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Biomedical subjects

S Kang

Publications and source records attributed to S Kang.

At least 145 records · Page 8Linked to original sources
PubMed1997

The retinoid X receptor agonist 9-cis-retinoic acid and the 24-hydroxylase inhibitor ketoconazole increase activity of 1,25-dihydroxyvitamin D3 in human skin in vivo.

1,25-Dihydroxyvitamin D3 [1,25(OH)2D3] transactivates its target genes via the vitamin D receptor (VDR). VDR functions in physiology as a dimer complexed with retinoid X receptor (RXR), whose natural ligand is 9-cis-retinoic acid (9-c-RA). Inactivation of 1,25(OH)2D3 occurs through a cytochrome P-450 24-hydroxylase (OHase). The promoter of the human 24-OHase gene contains a 1,25(OH)2D3-responsive enhancer element (VDRE). We have used this VDRE containing gene as an endogenous reporter for vitamin D3-mediated gene activation in vivo. Normal adult human skin was keratomed after a 2-d exposure to 1,25(OH)2D3, 9-c-RA, all-trans-RA, and ketoconazole. 1,25(OH)2D3 caused a concentration-dependent increase in 24-OHase mRNA expression as determined by northern blot analysis. The activity of epidermal 24-OHase was also induced by 1,25(OH)2D3. Compared with vehicle, neither of the RA isomers nor ketoconazole alone induced 24-OHase mRNA. Addition of 9-c-RA or t-RA to 1,25(OH)2D3, however, caused a synergistic increase in 24-OHase mRNA. Similarly, 1,25(OH)2D3 plus ketoconazole increased 24-OHase mRNA synergistically. Ketoconazole inhibited ex vivo 1,25(OH)2D3-induced epidermal 24-OHase activity. Thus, 24-OHase mRNA induction is a sensitive reporter of 1,25(OH)2D3 activity in vivo; RXR bound to VDR is not a silent partner in vivo, because 9-c-RA enhances 1,25(OH)2D3-liganded RXR/VDR stimulation of the VDRE containing 24-OHase gene; ketoconazole inhibition of 24-OHase enhances 1,25(OH)2D3 activity by impeding its breakdown. Thus, the synergistic response of human skin to topical 1,25(OH)2D3 and/or 1,25(OH)2D3 analogs plus RXR retinoids and/or ketoconazole may be exploited to give a desired biologic/therapeutic response with less 1,25(OH)2D3, minimizing the potential calcemic risk from systemic absorption of 1,25(OH)2D3.

Adult↗
PubMed1997

Unoccluded retinol penetrates human skin in vivo more effectively than unoccluded retinyl palmitate or retinoic acid.

The formation of all-trans retinoic acid is an oxidative process whereby retinol is converted to retinaldehyde and then to retinoic acid. Because retinol causes qualitative molecular changes similar to those produced by retinoic acid, we compared potency of retinol, retinaldehyde, and retinyl palmitate to retinoic acid and assessed the effects of occlusion. Retinoids were prepared in an experimental vehicle of 95% ethanol:propylene glycol (7:3) with anti-oxidant. Induction of retinoic acid 4-hydroxylase activity was the end point for comparison. Retinoic acid concentrations from 0.001% to 0.05% under occlusion produced a linear dose-response induction of 4-hydroxylase activity. The concentrations of the other retinoids under occlusion required to achieve significant induction of enzyme activity were 0.6% retinyl palmitate, 0.025% retinol, and 0.01% retinaldehyde. The linear dose-response was lost with retinoid concentrations in excess of 0.25% retinol or 0.5% retinaldehyde. Statistical analyses showed no difference in 4-hydroxylase activity between unoccluded and occluded retinol treated sites. By contrast, however, unoccluded sites treated with retinoic acid or retinyl palmitate had less induction of 4-hydroxylase activity than occluded sites. Retinol, retinaldehyde, and retinyl palmitate did not produce erythema but did increase epidermal thickness. Although retinol is a weaker retinoid than retinoic acid, the increased penetration of unoccluded retinol in comparison to unoccluded retinoic acid with this prototypic vehicle confers on retinol a more effective delivery of a retinoidal effect than unoccluded retinoic acid. Retinol at 0.25% may be a useful retinoid for application without occlusion because it does not irritate but does induce cellular and molecular changes similar to those observed with application of 0.025% retinoic acid.

Administration, Topical↗
PubMed1997

Linkage mapping and phenotypic analysis of autosomal dominant Pallister-Hall syndrome.

Pallister-Hall syndrome is a human developmental disorder that is inherited in an autosomal dominant pattern. The phenotypic features of the syndrome include hypothalamic hamartoma, polydactyly, imperforate anus, laryngeal clefting, and other anomalies. Here we describe the clinical characterisation of a family with 22 affected members and the genetic mapping of the corresponding locus. Clinical, radiographic, and endoscopic evaluations showed that this disorder is a fully penetrant trait with variable expressivity and low morbidity. By analysing 60 subjects in two families using anonymous STRP markers, we have established linkage to 7p13 by two point analysis with D7S691 resulting in a lod score of 7.0 at theta = 0, near the GLI3 locus. Deletions and translocations in GLI3 are associated with the Greig cephalopolysyndactyly syndrome. Although Greig cephalopolysyndactyly syndrome has some phenotypic overlap with Pallister-Hall syndrome, these two disorders are clinically distinct. The colocalisation of loci for these distinct phenotypes led us to analyse GLI3 for mutations in patients with Pallister-Hall syndrome. We have previously shown GLI3 mutations in two other small, moderately affected families with Pallister-Hall syndrome. The linkage data reported here suggest that these larger, mildly affected families may also have mutations in GLI3.

Abnormalities, Multiple↗
PubMed1997

Inhibition of neointimal proliferation of rat carotid artery by sulodexide.

Sulodexide, a glycosaminoglycan-containing compound, is known to have an antiproliferative effect on vascular smooth-muscle cells, in vitro, as well as antithrombotic and fibrinolytic effects. But there are few reports about the effect of neointimal proliferation in vivo. In this study, we examined whether Sulodexide was effective in the inhibition of neointimal proliferation after vascular injury. Ten-week-old Sprague-Dawley rats were subjected to vascular injury by endothelial denudation of the common carotid artery by using a balloon catheter. They were then allocated randomly into a control group (saline 2 ml for 3 days, and then 1 ml for 18 days, IM) and a treated group (Sulodexide 10 mg/kg/day for 3 days, and then 4 mg/kg/day for 18 days, IM). Three weeks after vascular injury, we analyzed the neointimal proliferation using morphometry. The neointimal proliferation was significantly reduced in the treated group compared to the control group (Ratio of neointimal area to medial area; 118.39 +/- 6.80% in the treated group, 177.25 +/- 17.25% in the control group). This result showed that Sulodexide might be effective in reducing the rate of restenosis after balloon angioplasty.

Angioplasty, Balloon↗
PubMed1997

[Protective effect of ciliary neurotrophic factor against the ototoxicity of gentamicin in guinea pigs].

The effect of ciliary neurotrophic factor (CNTF) on gentamycin induced deafness was observed by Preyer's reflex, auditory brainstem evoked potential, bioelectric response of the cochlea and histomorphological examination of surface preparation of cochlea. It was found that CNTF was capable of reducing ototoxicity of gentamicin in guinea pigs, thus protecting hair cells of cochlea and auditory nerves.

Animals↗
PubMed1997

[Expression of p53, c-erbB1, c-myc and p16 gene proteins in human glioma].

OBJECTIVE: To realize the significance of c-erbB1 and c-myc protooncogenes, p53 and p16 tumor suppressor genes in the development and pathologic diagnosis of human glioma. METHODS: The expression of p53, c-erbB1, c-myc and p16 gene proteins was detected immunohistochemically in 65 cases of glioma. The relationship between these results and the pathological grades was determined. RESULTS: The overexpression of mutant p53, c-erbB1 and c-myc was in accordance with the increasing grade of glioma malignancy, showing significant difference (P < 0.05) between the benign group and highly malignant group in p53 and c-erbB1, while the deletion of p16 protein was more frequent in the highly malignant group than in any other group. These 4 genes showed co-expression in some of the gliomas. CONCLUSIONS: The 4 genes, especially p53 and c-erbB1, play an important role in the development of glioma; the detection of these gene proteins has a positive significance on malignancy determination for glioma.

Astrocytoma↗
PubMed1997

[Minor alkaloids from the capsule of Papaver nudicaule L].

Two minor alkaloids were isolated from the capsule of Papaver nudicaule. On the basis of physicochemical methods and spectroscopic analysis, they were identified as chelidonine, 5-hydroxy-2-hydroxymethylpyridine. Chelidonine was isolated from this plant and 5-hydroxy-2-hydroxymethylpyridine was isolated from genus for the first time.

Alkaloids↗
PubMed1997

[Comparative study of the constituents from 10 Rhodiola plants].

The comparison of the components in 10 species of Rhodiola by GC method showed that sucrose and peak A, a unknown constituent, exist in all of 19 samples collected in the east area of Qinghai Province and in high quantities. However, salidroside, a known active component from the genus, is found from only 5 species with the quantity of more than 0.3%. There are 5 plants containing lotaustralin, a known oral toxic compound, and with the highest quantity in the plant of Rh. kirilowii. The content of the two compounds above varies as plants and habitats are different.

Chromatography, Gas↗
PubMed1997

Photoaging and topical tretinoin: therapy, pathogenesis, and prevention.

Repeated exposure to UV radiation from the sun causes premature skin aging. This photoaging is characterized by wrinkles, mottled pigmentations, dry and rough skin, and loss of skin tone. Since the clinical demonstration that the use of topical tretinoin can improve photoaged skin, a great deal of knowledge that may explain wrinkle effacement has been acquired. Central to this pursuit has been dermal collagen. In this article, we summarize evidence (mainly from humans) that implicates a deficiency of superficial dermal collagen as the cause of the dermal aspects of photoaging. In addition, a mechanism through which UV radiation can lead to reduced collagen is presented. Through our understanding of the pathophysiological mechanism of photoaging, our ability to treat and possibly prevent this skin condition is enhanced.

Administration, Cutaneous↗
PubMed1996

NUC-2, a component of the phosphate-regulated signal transduction pathway in Neurospora crassa, is an ankyrin repeat protein.

In response to phosphorus limitation, the fungus Neurospora crassa synthesizes a number of enzymes that function to bring more phosphate into the cell. The NUC-2 protein appears to sense the availability of phosphate and transmits the signal downstream to the regulatory pathway. The nuc-2+ gene has been cloned by its ability to restore growth of a nuc-2 mutant under restrictive conditions of high pH and low phosphate concentration. We mapped the cloned gene to the right arm of linkage group II, consistent with the chromosomal position of the nuc-2 mutation as determined by classical genetic mapping. The nuc-2' open reading frame is interrupted by five introns and codes for a protein of 1066 amino acid residues. Its predicted amino acid sequence has high similarity to that of its homolog in Saccharomyces cerevisiae, PHO81. Both proteins contain six ankyrin repeats, which have been implicated in the cyclin-dependent kinase inhibitory activity of PHO81. The phenotypes of a nuc-2 mutant generated by repeat-induced point mutation and of a strain harboring a UV-induced nuc-2 allele are indistinguishable. Both are unable to grow under the restrictive conditions, a phenotype which is to some degree temperature dependent. The nuc-2+ gene is transcriptionally regulated. A 15-fold increase in the level of the nuc-2+ transcript occurs in response to a decrease in exogenous phosphate concentration.

Amino Acid Sequence↗
PubMed1996

Cloning, characterization, and properties of seven triplet repeat DNA sequences.

Several neuromuscular and neurodegenerative diseases are caused by genetically unstable triplet repeat sequences (CTG.CAG, CGG.CCG, or AAG.CTT) in or near the responsible genes. We implemented novel cloning strategies with chemically synthesized oligonucleotides to clone seven of the triplet repeat sequences (GTA.TAC, GAT.ATC, GTT.AAC, CAC.GTG, AGG.CCT, TCG.CGA, and AAG.CTT), and the adjoining paper (Ohshima, K., Kang, S., Larson, J. E., and Wells, R. D.(1996) J. Biol. Chem. 271, 16784-16791) describes studies on TTA.TAA. This approach in conjunction with in vivo expansion studies in Escherichia coli enabled the preparation of at least 81 plasmids containing the repeat sequences with lengths of approximately 16 up to 158 triplets in both orientations with varying extents of polymorphisms. The inserts were characterized by DNA sequencing as well as DNA polymerase pausings, two-dimensional agarose gel electrophoresis, and chemical probe analyses to evaluate the capacity to adopt negative supercoil induced non-B DNA conformations. AAG.CTT and AGG.CCT form intramolecular triplexes, and the other five repeat sequences do not form any previously characterized non-B structures. However, long tracts of TCG.CGA showed strong inhibition of DNA synthesis at specific loci in the repeats as seen in the cases of CTG.CAG and CGG.CCG (Kang, S., Ohshima, K., Shimizu, M., Amirhaeri, S., and Wells, R. D.(1995) J. Biol. Chem. 270, 27014-27021). This work along with other studies (Wells, R. D.(1996) J. Biol. Chem. 271, 2875-2878) on CTG.CAG, CGG.CCG, and TTA.TAA makes available long inserts of all 10 triplet repeat sequences for a variety of physical, molecular biological, genetic, and medical investigations. A model to explain the reduction in mRNA abundance in Friedreich's ataxia based on intermolecular triplex formation is proposed.

Base Sequence↗
PubMed1996

TTA.TAA triplet repeats in plasmids form a non-H bonded structure.

CTG.CAG, CGG.CCG, and AAG.CTT triplet repeats proximal to or in disease genes expand by a non-Mendelian genetic process to cause several human hereditary syndromes. As part of our physical, biological, and genetic studies on the 10 possible triplet repeats, we discovered that the TTA.TAA repeat, isolated from the upstream region of the variant surface glycoprotein gene of Trypanosoma brucei, shows a propensity to adopt a non-H bonded structure under appropriate conditions. The other nine triplet repeat sequences do not exhibit this property. (TTA.TAA)n, where n = 90, 60, 30, and 18, cloned into pUC19 was studied by chemical and enzymatic probes as well as two-dimensional gel electrophoretic analyses under a variety of conditions. The helix opening was observed for all four inserts in supercoiled plasmids as a function of temperature, pH, metal ions, and buffer conditions using OsO4, diethyl pyrocarbonate, and chloroacetaldehyde probes. This unusual property of the TTA.TAA repeat suggests that it plays a different role from the other nine triplet repeats in gene expression.

Base Sequence↗
PubMed1996

Auto-regulation of retinoic acid biosynthesis through regulation of retinol esterification in human keratinocytes.

In this report, we describe an auto-regulatory loop in human keratinocytes, whereby all-trans retinoic acid (retinoic acid) regulates its own biosynthesis from all-trans retinol (retinol) through regulation of retinol esterification. Retinol esterification activity was low in normal proliferating human keratinocytes, cultured in retinoid-free media. Treatment of keratinocytes with retinoic acid induced retinol esterifying activity (8-fold). Induction of retinol esterifying activity was blocked by either actinomycin D or cycloheximide. Based on substrate specificity and inhibitor sensitivity, lecithin:retinol acyltransferase (LRAT) was identified as the retinoic acid-inducible retinol esterifying enzyme. Induction of LRAT by retinoic acid reduced conversion of retinol to retinoic acid by 50%. This reduction in retinoic acid synthesis resulted from sequestration of retinol as retinyl esters, since inhibition of LRAT restored retinoic acid synthesis to control levels. In normal human skin, undifferentiated keratinocytes, in the lowest cell layer, esterified retinol 4 times greater, than differentiating keratinocytes, in upper cell layers, reflecting an induced state, under conditions of retinol sufficiency. Regulation of LRAT activity by retinoic acid provides a novel mechanism through which retinoic acid can regulate its own level by controlling availability of retinol for conversion to retinoic acid. In human skin in vivo, retinyl esters synthesized in basal keratinocytes could undergo hydrolysis during differentiation and thus serve as a source of retinol for keratinocytes in upper layers of skin.

Acyltransferases↗
PubMed1996

CTG triplet repeats from the myotonic dystrophy gene are expanded in Escherichia coli distal to the replication origin as a single large event.

The expansion and contraction of CTG and CGG trinucleotide repeat sequences have been associated with several heritable genetic diseases. We developed a system for investigating the expansion of triplet repeat sequences in Escherichia coli in order to elucidate molecular mechanisms. Analysis of expanded regions using the interrupting CTA triplet sequence as a location marker within the CTG tract revealed that the expansion of large CTG repeats is one event rather than an accumulation of multiple small expansions and that the expansions occur more frequently in the region distal from the replication origin. Also, we showed that a loss of interruptions increases the expansion frequency. Thus, the instability of large triplet repeats in hereditary diseases occurs by a mechanism different from the instability in microsatellite sequences caused by defects in mismatch repair systems for certain sporadic cancers and hereditary non-polyposis colorectal cancers.

Base Sequence↗
PubMed1996

CTG triplet repeats from human hereditary diseases are dominant genetic expansion products in Escherichia coli.

The relative ability of the 10 triplet repeat sequences to be expanded in Escherichia coli was determined. Surprisingly, CTG tracts are expanded at least 8 times more frequently than any of the other nine triplets. Low levels of expansion were found also for CGG, GTG, and GTC. Thus, the structure of the CTG repeats and/or their utilization by the DNA synthetic systems in vivo must be quite different from the other triplets. These data further validate this genetically defined system for elucidating molecular mechanisms of expansion and may explain why most triplet repeat hereditary neuromuscular and neurodegenerative disease genes contain CTG repeats.

Base Sequence↗
PubMed1996

Molecular basis of sun-induced premature skin ageing and retinoid antagonism.

Damage to skin collagen and elastin (extracellular matrix) is the hallmark of long-term exposure to solar ultraviolet irradiation, and is believed to be responsible for the wrinkled appearance of sun-exposed skin. We report here that matrix-degrading metalloproteinase messenger RNAs, proteins and activities are induced in human skin in vivo within hours of exposure to ultraviolet-B irradiation (UVB). Induction of metalloproteinase proteins and activities occurred at UVB doses well below those that cause skin reddening. Within minutes, low-dose UVB upregulated the transcription factors AP-1 and NF-kappa B, which are known to be stimulators of metalloproteinase genes. All-trans retinoic acid, which transrepresses AP-1 (ref. 8), applied before irradiation with UVB, substantially reduced AP-1 and metalloproteinase induction. We propose that elevated metalloproteinases, resulting from activation of AP-1 and NF-kappa B by low-dose solar irradiation, degrade collagen and elastin in skin. Such damage, if imperfectly repaired, would result in solar scars, which through accumulation from a lifetime of repeated low-dose sunlight exposure could cause premature skin ageing (photoageing).

Adult↗