Identification of a sensitive urinary biomarker, selenium-binding protein 1, for early detection of acute kidney injury

Kim, Kyeong Seok,Yang, Hun Yong,Song, Hosup,Kang, Ye Rim,Kwon, JiHoon,An, JiHye,Son, Ji Yeon,Kwack, Seung Jun,Kim, Young-Mi,Bae, Ok-Nam,Ahn, Mee-Young,Lee, Jaewon,Yoon, Sungpil,Lee, Byung μ,Kim, Hyung TAYLOR & FRANCIS 2017 Journal of Toxicology and Environmental Health Vol.80 No.9

<P>Acute kidney injury (AKI) is associated with increased mortality rate in patients but clinically available biomarkers for disease detection are currently not available. Recently, a new biomarker, selenium-binding protein 1 (SBP1), was identified for detection of nephrotoxicity using proteomic analysis. The aim of this study was to assess the sensitivity of urinary SBP1 levels as an early detection of AKI using animal models such as cisplatin or ischemia/reperfusion (I/R). Sprague-Dawley rats were injected with cisplatin (6 mg/kg, once i.p.) and sacrificed at 1, 3, or 5 days after treatment. Ischemia was achieved by bilaterally occluding both kidneys with a microvascular clamp for 45 min and verified visually by a change in tissue color. After post-reperfusion, urine samples were collected at 9, 24, and 48 hr intervals. Urinary excretion of protein-based biomarkers was measured by Western blot analysis. In cisplatin-treated rats, mild histopathologic alterations were noted at day 1 which became severe at day 3. Blood urea nitrogen (BUN) and serum creatinine (SCr) levels were significantly increased at day 3. Levels of urinary excretion of SBP1, neutrophil gelatinase-associated lipocalin (NGAL), and a tissue inhibitor of metalloproteinase-1 (TIMP-1) were markedly elevated at day 3 and 5 following drug treatment. In the vehicle-treated I/R group, serum levels of BUN and SCr and AST activity were significantly increased compared to sham. Urinary excretion of SBP1 and NGAL rose markedly following I/R. The urinary levels of SBP1, NGAL, TIMP-1, and KIM-1 proteins excreted by AKI patients and normal subjects were compared. Among these proteins, a marked rise in SBP1 was observed in urine of patients with AKI compared to normal subjects. Based upon receiver-operator curves (ROC), SBP1 displayed a higher area under the curve (AUC) scores than levels of SCr, BUN, total protein, and glucose. In particular, SBP1 protein was readily detected in small amounts of urine without purification. Data thus indicate that urinary excretion of SBP1 may be useful as a reliable biomarker for early diagnosis of AKI in patients.</P>

Erythrophagocytosis of Lead-Exposed Erythrocytes by Renal Tubular Cells: Possible Role in Lead-Induced Nephrotoxicity

Kwon, So-Youn,Bae, Ok-Nam,Noh, Ji-Yoon,Kim, Keunyoung,Kang, Seojin,Shin, Young-Jun,Lim, Kyung-Min,Chung, Jin-Ho U.S. Dept. of Health, Education, and Welfare, Publ 2015 Environmental health perspectives Vol.123 No.2

<P>Background: Nephrotoxicity associated with lead poisoning has been frequently reported in epidemiological studies, but the underlying mechanisms have not been fully described.</P><P>Objectives: We examined the role of erythrocytes, one of the major lead reservoirs, in lead-associated nephrotoxicity.</P><P>Methods and results: Co-incubation of lead-exposed human erythrocytes with HK-2 human renal proximal tubular cells resulted in renal tubular cytotoxicity, suggesting a role of erythrocytes in lead-induced nephrotoxicity. Morphological and flow cytometric analyses revealed that HK-2 cells actively phagocytized lead-exposed erythrocytes, which was associated with phosphatidylserine (PS) externalization on the erythrocyte membrane and generation of PS-bearing microvesicles. Increased oxidative stress and up-regulation of nephrotoxic biomarkers, such as NGAL, were observed in HK-2 cells undergoing erythrophagocytosis. Moreover, TGF-β, a marker of fibrosis, was also significantly up-regulated. We examined the significance of erythrophagocytosis in lead-induced nephrotoxicity in rats exposed to lead via drinking water for 12 weeks. We observed iron deposition and generation of oxidative stress in renal tissues of lead-exposed rats, as well as the histopathological alterations such as tubulointerstitial lesions, fibrosis, and up-regulation of KIM-1, NGAL, and TGF-β.</P><P>Conclusions: Our data strongly suggest that erythrophagocytosis and subsequent iron deposition in renal tubular cells could significantly enhance nephrotoxicity following lead exposure, providing insight on lead-associated kidney damages.</P><P>Citation: Kwon SY, Bae ON, Noh JY, Kim K, Kang S, Shin YJ, Lim KM, Chung JH. 2015. Erythrophagocytosis of lead-exposed erythrocytes by renal tubular cells: possible role in lead-induced nephrotoxicity. Environ Health Perspect 123:120–127; http://dx.doi.org/10.1289/ehp.1408094</P>

Potentiation of Morphine's Antinociception by Group II and Group III Metabotropic Glutamate Receptors Agonists on a Rat Incisional Pain

Kim, Chang Mo,Choi, Jeong Il,Bae, Hong Beom,Kim, Seok Jai,Chung, Sung Tae,Kim, Ok Hwan,Yoon, Myung Ha The Korean Pain Society 2006 The Korean Journal of Pain Vol.19 No.2

Background: The aim of this study was to clarify the role of spinal groups II and III metabotropic glutamate receptors (mGluRs) with respect to postoperative pain at the spinal level. In addition, the nature of the pharmacological interaction between groups II and III mGluRs agonists and morphine was determined. Methods: Catheters were inserted into the intrathecal space of male SD rats. To induce postoperative pain, an incision was made in the plantar surface of the hind paw. A pharmacological characteristic for the interaction between groups II and III mGluRs agonists and morphine was evaluated using a fixed-dose analysis. Results: None of intrathecal group II and III mGluRs agonists modified the withdrawal threshold of the incisional pain. The administration of intrathecal morphine resulted in an increase of a dose dependent withdrawal threshold. A fixed-dose analysis revealed that the group III mGluRs agonist, ACPT-III, increased the antinociceptive action of morphine, while the group II mGluRs agonist, APDC, had no effect the antinociception of morphine. Conclusions: These results suggest that group II and III mGluRs may not play a direct modulatory role in the processing of postoperative pain at the spinal level. However, agonizing group III mGluRs may indirectly contributable to the potentiation of morphines antinociception in the spinal cord. Thus, the combination of morphine and a group III mGluRs agonist may be useful in the management of spinal postoperative pain.

Effect of Fermented Small Soybean Powder Mixed with Mulberry Leaf on Metabolic Improvement and Hexokinase Activity in Streptozotocin-induced Diabetic Rats

Kim, Sun-Mi,Han, Jin-Chul,Park, Hum-Dai,Ko, Ki-Sung,Lee, Dae-Hoon,Kim, Sung-Min,Kwon, Dong-Yeul,Kim, Jin-Sook,Kim, Ok-Hee,Hwang, Jin-Bong,Gung, Bae-Nahm,Choo, Young-Kug The Korean Nutrition Society 2006 Nutritional Sciences Vol.9 No.2

Beans are well known to be high-protein diets. Bean seeds contain arginine, lysine, or glycine-rich proteins which are effective to maintain lower glucose levels. In this study, the synergistic effect of fermented small soybean (Chounggukjang) and mulberry leaf on metabolism and hexokinase activity was investigated in streptozotocin (STZ)-induced diabetic rats. We divided 8 groups as follows: non-diabetic rat group fed with only water diet (NC: control), and STZ-induced diabetic rat groups fed with water (DC), fermented Rhynchosia Nulubilis (Bbc), fermented Glycine max Merr (Ybc), Bbc and YBc (BYbc), mulberry leaf and Bbc (MBbc), mulberry leaf and Ybc (MYbc), or the mulberry leaf, Bbc, and Ybc (MBYbc). Diabetes mellitus was induced in rats by subcutaneous STZ administration (70 mg/kg of body weight). All diet groups were fed with Chounggukjang in a powder form. Three ml of Chounggukjang solution (0.75 mg per gram of body weight) dissolved in distilled water was orally administered to all rat groups after STZ administration except for NC rat group. In groups fed with fermented soybeans, the body weight (increased), food efficiency ratio (FER) (increased), glucose level (decreased) and hexokinase (HK) activity (increased) significantly differed to NC. Among them, particularly in the groups fed with both fermented soybeans and mulberry leaf, kidney weight significantly decreased, whereas HK activity significantly increased compared to DC. These results suggest that Chounggukjang of both fermented soybeans and mulberry leaf is potentially used as an effective functional food to prevent diabetes complications.

Cigarette Smoking and Risk of Lung Cancer in Korean Men: The Seoul Male Cancer Cohort Study

Bae, Jong-Myon,Lee, Moo-Song,Shin, Myung-Hee,Kim, Dong-Hyun,Li, Zhong-Min,Ahn, Yoon-Ok KOREAN ACADEMY OF MEDICAL SCIENCE 2007 JOURNAL OF KOREAN MEDICAL SCIENCE Vol.22 No.3

<P>Lung cancer is the leading cause of cancer deaths in Korea. The aim of this study was to estimate lung cancer risk of cigarette smoking in Korean men by a 10-yr follow-up prospective cohort study using the primary databases. The number of subjects was 14,272 men, who had full information of smoking habits among participants in the Seoul Male Cancer Cohort Study (SMCC). Total 125,053 person-years were calculated by determining the number of days from the start of follow-up, January 1, 1993, until the date of lung cancer diagnosis, death from another cause, or the end of follow-up, December 31, 2002, followed by converting the number of days to years. The information of outcome was obtained by the database of Korea Central Cancer Registry, Seoul Regional Cancer Registry, and Korea Statistical Office. The relative risk (RR) and its 95% confidence interval (CI) values of smoking were calculated using Cox proportional hazards regression stratified on potential confounders. During the follow-up periods, 78 cases of lung cancer occurred. The cigarette smoking is the major risk factor and increases the 4.18-fold risk of lung cancer in Korean men. In order to control lung cancer, intervention of quitting smoking is needed.</P>

Methylated Organic Metabolites of Arsenic and their Cardiovascular Toxicities

Bae, Ok-Nam,Lim, Kyung-Min,Noh, Ji-Yoon,Kim, Keun-Young,Lim, Eun-Kyung,Chung, Jin-Ho Korean Society of ToxicologyKorea Environmental Mu 2008 Toxicological Research Vol.25 No.4

Recently, arsenic-toxicity has become the major focus of strenuous assessment and dynamic research from the academy and regulatory agency. To elucidate the cause and the mechanism underlying the serious adverse health effects from chronic ingestion of arsenic-contaminated drinking water, numerous studies have been directed on the investigation of arsenic-toxicity using various in vitro as well as in vivo systems. Neverthless, some questions for arsenic effects remain unexplained, reflecting the contribution of unknown factors to the manifestation of arsenic-toxicity. Interestingly, very recent studies on arsenic metabolites have discovered that trivalent methylated arsenicals show stronger cytotoxic and genotoxic potentials than inorganic arsenic or pentavalent metabolites, arguing that these metabolites could play a key role in arsenic-associated disorders. In this review, recent progress and literatures are summarized on the metabolism of trivalent methylated metabolites and their toxicity on body systems including cardiovascular system in an effort to provide an insight into the future research on arsenic-associated disorders.

Recent Trend in the Incidence of Premalignant and Malignant Skin Lesions in Korea between 1991 and 2006

Kim, Hei Sung,Cho, Eun Ah,Bae, Jung Min,Yu, Dong Soo,Oh, Shin Taek,Kang, Hoon,Park, Chul Jong,Lee, Jeong Deuk,Lee, Jun Young,Kim, Si-Yong,Kim, Hyung Ok,Park, Young Min The Korean Academy of Medical Sciences 2010 JOURNAL OF KOREAN MEDICAL SCIENCE Vol.25 No.6

<P>We evaluated the recent trend in the incidence of premalignant and malignant skin lesions between 1991 and 2006. Among 571,057 newly registered dermatology out-patients from our 8 affiliated university hospitals, 2,598 were diagnosed with a premalignant (899, 0.16%) or malignant skin lesions (1,699, 0.30%). Of 899 premalignant cases, 71.2% were actinic keratosis (AK), and 24.6% were Bowen's disease. Of 1,699 malignant cases, 46.2% were basal cell carcinoma, followed by squamous cell carcinoma (19.1%) and melanoma (7.1%). This 16-yr survey was divided equally into two time periods to compare the incidence of premalignant and malignant skin lesions at different time settings. Between 1991 and 1998, the incidence of cutaneous premalignancy was 0.10% which doubled during 1999-2006. For cutaneous malignancy, the incidence was 0.25% during 1991-1998 and 0.34% in 1999-2006. Incidence of AK among the new outpatients was 0.07% in 1991-1998 which staggered up to 0.15% in 1999-2006. These findings show an increase of both premalignant and malignant skin lesions, AK in particular in the dermatology outpatient-based incidence.</P>

Salsolinol, an endogenous neurotoxin, enhances platelet aggregation and thrombus formation

Bae, Ok-Nam,Kim, Young-Dae,Lim, Kyung-Min,Noh, Ji-Yoon,Chung, Seung-Min,Kim, Keunyoung,Hong, Suyoung,Shin, Sue,on, Jong-HyunYo,Chung, Jin-Ho Thieme 2008 Thrombosis and Haemostasis Vol.100 No.1

<B>Summary</B><P>Salsolinol, an endogenous neurotoxin, is known to be involved in the neuropathy of Parkinson’s disease and chronic alcoholism. In these diseases, increased thrombotic events are also commonly reported, yet the mechanism underlying remains poorly understood. Here we report that salsolinol can enhance agonist-induced platelet aggregation and granular secretion, which is essential in the thrombus formation. In rat and human platelets, agonist-induced platelet aggregation was significantly increased by salsolinol in a concentration-dependent manner. Agonist-induced granular secretions of serotonin and concomitant P-selectin expression were also augmented by salsolinol. α2-adrenergic blockers attenuated the salsolinol-enhanced aggregation and the inhibition of cyclic AMP generation was found, suggesting the involvement of α2-adrenergic receptor-mediated pathways in these events. In accord with the in-vitro results, in an arterial and venous thrombosis model in vivo in the rat, salsolinol shortened vessel occlusion time and increased thrombus formation, respectively. In conclusion, we demonstrated that sal-solinol can enhance agonist-induced aggregation and granular secretion in platelets through α2-adrenergic receptor activation, which resulted in the increased thrombus formation in vivo.These results suggest that salsolinol-enhanced platelet aggregation could be a possible contributing factor to the thrombotic events observed in Parkinson’s disease and alcoholism.</P>

Fabrication of Bi-2212/SrSO₄ Composite Superconductors by Melting Powder Mixtures

Kim, Kyu Tae,Jang, Seok Hern,Lim, Jun Hyung,Park, Eui Cheol,Joo, Jin Ho,Lee, Hoo Jeong,Hong, Gye Won,Kim, Chan Joong,Kim, Hye Rim,Hyun, Ok Bae Trans Tech Publications, Ltd. 2007 Materials science forum Vol.534 No.-

<P>We fabricated Bi-2212/SrSO4 composite superconductors by the melt casting process and evaluated the effects of the powder mixing method and melting temperature on their microstructure and superconducting properties. In the melt casting process, the Bi-2212 powders were mixed with SrSO4 by hand-mixing (HM) and planetary ball milling (PBM) and then the powder mixtures were melted at 1100°C~1200°C, solidified, and annealed. We found that the powder mixture prepared by PBM was finer and more homogeneously mixed than that prepared by HM, resulting in more homogeneous microstructure and smaller SrSO4 and second phases after annealing. The critical current (Ic) also varied significantly with the powder mixing method and the melting temperature. The Ic of the annealed rod prepared by PBM was 193 A at 77 K when melted at 1100°C, which is higher than that of the annealed rod prepared by HM (132 A). This enhancement in the Ic value for the former is considered to be due to its more uniform microstructure.</P>

Dosimetric comparisons of three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and helical tomotherapy in whole abdominopelvic radiotherapy for gynecologic malignancy.

Kim, Yong Bae,Kim, Joo Ho,Jeong, Kyung Keun,Seong, Jinsil,Suh, Chang Ok,Kim, Gwi Eon Adenine Press 2009 Technology in cancer research & treatment Vol.8 No.5

<P>OBJECTIVES: The goal of this study was to dosimetrically compare 3-dimensional radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), and helical tomotherapy (TOMO) plans for whole abdominopelvic radiotherapy (WART) in patients with gynecologic cancer. METHODS: Ten patients were selected for WART planning. Doses were prescribed to planning target volumes (PTVs) as the followings: 30 Gy to PTV-whole abdominopelvis (PTV-WA), 40 Gy to PTV-para-aortic lymph node (PTV-PALN), 44 Gy to PTV-pelvis, and 50 Gy to gross target volume (GTV) in 20 fractions. Dose to whole liver, both kidneys, and spinal cord were constrained below each tissue tolerance, and bone marrow (BM)-sparing technique was adopted in IMRT and TOMO. Dosimetric parameters and treatment times were compared among plans. RESULTS: Calculated doses in TOMO came most closely to the prescribed dose for coverage of PTV-WA, PTV-PALN, PTV-pelvis, and GTV compared to 3DCRT, and IMRT. In normal organs, TOMO had significantly better dosimetric profiles compared to IMRT and 3DCRT. TOMO significantly reduced V(20Gy), and mean dose of whole liver, both kidneys, and spinal cord. The use of BM-sparing technique (BMS) did not impair coverage of target volume in IMRT and TOMO. While IMRT showed no differences of irradiated BM dose using BMS, TOMO with BMS reduced half V(20Gy) of BM compared to TOMO without BMS. CONCLUSIONS: TOMO showed dosimetric superiority in target coverage, sparing BM, and other normal organs compared to 3DCRT and IMRT. Clinical experiences will be needed for evaluation of feasibility of WART using TOMO in patients with gynecologic cancer.</P>