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H J Oh

Publications and source records attributed to H J Oh.

33 records · Page 2Linked to original sources
PubMed1997

Hsp110 protects heat-denatured proteins and confers cellular thermoresistance.

The 110-kDa heat shock protein (hsp110) has long been recognized as one of the primary heat shock proteins in mammalian cells. It belongs to a recently described protein family that is a significantly diverged subgroup of the hsp70 family and has been found in organisms as diverse as yeast and mammals. We describe here the first analysis of the ability of hsp110 to protect cellular and molecular targets from heat damage. It was observed that the overexpression in vivo of hsp110 conferred substantial heat resistance to both Rat-1 and HeLa cells. In vitro heat denaturation and refolding assays demonstrate that hsp110 is highly efficient in selectively recognizing denatured proteins and maintaining them in a soluble, folding-competent state and is significantly more efficient in performing this function than is hsc70. hsp110-bound proteins can then be refolded by the addition of rabbit reticulocyte lysate or hsc70 and Hdj-1, whereas Hdj-1 does not itself function as a co-chaperone in folding with hsp110. hsp110 is one of the principal molecular chaperones of mammalian cells and represents a newly identified component of the primary protection/repair pathway for denatured proteins and thermotolerance expression in vivo.

Animals↗
PubMed1996

The 170 kDa glucose regulated stress protein is a large HSP70-, HSP110-like protein of the endoplasmic reticulum.

The existence of a family of unusually large and highly diverged hsp70-like proteins (the hsp110/SSE family) has recently been described. The 170 kDa glucose regulated stress protein (grp170) is a retained endoplasmic reticulum glycoprotein that may be involved in immunoglobulin folding and/or assembly. We describe here the cloning of the cDNA for grp170 and show that it, like hsp110, is a large and highly diverged hsp70-like polypeptide which shares specific features with hsp70 (the dnaK family) and the hsp110/SSE family, while also differing from both. Grp170 contains an ATP binding domain and binds ATP, it possesses a carboxyl terminal NDEL sequence, and its mRNA is anoxia inducible.

Adenosine Triphosphate↗
PubMed1996

3-Carboxy-20-keto steroids are dual uncompetitive inhibitors of human steroid 5 alpha-reductase types 1 and 2.

Steroidal 3-carboxy-20-ketones have been prepared within two structural series, the androsta-3,5-dienes and the estra-1,3,5-trienes, as potential inhibitors of types 1 and 2 steroid 5 alpha-reductase, the enzyme activity responsible for the final step in biosynthesis of dihydrotestosterone. These compounds are shown to be potent uncompetitive inhibitors of both human recombinant enzyme activities, defining a novel class of dual steroid 5 alpha-reductase inhibitors.

5-alpha Reductase Inhibitors↗
PubMed1994

Analysis of restriction enzyme-induced chromosome aberrations in the interstitial telomeric repeat sequences of CHO and CHE cells by FISH.

The interstitial telomeric sequences have been suggested to be more susceptible to chromosome breakage and rejoining. In the present study, we tested this possibility by analysing the behavior of intra-chromosomal telomeric sequences in restriction enzyme-treated CHO and CHE cells. These cell lines show large blocks of internal telomeric repeats adjacent to the centromeric regions of the chromosomes. In CHO cells, (TTAGGG)n repeats are localised only near the centromeric regions of many of the chromosomes while in CHE cells the telomeric repeat sequences are found at both the terminal and centromeric regions of the chromosomes. In CHO cells, 26% of the total aberrations induced by AluI and 22% of those induced by HinfI were found to be involved with internal telomeric repeat sequences. In CHE cells, which possess telomeric repeats at both the terminal and interstitial regions, 39% of the aberrations induced by AluI and PvuII showed telomeric repeat signals. The proportion of acentric fragments with a telomeric repeat signal was higher in CHE than in CHO cells. Some of the damaged cells displayed an intense signal indicating the possible amplification of these repeats by telomerase. These results are in accordance with the suggestion that non-telomeric locations of telomeric repeat sequences are more prone to chromosome breakage and misrepair.

Animals↗
PubMed1994

Recent developments in the assessment of chromosomal damage.

Ionizing radiation and restriction endonucleases are very efficient in inducing chromosomal aberrations (CAs). These aberrations are mainly consequences of misrepair of DNA double-strand breaks (DSBs). The fast repairing component of DSBs induced by ionizing radiation seems to be responsible for exchange aberration. Use of premature chromosome condensation technique in combination with DNA repair inhibitors such as ara A has given valuable information on the assessment of the frequencies of initial chromosome breaks and the kinetics of their repair following low LET radiation. The recently developed 'chromosome painting' technique using chromosome-specific libraries has also increased considerably the resolution of identifying and scoring of CAs. After low LET radiation, stable chromosome exchanges (translocations) are induced more frequently than unstable chromosome exchanges (dicentrics). Fluorescence in situ hybridization employing telomeric probe has made it possible to score efficiently exchange aberrations involving the acrocentric chromosomes of mouse. Chinese hamster cells have several intercalary telomeric sequences present in most of the chromosomes. These telomeric blocks have been found to be associated with chromosomal aberrations induced by restriction endonucleases and short wave UV and evidence has been obtained for apparent amplification of telomeric sequences at the break points.

Aneuploidy↗
PubMed1990

Steroidal A ring aryl carboxylic acids: a new class of steroid 5 alpha-reductase inhibitors.

A series of 17 beta-carbamoyl-1,3,5(10)-estratriene-3-carboxylic acids has been prepared and evaluated in vitro as inhibitors of human and rat prostatic steroid 5 alpha-reductase (EC 1.3.1.30). Potent inhibition of the human enzyme, in particular, was observed and preliminary studies using rat enzyme suggest that the inhibition results from the formation of an enzyme-NADP(+)-inhibitor complex. The compounds were synthesized from estrone, generally employing a differentiated bis-triflate carbonylation strategy.

5-alpha Reductase Inhibitors↗
PubMed1990

Inhibition of steroid 5 alpha-reductase by unsaturated 3-carboxysteroids.

A series of unsaturated steroids bearing a 3-carboxy substituent has been prepared and assayed in vitro as inhibitors of human and rat prostatic steroid 5 alpha-reductase (EC 1.3.1.30). It is proposed that the observed tight binding of the 3-androstene-3-carboxylic acids is due to mimicry of a putative, high-energy, enzyme-bound enolate intermediate formed during the NADPH-dependent conjugate reduction of testosterone by steroid 5 alpha-reductase. These compounds were prepared through palladium(0)-catalyzed carbomethoxylations of enol (trifluoromethyl)sulfonates derived from 3-keto precursors. Modification of A and B ring unsaturation and substitution at C-3, -4, -6, and -11 was explored. Mono- and dialkylcarboxamides were employed as 17 beta side chains to enhance inhibitory activity with the human enzyme.

5-alpha Reductase Inhibitors↗
PubMed1987

Synthesis, conformation, and dopaminergic activity of 5,6-ethano-bridged derivatives of selective dopaminergic 3-benzazepines.

To probe the suggestion that D-1 (DA1) dopamine receptors might possess an accessory pi-binding site in a location complementary to a suitably oriented aromatic ring (i.e., in an axial orientation approximately orthogonal to the catechol nucleus) in agonists such as 2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepine-7,8-diol (1) and 3',4'-dihydroxynomifensine (2) that are selective for this subtype, cis- and trans-2,3,4,8,9,9a-hexahydro-4-phenyl-1H-indeno[1,7-cd]azepine-6,7-diol were prepared. These compounds are 5,6-ethano-bridged derivatives of the D-1 selective dopamine receptor agonist 1. Introduction of the bridge reduces the conformational mobility of the parent molecule. Comprehensive conformational analyses by molecular mechanical methods indicated that both the cis and trans isomers could attain a conformation that places the phenyl substituent in an axial orientation. X-ray analysis of the trans isomer showed an axial disposition of the phenyl ring; however, NMR studies suggest that this conformation is fixed in the trans isomer, but not in the cis. The dopamine receptor binding affinity and intrinsic activity of the cis isomer were considerably greater than those of its trans counterpart; the cis isomer also demonstrated a high degree of selectivity for the D-1 subtypes. One possible explanation of these results, suggested by the molecular modeling studies, is that both the axial orientation of the phenyl postulated to be required for binding to the receptor and a putatively requisite location of the nitrogen in approximately the plane of the catechol ring can be attained only by the cis isomer in which the tetrahydroazepine ring is in a twist conformation. Conversely, these results might simply suggest a preference of the D-1 receptors for benzazepine agonists having the phenyl group in an equatorial orientation. Still another possibility is that the D-1 receptor binding site is in a sterically hindered area accessible only to compounds that are relatively planar. However, it requires an axial 1-phenylbenzazepine for strong binding. Thus, a conformationally flexible cis isomer could more readily achieve the different conformations required to both gain access to and bind with the D-1 site.

Animals↗
PubMed1986

Synthesis and dopaminergic activity of some halogenated mono- and dihydroxylated 2-aminotetralins.

In a series of 7,8-dihydroxy-1-phenyltetrahydro-3-benzazepine dopamine receptor agonists introduction of a chloro or fluoro substituent into the 6-position increases dopaminergic potency. Also, in this series replacement of the 7-hydroxyl group with a halogen results in inversion of activity from dopamine receptor agonist to antagonist. The present study was aimed at exploring the possibility that the structure-activity observations in the 3-benzazepine series of dopaminergic agents might be extrapolated to another class of dopamine receptor agonists, the 2-aminotetralins. Thus, a series of chloro- and fluoro-substituted mono- and dihydroxylated 2-aminotetralins was prepared and evaluated for dopaminergic properties in D-1 and D-2 receptor-related tests. Introduction of a chloro substituent into the 8-position of the prototype of this series, i.e. 2-amino-6,7-dihydroxytetralin (ADTN), resulted in a compound with a high degree of selectivity for the D-1 subpopulation of dopamine receptors; it was equally or more potent than ADTN in the D-1 receptor-related tests with greatly decreased effectiveness in the tests involving D-2 receptors. A similar effect was observed with 8-fluoro-ADTN; however, the N-(4-hydroxyphenethyl)-N-propyl derivative 4g of the 8-chloro-substituted ADTN showed marked D-2 binding affinity. Conversely, introduction of a chloro substituent into the 5-position of ADTN markedly decreased D-1 receptor affinity and efficacy. This effect was not seen with the related 5-fluoro derivative, suggesting D-1 receptors are more sensitive to bulk in the 5-position of ADTN than are the D-2 receptors. Replacement of either the 6- or 7-hydroxyl groups of ADTN with a chloro or fluoro substituent, in contrast, did not parallel the response seen in the benzazepine series (i.e., the compounds uniformly demonstrated less receptor affinity and did not have dopamine receptor antagonist activity); however, the decrease in agonist potency was less marked in the case of 2-amino-6-fluoro-7-hydroxytetralins than in the chlorinated monohydroxyaminotetralins. Thus, a parallelism in structure-activity relationships in the benzazepine and aminotetralin series of dopamine receptor agonists was not observed. The differences may reflect altered modes of receptor binding in the two series.

Animals↗
PubMed1986

6,7-Dichloro-1-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline . A structurally novel beta-adrenergic receptor blocking agent.

Replacement of the catecholic hydroxyl groups of the beta-adrenergic receptor agonist 6,7-dihydroxy-1-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline (trimetoquinol) with chloro substituents results in a compound with marked beta-adrenoceptor antagonist properties. This, therefore, parallels the similar transformation of the beta-adrenoreceptor agonist isoproterenol into the antagonist dichloroisoproterenol. In a test for inhibition of isoproterenol-induced enhancement of the rate of contraction of spontaneously beating guinea pig atrial pairs the resultant 6,7-dichloro-1-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline (6b) had a KB value of (6.7 +/- 2.3) X 10(-8) M. Although this is nearly 2 orders of magnitude less potent than propranolol (KB = 6.2 X 10(-10) M in this test), this compound represents the prototype of a new class of beta-adrenergic receptor blockers, and unlike dichloroisoproterenol it is not a partial agonist. It has physicochemical properties, e.g., pKa and distribution and partition coefficients, that differ from the prototypic beta-blockers. These altered properties might impart advantageous tissue distribution and altered pharmacological properties to the new molecule. This new beta-adrenoreceptor antagonist is suggested to merit further study.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Solid-phase synthesis of a combinatorial array of 1,3-bis(acylamino)-2-butanones, inhibitors of the cysteine proteases cathepsins K and L.

To more rapidly prepare members of the 1,3-bis(acylamino)-2-butanone class of cysteine protease inhibitors, a solid-phase synthesis was developed. 1-Azido-3-amino-2,2-dimethoxybutane (4), which has the two amino groups differentiated and the ketone protected as a a ketal, served as a surrogate for the 1,3-diamino-2-butanone core. Amine (4) was coupled to the BAL-resin-linked carboxylic acids derived from alpha-amino acid esters. Evaluation of a small combinatorial array by measuring inhibition constants (Ki,appS) against cathepsins K, L, and B provided some structure-activity relationship trends with respect to selectivity and potency. Novel, potent inhibitors of cathepsins K and L were identified.

Butanones↗
PubMedDate not supplied

Relationship between premature mortality and socioeconomic factors in black and white populations of US metropolitan areas.

OBJECTIVE: examined the association of mortality with selected socioeconomic indicators of inequality and segregation among blacks and whites younger than age 65 in 267 US metropolitan areas. The primary aim of the analysis was to operationalize the concept of institutional racism in public health. METHODS: Socioeconomic indicators were drawn from Census and vital statistics data for 1989-1991 and included median household income; two measures of income inequality; percentage of the population that was black; and a measure of residential segregation. RESULTS: Age-adjusted premature mortality was 81% higher in blacks than in whites, and median household income was 40% lower. Income inequality, as measured by the Gini coefficient, was greater within the black population (0.45) than within the white population (0.40; p < 0.001). To confirm that the proxy socioeconomic variables were relevant markers of population health status, regression analysis was performed initially on data for the total population. These variables were all independently and significantly related to premature mortality (p < or = 0.01; R(2) = 0.74). Income inequality for the total population was significantly correlated with premature mortality (r = 0.33). Black (r = 0.26) and white (r = 0.20) population-specific correlations between income inequality and premature mortality, while still significant, were smaller. Residential segregation was significantly related to premature mortality and income inequality for blacks (r = 0.38 for both); among whites, however, segregation was modestly correlated with premature mortality (r = 0.19) and uncorrelated with income inequality. Regional analyses demonstrated that the association of segregation with premature mortality was much more pronounced in the South and in areas with larger black populations. CONCLUSION: Social factors such as income inequality and segregation strongly influence premature mortality in the US. Ecologic studies of the relationships among social factors and population health can measure attributes of the social context that may be relevant for population health, providing the basis for imputing macro-level relationships.

Adolescent↗