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Biomedical subjects

H C Huang

Publications and source records attributed to H C Huang.

At least 91 records · Page 5Linked to original sources
PubMed1995

1,2-Diarylcyclopentenes as selective cyclooxygenase-2 inhibitors and orally active anti-inflammatory agents.

A series of 1,2-diarylcyclopentene methyl sulfones and sulfonamides have been shown to be remarkably potent and selective cyclooxygenase-2 (COX-2) inhibitors. The methyl sulfone analogs 7 showed excellent COX-2 activity, with IC50s ranging from 0.003 (7f,n) to 0.87 (7o) microM. In addition, most analogs of 7 showed no activity (IC50 > 100 microM) against the COX-1 enzyme. Replacement of the methyl sulfone moiety with a sulfonamide group gave a slightly more potent (typically 2-5-fold) but less selective COX-2 inhibitor, mainly due to an increase (20- > 100-fold) in COX-1 activity. However, in vitro COX-1/COX-2 selectivity for the sulfonamides 8 could be increased in many cases by simply incorporating a substituent at the 3-position of the phenyl group. Furthermore, in vitro selectivity increased with the size and number of substituents, as demonstrated in the selectivity trend of 8k (8000) > 8j (1900) > 8i (500) > 8h (100). More importantly, the sulfonamide COX-2 inhibitors showed greatly enhanced oral activity in the rat model of established adjuvant-induced arthritis, with inhibition values of 79.0% (8a), 81.5% (8c), and 83.0% (8g) at 1 mg/kg. On the basis of its overall biological profile, sulfonamide 8c was evaluated as a potential clinical candidate, displaying an ED50 of 22 mpk in the rat carrageenan-induced paw edema model and an ED50 of 0.16 mpk in the rat established adjuvant-induced arthritis model with no indication of gastrointestinal toxicity in rats and mice at 200 mpk. In addition, a preparative-scale synthetic route to sulfonamide 8c has been developed.

Administration, Oral↗
PubMed1995

Cloning and characterization of the endogenous retroviral-tRNA(Glu) multigene family from human genomes of different racial backgrounds.

An 8.3-kb human endogenous retroviral-tRNA(Glu) (HERV-E)-encoding cDNA clone and a 1.5-kb genomic clone were isolated from a Chinese-derived cervical cancer cell line, CC7T, and their sequences determined. The former is a full-length endogenous retroviral cDNA containing corresponding u5-gag-pol-env-u3-r regions. The latter is a partial retroviral DNA segment, covering the gag and pol genes. Analysis of normal human DNA by Southern blot hybridization with three specific HERV-E molecular DNA probes revealed complex restriction-fragment length polymorphisms (RFLP), implying that the human genome contains diverse proviral structures and dispersed integration sites. The complex patterns were virtually identical between DNAs from African-Americans, Asians and Caucasians, with only a few minor variations. The data suggest that these proviral sequences were mostly incorporated into the human genome before racial divergence and, hence, may serve as markers for distinct chromosomal sites.

Amino Acid Sequence↗
PubMed1995

Sequence comparison and computer modelling of cardiotoxins and cobrotoxin isolated from Taiwan cobra.

Six cardiotoxins and one neurotoxin isolated and purified from the Taiwan cobra venom (Naja naja atra) possess distinct pharmacological and biochemical properties despite the existence of a grossly similar tertiary structure among these toxins, i. e., a core consisting of a series of short loops and four disulfide bridges. A systematic structure comparison of these major toxin isoforms was made by the secondary-structure predictions together with computer model-building based on the primary sequences and the established X-ray and NMR structures of one published cardiotoxin isoform and cobrotoxin. It is of interest to find that some defined and subtle differences can be detected upon the superposition of these three-dimensional polypeptide chains, which may reflect the intrinsic differences in the surface hydrophobicity of cardiotoxins and cobrotoxin as revealed by hydropathy profiles of these toxins in one of three major loops. The differences seem to correlate with different inhibitory activities exhibited by cardiotoxins in contrast to the lack of activity by cobrotoxin on protein kinase C (PKC).

Amino Acid Sequence↗
PubMed1995

Differential correlation between translocation and down-regulation of conventional and new protein kinase C isozymes in C6 glioma cells.

Correlation between translocation and down-regulation of conventional protein kinase C alpha (cPKC alpha) and new PKC delta (nPKC delta) induced by 12-O-tetradecanoylphorbol 13-acetate (TPA) at different time courses (5 min, 30 min, 1 h, 3 h, 6 h, 10 h, 17 h, and 24 h) was studied in C6 glioma cells. From the dose-dependent translocations of these two isoforms by 10-min treatment with TPA (1, 3, 10, 30, 100, 300, and 1,000 nM), we found that cPKC alpha was translocated by 3-1,000 nM and nPKC delta was translocated by 10-1,000 nM TPA. Both isoforms were maximally translocated by 100-1,000 nM TPA, whereas 1 nM did not translocate these two isoforms. When the cells were treated with 1,000 nM TPA for 5 min to 17 h, the translocation of these two isoforms occurred rapidly after 5-min treatment and could be sustained for 1 h, whereas down-regulation occurred after 3-h treatment and almost complete down-regulation was observed after 17-h treatment. However, the extent of down-regulation of nPKC delta was greater than that of cPKC alpha at 3-, 6-, and 10-h treatment. Further studies by using different doses of TPA (100, 10, 3, and 1 nM) and extending the time to 24 h showed that cPKC alpha was more resistant to down-regulation. This conventional isoform was maintained at a translocation state even after long-term treatment with 3-100 nM TPA, and complete down-regulation was only shown after 1,000 nM treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain Neoplasms↗
PubMed1995

Inhibition of protein kinase C by snake venom toxins: comparison of enzyme inhibition, lethality and hemolysis among different cardiotoxin isoforms.

Cardiotoxins, neurotoxins and phospholipase A2 (PLA2) are three major classes of toxic components present in the Taiwan cobra, Naja naja atra of the Elapidae family. Cardiotoxins (or called cytotoxins), a group of major polypeptides of around 60 amino-acid residues present abundantly in the elapid family of snakes, comprise about 45-55% of the crude venom of Taiwan cobra. In contrast to another prominent group of structurally similar neurotoxins with well-established acetylcholine receptors and modes of action, cardiotoxins showed no defined cellular targets and very diverse pharmacological functions. A systematic structure/function comparison of these toxins was made by their relative inhibitory effects on protein kinase C (PKC) isolated from mouse brains. Lethality and hemolysis of various cardiotoxin isoforms were also compared in order to shed some insight on the biological targets and mechanisms of these surface-active amphiphilic polypeptides. A structure comparison of these cardiotoxins based on computer model-building revealed that some defined and subtle differences can be detected upon the superposition of these three-dimensional polypeptide chains, which may reflect the intrinsic differences in the hydrophobic peptide segments present on the surface loops of toxin molecules. The differences seem to correlate with different inhibitory activities exhibited by cardiotoxins in contrast to the lack of activity by cobrotoxin and PLA2 on PKC.

Animals↗
PubMed1995

Latex agglutination test for detection of tetanus antitoxins.

A rapid and easy method of slide agglutination test for the detection of human tetanus antitoxins was developed in this study. Testing reagents were prepared from carboxylated polystyrene latex particles with tetanus toxin by soluble carbodiimide. The test was performed on a glass slide with a drop of test sample and a drop of testing reagent. The agglutination reaction was usually completed within five minutes. Sensitivity of this test for tetanus antitoxins can be reached at 0.125 IU/ml. Therefore, the latex agglutination test can be used to determine the immune status of a patient in an emergency.

Agglutination↗
PubMed1994

Effects of baicalein and esculetin on transduction signals and growth factors expression in T-lymphoid leukemia cells.

The possible mechanisms of antiproliferative effect of baicalein were studied in human T-lymphoid leukemia cells (CEM cells) and compared with those of esculetin. Baicalein, esculetin and related compounds, baicalein, wogonin, esculin and scoparone, inhibited CEM cell proliferation. Baicalein exhibited the greatest antiproliferative activity with an IC50 of 4.7 +/- 0.5 microM and the maximal suppression of 91.5 +/- 1.4% in CEM cells. The protein tyrosine kinase activity in the CEM cells was significantly reduced by baicalein (10(-6)-10(-4) M) and esculetin (10(-4) M). Baicalein exhibited a greater inhibitory activity on the protein tyrosine kinase than did esculetin (74.1 +/- 3.3% vs. 64.6 +/- 2.8% inhibition at 10(-4) M). On the other hand, the protein kinase C activity stimulated by phorbol-12-myristate 13-acetate was reduced by directly incubating with baicalein (10(-6)-10(-4) M) and esculetin (10(-4) M). However, the inhibitory activities on protein kinase C did not show a dose-dependency. The reverse transcription-polymerase chain reaction analysis of platelet-derived growth factor-A (PDGF-A) and transforming growth factor-beta 1 (TGF-beta 1) messenger RNA levels demonstrates that baicalein and esculetin reduced the PDGF-A mRNA level, but less affected the TGF-beta 1 mRNA. Baicalein exhibited the greater reduction on the expression of PDGF-A mRNA than did esculetin. It is suggested that baicalein and esculetin may affect cell proliferation by direct inhibition of growth-related signal, protein tyrosine kinase, as well as reduction of mRNA expression of growth factor, platelet-derived growth factor.

Cell Division↗
PubMed1994

Antiproliferative effect of baicalein, a flavonoid from a Chinese herb, on vascular smooth muscle cell.

The effects of baicalein, baicalin and wogonin, the flavonoids from Scutellaria baicalensis, on the proliferative responses of cultured rabbit vascular smooth muscle cells were studied. The proliferative response was determined from the uptake of tritiated thymidine. In rabbit vascular smooth muscle cells, all three flavonoids dose dependently inhibited the proliferative response induced by 5% fetal calf serum at the dose range of 10(-6) to 10(-4) M. Baicalin and wogonin were less effective than baicalein as inhibitors of the serum-induced smooth muscle cell proliferation, indicating that the three hydroxyl groups on positions 5, 6 and 7 seem to be necessary and sufficient for full inhibitory activity against the proliferative response of smooth muscle cells. Baicalein had a greater inhibitory effect on the proliferative reponse stimulated by platelet-derived growth factor than on serum-stimulated proliferation. Baicalein, a flavonoid with antiproliferative and lipoxygenase-inhibitory activities, may be useful as another template for the development of better drugs to prevent the pathological changes of atherosclerosis and restenosis.

Animals↗
PubMed1994

Morphological evidence for the antiatherogenic effect of scoparone in hyperlipidaemic diabetic rabbits.

OBJECTIVE: Scoparone (6,7-dimethoxycoumarin), a coumarin isolated from a hypolipidaemic Chinese herb Artemisia scoparia, has vasodilator and antiproliferative activities and possesses free radical scavenging properties in vitro. The aim of the study was to investigate the morphological effects of scoparone in the antiatherogenic process in vivo by using hyperlipidaemic diabetic rabbits as an animal model. METHODS: Male New Zealand White rabbits were divided into three groups: control (normal), hyperlipidaemic diabetic, and scoparone treated hyperlipidaemic diabetic. The plasma concentration of total cholesterol and triglycerides were determined. The thickness of the tunica intima was measured on paraffin sections of the aortas stained with Movat's pentachrome. The aortic samples were also processed for scanning and transmission electron microscopy. RESULTS: Neither the lipid profile in the plasma nor the structures of the aortic wall from the control group showed abnormalities. In contrast, the aortas from the hyperlipidaemic diabetic group showed prominent atherosclerotic plaques. Large numbers of monocytes were found adherent to the luminal surface and a markedly thickened intima filled with many lipid laden foam cells was clearly observed. By comparison, the scoparone treated group showed less advanced atherosclerosis with a lower plasma cholesterol. In the scoparone treated rabbits, the proportion of the aortic surface area covered with macroscopic plaques was 30%, and the thickness of the tunica intima 17%, of that of the non-scoparone treated hyperlipidaemic diabetic rabbits. CONCLUSIONS: Scoparone has an antiatherogenic action in hyperlipidaemic diabetic rabbits.

Animals↗
PubMed1994

One exon of the human LSF gene includes conserved regions involved in novel DNA-binding and dimerization motifs.

The transcription factor LSF, identified as a HeLa protein that binds the simian virus 40 late promoter, recognizes direct repeats with a center-to-center spacing of 10 bp. The characterization of two human cDNAs, representing alternatively spliced mRNAs, provides insight into the unusual DNA-binding and oligomerization properties of LSF. The sequence of the full-length LSF is identical to that of the transcription factors alpha CP2 and LBP-1c and has similarity to the Drosophila transcription factor Elf-1/NTF-1. Using an epitope-counting method, we show that LSF binds DNA as a homodimer. LSF-ID, which is identical to LBP-1d, contains an in-frame internal deletion of 51 amino acids resulting from alternative mRNA splicing. Unlike LSF, LSF-ID did not bind LSF DNA-binding sites. Furthermore, LSF-ID did not affect the binding of LSF to DNA, suggesting that the two proteins do not interact. Of three short regions with a high degree of homology between LSF and Elf-1/NTF-1, LSF-ID lacks two, which are predicted to form beta-strands. Double amino acid substitutions in each of these regions eliminated specific DNA-binding activity, similarly to the LSF-ID deletion. The dimerization potential of these mutants was measured both by the ability to inhibit the binding of LSF to DNA and by direct protein-protein interaction studies. Mutations in one homology region, but not the other, functionally eliminated dimerization.

Alternative Splicing↗
PubMed1994

Intussusception of mucocele of the appendix: a case report.

A 63-year-old man had had repeated episodes of ileo-caecal intussusception, and a pre-operative barium enema revealed appendiceal mucocele as a leading cause. Resection of appendix and part of the caecum were undertaken through exploration. The post-operative course was smooth. This unusual etiology is reported and discussed.

Appendix↗
PubMed1994

A preliminary report on Borrelia burgdorferi infection in the Taiwan area.

A total of 273 serum specimens from different areas and sources were tested against Borrelia burgdorferi antigens by enzyme-linked immunosorbent assay method. Positive rates of serological reactions were 3% and 58% for healthy persons and syphilis patients, respectively. Obviously, there was a lot of cross-reaction in the venereal disease group. Meanwhile, positive rates were 3% and 13% in the sera collected from Taiwan and Orchid Island, respectively. This difference may reflect a less developed environment in the latter. Since reported cases of Lyme disease in Taiwan are rare, serologic tests are usually adapted for rapid diagnosis in common laboratories. As for disease confirmation, clinical observations, epidemiological data and exposure in an endemic area must also be considered.

Antibodies, Bacterial↗
PubMed1993

Synthesis and structure-activity relationships of nonpeptide, potent triazolone-based angiotensin II receptor antagonists.

2,5-Dibutyl-2,4-dihydro-4-[[2-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4' - yl]methyl]-3H-1,2,4-triazol-3-one, SC-51316, was synthesized as a potent and orally active angiotensin II (AII) receptor antagonist with a long duration of action. To explore the lipophilic pocket in the AII receptor interacting with the substituent at the 2-position of triazolone-based antagonists, a series of compounds were prepared and evaluated for receptor binding affinity and antagonism of AII-contracted rabbit aortic rings. It has been found that the pocket is very spacious and can accommodate different sizes of lipophilic groups and various functionalities. Acidic groups generally result in a slight decrease in binding affinity. Branched chains are unfavorable. The freedom of rotation around C2-C3 in the flexible side chain is crucial for good binding. The 2-phenylethyl-substituted triazolone analogue exhibits the highest in vitro potency among all compounds that have been synthesized.

Angiotensin Receptor Antagonists↗
PubMed1993

Pseudomonas syringae pv. syringae harpinPss: a protein that is secreted via the Hrp pathway and elicits the hypersensitive response in plants.

The ability of P. syringae to elicit the hypersensitive response in nonhost plants or pathogenesis in hosts is controlled by hrp genes. The P. syringae pv. syringae 61 hrpZ gene encodes harpinPss, a 34.7 kd extracellular protein that elicits hypersensitive necrosis in tobacco and other plants. HarpinPss is heat stable, glycine rich, dissimilar in amino acid sequence to any known protein, produced only in apoplastic fluid-mimicking minimal media, and secreted in a HrpH-dependent manner. The carboxy-terminal 148 amino acid portion of harpinPss contains two directly repeated sequences of GGGLGTP and QTGT and is sufficient and necessary for elicitor activity. The necrosis elicited by harpinPss is an active response of the plant, which can be inhibited by alpha-amanitin, cycloheximide, lanthanum chloride, or sodium vanadate.

Amanitins↗
PubMed1993

Antiproliferative effect of esculetin on vascular smooth muscle cells: possible roles of signal transduction pathways.

The effect of esculetin, a coumarin derivative with lipoxygenase inhibitor activity, on the proliferation response of cultured rabbit vascular smooth muscle cells was studied. Proliferation response was determined by the uptake of tritiated thymidine. Esculetin (10(-5)-10(-4) M) dose dependently inhibited the enhanced proliferation stimulated by 5% fetal calf serum. The structure-activity relationship of esculetin and eight other coumarin derivatives indicates that two adjacent phenolic hydroxyl groups at the C-6 and C-7 positions in the coumarin skeleton are necessary for the potent antiproliferative effect. The antiproliferative effects of other lipoxygenase inhibitors, 5,8,11,14-eicosatetraynoic acid (ETYA) and ketoconazole, were comparable to the effect of esculetin. However, esculetin exhibited the greatest maximal suppression. The enhanced releases of 12-hydroxyeicosatetraenoic acid (12-HETE), prostaglandin E2 and 6-keto-prostaglandin F1 alpha in the culture medium of smooth muscle cells stimulated by 5% fetal calf serum were significantly reduced by esculetin. Furthermore, the fetal calf serum-stimulated protein tyrosine kinase activity was reduced by esculetin (10(-5)-10(-4) M) in a dose-dependent manner. In contrast, the protein kinase C activity stimulated by phorbol-12-myristate-13-acetate was not affected by esculetin (10(-6)-10(-4) M). These results suggest that the antiproliferative effect of esculetin on vascular smooth muscle cells may be partly mediated through inhibition of protein tyrosine kinase and modulated by inhibition of lipoxygenase.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1993

Investigating the s-2 subsite selectivity of alkaline proteases in hydrolysis of diastereo-peptide esters and molecular-modeling interpretation.

Diastereomeric peptide-esters (Ala-Ala-AA2-Phe-OMe, AA2 = Gly, D- or L-Ala, Pro, Phe, Lys, and Glu) have been used as substrates, and the kinetic constants (Kcat and Km) of the three alkaline proteases, subtilisin Carlsberg, alcalase, and Nagarse (subtilisin BPN') catalyzed ester-hydrolysis, were measured to investigate the selectivity of the enzyme-catalyzed peptide esterhydrolysis. All three proteases preferred the substrate which had a small side-chain at the s-2 site. Thus, the substrates with a bulky side-chain at the p-2 site such as Phe, Pro, Glu, and Lys, hydrolyzed with a rate of about one-tenth that of Ala at the p-2 site, and the Kcat decreased as the size of the p-2 amino acid residue increased. The diastereoselectivity of the alkaline protease-catalyzed hydrolysis of each diastereomeric pair depended on the size of the amino acid residue at the p-2 position of the substrate. The substrates with a bulky side-chain at the p-2 site hydrolyzed with higher diastereoselectivity than did the substrates with a small side-chain at the p-2 site. Molecular modeling of the enzyme-substrate complex show that: for the enzyme complexed with a substrate which has L-L-L-L configuration, each residue of the L-L-L-L tetrapeptide filled in and was completely enclosed by the cleft of the four subsites of the enzyme. The side-chains of the residues were identically positioned within the pocket of the binding-site. For the complex of enzyme with substrate of L-L-D-L, the side-chain of the D-amino acid residue was far away from the s-2 subsite of the enzyme, and had close contact with the side-chains of Leu-126 and Ile-107 of the enzyme.

Amino Acid Sequence↗
PubMed1993

In vivo pharmacology of SC-51316, a nonpeptidic angiotensin II receptor antagonist.

The depressor activity of a novel nonpeptidic angiotensin II (AII) receptor antagonist, SC-51316 (2,5-dibutyl-2,4-dihydro-4-[[2-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4 '- yl]-methyl]-3H-1,2,4-triazol-3-one), is described. In anesthetized, ganglion-blocked rats, intravenous administration of SC-51316 inhibited the pressor response to an infusion of AII. To determine antihypertensive efficacy, conscious, spontaneously hypertensive rats were administered SC-51316 (30 mg/kg intragastrically) daily for 5 days. Blood pressure was reduced in a similar manner to that observed with the angiotensin converting enzyme inhibitor enalapril (10 mg/kg intragastrically). SC-51316 had no effect on heart rate. In conscious, sodium-deficient dogs, administration of SC-51316 (30 mg/kg orally) or enalapril (10 mg/kg orally) lowered blood pressure similarly over a 24 h observation period. Thus, SC-51316 antagonizes the activity of AII in vivo and is an orally active, antihypertensive agent.

Angiotensin II↗