Nephrotoxic Potential and Toxicokinetics of Melamine Combined with Cyanuric Acid in Rats

Kim, Ghee Hwan,Kang, Mi Jeong,Noh, Keumhan,Oh, Do Gyeong,Kang, Wonku,Jeong, Hye Gwang,Lee, Kwang Youl,Kim, Hangun,Kim, Hyung Sik,Jeong, Tae Cheon Taylor Francis 2014 Journal of toxicology and environmental health. Pa Vol.77 No.22

Taylor & Francis : NEPHROTOXIC POTENTIAL AND TOXICOKINETICS OF MELAMINE COMBINED WITH CYANURIC ACID IN RATS

( Ghee Hwan Kim ),( Mi Jeong Kang ),( Keum Han Noh ),( Do Gyeong Oh ),( Won Ku Kang ),( Hye Gwang Jeong ),( Kwang Youl Lee ),( Han Gun Kim ),( Hyung Sik Kim ),( Tae Cheon Jeong ) 전남대학교 약품개발연구소 2014 약품개발연구지 Vol.23 No.-

To investigate the nephrotoxic potential of melamine (MEL) and cyanuric acid (CA) in male Sprague-Dawley rats, 7-d repeated-dose studies were performed. The experimental groups of MEL100 and CAl00 were orally administered with MEL and CA at 100 mg/kg/d for 7 d, respectively. In groups dosed with MEL-cA mixtures, melamine and cyanuric acid (1:1) were simultaneously administered at 4, 20, or 100 mg/kg/d for 7 d (i.e., MEL-CA4, MEL-CA20, or MEL-CA 100, respectively). Body weights were not markedly affected in MEL 100, CA 100, and MEL-CA4 groups, but significantly reduced in MEL-CA 20 and 100 rats. Most parameters determined in sera and tissues were not markedly altered in MEL 100, CA 100, and MEL-CA4-treated rodents. However, BUN, creatinine, total protein, and kidney weights were significantly increased in MEL-CA20- and MEL-CA100-treated animals. Renal histopathologic findings also revealed signs of toxicity, including tubular dilatation, crystal deposition, granulomatous tubulo-interstitial inflammation, and tubular necrosis with regeneration. Data suggested that the combination of MEL and CA might be responsible for observed nephrotoxicity that was not seen following individual exposure to either MEL or CA alone. Subsequently, the concentrations of MEL and CA were determined in serum, urine, and kidney tissues by using liquid chromatography-mass spectrometry. Toxicokinetic studies indicated that MEl or CA alone might be eliminated almost completely within 24 h after dosing showing no accumulation in kidney. However, the combined MEL-CA dose produced marked accumulation of chemicals in blood and kidneys. These results suggested that combined MEL and CA might produce renal toxicity due to significant chemical accumulation in kidney accompanied by low excretion.

Medicinal Chemistry : NEPHROTOXIC POTENTIAL AND TOXICOKINETICS OF MELAMINE COMBINED WITH CYANURIC ACID IN RATS

( Ghee Hwan Kim ),( Mi Jeong Kang ),( Keum Han Noh ),( Do Gyeong Oh ),( Won Ku Kang ),( Hye Gwang Jeong ),( Kwang Youl Lee ),( Han Gun Kim ),( Hyung Sik Kim ),( Tae Cheon Jeong ) 영남대학교 약품개발연구소 2015 영남대학교 약품개발연구소 연구업적집 Vol.25 No.-

To investigate the nephrotoxic potential of melamine (MEL) and cyanuric acid (CA) in male Sprague-Dawley rats,7-d repeated-dose studies were performed. The experimental groups of MEL100 and CA100 were orally administered with MEL and CA at 100 mg/kg/d for 7 d, respectively. In groups dosed with MEL-CA mixtures, melamine and cyanuric acid (1:1) were simultaneously administered at 4, 20, or 100 mg/kg/d for 7 d (i.e., MEL-CA4, MEL-CA20, or MEL-CA100, respectively). Body weights were not markedly affected in MEL100, CA100, and MEL-CA4 groups, but significantly reduced in MEL-CA 20 and 100 rats. Most parameters deter-mined in sera and tissues were not markedly altered in MEL100, CA100, and MEL-CA4-treated rodents, However, BUN, creatinine, total protein, and kidney weights were significantly increased in MEL-CA20-and MEL-CA100-treated animals. Renal histopathologic findings also revealed signs of toxicity, including tubular dilatation, crystal deposition, granulomatous tubu-lo-interstitial inflammation, and tubular necrosis with regeneration. Data suggested that the combination of MEL and CA might be responsible for observed nephrotoxicity that was not seen following individual exposure to either MEL or CA alone. Subsequently, the concentra-tions of MEL and CA were determined in serum, urine, and kidney tissues by using liquid chromatography-mass spectrometry. Toxicokinetic studies indicated that MEL or CA alone might be eliminated almost completely within 24 h after dosing showing no accumulation in kidney. However, the combined MEL-CA dose produced marked accumulation of chemicals in blood and kidneys. These results suggested that combined MEL and CA might produce renal toxicity due to significant chemical accumulation in kidney accompanied by low excretion.

원보 : LC/MS/MS를 이용한 비글견의 혈장 중 Doxifluridine 및 5-Fluorouracil의 동시 분석법 Validation

김기환 ( Ghee Hwan Kim ),김원 ( Won Kim ),김진성 ( Jin Sung Kim ),김경일 ( Qing Ri Jin ),강원구 ( Won Ku Kang ),이종화 ( Jong Hwa Lee ),하정헌 ( Jung Heun Ha ),정은주 ( Eun Ju Jeong ) 한국약제학회 2007 Journal of Pharmaceutical Investigation Vol.37 No.3

배자와 태아에서 하악골의 형태발생 및 교원질 발현에 관한 면역조직화학적 연구

국윤아,김상철,김은철,김오환,김정기 대한치과교정학회 1996 대한치과교정학회지 Vol.26 No.2

치아 위치에 영향을 미치는 악안면의 성장 발육에서 Meckel 연골발생전 후의 하악골 형성과정과 교원 단백질 분포 및 발현정도를 알아보고자 좌고를 측정하여 태령을 결정한 후 4주부터 38주까지 50례의 배자와 태아를 대상으로 통법에 따른 조직절편을 제작하였으며 Hematoxylin과 Eosin, Alcian blue-pas와 Goldner의 Masson Trichrome 염색, 그리고 제1형과 제2형 교원 단백질에 대한 면역조직화학 염색을 시행하였다. 좌고 20.5 MM 배자에서 Meckel 연골이 출현하였으며, 좌고 22mm에서 38mm까지 하악골 외방에 신생골을 형성하고, 좌고 60mm태아에서 Meckel 연골이 점유하던 공간이 신생골로 채워져 연골내골화가 뚜렸하게 관찰되었으나, 좌고 240mm에서 Meckel 연골이 거의 소실되었다. 교원질에 대한 면역 염색결과에서 Mackel 연골 출현전 제1형 교원질 발현은 주로 상, 하악돌기의 구강상피에 국한되어 관찰되었고 제2형교원질 발현은 상대적으로 약간 적었다. Meckel 연골 출현 및 신생골 형성시기는 제1형교원질이 주로 치제상피와 신생골에서 약양성의 발현을 보였으며, Meckel 연골 및 신생골에서는 제1형보다 제2형의 교원질이 많이 발현되었다. 막내골화시기에는 제1형 교원질이 골아세포 및 골기질에서 중등도로 발현되었으나, 제2형에서는 경미하게 나타나 Meckel 연골형성전 후 제2형에서 제1형으로 발현전환이 있었다. Underlying malocclusions and dentofacial deformities are often related to variations in the craniofacial development. Type I and type Ⅱcollagens are considered the major collagens of bone and cartilage respectively. Monitoring the patterns of those protein expressions during development will provide a basis for the understanding of normal and abnormal growths. This study was undertaken to investigate the morphogenetic changes and the expression patterns of type I and Ⅱcollagen proteins involved in the developing mandible of human embryos and fetuses. 50 embryos and fetuses were studied with Hematoxylin and Eosin, Alcian blue-PAS, Masson Trichrome, and Immunohistochemical stains. The results were as follows: 1. A 13.5mm embryo showed the stomatodeum with dental lamina, maxillary and mandibular processes. Meckel's cartilage appeared in the mandibular arch of a 20.5mm embryo. New bone formation was bilaterally initiated at the outer side of middle portion of Meckel's cartilage of 22-38 mm embryos. 2. Meckel' cartilage was resorbed at the 15th week fetus. The endochondral ossification was observed where there was direct replacement of cartilage by bone. Meckel' cartilage disappeared and membraneous ossification were observed at the 25th week. 3. Before the appearance of Meckel's cartilage, the expression of type I collagen was moderate at the odontogenic epithelium of maxillary & mandibular process, but mild for the expression of type Ⅱ collagen. 4. During the appearance of Meckel's cartilage and new bone formation, the immunoactivity of type Ⅱ collagen was more expressed than type I collagen at the Meckel's cartilage and new bone. 5. During intramembranous bone formation, the expression of type Ⅱcollagen was rare in the bony trabeculae. There was a switch for the expression of collagens from type Ⅱto type I during the appearance of Meckel's cartilage.

APX-115, a first-in-class pan-NADPH oxidase (Nox) inhibitor, protects db/db mice from renal injury

Cha, Jin Joo,Min, Hye Sook,Kim, Ki Tae,Kim, Jung Eun,Ghee, Jung Yeon,Kim, Hyun Wook,Lee, Ji Eun,Han, Jee Young,Lee, Gayoung,Ha, Hun Joo,Bae, Yun Soo,Lee, Sae Rom,Moon, Sung Hwan,Lee, Sung Chan,Kim, Ga Nature Publishing Group 2017 Laboratory investigation Vol.97 No.4

<P>Recent studies have suggested that renal Nox is important in the progression of diabetic nephropathy. Therefore, we investigated the effect of a novel pan-NOX-inhibitor, APX-115, on diabetic nephropathy in type 2 diabetic mice. Eight-week-old db/m and db/db mice were treated with APX-115 for 12 weeks. APX-115 was administered by oral gavage at a dose of 60 mg/kg per day. To compare the effects of APX-115 with a dual Nox1/Nox4 inhibitor, db/db mice were treated with GKT137831 according to the same protocol. APX-115 significantly improved insulin resistance in diabetic mice, similar to GKT137831. Oxidative stress as measured by plasma 8-isoprostane level was decreased in the APX-115 group compared with diabetic controls. All lipid profiles, both in plasma and tissues improved with Nox inhibition:APX-115 treatment decreased Nox1, Nox2, and Nox4 protein expression in the kidney. APX-115 decreased urinary albumin excretion and preserved creatinine level. In diabetic kidneys, APX-115 significantly improved mesangial expansion, but GKT137831 did not. In addition, F4/80 infiltration in the adipose tissue and kidney decreased with APX-115 treatment. We also found that TGF-beta stimulated ROS generation in primary mouse mesangial cells (pMMCs) from wild-type, Nox1 KO, and Duox1 KO mice, but did not induce Nox activity in pMMCs from Nox2 knockout (KO), Nox4 KO, or Duox2 KO mice. These results indicate that activating Nox2, Nox4, or Duox2 in pMMCs is essential for TGF-beta-mediated ROS generation. Our findings suggest that APX-115 may be as effective or may provide better protection than the dual Nox1/Nox4 inhibitor, and pan-Nox inhibition with APX-115 might be a promising therapy for diabetic nephropathy.</P>

Clinicopathologic Characteristics and Mutational Status of Succinate Dehydrogenase Genes in Paraganglioma of the Urinary Bladder: A Multi-Institutional Korean Study

Park, Sanghui,Kang, So Young,Kwon, Ghee Young,Kwon, Ji Eun,Kim, Sang Kyum,Kim, Ji Yeon,Kim, Chul Hwan,Kim, Hyun-Jung,Moon, Kyung Chul,Pyo, Ju Yeon,Park, Won Young,Park, Eun Su,Sung, Ji-Youn,Sung, Sun College of American Pathologists; 1999 2017 ARCHIVES OF PATHOLOGY AND LABORATORY MEDICINE Vol.141 No.5

소아 잠복 결핵 감염 진단에 있어서 투베르쿨린 피부반응 검사와 결핵 특이항원 자극 Interferon-γ 분비능 측정의 비교

전진경,김창기,김현숙,정귀영,인요한,김기환,이택진,전지현,김동수,Chun, Jin-Kyong,Kim, Chang Ki,Kim, Hyun Sook,Jung, Ghee Young,Linton, John A.,Kim, Ki Hwan,Lee, Taek Jin,Jeon, Ji Hyun,Kim, Dong Soo 대한소아청소년과학회 2008 Clinical and Experimental Pediatrics (CEP) Vol.51 No.9

목 적 : 결핵 감염 관리에 있어서 잠복 결핵 감염을 찾아 내어 예방적 화학요법을 시행하는 것은 주요 핵심이다. 결핵에 노출된 소아에서 잠복 결핵 감염 진단을 위해 투베르쿨린 피부반응과 최근 널리 쓰이기 시작한 체외 검사법으로 결핵 특이항원 자극에 의한 T 세포의 $IFN-{\gamma}$ 분비능 측정 (QFT-G IT)이 있다. 잠복 결핵 감염 진단에 있어 두 검사법의 차이를 알아보고자 본 연구를 진행하였다. 방 법 : 2006년 10월 1일부터 2007년 4월 30일까지 6개월 간 총 111명의 소아를 대상으로 투베르쿨린 반응과 QFT-G IT 검사를 시행하였고, 동일 기간 내인 2개월 간 진단 된 성인 결핵 환자 29명에서 동일한 검사 결과를 후향적으로 알아보았다. 결 과 : 결핵 환자와의 가까운 접촉력을 주소로 내원한 무증상의 환자 33명 중 15% (5명)에서 QFT-G IT 검사 양성 소견을 보였고, 투베르쿨린 피부반응은 42% (14명)에서 양성결과를 보여 두 검사 간의 일치율은 낮았다(${\kappa}=0.39$). 성인 결핵 환자에서 QFT-G IT 양성율은 86.2%였고, 결핵균 배양 검사 양성율은 48.2%였다. 배양검사 양성이면서 QFT-G IT 음성이었던 환자는 12.5%였다. 결 론 : 소아에서 잠복 결핵 감염을 진단함에 있어 가족력을 근저에 둔 투베르쿨린 피부반응 검사를 시행하되 접촉력이 불분명하거나 지속적이지 않았을 경우 혹은 BCG 접종 효과로 의심되는 경우 결핵균 특이항원 자극 $IFN-{\gamma}$ 분비능 측정이 보조적 수단으로 사용 될 수 있을 지는 아직 확실하지 않으며 향후 수년 간 다 기관 연구가 필요하다. Purpose : Surveillance for detecting and managing latent tuberculosis infection (LTBI) is a key component of tuberculosis control. The classic surveillance tool, the tuberculin skin test (TST), may have some limitations when used in the Bacillus Calmette-$Gu{\acute{e}}rin$ (BCG)-vaccinated population. The object was to perform a blood test $QuantiFERON^{(R)}$-TB Gold In Tube (QFT-G IT) based on the detection of interferon-$\gamma$ ($IFN-{\gamma}$) released by T cells in response to Mycobacterium tuberculosis-specific antigens, and to compare the efficacy of this new diagnostic tool for LTBI with that of TST. Methods : For six months, between October 1, 2006 and April 30, 2007, data were collected from 111 patients under 15 years of age at Severance Children's Hospital. TST and QFT-G IT tests were performed with children with or without contact histories of tuberculosis. In addition to these tests, we examined comparative data from 29 adults who had tuberculosis, to detect false negative rates in the QFT-G IT method. Results : Thirty-three children had household contact histories. In this group, 15% and 42% of cases were found to be positive using the QFT-G IT assay and TST, respectively. Agreement was low between these two tests (${\kappa}=0.39$). In the adult active tuberculosis group, the QFT-G IT false negative rate defined as a positive culture and a negative QFT-G IT result was 12.5%. Conclusion : In diagnosing LTBI in children, the usefulness of a whole-blood $IFN-{\gamma}$ assay employing TB-specific antigens will be revealed only by examining additional longitudinal clinical data; this study serves as a starting point in that process.

LC/MS/MS를 이용한 원숭이 혈액에서의 Doxifluridine과 대사체 5-FU 동시분석법 개발 및 Validation

우영아,김기환,김원,이종화,정은주,김진호,박귀례,김충용,Woo, Young-Ah,Kim, Ghee-Hwan,Kim, Won,Lee, Jong-Hwa,Jeong, Eun-Ju,Kim, Jin-Ho,Park, Kui-Lea,Kim, Choong-Yong 대한약학회 2007 약학회지 Vol.51 No.3

A reverse-phase high performance liquid chromatography method with electrospray ionization and detection by mass spectrometry is described for the simultaneous determination of doxifluridine and its active metabolite 5-flu-orouracil (5-FU) in monkey serum. The method has greater sensitivity and simpler process than previous published methods with good accuracy and precision. A proper liquid/liquid extraction was used to extract simultaneously doxifluridine and 5-FU which has considerable difference in the polarity. Extracts were analyzed using LC/MS/MS providing a short analysis time within 5 min. The lower limit of quantification was validated at 10.0 ng/ml of serum for both doxifluridine and 5-FU. Accuracy and precision of quality control (QC) samples for both analytes met FDA Guidance criteria of ±15% for average QC accuracy with coefficients of variation less than 15%. The method will be applicable for preclinical studies and bioequivalence studies.

변형 주관절에 뒤따른 척골 신경 마비에 대한 Medial Epicondylectomy

김종기,이기연,유영락,김남규,정환영 대한신경외과학회 1974 Journal of Korean neurosurgical society Vol.3 No.2

We have reported our experience with 5 cases, each of whom had tardy ulnar palsy, which was treated by media) epiccndylectomy without anterior transplantation of ulnar nerve, and each of whom had good result in 2 yearsfollow-up study. All patients had cubitus valgus deformity which was followed to the fracture-dislocation of the elbow region. The operative procedure employed in this sreies is carried out with the patient spine, the humerus abducted end externally rotated, and the elbow flexed so that the extensor surface of the forearm may rest comfortably en a padded arm board. A skin incision 5 to 6 cm long made parallel to the ulnar nerve but a centimeter or more in front of it, centered on the prominence of the condyle. After fully exposing the medial epicondyle and the supracondylar ridge sub-periosteally, they are removed with rongeurs. No sharp edge should be left and the bone should be removed sufficiently checking X-ray during the operation for the evaluation of bone shape hidden in the soft tissues. Following epicodylectomy, all patients gained relief from pain and had gradual ??turn of motor function. Because of less risk to traumatize to nerve branches, to interfere with blood supply, and to adhere the neighboring tissues, end of ability to move the elbow through a full range immediately, we believe this method gives results superior to anterior transplentation operation.