Discovery of urinary metabolomic biomarkers for early detection of acute kidney injury

Won, A Jin,Kim, Siwon,Kim, Yoon Gyoon,Kim, Kyu-Bong,Choi, Wahn Soo,Kacew, Sam,Kim, Kyeong Seok,Jung, Jee H.,Lee, Byung Mu,Kim, Suhkmann,Kim, Hyung Sik The Royal Society of Chemistry 2016 Molecular bioSystems Vol.12 No.1

<P>The discovery of new biomarkers for early detection of drug-induced acute kidney injury (AKI) is clinically important. In this study, sensitive metabolomic biomarkers identified in the urine of rats were used to detect cisplatin-induced AKI. Cisplatin (10 mg kg(-1), i.p.) was administered to Sprague-Dawley rats, which were subsequently euthanized after 1, 3 or 5 days. In cisplatin-treated rats, mild histopathological alterations were noted at day 1, and these changes were severe at days 3 and 5. Blood urea nitrogen (BUN) and serum creatinine (SCr) levels were significantly increased at days 3 and 5. The levels of new urinary protein-based biomarkers, including kidney injury molecule-1 (KIM-1), glutathione S-transferase-alpha (GST-alpha), tissue inhibitor of metalloproteinase-1 (TIMP-1), vascular endothelial growth factor (VEGF), calbindin, clusterin, neutrophil, neutrophil gelatinase-associated lipocalin (NGAL), and osteopontin, were significantly elevated at days 3 and 5. Among urinary metabolites, trigonelline and 3-indoxylsulfate (3-IS) levels were significantly decreased in urine collected from cisplatin-treated rats prior to histological kidney damage. However, carbon tetrachloride (CCl4), a hepatotoxicant, did not affect these urinary biomarkers. Trigonelline is closely associated with GSH depletion and results in insufficient antioxidant capacity against cisplatin-induced AKI. The predominant cisplatin-induced AKI marker appeared to be reduced in urinary 3-IS levels. Because 3-IS is predominantly excreted via active secretion in proximal tubules, a decrease is indicative of tubular damage. Further, urinary excretion of 3-IS levels was markedly reduced in patients with AKI compared to normal subjects. The area under the curve receiver operating characteristics (AUC-ROC) for 3-IS was higher than for SCr, BUN, lactate dehydrogenase (LDH), total protein, and glucose. Therefore, low urinary or high serum 3-IS levels may be more useful for early detection of AKI than conventional biomarkers.</P>

Palmes Tube를 이용한 지역별 NO₂농도와 직종별 NO₂개인 폭로량에 관한 연구

김준연,박순우,김동일,장봉기,정경동,김두희,홍대용,정갑열,김용규,이종섭,유일수,김정만 동아대학교 의과대학 부설 산업의학연구소 1992 산업의학연구소 논총 Vol.- No.1

Indoor air quality is important to human wellbeing because people their spend much of time indoors. Current efforts to reduce ventilation rates in building may conserve energy but may also passibly empair human health and welfare through increased levels of indoor contaminants. Nitrogn dioxide( NO₂)has been regarded as one of the important indoor air pollutants. This report updates the assessment of NO₂concentrations at indoor & vehicle road and personal NO₂exposure levels by job groups in four urban cities. NO₂concentrations were measured using the diffusion tube method on 671 subjects in four cities(Pusan, Taegu, Chinju. Iri) from Dec. 1988 to Feb, 1989 and from Dec. 1989 to Feb. 1990. The results of the study obtained were as follows. Ⅰ. Indoor & vehicle road NO₂levels 1. The mean NO₂level was 37.8±19.6(8∼189)ppb and the highest with 42.2±20.5ppb at Bus & Taxi. 2. The NO₂levels by area were as follows: Pusan city, 38.3±20.3ppb: Taegu city, 41.1±17.6ppb: Chinju city, 33.0±19.4ppb: Iri city, 35.8±20.6ppb. 3. The site of the highest NO₂level in Pusan, Taegu, Chinju and Iri city were as follows: Bus & Taxi, 45.4ppb: Vehicle road, 50.8ppb: Bus & Taxi, 37.5ppb: Bus & Taxi. 45.0ppb. Ⅱ. Personal NO₂exposure level 1. The mean level of personal NO₂exposure was 42.7 ±23.1(6∼145)ppb and the highest with 54.0±25.5ppb at office workers. 2. Personal NO₂exposure levels by area were as follows: Pusan city 44.8±20.2ppb: Taegu city, 50.6±24.3ppb: Chinju city, 47.1±23.2ppb: Iri city, 48.0±27.0ppb. 3. The job group of the highest personal NO₂exposure level in Pusan, Taegu, Chinju and Iri city were as follows: Office workers, 50.3ppb: Bus & Taxi drivers, 63.8ppb: Office workers, 59.8ppb: Office workers, 60.0ppb.

측뇌실내 종괴의 감별진단 및 수술적 치료

김동규,김봉수,이상형,심기범,왕규창,정희원,김현집,조병규,최길수,한대희 대한신경외과학회 1993 Journal of Korean neurosurgical society Vol.22 No.2

We present a series of 42 patients with the lateral ventricular mass lesions who underwent operative removal between 1979 and 1992 at the Seoul National University Hospital. These lesions included 29 tumors, 10 benign cysts and 3 arteriovenous malformations. There were 20 lesions in the trigone, 14 in the frontal horn, 6 in the body, and 2 in the temporal horn. Together with the age of the patient, the location in the lateral ventricle and the CT or MR patterns, the range of the differential diagnosis of the lesions can be narrowed. The mass were removed by various surgical approaches ; 11 by the middle frontal gyrus, 10 by the superior parieto-occipital, 13 by the middle temporal gyrus, 4 by the anterior transcallosal, 2 by the posterior transcallosal and 3 by the combined approaches. The superior parieto-occipital approach left postoperative morbidities in 64% and other approaches in 20 to 25% of the cases. These morbidities included hemiparesis, hemianopsia, aphasia, memory distubance and seizure. Most hydrocephalus disappeared without the shunting procedure after removal of the lateral ventricular mass. The high frequency of postoperative complications in the superior parieto-occpital approach require meticulous consideration in the selection of this approach.

독성물질의 세포사 기전 및 세포사 유발물질의 검색법 개발에 관한 연구(Ⅰ) : 독성물질로 인한 파킨슨병 모델에서의 세포사 기전 연구 Study on the cell-death mechanisms of toxin-induced parkinsonism

강태석,김종민,서경원,김영옥,김준규,오재호,이윤동,김규봉,오정자,송연정,임종준,전범석,문전옥,최광식 식품의약품안전청 2000 식품의약품안전청 연보 Vol.4 No.-

MPTP 독성물질이 도파민성 신경세포에 선택적으로 작용하여 산화성 손상에 의한 신경세포사를 일으키는 것을 이용하여 파킨슨병의 동물모델을 만들고, 이를 통해서 아폼토시스를 비롯한 포사의 기전에 대한 연구 및 너코틴의 신경세포 보호효과 여부를 판정하는 실험을 병행하고자 하였다. 파킨슨꾐의 동물모델을 MPTf 독성 물질을 이용하여 확립하였으며, MPTP(30mgag, i.p.)를 투여한 후 1, 2,3, 4, 5일째 흑질 조직을 채춰하여 tarm로 박걸하여 tyrosine hydroxylase 면역조직화학염색을 수행하여 cell countif우한 결과, control은 57.635ce11s, 1일째 친.OfDells,2일째 57.9±6cells,3일릴 없.3±죠ells, 4일째 49.0츠3cells, 5일째 39.4±Scells료 4, 3일째 뚜렷한 신경세포 수의 감소를 보였다. 신경세포사 기전 규명을 위한 아폼토시스 분걱에서는 벼PTP 투여 후 1, 2, 3, 4, 5일째 조직을 채취하여 Hoechst staining, TUNEL staining을 수곡하였는데 양성 반응을 보인 신경세포는 관찰되지 않아. 아폼토시스로 인한 세포사가 관찰되지 않았다. bIPTP 파킨슨병 동물모델에서 nicotine 보호효과 탐색에 관한 실험은 nicat푸e 0.2mgAg을 5일 퐁안 투여 후 리『fP(30mgag)를 CS7Bt/6 마은스에 복강 내주사로 nicotine과 병용 투여한 후 1, 2, 3, 4, 5일째 뇌를 적출하땄다. 신경세포사가 뚜렷이 관찰되기 시작하는 4, 5일째의 신경세포 수의 감소 정도를 20. 30% 정도 약화시키는 경향을 보였으나, nicotine 보호효과에 대한 추가 실헝이 현재 수행 중에 있다. The cause of Parkinson's disease (PD) is largely unknown. However, free radical toxicit? may plaf a role ip. the degeneration of substantia nigra, which is the Hajorfocus of pathological damages in PD. Recently, a neuroprotective effect of nicotine in PD has been suggested. Therefore, the mechanism of neurodegenerafion and protective potential o( nicotine in PD were investigated in the experimental modeB of Pll using a neurotoxin, C57BL/6mice were administered with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg,j.p.). The degree of neurodegenerafion was determined by immunohistochemical stainiHB oftyrosine hydroxylase (TH). TH-positive cells on nigral sections were found 56.0 ±4, 57.9 ±6,52.315ce11s, 49.0±3cells, and 39,4±Scells at days 1, 2, 3, 4, 5, respectively (controls : 57.6±Scells). Hoechst and TUNEL staining showed no evidence of apoptosis. The exandnation on themice co-adrunistered with nicotine(0.2mgAg) and MPTP(30mgag) revealed a tendency ofnicotine protective effects. At days 4 and 5, the degree of TH-positive cells was decreased by20-30%, In corclusiffn, the role of apoptosis was not evidenced in this MPTP modeB of PB.The possible proteccon by nicotine should be elucidated with further studies.

老齡者의 建康을 위한 生活習慣 實態調査

申東敏,長鳳愚,李揆文,金賢俊,金昌範,崔宗洙,崔鍾晥,李鍾珏,金圭碩,趙庚旭,金鍾聲,朴鍾振 平生體育硏究所 論文集 1987 平生體育硏究所 論文集 Vol.2 No.-

With a view to examining the habit and method in which old people maintain and improve their health, we consulted 551 men and 444 women who were over 65 years old, and concluded as follows: 1. Habit of eating It's been revealed that most of the old people keep a regular eating hour, control the quantity of meal or eat a little food, and prefer vegetables to meat. 2. Mental health Old people feel the necessity for mental health and most of them (about 80%) keep good mental health without becoming pessimistic. Their chief concenrs have turned out to be about their sons and daughters and their own health and finance. 3. Managing Good Health It has been revelaed that old people do not possess any special kind of secret to keep good health but taking plenty of rest, regular meal, and proper exercise, and many of them (about 60%) have been shown to eat invigorant food that they can easily get around their living area. 4. Physical Functions It has been revealed that many old people are conscious of some symptoms about their parts of body and about to percent of them suffers from neuralgia. Some measures like medical aid especially for old people need to be taken as soon as possible. As we have found that the health-keeping method of old people consists plenty of rest, proper exercise, and appropriate nutrition, we can conclude that the recreatonal and culture facilities and programs for keeping old people in good health should be developed. It is also necessary to study food that contribute to their health and develop ways to get rid of the stresses to which they are exposed in their daily life. Presides, it is natural that government found an administrative department to deal with these matters effectively.

Medicinal Chemistry : EVALUATION OF CADMIUM-INDUCED NEPHROTOXICITY USING URINARY METABOLOMIC PROFILES IN SPRAGUE-DAWLEY MALE RATS

( Yu Kyung Lee ),( Eun Young Park ),( Shi Won Kim ),( Ji Yeon Son ),( Tae Hyung Kim ),( Won Gu Kang ),( Tae Chun Jeong ),( Kyu Bong Kim ),( Seung Jun Kwack ),( Jae Won Lee ),( Suh Mann Kim ),( Byung M 영남대학교 약품개발연구소 2015 영남대학교 약품개발연구소 연구업적집 Vol.25 No.-

The aim of this study was to investigate urinary metabolomics profiles associated with cadmium (Cd)-induced nephrotoxicity and their potential mechanisms. Metabolomic profiles were measured by high-resolution 1H-nuclear magnetic resonance (NMR) spectroscopy in the urine of rats after oral exposure to CdCl2 (1, 5, or 25 mg/kg) for 6 wk. The spectral data were further analyzed by a multivariate analysis to identify specific urinary metabolites. Urinary excretion levels of protein biomarkers were also measured and CdCl2 accumulated dose-dependently in the kidney. High-dose (25 mg/kg) CdCl2 exposure significantly increased serum blood urea nitrogen (BUN), but serum creatinine (sCr) levels were unchanged. High-dose CdCl2 (25 mg/kg) exposure also significantly elevated protein-based urinary biomarkers including osteopontin, monocyte chemoattractant protein-1 (MCP-1), kidney injury molecules-1 (Kim-1), and selenium-bingding protein 1 (SBP1) in rat urine. Under these conditions, six urinary metabolites (citarate, serine, 3-hydroxyisovalerate, 4-hydroxyphentllactate, dimethylamine, and betaine) were involved in mitochondrial energy metabolism. In addition, a few number of amino acids such as glycine, glutamate, tyrosine, proline, or phentlalanine and carbohydrate (glucose) were altered in urine afrer CdCl2 exposure. In particular, the metabolites involved in the glutathione biosynthesis pathway, including cysteine, serine, methionine, and glutamate, were markedly decreased compared to the control. Thus, these metabolites are potential biomarkers for detection of Cd-induced nephrotoxicity. Our results further indicate that redox metabolomics pathways may be associated with Cd-mediated chronic kidney injury. These findings provide a biochemical pathway for better understanding of cellulat mechanism underlying Cd-induced renal injury in hunmans.

정태회로 해석에 의한 전력부하로서의 유도전동기 시뮬레이션 및 축약

金正勳,李鳳容,高太奎 弘益大學校 科學技術硏究所 1991 科學技術硏究論文集 Vol.1 No.-

This paper presents a static circuit model for static and dynamic simulation of induction motors and aggregation of motors. Instead of usual T-circuits, equivalent π-circuit has been proposed so that power inputs into motor terminals can very easily calculated with very well known load flow method. It has been shown that, with wide range variation of applied voltage and frequency, successful static simulations can be performed and further the proposed static model can be used to simulate dynamic characteristics.

산성 과망간산염법에 의한 화학적 산소 요구량의 측정에 있어서 시료량과 적정액량과의 관계

金奉圭 東亞大學校 大學院 1980 大學院論文集 Vol.4 No.1

JIS K 0102 13의 산성 과망간산염법에 의한 화학적 산소 요구량(COD)의 측정에서 시료량(V)과 과망간산염의 표준용액의 적정액량(a)과의 사이에 경험식(실험식)으로 표시되는 두 대수직선 관계식 log a = log k + n log V …………(1) 이 적정액량(2∼7)㎖의 범위내에서 도시 하수 및 표준물질에 대하여 성립한다는 것이 보고되었다. 이 관계를 실험실에서 행해지고 있는 산화환원적정에 적용하여 보았다. COD를 측정할 때 적정액량 5㎖에 대응하는 시료용액의 부피 V( )를 결정한다는 것은 매우 어려운 일이었다. 본 연구에서는 식(1)에서 유도되는 식 log V( ) = log V + {log(5/a) × log(V'/V)} / log(a'/a)을 이용하여 일정량의 시료량(V)과 적정액량(a)을 2회 측정함으로써 COD( )를 산출하는 데 필요하 시료량(V( ))을 간단하게 산출할 수가 있었다. 그리하여 그 결과를 보고한다. The experimental equation, linearty relationship of two logarithm, log a = log k + n log V that show between the sample volume (V) and the titrant volume (a) of standard solution of potassium permanganate in measurement of Chemical Oxygen Demand (COD) by acidic permanganate method of JIS K 0102 (The examination method of industrial wastewater), is known to correspond to urban sewage and standard solution. This relationship turned to account for the experiment oxidation and reduction titration. .

두개골의 두께: 일차연구

김수관,김운규,김봉균,장현선 대한악안면성형재건외과학회 2000 Maxillofacial Plastic Reconstructive Surgery Vol.22 No.6

The purpose of this study was to investigate the mean cranial bone thickness at various points of the bone and to serve as a clinical guide for choosing a bone graft. Twelve bones were obtained from 6 Korean adult skulls for this study. The mean bone thickness at each point of the 17 points of the bone and at the corresponding points of the opposite bone was obtained in all skulls studied. The thinnest part of the parietal bone was 5.92mm. The thickest part of the parietal bone was 7.58mm. The mean bone thickness at each point of measurements on two opposite bones was compared using the paired Student's t-test. The mean thickness did not differ significantly. The thickness in the same bone varied widely depending on the points of measurement.

연작업자들에서 혈중 및 골중 연량과 조혈기능 지표 사이의 관련성에 ALAD 다형질성이 미치는 영향

김화성,이성수,김용배,황보영,리갑수,안규동,장봉기,이병국 大韓産業醫學會 2001 대한직업환경의학회지 Vol.13 No.1

목 적 : 혈중 연량 및 골중 연량과 조혈기능의 생화학적 지표사이의 관련성에 f-aminolevinicacid dehydratase 효소의 유전형질의 다형질성이 어떠한 영향을 주는지를 알아보고자 연작업자 450명을 연폭로군으로 연폭로가 없는 85명을 대조군으로 선정하였다. 방 법 : 조혈기능의 생화학적 지표로는 혈중ZPP, 요중 ALA, 혈색소 및 혈구용적치를 택하였고, 이들 상호관계에 영향을 줄 수 있는 교란변수로서 성, 연령, BMI, 흡연습관, 음주습관 및 연작업자들의 경우 연폭로 기간을 조사하였다. 결 과 : 동형유전형질인 ALADI을 가진 연작업자들은 407명으로 전체의 90.4 %이었으며, 대조군에서도 77명으로 전체의 90.6 %로서 양군간에 차이가 없었다.동형 유전형질을 가진 연작업자들보다 이형 유전형질을 가진 연작업자들의 골중 연량과 혈중 ZPP의 평균값이 적었으나 통계적으로 유의하지 않았고 나머지 연구변수들의 평균도 유전형질의 구분에 따른차이는 없었다. 성, 직력, BMI, 흡연여부, 음주여부 등의 흔란변수를 통제한 후 혈중 연량 및 골중 연량과 ALAD유전형질이 혈색소에 미치는 영향을 구한 바 혈중 연량과 골중 연량만이 혈색소에 유의한 영향을 주었을뿐 ALAD 유전형질은 유의한 영향이 없었다. 반면에 혈구용적치의 경우에는 혈중 연량과 골중 연량 그리고 유전형질 모두가 유의한 영향을 주지 못했다.요중 ALA를 종속변수로 하고 관련 혼란변수를 통제한 후 혈중 연량과 ALAD 유전형질 그리고 양자의 교호작용을 독립변수로 한 회귀분석들에서 혈중 연량 및 골중 연량과 ALAD 유전형질 모두가 주효과(main effect) 및 교호작용(effect modifies-tion)이 유의하석 이형 ALAD 유전형질을 가진 연작업자들의 ALAU가 동형의 유전형질을 가진 연작업자들보다 상대적으로 낮은 값을 나타냈다.혈중 ZPP를 종속변수로 하고 관련 혼란변수를 통제한 후 혈중 연량과 ALAD 유전형질 그리고 양자의 교호작용을 독립변수로 한 회귀분석들에서 혈중연량 및 골중 연량과 ALAD 유전형질 모두가 음의주효과(maln effect)가 나타나서 이형 유전형질의 연작업자들의 혈중 ZPP가 동형 유전형질의 연작업자보다 상대적으로 적은 값을 나타냈으나 교호작용(effect modification)은 없었다. 결 론 : 상기 결과로 미루어 ALAD 유전형질은 혈색소에는 유의한 영향을 주지 못했으나 ALAU 및 혈중 ZPP에는 유의한 영향을 주어 동형의 유전형질인 연작업자보다 이형의 유전형질 연작업자들이 상대적으로 낮은 ALAU와 혈중 ZPP값을 보여주어이형유전형질이 연에 보호효과가 있다는 가설을 돼받침하였다 Objectives : To evaluate the effect of ALAD polymorphism on the relationship of blood and bone lead with hematologic biomarkers in lead exposed workers, 450 lead exposed workers and 85 non-lead exposed workers were selected. Methods : Blood lead and tibia bone lead were selected as parameters of lead exposure and blood ZPP, urinary ALA (ALAU) , hemoglobin (Hb) and hematocrit (Hct) were chosen as parameters of hematologic effect of lead exposure. Genotype of each subject was assayed and expressed as ALADI and ALAD2. Demographic information such as sex, age and personal habit of smoking and drinking were collected. Job duration of lead exposed workers was also obtained. Results : The overall prevalence of the variant allele, ALAD2 in lead exposed workers was 9.6 %(43 out of 450 lead workers) which was not differed from control workers (9.4 % : 8 out of 85) . The means of tibial lead and blond ZPP in lead workers with ALAD2 were lower than those of lead workers with ALAD1, but the differences were not statistically significant. After adjusting for possible confounders (sex, job duration, BMI, drinking and smoking status) only blood lead and bone lead contributed negatively to the level of hemoglobin with statistical significance without any contribution of ALAD genotype. On the other hand, no significant effect of blood lead, bone lead and ALAD genotype were observed on the level of hematocrit after controlling possible confounder. ALAD genotype in the multiple regression analysis of blood lead fed bone lead with log transformed urinary ALA (LogALAU) after adjusting for possible confounders showed significant main and interaction effect on LogALAU simultaneously, which resulted lower LogALAU in lead exposed workers of ALAD2 than ALAD1. It was also observed only main effect of ALAD gene type on blood ZPP after adjusting possible confounder resulting lower ZPP in lead workers of ALAD2 than ALAD1. Conclusions : With above results, it was found that ALAD polymorphism did not affect on the level of hemoglobin and hematocrit, but ALAD polymorphism made significant effect on the association of blood and bone lead with urinary ALA and blood ZPP. The lower urinary ALA and blood ZPP in ALAD2 lead workers suggested that ALAD2 genotype may be supportive for the protective effect of lead.