Natural products used as a chemical library for protein–protein interaction targeted drug discovery

Jin, Xuemei,Lee, Kyungro,Kim, Nam Hee,Kim, Hyun Sil,Yook, Jong In,Choi, Jiwon,No, Kyoung Tai Elsevier 2018 Journal of molecular graphics & modelling Vol.79 No.-

<P><B>Abstract</B></P> <P>Protein–protein interactions (PPIs), which are essential for cellular processes, have been recognized as attractive therapeutic targets. Therefore, the construction of a PPI-focused chemical library is an inevitable necessity for future drug discovery. Natural products have been used as traditional medicines to treat human diseases for millennia; in addition, their molecular scaffolds have been used in diverse approved drugs and drug candidates. The recent discovery of the ability of natural products to inhibit PPIs led us to use natural products as a chemical library for PPI-targeted drug discovery. In this study, we collected natural products (NPDB) from non-commercial and in-house databases to analyze their similarities to small-molecule PPI inhibitors (iPPIs) and FDA-approved drugs by using eight molecular descriptors. Then, we evaluated the distribution of NPDB and iPPIs in the chemical space, represented by the molecular fingerprint and molecular scaffolds, to identify the promising scaffolds, which could interfere with PPIs. To investigate the ability of natural products to inhibit PPI targets, molecular docking was used. Then, we predicted a set of high-potency natural products by using the iPPI-likeness score based on a docking score-weighted model. These selected natural products showed high binding affinities to the PPI target, namely XIAP, which were validated in an <I>in vitro</I> experiment. In addition, the natural products with novel scaffolds might provide a promising starting point for further medicinal chemistry developments. Overall, our study shows the potency of natural products in targeting PPIs, which might help in the design of a PPI-focused chemical library for future drug discovery.</P> <P><B>Highlights</B></P> <P> <UL> <LI> This paper provides <I>in silico</I> drug discovery strategy to identify natural products capable to inhibit the protein–protein interactions. </LI> <LI> The predicted PPI inhibitor-like natural products were validated in an in vitro experiment. </LI> <LI> The XIAP inhibitor LENP0044 could be used as a potent template for further chemical optimization. </LI> <LI> Natural products can be used as potent candidates in the design of a PPI-focused chemical library for drug discovery. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Comparison of Hanwoo with Holstein of OPU derived Embryo and Offspring Production

Jong‐In Jin,Byung‐Hyun Choi,Seong‐Su Kim,Hyun‐Tae Jo,Il‐Keun Kong 한국동물생명공학회(구 한국동물번식학회) 2011 발생공학 국제심포지엄 및 학술대회 Vol.2011 No.1

The objective of this study was to evaluate the comparison of production efficiency of oocytes and OPU (ovum pick‐up) derived embryos of Hanwoo with Holstein. The OPU session of each species (6 cows) was carried out from the Hanwoo (106 sessions) and Holstein (114 sessions) at intervals of 3 4 days (2 times per week) for 3 months. Cumulus‐oocyte‐complexes (COCs) retrieved were classified into 4 grades by the status of oocyte cytoplasm and cumulus cells. The COCs collected were matured in vitro in TCM‐199 supplemented with 10% FBS, 10 mg/ml FSH and 1 mg/ml estradiol‐ 17β in 5% CO2 and over 99% humidity for 24 h. After 24 h co‐incubation with post‐thaw sperm, the presumed zygotes were cultured in CR1aa medium with 4 mg/ml BSA for 3 days and then changed CR1aa medium with 10% of FBS for another 3 4 days. The Mean number of aspirated follicles and collected oocytes were not significantly different between Hanwoo and Holstein spacies (10.4±0.42 vs. 11.4±0.41 and 7.5±0.38 vs. 6.1±0.37 per session). But the collection rate of oocytes from aspirated follicles were significantly higher in Hanwoo (72.8%) than that in Holstein (53.6%) (p< 0.05). Furthermore, the average number of good quality oocytes (Grade I and II) was 5.9±0.28 and 4.1±0.27 (Mean±SD), and the cleavage rate and the development rate to blastocysts was significantly (p<0.05) higher in Hanwoo (40.0%) than Holstein (21.6%). The OPU derived embryos of Hanwoo were transferred 83 times into 52 recipients and then 42 calves were produced from 44 pregnancy recipients. In conclusion, the efficiency of OPU derived embryo was significantly different between Hanwoo and Holstein species. In vitro culture system for OPU derived embryo production should be optimized for industrialization and the improvement of livestock.

Glucagon 및 Cycloheximide 投與에 의한 흰쥐 肝細胞 lysosome의 變化에 관한 超微形態學的 硏究

이진식,김익동,배한익,서인수,김중길,곽정식,손태중 慶北大學校 醫科大學 1983 慶北醫大誌 Vol.24 No.2

저자는 체중 30∼35gm 정도의 ICR계 생쥐에 체중 100gm당 100㎍의 glucagon을 그리고 체중 100gm당 0.15mg의 cycloheximide를 각각 단독으로 또 이들을 같이 복강내에 병합 투여하여, 이때 간세포에 일어나는 형태학적 변화와 아울러 lysosome막의 유래의 일단을 알아보기 위한 실험성적을 요약하면 다음과 같다. 광학현미경적으로는 중심정맥 주위의 간세포이 종창과 한국성 지발변화가 나타났었는데, 그 정도는 glucagon 단독투여군과 cycloheximide와 glucagon을 병합투여한 군에서는 다같이 중등도로 일어났었다. 전자현미경적으로는 glucagon 단독투여 군에서는 간세포에 있어서의 lysosome의 현저한 증가, 특히 autophagic vacuole의 증가, 세포핵의 비대 및 핵소체수의 증가, 그리고 kupffer세포의 탐식 작용의 증가등이고 cycloheximide 단독투여군에서는 경한 lysosome의 증가, RER의 확장, 단열, ribosome의 탈락, free ribosome의 증가, Golgi complex의 위축, SER의 감소, mitochondria의 종창 및 공포화와 lipid droplet의 증가 등이다. 그리고 glucagon과 cycloheximide 병합투여군에서는 상기한 두가지 단독투여군의 소견과 여기에 더하여 peroxisome의 증가가 일어났으며, 이들 변화중 특히 autophagic vacuole의 증가는 glucagon 단독투여군보다 좀더 현저한 경향이었다. 이상의 연구성적으로 보아, glucagon은 간세포에 있어서 autophagy를 증가시킬 뿐 아니라, 핵에도 작용하여 그 비대를 일으키며, 이때 cycloheximide를 투여하여 단백합성을 억제하여도 autophagy를 저해하지는 않는다고 믿어진다. 따라서 autophagic vacuole의 한계막은 새롭게 신생된다기 보다는 세포내의 기존의 막, 예를 들면 SER, RER, Golgi막등 막성 성분에서 유래될 가능성이 지금으로서는 더 많은 것으로 생각된다. Glucagon은 autophagic vacuole을 증가시킬 뿐 아니라, cycloheximide를 투여한 후 glucagon을 투여한 경우에는 autophagic vacuole의 증가와 더불어 peroxisome도 증가시킬 것으로 추정된다. In order to investigate the morphologic changes and origin of membrane of lysosomes, the author administered glucagon, 100㎍ per 100gm of body weight, cycloheximide, 0.15㎎ per 100 gm of body weight and both to the healthy male ICR mice intraperitoncally. Each hepatic tissue was observed by light microscope and electron microscope. The results were summarized as follows. Light microscopically, swelling of heaptocytes and focal fatty change appeared around the-central vein. The severity of these changes was mild in the group administered glucagon and was moderate in groups administered cycloheximide alone, both cycloheximide and glucagon. Electron microscopically, in the group administered glucagon, marked increase of lysosomes, particularly autophagic vaculoles, enlargement of nuclei with increase of nuclcoli in thc hepatocytes and increase of phagocytosis in kupffer cells were appeared. In the group administered cycloheximide, slight increase of lysosomes, dilatation and fragmentation of RER, shedding of ribosomes, increase of free ribosomes, atrophy of Golgi complex, decrease of SER, swelling and vacuolizatlon of mitochondria, and increase of lipid droplets occured. In thr group aiministered both cycloheximide and glucagon, above findings in each group and additional increase of peroxisomes appeared. In these changes, increase of autophagic varuoles was more prominent in the group administered glucagon. From the above results, it is believed that glucagon induces enlargement of nuclei as increase of autophagy in the hepatocytes. At this time, in spite of suppression of protein synthesis by administration of cycloheximide, the autophage was not inhibited. Therefore it is more possible that the limiting membrane of autophagic vacuoles originates from preexisting membrane rather than front de novo synthesis. when glucagon was administered after administration of cycloheximide, peroxisomes as well as autophagic vacuoles were increased.

개 시상하부의 Neuropeptides에 대한 면역조직화학적 연구

장인엽,정윤영,김종중,문정석,김준수,모근석,임용,유호진 朝鮮大學校 附設 醫學硏究所 1996 The Medical Journal of Chosun University Vol.21 No.1

The distribution and localization of somatostatin(SOM), neuropeptide Y(NPY), vasopressin(VP), and oxytocin(OT) were studied with a immunohistochemical technique in the canine hypothalamus. The SOM-immunoreactive perikarya were concentrated in the anterior periventricular and the arcuate nuclei. Immunoreactive terminals were observed in the arcuate, the ventromedial hypothalamic, the suprachismatic nuclei and the external layer of the median emmence. A great number of NPY-immunoreactive cell bodies were found in the arcuate nucleus and NPY fibers were located throughout the hypothalamus with the highest concentration especially in the paraventricular (PVN) and the acuate nuclei. Moderately or densely stained fibers were also observed in the median eminence, the suprachiasmatic. the periventricular, the ventromedial hypothalamic, the dorsomedial hypothalamic and the medial preoptic nuclei, and the stria terminalis. Both VP-and OT-containing perikarya were found mainly in the PVN and supraoptic nucleus(SON). but a few were seen in the perifornical area, the lateral hypothalamus, the dorsal hypothalamic and the periventricular nucleus. The fibers originated from the PVN were projected to the SON via ventral or dorsal area of the fornix.

법랑모세포 분화와 법랑질 형성과정에서 OD314, Apin protein의 발현 및 기능

박종태,최용석,김흥중,정문진,오현주,신인철,박주철,손호현 대한치과보존학회 2006 Restorative Dentistry & Endodontics Vol.31 No.6

본 연구에서는 법랑모세포 분화와 법랑질 형성에 연관이 있는 OD314 일명 Apin protein의 기능을 밝힐 목적으로, in-situ hybridization에 의한 OD314 mRNA 발현과 법랑모세포 세포주에서 OD314 enamel matrix protein의 발현, 그리고 OD314 유전자를 과발현/억제시킬 수 있는 construct를 제작한 후 법랑질 형성 중에 OD314의 기능을 알아보고자 RT-PCR를 시행하여 다음과 같은 결과를 얻었다. 1. OD314 mRNA는 발생중인 상아모세포보다 법랑모세포에서 강하게 발현되었다. 2. Tuftelin은 석회화 결정이 형성되는 14일까지 발현이 지속되고, 그 이후부터 점차 감소하였다. Amelogenin과enamelin은 7일부터 그 발현이 점점 감소하였다. 3. U6-OD314 siRNA construct를 이용하여 transfection한 법랑모세포 세포주는 OD314와 tuftelin,MMP2 mRNA 발현이 감소하였으며, CM-OD314를 transfection하여 OD314의 과발현을 유도한 경우에는 OD314와 MMP20 mRNA의 발현이 뚜렷이 증대되었다. 이 결과는 OD314가 법랑모세포의 분화와 법랑질의 형성 그리고 석회화 과정에 중요한 역할을 하는 새로운 인자임을 시사한다. This study was aimed to elucidate the biological function of OD314 (Apin protein), which is related to ameloblast differentiation and amelogenesis. Apin protein, calcifying epithelial odontogenic (pindborg) tumors (CEOTs)-associated amyloid, were isolated from CEOTs, and has similar nucleotide sequences to OD314. We examined expression of the OD314 mRNA using in-situ hybridization during tooth development in mice. Expression of OD314 and several enamel matrix proteins were examined in the cultured ameloblast cell line up to 28 days by reverse transcription-polymerase chain reaction (RT-PCR) amplification. After inactivation and over-expression of the OD314 gene in ameloblast cell lines using U6 vector-driven RNA interference and CMV-OD314 construct, RT-PCR were performed to evaluate the effect of the OD314 during amelogenesis. The results were as follows: 1. In in-situ hybridization, OD314 mRNAs were more strongly expressed in ameloblast than odontoblast. 2. When ameloblast cells were cultured in the differentiation and mineralization medium for 28 days, the tuftelin mRNA expression was maintained from the beginning to day 14, and then gradually decreased to day 28. The expressions of amelogenin and enamelin were gradually decreased according to the ameloblast differentiation. 3. Inactivation of OD314 by U6-OD314 siRNA construct down-regulated the expression of OD314, MMP-20, and tuftelin, whereas over-expression of OD314 by CMV-OD314 construct up-regulated the expression of OD314 and MMP-20 without change in tuftelin. These results suggest that OD314 is considered as an ameloblast-enriched gene and may play the important roles in ameloblast differentiation and mineralization.

白鼠感染 肝吸蟲幼蟲에 대한 Praziquantel(Biltricide^(�))의 殺蟲效果에 대하여

林漢鍾,梁元容,宋寅喆,金洙鎭 최신의학사 1981 最新醫學 Vol.24 No.4

공단지역 및 청정지역 식물 잎권의 잎표면세균 및 내산성세균의 분포

안종훈,방숙진,한남정,송왕영,황소영,이인수,박성주 대전대학교 이과대학 기초과학연구소 1997 自然科學 Vol.- No.-

산성강하물의 영향을 받는 대천공단지역과 영향을 받지 않는 청정지역인 대전 계족산 자연휴양림에서 자라는 밤나무(Castanea crenat)의 잎표면에서 서식하는 총세균수, 생존세균수, 종속영양세균수, 내산성세균수를 1996년 8월부터 1997년 8월까지 5회에 걸쳐 조사하였다. 공단지역 잎표면 평균 총세균수, 생존세균수 및 종속영양세균수는 각각 9.9×10^(5) cell/㎠, 1.6×10⁴cell/㎠, 7.1×10³cell/㎠,로서 청정지역에 비하여 각각 1.5배, 2배, 2.6배 정도로 관찰되었다. MPN법으로 측정한 pH 5.6애서의 잎표면 내산성세를수는 공단지역 3.3×10⁴, 청정지역 3.4×10⁴MON/㎠로 거의 같았고, pH 4.0에서의 내산성세균수는 공단지역애서 1.9×10^-(-1)MPN/㎠인 반면 청정지역에서는 전혀 검출되지 않았다. pH 3.0에서의 내산성 잎표면세균수는 공단지역과 청정지역의 잎권 어느 곳에서도 검출되지 않았다. 한편 계절별 잎표면세균수의 분포는 대체로 잎이 나기 시작하여 크기가 가장 작은 5월에 최대를, 그리고 낙엽이 지는 11월에 최소를 나타내었다. 이런 결과는 공단지역의 대기오염물질의 침적이 주변의 식물 잎표면 세균수를 감소시키지는 않으며, 특히 산성강하물의 영향으로 내산성세균수가 증가함을 보여주고 있다. Total, direct viable count, and acid-tolerant epiphytic bacterial population sizes were quantified on leaves of chestnut tree (Castanea crenata S. et Z.) near Taejon Industrial Estate affected by acid precipitation and deposition as well as in the clean natural forest area, Mt. Kyejok, in Taejon city from August 1996 to August 1997. Geometric mean numbers of total, direct viable count, and acid-tolerant epiphytic bacteria were 9.9×10^(5) cell/㎠, 1.6×10^(6)cell/㎠, and 7.1×10³cfu/㎠ respecfvely, being 1.5, 2, and 2.6 times those in the clean area. Acid-to-lerant epiphytic bfcterial numbers at pH 5.6 by MPN method were 3.3×10" in the industrial area, about the same as the number,3.4×104 MPNicni, of the clean area. Acid-tolerant bacterial number at pH 4.0 was 1.9×10^(-1)MPN/㎠ in the industrial area, whereas none was detected in the clean area. Acid-tolerant bacteria at pH 3.0 were not detected at all in the industrial area as well as in the clean area. Epiphytic bacterial population sizes were generally the greatest in May when leaves are emerged and grew but the lowest in November when defoliation occurs. These results showed that air pollutant deposition on leaves did not cause a deuease of epiphytic bacteria at least and acid deposition on leaves did cause an increase of acid-tolerant bacteria.

Poster Session : PS 0033 ; Cardiology : Impact of Metabolic Syndrome and Obesity on Clinical Outcomes After Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction

( Uh Jin KIM ),( Seunghun LEE ),( Myung Ho JEONG ),( Ju Han KIM ),( HyukJin PARK ),( Ji Eun KIM ),( Youngkeun AHN ),( Jong Hyun KIM ),( Shung Chull CHAE ),( Young Jo KIM ),( Seung Ho HUR ),( In Whan S 대한내과학회 2014 대한내과학회 추계학술대회 Vol.2014 No.1

Background: The correlation between obesity and metabolic syndrome (MetS) remains unclear. This study aims to investigate impact of obesity phenotype on clinical outcomes with ST-segment elevation myocardial infarction (STEMI). Methods: We analyzed in-hospital mortality and major adverse cardiac events (MACE) of 2,606 obese patients who underwent primary percutaneous coronary intervention (PCI) in the Korea Acute Myocardial Infarction Registry from November 2005 to October 2010. Patients were divided into two groups: unhealthy (any of the Mets components) obesity (BMI =25 kg/m2) and healthy (none of the Mets components) obesity. Results: The unhealthy obesity group was composed of 703 patients (27%) and healthy obesity group 1,903 patients (73%). Unhealthy obesity was more frequent in female (25.9% vs. 10.1%, P<0.001) and multi-vessel disease (53.1% vs. 47.6%, P=0.012). There were no signifi cant differences in other baseline characteristics, angiographic and procedural fi ndings, and prescribed medications between two groups. The overall incidence of complications after PCI (13.1% vs. 10.7%, P=0.097) and in-hospital mortality (1.9% vs. 1.6%, P=0.521) were similar in unhealthy obesity group compared with healthy obesity group. By the multivariate Cox regression analyses, the presence of Mets in obese patients was not an independent factor for predicting the adjusted MACE rate at one-month (HR 1.19, 95% CI 0.56-2.54, P=0.645), six-month (HR 1.48, 95% CI 0.94-2.32, P=0.088), and twelve-month (HR 1.10, 95% CI 0.75-1.61, P=0.622). Conclusions: Obesity phenotype is not an independent prognostic factor for patients with STEMI who undergoing primary PCI. The risk stratifi cation by presence or absence of Mets is not useful in these patients.

뇌동맥류파열에 의한 뇌지주막하출혈 환자의 수술시기에 따른 예후 분석

손진열,박인성,황수현,백선하,김은상,정진명,김재형,한종우 대한신경외과학회 1999 Journal of Korean neurosurgical society Vol.28 No.3

국제해운항만로지스틱스에 있어서 항만경쟁력의 평가에 관한 연구 : 계층퍼지분석법의 적용 An Application of Hierarchical Fuzzy Process

김진구,여기태,이종인 한국로지스틱스학회 2002 로지스틱스연구 Vol.10 No.2

본 연구의 목적은 국제해운항만로지스틱스에 있어서 근간이 되는 경쟁항만의 현황을 조사하고, 실제 경쟁을 주도하는 구성요소를 파악하며, 항만경쟁력 평가모델을 개발하고, 평가모델에 각 항만의 구성요소별 data를 투입하여 실제 경쟁능력을 파악하는 것이다. 연구의 방법론은 속성간 중복도를 고려하여 연산 할 수 있는 계층퍼지분석법(HFP : Hierarachical Fuzzy Process)을 도입하였다. 그리고, 연구의 범위는 급변하는 국제해운항만로지스틱스에 있어서 가장 관심의 대상이 되고 있는 동북아시아국가 및 동남아시아국가의 컨테이너항문 중 2000년 컨테이너 처리실적 상위 20위 내에 위치한 항만을 대상으로 하였다. 연구의 결과 싱가포르 항만이 연구대상지역에서는 가장 경쟁력이 뛰어난 것으로 나타났다. 향후 연구과제로, 본 연구의 항만경쟁력 평가기법으로 채택된 HFP방법에 있어서 엄밀히 고려하지 못한 다수의사결정그룹(Multiple Decision-Making Group : MDMG)의 해결을 위한 보완적 연구가 더 필요하다. The purpose of this study is to grasp the real competitiveness of ports in international shipping and port logistics, by 1) examining the status of competitive ports, 2) grasping the components that lead the actual competition, 3) developing evaluation models of port competitiveness, and 4) putting component data of each port into these same evalation models. The research method which was used in this study accounted for overlapping between attributes, and introduced the HEP(Hierarchical Fuzzy Process) method that can perform an operation. The scope of this study covers the top 20 Northeast and Southeast Asian ports with respect to container handling in 2000. This has direct competition in attracting cargo from East Asia. The results of this study showed that the competitive power of Singapore Port was the highest among the ports of East Asia. Derived from the empirical study, the attempt to grasp the real port competitiveness in dynamic port activities is the merit of this study, especially in the rapidly changing environments of international shipping and port logistics. In order to reinforce this study, it needs further compensative research because the HFP method adopted as an evaluation model of port competitiveness in this study was not strictly considered enough to solve the problems such as MDMG(Multiple Decision-Making Group).