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Biomedical subjects

M K Cho

Publications and source records attributed to M K Cho.

At least 19 recordsLinked to original sources
PubMed2006

Hydrogen peroxide-producing Lactobacilli in the vaginal flora of pregnant women with preterm labor with intact membranes.

OBJECTIVES: To investigate the role of vaginal infection in preterm delivery, we studied characteristics of vaginal discharge related to hydrogen peroxide-producing Lactobacilli. METHODS: Vaginal specimens were obtained from 66 women with normal pregnancy and 30 women with preterm labor with intact membranes. pH, leukocyte counts on wet smear, and scores by Nugent criteria on Gram stain were measured. Lactobacilli were tested for their production of hydrogen peroxide. RESULTS: Leukocyte levels in wet smears and Nugent scores of Gram-stained smear of women with preterm labor with intact membranes were significantly higher than those of normal pregnant women (P<0.01, P<0.05). Hydrogen peroxide-producing Lactobacilli levels in the vaginal flora of women with preterm labor with intact membranes were significantly lower (P<0.01). CONCLUSION: Distribution of hydrogen peroxide-producing Lactobacilli in vaginal flora as defense factors for infection may have an important role in the pathophysiology of preterm labor.

Adult↗
PubMed2001

Effects of cysteine on the pharmacokinetics of intravenous phenytoin in rats with protein-calorie malnutrition.

The effects of cysteine on the pharmacokinetics of phenytoin and one of its metabolites, 5-(p-hydroxyphenyl)-5-phenylhydantoin (pHPPH) were investigated after intravenous administration of phenytoin, 25 mg/kg, to control rats (4-week fed on 23% casein diet) and rats with PCM (protein-calorie malnutrition, 4-week fed on 5% casein diet) and PCMC (PCM with oral cysteine supplementation, 250 mg/kg, twice daily starting from the fourth week). In rats with PCM and PCMC, the phenytoin hydroxylation (to form pHPPH) activities were significantly smaller (164, 103 and 95.3 pmol/min per mg protein for the control rats, and rats with PCM and PCMC, respectively) than that in control rats. In rats with PCMC, the intrinsic clearance of phenytoin, CL(int) was significantly slower than those in control rats and rats with PCM (0.175, 0.131 and 0.044 ml/min). The above data suggested that the formation of pHPPH could be reduced in rats with PCM and PCMC. This was supported by significantly smaller 24-h urinary excretion of pHPPH (54.7, 35.6 and 32.5% of intravenous dose of phenytoin) in rats with PCM and PCMC than that in control rats. In rats with PCM, the maximum velocity (0.344, 0.203 and 0.196 microg/min), apparent volume of distribution in central compartment (44.4, 65.4 and 72.2 ml/kg) of phenytoin, and total area under the plasma concentration-time curve from time zero to time infinity (609, 714 and 1210 microg min/ml), renal clearance (20.5, 13.4 and 4.67 ml/min per kg) and 24-h urinary excretion (54.7, 35.6 and 32.5% of intravenous dose of phenytoin) of pHPPH were not returned to control levels by cysteine supplementation (rats with PCMC). This could be mainly due to the fact that the phenytoin hydroxylation activity in rats with PCMC was not returned to control level.

Algorithms↗
PubMed2001

Effects of cysteine on the pharmacokinetics and pharmacodynamics of intravenous and oral azosemide in rats with protein-calorie malnutrition.

The effects of cysteine on the pharmacokinetics and pharmacodynamics of azosemide were investigated after intravenous (10 mg/kg) and oral (20 mg/kg) administration to male Sprague-Dawley rats fed on 23% protein diet (control rats), and 5% protein diet with (rats with PCMC) or without (rats with PCM) oral cysteine (250 mg/kg, twice daily for the fourth week) for 4 weeks. After intravenous administration to rats with PCMC, some pharmacokinetic parameters restored fully or more than the level of control rats; the time-averaged nonrenal clearance (2.70 versus 2.32 ml/min/kg) and apparent volume of distribution at steady state (160 versus 189 ml/kg) were comparable to those in control rats, however, the terminal half-life (34.7 versus 57.2 min) and mean residence time (73.3 versus 99.3 min) were significantly shorter, area under the plasma concentration-time curve from time zero to time infinity (AUC, 1930 versus 2680 microg min/ml) was significantly smaller, and time-averaged renal (2.24 versus 1.21 ml/min/kg) and total body (CL, 4.98 versus 3.65 ml/min/kg) clearances were significantly faster than those in control rats. This could be mainly due to significantly faster renal clearance and at least partly due to increased cytochrome P450 1A2 activity by cysteine supplementation. After intravenous administration to rats with PCMC, the total amount of 8-hr urinary excretion of unchanged azosemide was significantly greater (457 versus 305 microg/g body weight), however, the 8-hr urine output (15.3 versus 31.1 ml/g kidney) was not significantly different between control rats and rats with PCMC. This could be due to the fact that urine output seemed to reach an upper plateau from 10 mg/kg dose of azosemide in rats.

Administration, Oral↗
PubMed2001

Prevention of c-Jun/activator protein-1 activation and microsomal epoxide hydrolase induction in the rat liver by cysteine during protein-calorie malnutrition.

Protein-calorie malnutrition (PCM), a major global health problem, arises during protein and/or energy deficit due to disease and nutritional inadequacy. To date, cellular adaptive responses and gene expression associated with PCM remain poorly understood. In view of the primary role of the liver in energy conversion, the present study was designed to investigate changes in hepatic morphology and molecular alterations during PCM. PCM caused marked decreases in the cytoplasmic eosinophilic content and nuclear shrinkage in the hepatocytes with a decrease in glutathione content. The nuclear activator protein-1 (AP-1) complex was activated in the liver of PCM rats. AP-1-binding activity of nuclear extracts produced from PCM rats was reduced by the presence of anti-c-Jun antibody. Microsomal epoxide hydrolase (mEH), a phase II detoxifying enzyme, was 4-fold induced, with a 20-fold increase in the mRNA level during PCM. In contrast to the PCM-induced changes in hepatic morphology, PCM rats supplemented with cysteine showed an increase in the GSH level and well-preserved hepatic structures with mild fat degeneration. Cysteine supplementation inhibited the activation of AP-1 and the induction of mEH in PCM rats. These results provided evidence: (i) that PCM alters liver morphology with a decrease in the glutathione level; (ii) that cysteine may serve as a key element responsible for preserving hepatic morphology and maintaining the glutathione level; and (iii) that cysteine was active in preventing the activation of AP-1 and mEH induction in the liver during PCM.

Animals↗
PubMed2001

Activation of phosphatidylinositol 3-kinase and Akt by tert-butylhydroquinone is responsible for antioxidant response element-mediated rGSTA2 induction in H4IIE cells.

The protective adaptive response to electrophiles and reactive oxygen species is mediated by enhanced expression of phase II detoxifying genes, including glutathione S-transferases, through activation of antioxidant response element (ARE). The current study was designed to investigate the role of phosphatidylinositol 3-kinase (PI3-kinase)-Akt and mitogen-activated protein (MAP) kinase signaling pathways in the induction of rGSTA2 by tert-butylhydroquinone (t-BHQ). Nuclear ARE complex was activated 1 to 6 h after treatment of H4IIE cells with t-BHQ. The rGSTA2 mRNA level was elevated 6 to 24 h after t-BHQ treatment, which led to the enzyme induction. Activities of PI3-kinase and Akt were increased 10 min through 6 h after t-BHQ treatment, whereas wortmannin or LY294002, PI3-kinase inhibitors, completely abolished ARE binding activity and increases in rGSTA2 mRNA and protein. Extracellular signal-regulated kinase (ERK), p38 MAP kinase, and c-Jun N-terminal kinase (JNK) were all activated by t-BHQ. Treatment with PD98059, an ERK inhibitor, however, increased rGSTA2 mRNA and further enhanced t-BHQ-induced expression of rGSTA2. Neither SB203580 nor overexpression of JNK1 dominant negative mutant altered t-BHQ-inducible rGSTA2 expression. These results demonstrated that t-BHQ activated PI3-kinase and Akt, which was responsible for ARE-mediated rGSTA2 induction, and that ERK might negatively regulate rGSTA2 expression, whereas activation of p38 MAP kinase or of JNK by t-BHQ was not associated with the enzyme induction.

Animals↗
PubMed2001

No effect of cysteine on the pharmacokinetics of intravenous azosemide in rats with protein-calorie malnutrition by pretreatment with 3-methylcholanthrene.

The effects of cysteine on the pharmacokinetics of azosemide were investigated after intravenous administration of drug, 10 mg/kg, to male Sprague-Dawley rats pretreated with 3-methylcholanthrene fed on 23% protein diet (control rats) and 5% protein diet without (rats with protein-calorie malnutrition, PCM) or with (rats with PCMC) oral cysteine (250 mg/kg, twice daily starting from the fourth week) for 4 weeks. After intravenous administration to rats with PCM, the metabolites of azosemide excreted in urine and recovered from gastrointestinal tract decreased significantly than those in control rats, however, the plasma concentrations, total area under plasma concentration-time curve from time zero to time infinity (AUC) and time-averaged total body clearance (CL) were not significantly different between two groups of rats. It was reported that after intravenous administration of azosemide, 10 mg/kg, to rats with PCMC without pretreatment 3-methylcholanthrene, some pharmacokinetic parameters restored fully or more than the level of control rats; the time-averaged nonrenal clearance and apparent volume of distribution at steady state were comparable to those in control rats, but the terminal half-life and mean residence time were significantly shorter, AUC was significantly smaller, and time-averaged renal clearance and CL were significantly faster than those in control rats. However, the above mentioned effects of cysteine on the pharmacokinetic parameters of azosemide in rats with PCM were not observed with pretreatment with 3-methylcholanthrene.

Animals↗
PubMed2000

Policies on faculty conflicts of interest at US universities.

CONTEXT: Despite federal regulations on faculty conflicts of interest in federally funded research, academic-industry ties are common, and evidence exists that financial considerations bias the research record. Public scrutiny of these ties is increasing, especially in cases where researchers have financial interests in the corporate sponsors of their clinical research. OBJECTIVE: To review policies on conflict of interest at major biomedical research institutions in the United States. DESIGN: Cross-sectional survey and content analysis study conducted from August 1998 to February 2000. SETTING AND PARTICIPANTS: The 100 US institutions with the most funding from the National Institutes of Health in 1998 were initially sampled; policies from 89 institutions were available and included in the analysis. MAIN OUTCOME MEASURES: Process for disclosure, review, and management of conflicts of interest and specified management strategies or limitations, according to the institutions' faculty/staff conflict of interest policies. RESULTS: Content of the conflict of interest policies varied widely across institutions. Fifty-five percent of policies (n = 49) required disclosures from all faculty while 45% (n = 40) required them only from principal investigators or those conducting research. Nineteen percent of policies (n = 17) specified limits on faculty financial interests in corporate sponsors of research, 12% (n = 11) specified limits on permissible delays in publication, and 4% (n = 4) prohibited student involvement in work sponsored by a company in which the faculty mentor had a financial interest. CONCLUSIONS: Most policies on conflict of interest in our sample of major research institutions in the United States lack specificity about the kinds of relationships with industry that are permitted or prohibited. Wide variation in management of conflicts of interest among institutions may cause unnecessary confusion among potential industrial partners or competition among universities for corporate sponsorship that could erode academic standards. It is in the long-term interest of institutions to develop widely agreed-on, clear, specific, and credible policies on conflicts of interest. JAMA. 2000;284:2203-2208.

Biomedical Research↗
PubMed2000

The effect of cysteine on the altered expression of class alpha and mu glutathione S-transferase genes in the rat liver during protein-calorie malnutrition.

Protein-calorie malnutrition (PCM) represents a global health problem. The breakdown rate of glutathione S-transferase (GST) subunits determines their differential contents during protein depletion. Hepatic GST expression and the underlying mechanistic basis were investigated in PCM rats. PCM caused no change in rGSTA1/2 subunit. In contrast, rGSTA3/5 subunit was 2.4-fold induced during PCM, while the levels for rGSTM1 and M2 subunits were 30% and 70% suppressed. Increased GSTA3/5 expression was significantly prevented by cysteine or methionine treatment, although such treatment failed to restore the rGSTM2 level. In contrast to differential GST protein expression, PCM caused a 5-10-fold increase in rGSTA2/A3/A5 and M1 mRNAs, whereas rGSTM2 mRNA was 70% decreased. The elevations in rGSTA2/A3/A5 and M1 mRNAs were completely abolished by cysteine or methionine treatment during PCM, although the rGSTM2 mRNA level was not restored. PCM induced oxidative stress in the liver, as evidenced by protein carbonylation. Antioxidant response element (ARE)-binding activity of nuclear extracts from PCM rats was increased, which was immunodepleted with anti-Nrf-1/2 antibodies. Activation of nuclear ARE-binding proteins was inhibited by cysteine. Data showed that hepatic GSTs were differentially expressed during PCM, that certain GST mRNAs were increased with the ARE activation, and that cysteine was active in preventing increases in GST mRNAs and ARE activation.

Animals↗
PubMed2000

Induction of class alpha glutathione S-transferases by 4-methylthiazole in the rat liver: role of oxidative stress.

The expression of glutathione S-transferase (GST) is a crucial factor in determining the sensitivity of cells and organs in response to a variety of toxicants. Expression of class alpha GST genes by methyl-substituted thiazoles was assessed in the rat liver. Northern blot analysis revealed that 4-methylthiazole (4-MT) elevated rGSTA2, A3, A5 and M1 mRNAs in the liver by 19-, 4-, 6- and 9-fold at 24 h after treatment, respectively, as compared to control. Consecutive 3-day treatment with 4-MT resulted in 4- to 7-fold increases in rGSTA and M1 mRNAs. Multiple treatments with 5-methylthiazole (5-MT) caused marginal increases in GST mRNAs in spite of the large increases in certain GST mRNAs at 24 h. Either 4, 5-dimethylthiazole (DT) or 2,4,5-trimethylthiazole (TT) minimally affected the rGSTA and rGSTM mRNA expression at 1-3 day(s). Western blot analysis showed that 4-MT induced rGSTA1/2, rGSTA3/5 and rGSTM1 proteins by 2.6-, 2.1- and 2.1-fold at 3 days, respectively, while other methylthiazoles failed to induce the GST subunits. Starving rats were treated with a lower dose of methylthiazoles to study the role of oxidative stress in the mRNA expression. The levels in rGSTA2/3/5 mRNAs were significantly enhanced by 4-MT in starving rats, whereas rGSTM1/2 mRNAs were not further increased. Other methylthiazoles were inactive in enhancing the mRNAs in starving animals. Pretreatment of starving rats with either cysteine or methionine completely prevented the increases in class alpha GST mRNAs by 4-MT. Data showed that 4-MT induces class alpha GSTs with the increases in the mRNAs, whereas 5-methyl-, dimethyl- and trimethyl-substituted thiazoles were minimally active. Increases in the class alpha GST mRNAs by 4-MT may be associated with the oxidative stress in hepatocytes, as supported by starvation and sulfur amino acid experiments.

Animals↗
PubMed2000

Enhanced expression of rat hepatic microsomal epoxide hydrolase by methylthiazole in conjunction with liver injury.

Microsomal epoxide hydrolase (mEH) is inducible by a number of xenobiotics. Induction of mEH by certain chemopreventive agents may implicate the protective effect. In contrast, many of carcinogenic agents also induce the enzyme. The hepatotoxicity and mEH expression by methylthiazoles, which are incorporated as functional groups in a number of therapeutic agents, were assessed in the rat liver to study the structural basis for the enzyme induction and the correlative enzyme expression with hepatotoxicity. Among the methylthiazoles examined, 4-methylthiazole (MT) at the daily dose of 1.17 mmol/kg body weight caused hepatic necrosis and degeneration after 1-3 consecutive daily treatment(s), whereas 4, 5-dimethylthiazole (DT) and 2,4,5-trimethylthiazole (TT) elicited no toxicity. Treatment of rats with MT at the daily dose of 1.17 mmol/kg increased the mEH mRNA by 17- and 7-fold at day 1 and day 3, respectively, relative to control. Whereas DT caused 5- and 2-fold increases in mEH mRNA at day 1 and day 3, respectively, TT minimally affected mEH expression. The mRNA increase was consistent with the protein induction. Hence, the methylthiazole causing hepatotoxicity was more active in inducing the enzyme. Whereas treatment with MT at the dose of 0.35 mmol/kg caused no hepatotoxicity, MT caused hepatic necrosis in starving rats. Northern blot analysis showed that the mEH mRNA level was increased to a greater extent by MT in starving rats than in control animals. Conversely, treatment of starving rats with either cysteine or methionine prior to MT prevented the hepatic necrosis. Elevation of the mEH mRNA by MT in starving animals was also inhibited by either cysteine or methionine pretreatment. These results demonstrated that the methylthiazole which caused hepatotoxicity also up-regulated mEH expression, whereas other methylthiazoles showing no toxicity minimally increased the gene expression. The observation that the extent of mEH expression by MT was highly associated with that of liver injury raised the notion that mEH expression by xenobiotics may not necessarily represent the beneficial and protective effects.

Animals↗
PubMed2000

Patenting human genetic material: refocusing the debate.

The biotechnology industry has become firmly established over the past twenty years and gene patents have played an important part in this phenomenon. However, concerns have been raised over the patentability of human genetic material, through public protests and international statements, but to little effect. Here we discuss some of these concerns, the patent authorities' response to them, and ways in which to address these issues and to move the debate forward using current legal structures.

Bioethics↗
PubMed1999

Suppression of rat hepatic cytochrome P450s by protein-calorie malnutrition: complete or partial restoration by cysteine or methionine supplementation.

Pharmacokinetic profiles of therapeutic agents are altered by protein-calorie malnutrition (PCM). The current study was designed to determine the expression of hepatic cytochrome P450s in rats after protein restriction and to investigate its molecular basis. Western blot analysis revealed that rats with protein restriction for 4 weeks exhibited marked suppression in the hepatic P450 1A2, 2C11, 2E1, and 3A1/2 levels. Northern blot analysis showed that hepatic P450 1A2, 2C11, and 3A1/2 mRNAs were significantly decreased in the state of PCM. The P450 2E1 mRNA level was slightly decreased in PCM rats, suggesting the possibility that expression of P450 2E1 affected by PCM might result from the transcriptional and/or posttranscriptional regulation. PCM-induced changes in most P450 expression completely or partially returned to control levels by a week of cysteine supplementation. Cysteine also prevented decreases in P450 1A2, 2C11, 2E1, and 3A1/2 mRNA levels by PCM. Methionine was minimally active in restoring the P450 expression. A metabolic change in hepatic ethoxyresorufin dealkylase activity in PCM rats was consistent with the P450 apoprotein and mRNA levels. Although the plasma concentrations of azosemide, a loop diuretic, primarily metabolized by cytochrome P450 1A, increased in protein-deprived rats, cysteine supplementation significantly reduced the increased plasma concentrations of the drug. The altered pharmacokinetic parameters of azosemide in PCM rats returned to those of control after cysteine supplementation, corroborating the conclusion that cysteine was effective in restoring cytochrome P450 expression and metabolic activities.

Animals↗
PubMed1999

Commercialization of BRCA1/2 testing: practitioner awareness and use of a new genetic test.

It was our purpose to determine the characteristics of practitioners in the United States who were among the first to inquire about and use the BRCA1 and BRCA2 (BRCA1/2) genetic tests outside of a research protocol. Questionnaires were mailed to all practitioners who requested information on or ordered a BRCA1/2 test from the University of Pennsylvania (UPenn) Genetic Diagnostics Laboratory (GDL) between October 1, 1995 and January 1, 1997 (the first 15 months the test was available for clinical use). The response rate was 67% of practitioners; 54% (121/225) were genetic counselors, 39% (87/225) were physicians or lab directors. Most physicians were oncologists, pathologists, or obstetrician/gynecologists, but 20% practiced surgery or internal or general medicine. Fifty-six percent (125/225) had ordered a BRCA1/2 test for a patient; most of the rest had offered or were willing to offer testing. Of those who had offered testing, 70% had a patient decline BRCA1/2 testing when offered. Practitioners perceived that patients' fear of loss of confidentiality was a major reason for declining. Nearly 60% of practitioners reported that their patients had access to a genetic counselor, but 28% of physicians who ordered a BRCA1/2 test reported having no such access, despite the GDL's counseling requirement. The proportion of physicians reporting no access to genetic counselors for their patients increased from 22.4% in the first half of the study to 50% in the last half. Many practitioners have an interest in BRCA1/2 testing, despite policy statements that discourage its use outside of research protocols. Practitioner responses suggest that patient interest in testing seems to be tempered by knowledge of potential risks. An apparent increase in patient concern about confidentiality and inability to pay for testing could indicate growing barriers to testing. Although most practitioners reported having access to counseling facilities, perceived lack of such access among an increasing proportion of practitioners indicates that lab requirements for counseling are difficult to enforce and suggests that an increasing proportion of patients may not be getting access to counseling.

Awareness↗