Biomedical subjects

S J Chung

Publications and source records attributed to S J Chung.

At least 73 records · Page 4Linked to original sources

PubMed1994

Thioredoxin-dependent peroxide reductase from yeast.

A 25-kDa antioxidant enzyme that provides protection against oxidation systems capable of generating reactive oxygen and sulfur species has previously been identified. The nature of the oxidant eliminated by, and the physiological source of reducing equivalents for, this enzyme, however, were not known. The 25-kDa enzyme is now shown to be a peroxidase that reduces H2O2 and alkyl hydroperoxides with the use of hydrogens provided by thioredoxin, thioredoxin reductase, and NADPH. This protein is the first peroxidase to be identified that uses thioredoxin as the immediate hydrogen donor and is thus named thioredoxin peroxidase (TPx). TPx exists as a dimer of identical 25-kDa subunits that contain 2 cysteine residues, Cys47 and Cys170. Cys47-SH appears to be the site of oxidation by peroxides, and the oxidized Cys47 probably reacts with Cys170-SH of the other subunit to form an intermolecular disulfide. Mutant TPx proteins lacking either Cys47 or Cys170, therefore, do not exhibit thioredoxin-coupled peroxidase activity. The TPx disulfide is specifically reduced by thioredoxin, but can also be reduced (less effectively) by a small molecular size thiol. The Saccharomyces cerevisiae thioredoxin reductase gene was also cloned and sequenced, and the deduced amino sequence was shown to be 51% identical with that of the Escherichia coli enzyme.

Amino Acid Sequence↗

PubMed1994

Characterization of a sodium-dependent taurine transporter in rabbit choroid plexus.

Taurine, a beta-amino acid, plays an important role as a neuromodulator and is necessary for the normal development of the brain. Since de novo synthesis of taurine in the brain is minimal and in vivo studies suggest that taurine does not cross the blood-brain barrier, we examined whether the choroid plexus, the blood-cerebrospinal fluid barrier, plays a role in taurine transport in the central nervous system. The uptake of [3H]taurine into ATP-depleted choroid plexus from rabbit was substantially greater in the presence of an inwardly directed Na+ gradient, whereas in the absence of a Na+ gradient taurine accumulation was negligible. A transient inside-negative potential gradient enhanced the Na(+)-driven uptake of taurine into the tissue slices, suggesting that the transport process is electrogenic. Na(+)-driven taurine uptake was saturable with an estimated Vmax of 111 +/- 20.2 nmol/g per 15 min and a Km of 99.8 +/- 29.9 microM. The estimated coupling ratio of Na+ and taurine was 1.80 +/- 0.122. Na(+)-dependent taurine uptake was significantly inhibited by beta-amino acids, but not by alpha-amino acids, indicating that the transporter is selective for beta-amino acids. Na(+)-dependent taurine uptake showed some selectivity for anions: the accumulation was comparable in the presence of Cl-, Br- and thiocyanate whereas I-, SO4(2-) and gluconate did not stimulate the uptake significantly. Collectively, our results demonstrate that taurine is transported in the choroid plexus via a Na(+)-dependent, saturable and apparently beta-amino acid selective mechanism. This process may be functionally relevant to taurine homeostasis in the brain.

Animals↗

PubMed1994

Formula expressing a relationship among lesion thickness and time after diagnosis and survival probability in patients with malignant melanoma.

A microcomputer program in BASIC for predicting the survival probability as a function of lesion thickness and time after diagnosis is designed. The New York University-Melanoma Cooperative Group (NYU-MCG) shows 10-year survival rates of patients with malignant melanoma broken into four lesion-thickness groups (Cancer Journal for Clinicians, 41 (1991) 201-226). The formula used in this program is derived from the survival data of NYU-MCG. A mathematical 'probacent'-probability model previously published by the author is employed in this study. Analysis of the computer-assisted predicted and the NYU-MCG reported survival probability data indicates that the program is accurate and reliable with a close agreement in expressing survival probability and that it may be of value for prognostic evaluation of patients.

Humans↗

PubMed1994

A modified product inhibition model describes the nonlinear pharmacokinetics of nicorandil in rats.

Nicorandil, a vasodilator which acts through both cyclic GMP accumulation and K+ channel opening, has been used in the treatment of various cardiovascular diseases. We have examined the pharmacokinetics of nicorandil in the rat as a function of dose, as both i.v. boluses (9 doses, 0.75-12 mg, n = 1.4 per dose), and as a 5-hr infusion followed by a 5-hr washout (6 doses, 10-500 micrograms/kg/min, n = 3 per dose). Plasma nicorandil concentrations were determined by HPLC. Nicorandil plasma concentrations increased disproportionately with dose, but nicorandil elimination obeyed apparent monoexponential kinetics, and the apparent half-life (t1/2) increased with dose. In addition, the approach to apparent steady-state during the infusion phase was not overtly sensitive to the drastic changes in t1/2 observed. Pharmacokinetic modelling with several nonlinear models, viz: Michaelis-Menten with parallel first-order, cosubstrate depletion and competitive product inhibition, were carried out. Addition of the sulfhydryl donor, N-acetyl-L-cysteine, did not change the pharmacokinetics of nicorandil, providing experimental indication that a cosubstrate depletion model might not be applicable. To described the unique pharmacokinetics, a modified product inhibition model was developed. This new model includes the classic competitive product inhibition equation, describing both parent and product kinetics, and it incorporates, in addition, separate first-order elimination rate constants for both nicorandil and the inhibition metabolite. Experimental evidence showed that N-(2-hydroxyethyl) nicotinamide, the major metabolite of nicorandil in rats, and nicotinamide (niacinamide) itself, indeed inhibited nicorandil elimination.

Animals↗

PubMed1993

Relationship between nitroglycerin-induced vascular relaxation and nitric oxide production. Probes with inhibitors and tolerance development.

We have shown previously that nitric oxide (NO) is generated from nitroglycerin (NTG) through enzyme-mediated reactions in the bovine coronary artery smooth muscle cell, but it is not known whether this metabolic conversion plays a significant role in the pharmacologic action of NTG, viz. relaxation. In this study, we developed a technique that allowed direct measurement of NO from intact bovine coronary arterial rings that were incubated previously with NTG, and examined whether changes in NTG-induced relaxation were accompanied by parallel changes in NO generation. Co-incubation of the vascular preparations with a potent inhibitor of glutathione-S-transferases (GSTs), bromosulfophthalein (up to 200 microM), did not affect NTG-induced relaxation, nor did it alter NO generation from NTG in the preparation. In contrast, 1-chloro-2,4-dinitrobenzene (CDNB), a GST substrate, inhibited NO generation as well as the relaxation response of NTG in the intact vascular tissue preparation. CDNB, however, did not decrease the relaxant responses of nifedipine and isoproterenol. Thus, the inhibitory effect of CDNB on NTG-induced relaxation and NO production appeared specific. When bovine coronary rings were made tolerant to NTG by pretreatment with 0.44 mM NTG for 1 hr, the EC50 was shifted to the right 162-fold, and NO generation was also reduced in intact rings and tissue homogenates. However, when the homogenates were further subfractionated to microsomes and cytosols, or when homogenates were allowed to stand for a similar time period necessary for subfractionation, the difference in NO production from control versus tolerant tissue preparations disappeared. It is possible, therefore, that the NTG-induced tolerance process might have been partially reversed during this time period. Results of this study identified CDNB as an apparently specific inhibitor of NTG action, but showed that GST-mediated reactions were probably not involved in the metabolic activation of NTG. Our results also indicated that tissue NO generation from NTG was positively related to the relaxation responses generated by this nitrovasodilator.

Animals↗

PubMed1993

Formulas predicting survival in patients with heart transplantation.

Kirklin et al. (J Heart Transpl. 7 (1988) 331-336) reported survival data in 132 patients who underwent heart transplantation. Survival was evaluated by using the product-limit method of Kaplan-Meier and maximum likelihood method. In addition, the effect of pulmonary vascular resistance on survival was estimated by using multivariate analysis. A microcomputer program in BASIC for predicting the survival probability after transplantation in patients with heart transplantation is designed. The formula used in this program is derived from the survival data reported by Kirklin et al. (J Heart Transpl. 7 (1988) 331-336). A mathematical model of the 'probacent'-probability equation and a computer program previously published by the author are employed in this study. Analysis of the computer-assisted predicted values and the data reported by Kirklin et al. (J Heart Transpl. 7 (1988) 331-336) indicates that the program is accurate and reliable with a complete agreement in expressing survival probability as a function of time after heart transplantation. The computer-assisted predictive formula can determine the relationship between the time and the survival probability and may be of value for prognostic evaluation of patients. The computer-assisted mathematical model of the 'probacent'-probability equation may be proposed as a general approximation method to make useful predictions of probable outcomes in various biomedical phenomena.

Algorithms↗

PubMed1992

Biochemical mechanism of organic nitrate action.

Increasing evidence suggests that organic nitrate action derives from their metabolic conversion to nitric oxide (NO) in the vascular smooth muscle cell. The primary catalytic activity of this process appears to reside at the cellular plasma membrane. There is no concrete evidence to indicate that NO formation is preceded by the production of inorganic nitrite ion or that the NO produced needs to form S-nitrosothiols before it can activate guanylate cyclase to produce cyclic guanosine 3',5'-monophosphate (cGMP). Although sulfhydryl donors can partially reverse nitroglycerin-induced tolerance in patients, this phenomenon (by itself) is not sufficient to implicate intracellular sulfhydryl depletion as an operating mechanism of clinical nitrate tolerance. This is because sulfhydryl donors can react with nitroglycerin extracellularly to form S-nitrosothiols, and nonsulfhydryl compounds, such as enalapril and hydralazine, can prevent the development of in vivo nitrate tolerance. In addition to the cellular biochemical reactions, organic nitrates also produce systemic biochemical effects through altering neurohormonal status. These systemic effects may contribute significantly to the development of nitrate tolerance in therapeutic situations.

Animals↗

PubMed1992

A common enzyme may be responsible for the conversion of organic nitrates to nitric oxide in vascular microsomes.

We compared the nitric oxide (NO)-generating behavior of nitroglycerin (NTG), pentaerythritol trinitrate (PEtriN) and isosorbide dinitrate (ISDN), in the microsomal preparation of bovine coronary artery smooth muscle cells. The comparative NO generating activities among these nitrates were consistent with their relative reported vasodilating activities. Consistent with our previous observations with NTG, 400 microM bromosulfophthalein did not affect NO generation from PEtriN and ISDN in vascular microsomes while 400 microM 1-chloro-2,4-dinitrobenzene completely inhibited NO generation from these nitrates. Gel filtration chromatography with solubilized microsomes of bovine aortic smooth muscle cells showed the primary activity of NO generation from all three nitrates to be eluted at about 200 kD, consistent with that found with solubilized microsomes from the bovine coronary artery microsomes. These results suggest that organic nitrates may be converted to NO by one common enzyme in vascular microsomes.

Amino Acid Oxidoreductases↗

PubMed1992

Relationship among age, serum cholesterol level and population percentile in adults.

The data of the National Health and Nutrition Examination Survey comprehensively have shown that distributions of serum cholesterol levels in the US adult population are age and sex dependent. General formulas were constructed and published by the author on the basis of the data of the National Health and Nutrition Examination Survey to predict the population percentile for serum cholesterol levels by age. A mathematical model and a computer program previously published by the author were employed in the study. Analysis of the computer-assisted predicted and the National Health and Nutrition Examination Survey-reported percentiles indicated that the designed program for calculating the formulas was accurate and reliable. The formula could determine the relationship among adult age, serum cholesterol level and population percentile. A comprehensive table and nomograms that show the relationship among age, serum cholesterol level and population percentile in men and women for each year group between 20 and 79 years of age are obtained in this study, using the previously published formulas. The population percentiles predicted by the formula may reflect the relative degrees of risk for coronary heart disease. The population percentile, simultaneously expressed as 'risk percentile', may be used as a parameter of risk assessment for coronary heart disease for all adult ages and sexes. Seventy-five population percentile of serum cholesterol level is suggested as a cutoff point of high 'risk percentile' for coronary heart disease. This information on the percentile may have a preventive diagnostic value for detection, evaluation and treatment of patients with high cholesterol levels. The comprehensive table and nomograms showing the relationship among age, serum cholesterol level and population percentile may be hopefully available to clinicians and useful in their medical practice and may also be helpful in future clinical investigation.

Adult↗

PubMed1992

Conversion of nitroglycerin to nitric oxide in microsomes of the bovine coronary artery smooth muscle is not primarily mediated by glutathione-S-transferases.

The pharmacological action of organic nitrate vasodilators [e.g., nitroglycerin (NTG)] is thought to be mediated through metabolic conversion to nitric oxide (NO); conversion leads to vasodilatation, whereas diminished conversion in chronic therapy may lead to pharmacological tolerance. The biochemical nature of this process, however, is poorly understood. Glutathione-S-transferases (GST) have been shown to metabolize organic nitrates in the liver, but it is not known whether these enzymes are involved in this pharmacologically relevant process. We, therefore, compared the activities of conversion of NTG to NO vs. those of GST in microsomal suspensions of bovine coronary artery smooth muscle tissue. A classical GST substrate, 1-chloro-2,4-dinitrobenzene, inhibited NO production in microsomes, suggesting possible involvement of GST in organic nitrate activation. However, GST activity derived from microsomes exhibited a different heat lability profile compared to that of NO generation. Known inhibitors of GST (viz., indomethacin and bromosulfophthalein) did not alter the NO-generating activity in microsomes. Glutathione was a critical cofactor for GST, but not for NO generation from NTG, and thiols other than glutathione (e.g., N-acetyl-L-cysteine and thiosalicylic acid) also could facilitate NO production. Moreover, comparison to a commercially available purified liver GST preparation showed that, at the same GST activity toward 1-chloro-2,4-dinitrobenzene, the microsomal incubation produced about 8 times more NO than the purified liver GST. Radiation inactivation analysis of the functional molecular sizes of GST and the NO-producing enzyme(s) suggested that the enzymes were of different molecular weights (54 kD and 160 kD, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Formula predicting survival in patients with acute myelogenous leukemia.

A microcomputer program in BASIC for predicting the survival probability after diagnosis of acute myelogenous leukemia in patients is designed. Formulas used in this program are derived from the data published by Feigl and Zelen. A mathematical model and a computer program previously published by the author are employed in this study. Analysis of the computer-assisted predicted and the Feigl and Zelen's reported data has shown that the program is fairly accurate and reliable with close agreement in expressing survival probability as a function of white cell count and time after diagnosis.

Humans↗

PubMed1990

Formula predicting carcinoma-free probability in rats exposed to carcinogen DMBA.

The Weibull distribution is a generalization of the exponential distribution. Pike (Biometrics, 22 (1966) 142-161) used the Weibull distribution in the analysis of carcinogenesis experiments on rats. A formula of conversion that allows mathematical conversion of the Weibull distribution to the generalized lognormal distribution is constructed in this study. This formula is applied to the Pike's data on carcinoma-free probability in rats exposed to carcinogen DMBA. A mathematical model and a computer program previously published by the author are employed in this study. Analysis of the computer-assisted predicted and the Pike's reported data on carcinoma-free probability indicates that a close agreement is present between both data. It seems to the author that a generalized lognormal distribution of the carcinoma-free probability in rats exposed to carcinogen can be derived from the formula of conversion. In addition the generalized lognormal distribution may be proposed as a method of parametric analysis of survival data on estimates by non-parametric product-limit method of Kaplan-Meier in certain biological phenomena.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1990

Formulas predicting the percentile of heart weights by body weight in subjects from birth to 19 years of age.

The values reported by Scholz and his coworkers [Mayo Clin Proc, 63 (1988) 126-136,637] show that distributions of normal heart weights in the period of body growth from birth to 19 years of age are age and sex dependent and actually more dependent on body weight. General formulas are constructed on the basis of the values of Scholz and his coworkers to predict percentile in the population for heart weights by body weight. A mathematical model and a computer program previously published by the author are employed in this study. Analysis of the computer-assisted predicted values and the data on heart weights for specific body weights and percentiles reported by Scholz and his coworkers indicates that the designed computer program for calculating the formula is accurate and reliable. The formulas can determine the mathematical relationship among body weight, heart weight and population percentile. It seems to the author that the computer-assisted predictive formula has limited values in its clinical application since heart weights are to be evaluated practically only in autopsy service in pathology, but that a similar mathematical model as used in this study would be applicable in analysis of other clinical, age- and sex-dependent measurable parameters.

Adult↗

PubMed1990

Formulas predicting the percentile of serum cholesterol levels by age in adults.

The data of the National Health and Nutrition Examination Survey comprehensively have shown that distributions of serum cholesterol levels in the US adult population are age and sex dependent. General formulas have been constructed on the basis of the data of the National Health and Nutrition Examination Survey to predict the adult percentile in the population for serum cholesterol levels by age. A mathematical model and a computer program previously published by the author were employed in this study. Analysis of the computer-assisted predicted and the National Health and Nutrition Examination Survey-reported percentiles indicated that the designed program for calculating the formula was accurate and reliable. The formulas can determine the relationship among adult age, serum cholesterol level, and population percentile. It has been reported that adult individuals tend to have persistently the same percentiles of their serum cholesterol levels in the population with increasing ages in the absence of cholesterol-altering intervention. The percentiles predicted by the formula may reflect the relative degrees of risk for coronary heart disease. This information on the percentile may have a preventive diagnostic value for the detection, evaluation, and treatment of patients with high cholesterol levels. The percentile may be used as a parameter of risk assessment for coronary heart disease for all adult ages and sexes. However, clarification of a probable relationship between high percentiles (like high cholesterol levels) and coronary heart disease, and justification of the use of percentiles as a risk parameter, must await further clinical investigation.

Adult↗

PubMed1990

Identification of the subcellular site for nitroglycerin metabolism to nitric oxide in bovine coronary smooth muscle cells.

The vasodilating action of nitroglycerin (NTG) is thought to be mediated by its metabolic activation to nitric oxide (NO) in the vascular smooth muscle cell, but the site at which this process occurs has not been defined. To determine which cellular component is primarily responsible for this metabolic activation, subcellular fractions of bovine vascular smooth muscle cells were prepared and incubated with NTG along with cofactors. Time-dependent headspace NO concentrations generated in these preparations were determined directly by chemiluminescence detection. A mathematical model was developed to relate headspace NO with the NO-generating activity in each incubation, correcting for the concurrent processes of NO partitioning between the headspace and the incubation medium, and NO degradation in these two phases. The estimated NO-generating activities from different subcellular fractions were well correlated with the activities of two enzyme markers of the plasma membrane (K(+)-activated ouabain sensitive p-nitrophenyl phosphatase and 5'-nucleotidase), but not with those of the mitochondria, endoplasmic reticulum or the cytosol. These results indicate that the enzyme(s) responsible for the metabolic activation of NTG, and possibly other organic nitrate vasodilators, are associated with the plasma membrane in bovine coronary smooth muscle cells.

Analysis of Variance↗

PubMed1989

Computer-assisted predictive mathematical relationship between time after diagnosis and survival probability in patients with chronic leukemias.

A microcomputer program in BASIC for predicting the survival probability by the time after diagnosis in patients with chronic leukemias is designed. Formulas used in this program are derived from the data published by Feinleib and MacMahon (Blood 15 (1960) 332-349). A general equation previously published by the author is applied in this study to calculate the survival probability. Analysis of the computer-assisted predicted and Feinleib and MacMahon's observed data has shown that the program is fairly accurate and reliable with a close agreement in expressing survival probability as a function of the time after diagnosis. The computer-assisted predictive formulas can determine the relationship between the time and the survival probability, and may be of value for prognostic evaluation of patients with chronic leukemias.

Chronic Disease↗

PubMed1989

Computer-assisted predictive mathematical relationship among electroshock voltage and duration and occurrence of convulsion in mice.

A microcomputer program in BASIC for predicting percentage of occurrence of electroshock-induced convulsion in mice was designed. A formula published by the author to express the mathematical relationship among the drug dose, the time, and the biological response was used in this program. Analysis of the actual, and the computer-assisted predicted percentages of occurrence of convulsion has shown that the program is fairly accurate in expressing convulsion response of mice as a function of the voltage and the duration.

Animals↗

PubMed1989

Computer-assisted predictive mathematical relationship among plasma acetaminophen concentration and time and hepatotoxicity in man.

A microcomputer program in BASIC for predicting hepatoxicity in man resulting from a single overdosage ingestion of acetaminophen was designed. A formula used in this program is derived from the data reported by Prescott and his coworkers (Lancet i (1971) 519-522). Analysis of the actually reported and the computer-assisted predicted data has shown that the computer-assisted predictive formula may be clinically helpful in determining if the plasma acetaminophen level is in the toxic or nontoxic range.

Acetaminophen↗