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Biomedical subjects

C H He

Publications and source records attributed to C H He.

At least 19 recordsLinked to original sources
PubMed2003

Disruption of the Saccharomyces cerevisiae cell-wall pathway gene SLG1 causes hypersensitivity to the antitumor drug bleomycin.

Bleomycin is an antitumor drug that damages DNA via a free radical-dependent mechanism, and yeast mutants defective in DNA repair are hypersensitive to the drug. To identify possible pathways that may contribute to bleomycin resistance in yeast, we characterized a panel of bleomycin-sensitive mutants that were previously isolated by insertion mutagenesis using the transposon miniTn3::Leu2::LacZ::AMP( R). One of these mutants harbored a single insertion in the SLG1 gene, which encodes a cell membrane protein that senses cell wall stress, and functions to maintain cell wall function by activating the protein kinase C signaling pathway. Deletion of the SLG1 gene in parental strains caused hypersensitivity to bleomycin, and this correlated with an accumulation of damaged DNA. A plasmid that expresses the native SLG1 gene or that increases PKC1 gene dosage restored bleomycin resistance to the slg1Delta mutant. Two-dimensional gel electrophoresis revealed that exposure to bleomycin triggered the expression of certain proteins, presumably to maintain cell wall function, in a Slg1-dependent manner. In addition, mutants lacking cell wall function were found to be hypersensitive to bleomycin. We conclude that mutants deficient in proteins that maintain cell wall function are severely compromised in their ability to limit bleomycin entry into the cell. Therefore, these mutants are burdened with increased genotoxicity upon exposure to bleomycin in the medium. Our results show that major mechanisms other than DNA repair are operating in yeast to mediate bleomycin resistance.

Antibiotics, Antineoplastic↗
PubMed2001

Crystal structure of human epidermal growth factor and its dimerization.

Epidermal growth factor (EGF) is a typical growth-stimulating peptide and functions by binding to specific cell-surface receptors and inducing dimerization of the receptors. Little is known about the molecular mechanism of EGF-induced dimerization of EGF receptors. The crystal structure of human EGF has been determined at pH 8.1. There are two human EGF molecules A and B in the asymmetric unit of the crystals, which form a potential dimer. Importantly, a number of residues known to be indispensable for EGF binding to its receptor are involved in the interface between the two EGF molecules, suggesting a crucial role of EGF dimerization in the EGF-induced dimerization of receptors. In addition, the crystal structure of EGF shares the main features of the NMR structure of mouse EGF determined at pH 2.0, but structural comparisons between different models have revealed new detailed features and properties of the EGF structure.

Crystallization↗
PubMed2001

Identification of activating transcription factor 4 (ATF4) as an Nrf2-interacting protein. Implication for heme oxygenase-1 gene regulation.

Nrf2 regulates expression of genes encoding enzymes with antioxidant (e.g. heme oxygenase-1 (HO-1)) or xenobiotic detoxification (e.g. NAD(P)H:quinone oxidoreductase, glutathione S-transferase) functions via the stress- or antioxidant-response elements (StRE/ARE). Nrf2 heterodimerizes with small Maf proteins, but the role of such dimers in gene induction is controversial, and other partners may exist. By using the yeast two-hybrid assay, we identified activating transcription factor (ATF) 4 as a potential Nrf2-interacting protein. Association between Nrf2 and ATF4 in mammalian cells was confirmed by co-immunoprecipitation and mammalian two-hybrid assays. Furthermore, Nrf2.ATF4 dimers bound to an StRE sequence from the ho-1 gene. CdCl(2), a potent inducer of HO-1, increased expression of ATF4 in mouse hepatoma cells, and detectable induction of ATF4 protein preceded that of HO-1 (30 min versus 2 h). A dominant-negative mutant of ATF4 inhibited basal and CdCl(2)-stimulated expression of a StRE-dependent/luciferase fusion construct (pE1-luc) in hepatoma cells but only basal expression in mammary epithelial MCF-7 cells. A dominant mutant of Nrf2 was equally inhibitory in both cell types in the presence or absence of CdCl(2). These results indicate that ATF4 regulates basal and CdCl(2)-induced expression of the ho-1 gene in a cell-specific manner and possibly in a complex with Nrf2.

Activating Transcription Factor 3↗
PubMed2000

Crystallization and preliminary X-ray diffraction studies of human epidermal growth factor.

Human epidermal growth factor (hEGF), a 6.2 kDa protein of 53 amino acids with three internal disulfide bridges, has been crystallized by the hanging-drop method. hEGF crystallizes in space group P3(1)21 (or P3(2)21) using MgCl(2) as precipitant, with unit-cell parameters a = b = 61.4, c = 87.0 A. Another type of crystal, obtained using NaCl as precipitant, belongs to a tetragonal point group and has unit-cell dimensions a = b = 102.5, c = 166.6 A. The trigonal crystals with the smaller unit cell diffract X-rays better and a native data set from a single crystal has been collected to 3.0 A resolution.

Crystallization↗
PubMed1999

A new furofuran mono-lactone from Forsythia suspensa.

A new furofuran mono-lactone, named forsythenin, was isolated from the fruits of Forsythia suspensa, together with the known compounds, ocotillone, ocotillol monoacetate, (6'-O-palmitoyl)-sitosterol-3-O-beta-D-glucoside and palmitic acid. The structure of the new compound was elucidated on the basis of spectroscopic means and X-ray crystallography.

Bridged Bicyclo Compounds, Heterocyclic↗
PubMed1999

An allele of the yeast RPB7 gene, encoding an essential subunit of RNA polymerase II, reduces cellular resistance to the antitumor drug bleomycin.

Bleomycin is an antitumor drug that kills cells by introducing lesions in DNA. Thus, normal cells exposed to bleomycin must rely on efficient DNA repair mechanisms to survive. In the yeast Saccharomyces cerevisiae, the transcriptional activator Imp2 is required to fend off the toxic effects of bleomycin. However, it remains unclear whether Imp2 controls the expression of a protein that either repairs bleomycin-induced DNA lesions, or detoxifies the drug, and or both. To gain further insight into the mechanisms by which yeast cells mount a response towards bleomycin, we began to sequentially characterize the genetic defect in a collection of bleomycin-sensitive mutants that were previously isolated by mini-Tn3 transposon mutagenesis. A rescue plasmid designed to integrate at the site of the mini-Tn3 insertion was used to identify the defective gene in one of the mutant strains, HCY53, which was not allelic to IMP2. We showed that in strain HCY53, the mini-Tn3 was inserted at the distal end of an essential gene RPB7, which encodes one of the two subunits, Rpb4-Rbp7, that forms a subcomplex with RNA polymerase II. Since rpb7 null mutants are nonviable, it would appear that the rpb7::mini-Tn3 allele produces a protein that retains partial biological function thus permitting cell viability, but which is unable to provide bleomycin resistance to strain HCY53. The defective phenotype of strain HCY53 could be corrected by a plasmid bearing the entire RPB7 gene. Two dimensional gel analysis revealed that the expression of several proteins were diminished or absent in the rpb7::mini-Tn3 mutant when challenged with bleomycin. These results are in accord with our previous report that bleomycin resistance in yeast is controlled at the transcriptional level.

Alleles↗
PubMed1997

[Current status of HIV infection in Yunnan Province of China].

In cooperation with the Chinese Academy of Preventive Medicine and Yunnan Province Provincial Office for AIDS Control and Prevention, we studied the current status of HIV infection intravenous drug users (IVDUs) and other high risk groups in Yunnan province of China. As of the end of 1995, 1,807 HIV cases were officially reported (Positive rate was 0.6%), of which 1,278 (77.9%) were IVDUs, and 24 were their spouses. The majority of cases were found among the Dai minority male farmers near Ruili which borders on Myammar, but HIV also appears to be spreading among the Han people. HIV antibody positive rates among commercial sex workers, pregnant women and blood donors were 0.2%, 0.07% and 0.04%, respectively. A system for surveillance of HIV has been developed, but preventive strategies to cope with HIV epidemic are not sufficient. As HIV/AIDS is now a global issue, (1) the integration and coordination of such preventive strategies in cooperation with community health workers, (2) general health education for condom use promotion and (3) care of psychological vulnerable person such as IVDUs, should be developed.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Functional mitochondria are essential for Saccharomyces cerevisiae cellular resistance to bleomycin.

The antitumor activity of bleomycin is associated with its ability to produce DNA lesions. The cellular process that repairs bleomycin-induced DNA lesions is not entirely clear. To understand how these DNA lesions are repaired in eukaryotic cells, we used mini Tn3 : : LEU2 :: LacZ transposon mutagenesis to isolate yeast mutants that were hypersensitive to bleomycin. One of the mutants, HCY69, was characterized further and found to be 4- and 3-fold more sensitive, respectively, to bleomycin and hydrogen peroxide, as compared to the parent. The mutant displayed parental resistance to a variety of other DNA-damaging agents. Plasmid rescue and DNA sequence analysis revealed that the transposon interrupted the OXA1 gene, which encodes a protein required to process one of the subunits, cox II, of the cytochrome oxidase complex in mitochondria. A plasmid carrying the native OXA1 gene fully restored drug resistance to strain HCY69. Our data strongly suggest that functional mitochondria are required for cellular protection against the toxic effects of bleomycin.

Bleomycin↗
PubMed1996

A Saccharomyces cerevisiae phleomycin-sensitive mutant, ph140, is defective in the RAD6 DNA repair gene.

The antibiotic bleomycin is used as an anticancer agent for treating a variety of tumours. The antitumour effect of bleomycin is related to its ability to produce lesions such as apurinic/apyrimidinic sites and single- and double-strand breaks in the cellular DNA. Phleomycin is a structurally related form of bleomycin, but it is not used as an anticancer agent. While phleomycin can also damage DNA, neither the exact nature of these DNA lesions nor the cellular process that repairs phleomycin-induced DNA lesions is known. As a first step to understand how eukaryotic cells provide resistance to phleomycin, we used the yeast Saccharomyces cerevisiae as a model system. Several phleomycin-sensitive mutants were generated following gamma-radiation treatment and among these mutants, ph140 was found to be the most sensitive to phleomycin. Molecular analysis revealed that the mutant ph140 harbored a mutation in the DNA repair gene RAD6. Moreover, a functional copy of the RAD6 gene restored full phleomycin resistance to strain ph140. Our findings indicate that the RAD6 protein is essential for yeast cellular resistance to phleomycin.

4-Nitroquinoline-1-oxide↗
PubMed1995

Rearranged taxoids from Taxus yunnanensis.

Two rearranged 2(3-->20)abeotaxanes were isolated from the leaves and stems of Taxus yunnanensis, and designated as taxin B and 2-deacetyltaxin B. The structure of taxin B with a unique 6/10/6 skeleton was deduced on the basis of 1H-NMR, 13C-NMR, 1H-1H COSY, DEPT, NOE, and mass spectra and confirmed by X-ray crystallographic analysis. The structure of 2-deacetyltaxin B is elucidated by analog.

Alkaloids↗
PubMed1995

[Clinical study of sperm intro-fallopian transfer].

To explore the new technique of assistant pregnancy, we transferred sperm into fallopian tubes by laparoscopy Via an operation named sperm intra-fallopian transfer (SIFT). Twenty-nine infertile women (eighteen patients in natural menstrual cycle group, the others in the group of stimulated ovulation cycle) had their fallicle development with B ultrasonic scanning monitored. Patients were examined by laparoscopy before ovulation, then prepared sperm was transferred into fallopian tubes. Amony twenty-nine patients who had SIFT, three were pregnant in the operation month. The rate of pregnancy in operation month was 10. 3%, The rate of pregnancy during six months after SIFT was 31.0% (9 cases). Amony fifteen patients with "real" unexplained infertility, the rate of pregnancy during six months after SIFT was 46.7%. This preliminary result, showed that on the basis of skilled technique of laparoscopy, SIFT is a new, simple, safe, economic and effective method in treating infertility.

Adult↗
PubMed1993

Pharmacokinetic study of RU 486 and its metabolites after oral administration of single doses to pregnant and non-pregnant women.

RU 486 and three of its metabolites (RU 42633-monodemethyl, RU 42848-didemethyl, and RU 42698-hydroxymetabolite) were determined by HPLC in plasma from nine non-pregnant and 36 pregnant women. Each non-pregnant subject took an oral dose of RU 486 (25, 100, 400 and 600 mg consecutively) once per menstrual cycle. Six of the nine women also received a dose of 200 mg. The 36 pregnant women were randomized into four groups which were given a single dose of 25, 100, 400 or 600 mg RU 486. Blood samples were taken up to 120 h after dosing. Peak concentrations of RU 486 occurred on most occasions within 2 h. Plasma concentrations at 1 h and at 24 h increased in proportion to log dose. There was a wide variability (up to ten-fold) in the pharmacokinetic parameters within each dose group. Plasma concentrations of RU 42633 were similar to those of RU 486 but concentrations of RU 42848 and RU 42698 were much lower. As with RU 486, the plasma concentrations of the metabolites were maintained at high levels for up to 48-72 h after dosing. The findings were consistent with a rapid metabolism of RU 486 to RU 42633; removal of the second methyl group leading to RU 42698 occurred much more slowly and to a much less extent than removal of the first. There appeared to be no significant differences between the non-pregnant and pregnant women in either the plasma concentrations or pharmacokinetic parameters of RU 486 and its metabolites.

Administration, Oral↗
PubMed1993

[Studies on diterpenoids from leaves of Tripterygium wilfordii].

Tripterygium wilfordii Hook f. has been used as a medicinal herb in traditional Chinese medicine and as an insecticide by the Chinese for hundreds of years. Recently, this plant has been used to treat cancer, rheumatic arthritis and various skin diseases in some Chinese clinics. It is of interest to note that Tripterygium also showed significant antifertility activities. The active principles of the anti-inflammatory, immunosuppressive and antifertile actions in Tripterygium are diterpenoid containing triepoxides, but information on its chemistry is limited to the woody part of the root and the root bark. Recently, we have studies the leaves of Tripterygium (collected at Zhejiang province, China), and isolated two novel diterpenoids by chromatography named tripdioltonide (8) and 13,14-epoxide 9,11,12-trihydroxytriptolide (9), besides triptonide (1), triptolide (2), tripdiolide (3), triptolidenol (4), 16-hydroxyl-triptolide (5), tripchlorolide (6) and triptriolide (7). Their structures were established by chemical reactions, TLC, UV, MS, IR, 1H-1H COSY, 1H-13C COSY, DEPT spectrometric investigation. The structure of tripdioltonide was further confirmed by X-ray analysis.

Diterpenes↗
PubMed1991

A multicenter clinical study on two types of levonorgestrel tablets administered for postcoital contraception.

Contraceptive efficacy, cycle control and side effects of two types of 0.75 mg levonorgestrel tablets taken postcoitally during the periovulatory period of one cycle were studied in a multicenter trial involving 361 women. No significant differences were found between the two types of levonorgestrel pills in terms of contraceptive efficacy, cycle control and side effects. The failure rate observed (1.4% per treated cycle) was similar to that reported for other hormonal approaches to emergency postcoital contraception. Intermenstrual bleeding or spotting occurred in 11.5% of the cycles and anovulation as assessed from BBT charts in 14.4% of cycles. One or more side effects were reported by 22.2% of subjects. The relatively frequent occurrence of cycle disturbances and subjective side effects make it unlikely that the repeated postcoital use of levonorgestrel would be an acceptable routine method of contraception for most women.

Adult↗