAC) expression as a predictive marker in lung cancer patients who were treated with immune checkpoint inhibitors (ICIs) and the role of HDACi and ICI combination treatment in the mouse tumor model were analyzed.Materials and Methods The overall response rate (ORR) and progression-free survival (PFS) were analyzed by the expression of HDAC. <i>In vitro</i> assay, the mRNA and protein expression levels of cytokines and programmed death-ligand 1 (PD-L1) were analyzed after HDACi treatment. <i>In vivo</i> assay, TC-1 tumor-bearing mice were treated with HDACi and mouse programmed cell death 1 (PD-1) inhibitor.Results The HDAC6 low expression group showed high ORR and prolonged PFS. When the selective HDAC6 inhibitor was administered to the A549 cell line, the levels of interleukin-1β and interleukin-6 decreased and the expression of PD-L1 was reduced. Mice that received both the mouse PD-1 inhibitor and pan-HDACi had a smaller tumor size than that of the mice from the control group. Moreover, mice treated with the mouse PD-1 inhibitor and pan-HDACi generated greater numbers of E7-specific CD8+ T cells.Conclusion HDAC6 expression can predict the prognosis of non–small cell lung cancerpatients who were treated with ICIs. Furthermore, co-treatment with HDACi and PD-1 inhibitor was shown to decrease the tumor growth rate and create a favorable tumor microenvironment for cytotoxic T lymphocytes in the TC-1 mouse model.