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Biomedical subjects

D C Yang

Publications and source records attributed to D C Yang.

At least 19 recordsLinked to original sources
PubMed2003

BNips: a group of pro-apoptotic proteins in the Bcl-2 family.

BNip (formerly known as Nip) proteins, including homologues isolated from human, mouse and Caenorhabditis. elegans, are a relatively new subgroup of the Bcl-2 family. These proteins are classified into this family based on limited sequence homology with the Bcl-2 homology domain 3 and carboxyl terminal transmembrane domain. BNip proteins were first discovered based on their interaction with the adenovirus E1B 19 kDa/Bcl-2 family protein and since then, their roles in cell death pathways have been actively studied. However, the precise mechanisms by which the BNip proteins induce apoptosis and/or necrosis remain to be determined. To advance our knowledge, we have provided a summary and review of current literature regarding BNip proteins including comparative sequence analysis, mutational mapping of the functional domains, and cell death mechanisms involving disruption of mitochondrial homeostasis. Since BNip proteins are expressed at high levels in the heart as compared to other organs, their roles in cardiomyocyte injury during hypoxia or viral infection is a focus of this review. Finally, we discuss potential directions for further study on this increasingly important group of pro-apoptotic proteins.

Animals↗
PubMed2002

Production of herbicide-resistant transgenic Panax ginseng through the introduction of the phosphinothricin acetyl transferase gene and successful soil transfer.

Herbicide-resistant transgenic Panax ginseng plants were produced by introducing the phosphinothricin acetyl transferase (PAT) gene that confers resistance to the herbicide Basta (bialaphos) through Agrobacterium tumefaciens co-cultivation. Embryogenic callus gathered from cotyledon explants of P. ginseng were pre-treated with 0.5 M sucrose or 0.05 M MgSO(4 )before Agrobacterium infection. This pre-treatment process markedly enhanced the transient expression of the beta-glucuronidase (GUS) gene. Embryogenic callus was initially cultured on MS medium supplemented with 400 mg/l cefotaxime for 3 weeks and subsequently subcultured five times to a medium containing 25 mg/l kanamycin and 300 mg/l cefotaxime. Somatic embryos formed on the surfaces of kanamycin-resistant callus. Upon development into the cotyledonary stage, these somatic embryos were transferred to a medium containing 50 mg/l kanamycin and 5 mg/l gibberellic acid to induce germination and strong selection. Integration of the transgene into the plants was confirmed by polymerase chain reaction and Southern analyses. Transfer of the transgenic ginseng plantlets to soil was successfully accomplished via acclimatization in autoclaved perlite. Not all of the plantlets survived in soil that had not been autoclaved because of fungal infection, particularly in the region between the roots and leaves. Transgenic plants growing in soil were observed to be strongly resistant to Basta application.

Acclimatization↗
PubMed2001

Magnesium ion-mediated binding to tRNA by an amino-terminal peptide of a class II tRNA synthetase.

Aspartyl-tRNA synthetase is a class II tRNA synthetase and occurs in a multisynthetase complex in mammalian cells. Human Asp-tRNA synthetase contains a short 32-residue amino-terminal extension that can control the release of charged tRNA and its direct transfer to elongation factor 1 alpha; however, whether the extension binds to tRNA directly or interacts with the synthetase active site is not known. Full-length human AspRS, but not amino-terminal 32 residue-deleted, fully active AspRS, was found to bind to noncognate tRNA(fMet) in the presence of Mg(2+). Synthetic amino-terminal peptides bound similarly to tRNA(fMet), whereas little or no binding of polynucleotides, poly(dA-dT), or polyphosphate to the peptides was found. The apparent binding constants to tRNA by the peptide increased with increasing concentrations of Mg(2+), suggesting Mg(2+) mediates the binding as a new mode of RNA.peptide interactions. The binding of tRNA(fMet) to amino-terminal peptides was also observed using fluorescence-labeled tRNAs and circular dichroism. These results suggest that a small peptide can bind to tRNA selectively and that evolution of class II tRNA synthetases may involve structural changes of amino-terminal extensions for enhanced selective binding of tRNA.

Amino Acid Sequence↗
PubMed2001

Subcutaneous whole-body radionuclide venography using Tc-99m in vivo tagged red blood cells.

PURPOSE: The accurate diagnosis of deep vein thrombosis (DVT) is essential to prevent its complications and to initiate appropriate treatment. Doppler ultrasound (DUS), contrast venography, and intravenous radionuclide venography have been used for many years to detect DVT. However, obtaining venous access in the foot for injection of contrast agent can be difficult. METHODS: The authors introduce the technique of subcutaneous radionuclide venography using Tc-99m in vivo tagged red blood cells and compare it with DUS, a widely used method. Sixty patients (120 lower extremities) underwent subcutaneous radionuclide venography and DUS. RESULTS: The concordance rate was 94% in the femoral veins and 95% in the popliteal veins. Subcutaneous radionuclide venography revealed 10 iliac vein thromboses and 2 inferior vena cava thromboses that were not detected by DUS. CONCLUSIONS: Subcutaneous radionuclide venography is a useful alternative method for detecting DVT. It is particularly valuable for evaluating DVT in the iliac veins and in the inferior vena cava.

Adult↗
PubMed2000

Selective cyclooxygenase-2 inhibitors: heteroaryl modified 1,2-diarylimidazoles are potent, orally active antiinflammatory agents.

A series of heteroaryl modified 1,2-diarylimidazoles has been synthesized and found to be potent and highly selective (1000-9000-fold) inhibitors of the human COX-2. 3-Pyridyl derived COX-2 selective inhibitor (25) exhibited excellent activity in acute (carrageenan induced paw edema, ED(50) = 5.4 mg/kg) and chronic (adjuvant induced arthritis, ED(50) = 0.25 mg/kg) models of inflammation. The relatively long half-life of 25 in rat and dog prompted investigation of the pyridyl and other heteroaromatic systems containing potential metabolic functionalities. A number of substituted pyridyl and thiazole containing compounds (e.g., 44, 46, 54, 76, and 78) demonstrated excellent oral activity in every efficacy model evaluated. Several orally active diarylimidazoles exhibited desirable pharmacokinetics profiles and showed no GI toxicity in the rat up to 100 mg/kg in both acute and chronic models. The paper describes facile and practical syntheses of the targeted diarylimidazoles. The structure-activity relationships and antiinflammatory properties of a series of diarylimidazoles are discussed.

Administration, Oral↗
PubMed2000

Reduction in serum IL-6 after vacination of breast cancer patients with tumour-associated antigens is related to estrogen receptor status.

Elevated serum IL-6 concentrations have been associated with poor prognosis in a variety of cancers, and decreases in serum IL-6 concentrations have been reported after chemotherapy. We have demonstrated that serum IL-6 concentrations are elevated in breast cancer patients [normal women 0.7 +/- 2.5 pg/ml (n=36), breast cancer patients 38.3 +/- 138.7 pg/ml (n = 111)]. After vaccination of breast cancer patients with a combination of tumour-associated antigens and biological adjuvants (IL-2 and GM-CSF), the concentration of IL-6 decreased significantly (P<0.05) to 8.1 +/- 14.6 pg/ml (n=85). Other studies have shown that oestrogen suppresses IL-6 production in oestrogen receptor positive breast cancer cells. We have demonstrated that the decrease in IL-6 associated with vaccination is related to the oestrogen receptor status of the tumours from breast cancer patients, as a decrease in IL-6 from 124.0 +/- 267.5 pg/ml (n=26) to 6.2 +/- 11.0 pg/ml (n=34) only occurs in patients with oestrogen receptor negative tumours. The IL-6 concentration in breast cancer patients with oestrogen receptor positive tumours remained unchanged (9.5 pg/ml before vaccination, and 9.3 pg/ml after vaccination). These results suggest that postmenopausal women with oestrogen receptor negative breast cancers, who do not respond well to either hormonal therapy with tamoxifen or adjuvant chemotherapy, may have a significant response to vaccination with autologous tumour-associated antigens.

Adult↗
PubMed2000

Vaccination with a mixed vaccine of autogenous and allogeneic breast cancer cells and tumor associated antigens CA15-3, CEA and CA125--results in immune and clinical responses in breast cancer patients.

In breast cancer there is often overexpression of the breast cancer antigen CA15-3, the carcinoembryonic antigen (CEA) and the ovarian cancer antigen CA125, which makes them potential target antigens for immunotherapy. In this study, we used a multi-antigen vaccine, which included the following antigens: autologous breast cancer cells (AUTOC), allogeneic breast cancer MCF-7 cells (ALLOC), and the tumor associated antigens CA15-3, CEA and CA125, plus low doses of granulocyte/macrophage-colony-stimulating factor (GM-CSF) and interleukin 2 (IL-2). Forty-two breast cancer patients received weekly subcutaneous vaccination at the 1st, 2nd, 3rd, 7th, 11th and 15th weeks. Their lymphocyte proliferative responses to AUTOC, ALLOC, CA15-3, CEA and CA125 were tested in lymphocyte blastogenesis assays (LBA) before and after vaccination. The disease stage and serum CA15-3, CEA and CA125 concentrations were also determined pre- and post-vaccination. We found that the vaccine was safe, and the only major side effects were swelling at the site of injection, muscle pain, and weakness or fatigue. The vaccine induced a significant increase in post-vaccination lymphocyte proliferative responses to AUTOC, CA15-3, CEA and CA125 but not ALLOC, compared to pre-vaccination (p < 0.05, p < 0.01, p < 0.05, p < 0.01 and p > 0.05, respectively, a paired t Test). Computed tomography (CT), ultrasound or bone scan showed evidence of disease improvement in 2 (12%) patients after vaccination. Hepatic metastases were reduced in size and number and some actually disappeared one patient. Metastatic disease in the L5 vertebra and the skull decreased in size and some osteolytic sites completely healed in a second patient. In addition, 7 patients (44%) had stable disease and 7 patients (44%) had disease progression. We did not find vaccination significantly reduced serum tumor markers CA15-3, CEA and CA125 of these breast cancer patients. These results suggest that the vaccine mixture of autologous and allogeneic breast cancer cells and tumor associated antigens plus GM-CSF and IL-2 can be administered safely to breast cancer patients and there is evidence for improved immunity and clinical efficacy.

Adult↗
PubMed2000

Troglitazone inhibits mitogenic signaling by insulin in vascular smooth muscle cells.

Troglitazone (TRO) is an oral insulin-sensitizer that has direct effects on the vasculature to inhibit cell growth and migration. In vascular smooth muscle cells (VSMCs), insulin transduces a mitogenic signal that is dependent on the ERK1/2 MAP kinases. We examined the effects of TRO on this pathway and found that it inhibits mitogenic signaling. In quiescent VSMCs, insulin (1 microM) induced a 3.2-fold increase in DNA synthesis. TRO (1-20 microM) inhibited insulin-stimulated DNA synthesis by 72.8% at the maximal concentration. TRO at I and 10 microM had no significant effect on insulin-stimulated ERK1/2 activity. At 20 microM, however, TRO modestly enhanced insulin-stimulated ERK1/2 activity by 1.5-fold. ERKs transduce a mitogenic signal by phosphorylating transcription factors such as Elk-1. which regulate critical growth-response genes. We used GAL-Elk-1 expression plasmids to detect ERK-dependent activation of Elk-1. TRO at 1-20 microM potently inhibited insulin-stimulated, ERK1/2-dependent Elk-1 transcription factor activity. Neither early steps in insulin signaling nor the phosphatidylinositol 3-kinase (PI3K) branch of this pathway were affected by TRO, because it had no effect on IRS-1 phosphorylation, PI3K/IRS-1 association, or Akt phosphorylation. Because TRO is a known ligand for the nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma), we tested two other ligands for this receptor, rosiglitazone (RSG) and 15-deoxy-delta12,14 prostaglandin J2 (15d-PGJ2). Both also inhibited insulin-induced DNA synthesis. In summary, these data show that TRO inhibits mitogenic signaling by insulin at a point distal of ERK1/2 activation, potentially by a PPARgamma-mediated inhibition of ERK-dependent phosphorylation and activation of nuclear transcription factors that regulate cell growth.

Animals↗
PubMed2000

[Construction of the physical map of Pi-2(t), a blast resistance gene in rice].

In an effort to clone a rice blast resistance gene, Pi-2(t), a BAC contig consisting of 22 BAC clones covering the whole Pi-2(t) region, was constructed using marker-based chromosome landing and chromosome walking. The genetic span of this physical map is 8 cM, but the physical size is 925 kb. The physical map forms the base of further isolation and cloning of Pi-2(t) gene, it will provide new markers for molecular marker-aided selection of new blast resistance materials in rice.

Chromosome Mapping↗
PubMed1999

Cholera toxin induces tumor necrosis factor alpha production in human monocytes.

Cholera toxin covalently ADP-ribosylates the a subunit of Gs proteins. The modified Gsalpha activates adenylate cyclase and leads to a dramatic increase in intracellular cAMP. The effect of cholera toxin on the production of tumor necrosis factor (TNF-alpha), a critical mediator of toxicity for a number of bacterial and viral infections, has not been examined. Here we show that cholera toxin stimulated human monocytes to secrete TNF-alpha. The subunit A of cholera toxin alone also induced TNF-alpha production, suggesting that TNF-alpha production is mediated through ADP-ribosylation activity of the toxin. Inhibitors of ADP-ribosylation such as 3-aminobenzamide and niacinamide blocked TNF-alpha induction. However, cyclic AMP analogs and adenylate cyclase activator forskolin did not induce TNF-alpha production in monocytes, suggesting that TNF-alpha induction is independent of cAMP. Furthermore, cholera toxin-induced TNF-alpha production was suppressed by protein kinase C inhibitors H7 and sphingosine and by phospholipase C inhibitors U73122 and ET-18-OCH3, suggesting that PLC and PKC mediate TNF-alpha induction. Cholera toxin-mediated induction of TNF-alpha occurs at the transcription level as demonstrated by the time-dependent expression of TNF-alpha mRNA. These results raise the possibility that TNF-alpha may play an important role in cholera toxin-mediated toxicity and demonstrate that cholera toxin activates TNF-alpha production through PLC-dependent and cAMP-independent pathways. The probable mechanisms of signal transduction from cholera toxin to PLC in monocytes will be discussed.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1999

Production of tumor necrosis factor alpha in human T lymphocytes by staphylococcal enterotoxin B correlates with toxin-induced proliferation and is regulated through protein kinase C.

The superantigen staphylococcal enterotoxin B (SEB) simultaneously binds both the major histocompatibility complex (MHC) class II receptor on monocytes and the T-cell receptor (TCR) on T lymphocytes, resulting in a range of cell responses including induction of tumor necrosis factor alpha (TNF-alpha). In this study, we have used mixed cultures of human peripheral blood monocytes and lymphocytes to investigate biochemical events controlling SEB induction of TNF-alpha. TNF-alpha production induced by SEB in mixed cultures is more closely associated with T cells than with monocytes: (i) a TCR-binding-site mutant of SEB (N23F) is less active in TNF-alpha induction than an MHC class II receptor-binding-site mutant (F44R), and (ii) flow cytometric analysis indicated that SEB induced TNF-alpha production in T cells but not in monocytes. Pretreatment of cells with inhibitors of signal transduction pathways was employed to further define events in SEB-induced TNF-alpha production. Neither protein kinase A inhibitors nor two protein tyrosine kinase inhibitors altered SEB-induced TNF-alpha production. In contrast, SEB induced protein kinase C (PKC) translocation, and pretreatment of cultures with inhibitors of PKC blocked TNF-alpha induction. Alteration of levels of diacylglycerol (DAG), an activator of PKC, by treatment with inhibitors of phospholipase C or DAG kinase also altered SEB-induced TNF-alpha production. These data suggest that PKC activation plays a critical role in SEB-induced TNF-alpha production in human T cells.

Cells, Cultured↗
PubMed1998

Distributing working versions of published mathematical models for biological systems via the Internet.

Mathematical models are useful tools for investigating complex systems. By representing physiological systems as models, theories can be tested quantitatively against data from the system. Models can be used to explore new theories prior to experimentation and to design studies to optimize experimental resources. They can also be used as teaching tools to illustrate physiochemical principles. In spite of their usefulness and the time invested in developing models, published models are often underused due to the difficulty in obtaining working versions of the model. To address this problem we have designed a library for mathematical models of biological systems on the Internet. The library contains published models of biological systems in formats compatible with several modeling packages, from the fields of physiology, metabolism, endocrinology, biochemistry, and chemistry. The models can be viewed graphically, model solutions can be viewed as plots against data, and models can be downloaded to be run with software on the user's own system. The address of the library is: http://biomodel.georgetown.edu/model/ Investigators are invited to submit working versions of published models to the library. Models can be submitted electronically at the time a manuscript is accepted for publication. As journals go online, articles containing models can be linked to working versions of the models in the library. By increasing access to working versions of models, more of the investment in kinetic studies and model development can be realized.

Computer Simulation↗
PubMed1996

Ubiquitinylation of transcription factors c-Jun and c-Fos using reconstituted ubiquitinylating enzymes.

Recombinant c-Jun and c-Fos were ubiquitinylated by the ubiquitin carrier enzymes E214K, E220K, or E232K in the presence of the ubiquitin-activating enzyme, E1. Addition of ubiquitin protein ligase E3 substantially enhanced the E214K-mediated ubiquitinylation of c-Jun and c-Fos. Truncated c-Jun and c-Fos mutant proteins including wbJun and wbFos were also ubiquitinylated under the same conditions, suggesting the sites of ubiquitinylation are located within the dimerization and DNA binding domains of c-Jun and c-Fos. The E3-dependent ubiquitinylation of c-Jun was inhibited upon the heterodimerization of c-Jun with c-Fos. Further addition of E220K significantly enhanced ubiquitinylation of c-Jun in the heterodimer suggesting a regulatory role of E220K. Polyubiquitinylated c-Jun, wbFos, and wbJun, but not E220K-ubiquitinylated c-Jun, were readily degraded by the ATP-dependent 26 S multicatalytic proteases. These results suggest that the temporal control of c-Jun and c-Fos may be regulated through the ubiquitinylation pathways, and the ubiquitinylation of c-Jun and c-Fos may in turn be regulated in response to the heterodimerization between them and the cooperation between E220K and E3 mediated polyubiquitinylation.

Adenosine Triphosphate↗
PubMed1996

Giant hepatic hemangioma studied with intravenous total body arteriography technique. A case report.

Hepatic hemangiomas are the most common benign tumors of the liver. They are usually single, small, and asymptomatic. However, giant hepatic hemangiomas have been reported in the past, usually detected as incidental findings. Radionuclide blood pool imaging studies are used to confirm the presence of a hemangioma. This report describes a case of a giant hepatic hemangioma detected using intravenous total-body arteriography, done as a part of radionuclide blood pool hemangioma study. This simple addition to the regular RBC blood pool hemangioma study helps to determine the size of the liver in the early arterial phase and shows obvious increased blood pool activity in the delayed phase. It is also useful in detecting lesions in other parts of the body when present.

Adult↗
PubMed1996

Isolation and identification of metabolites of leukotriene A4 hydrolase inhibitor SC-57461 in rats.

The metabolic fate of SC-57461, N-methyl-N-[3-[4-(phenylmethyl)-phenoxy]propyl]-beta-alanine, a potent and specific inhibitor of the leukotriene A4 hydrolase, was determined by LC/MS/MS, NMR and GC/MS in male Sprague-Dawley rats. The major metabolites of SC-57461 in rats were the desmethyl metabolite, the hydroxylated metabolite, the N-oxide metabolite, the hydroxylamine metabolite, and the propionic acid metabolite. The N-oxide metabolite was found to be stable in the rat plasma and urine, but was unstable in most organic solvents (methanol, acetonitrile, and methylene chloride, etc.) because of the classic Cope reaction of the N-oxide, which led to the formation of the corresponding hydroxylamine product and acrylic acid. The hydroxylamine metabolite and acrylic acid were reactive in the biomatrix and could not be isolated in the in vivo samples. However, formation of the hydroxylamine metabolite and acrylic acid from the N-oxide metabolite in methylene chloride was verified by NMR. The propionic acid metabolite was found to be the common metabolite shared by SC-57461, N-oxide metabolite, as well as the hydroxylamine metabolite, which suggested a sequential metabolism of SC-57461 in rats. The ultimate fate of the propionic acid metabolite was incorporation into rat glycerolipid metabolism as a result of its structural similarity to aryl-substituted propionic acid, a known class of compounds that can be incorporated into rat glycerolipid metabolism. Finally, the isolated hydroxylated metabolite and the N-desmethyl metabolite were found to have excellent inhibitory effects toward leukotriene A4 hydrolase and therefore were the major active metabolites of SC-57461 in rats.

Administration, Oral↗