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Biomedical subjects

C Tang

Publications and source records attributed to C Tang.

At least 37 records · Page 2Linked to original sources
PubMed1999

SU5416 is a potent and selective inhibitor of the vascular endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine kinase catalysis, tumor vascularization, and growth of multiple tumor types.

SU5416, a novel synthetic compound, is a potent and selective inhibitor of the Flk-1/KDR receptor tyrosine kinase that is presently under evaluation in Phase I clinical studies for the treatment of human cancers. SU5416 was shown to inhibit vascular endothelial growth factor-dependent mitogenesis of human endothelial cells without inhibiting the growth of a variety of tumor cells in vitro. In contrast, systemic administration of SU5416 at nontoxic doses in mice resulted in inhibition of subcutaneous tumor growth of cells derived from various tissue origins. The antitumor effect of SU5416 was accompanied by the appearance of pale white tumors that were resected from drug-treated animals, supporting the antiangiogenic property of this agent. These findings support that pharmacological inhibition of the enzymatic activity of the vascular endothelial growth factor receptor represents a novel strategy for limiting the growth of a wide variety of tumor types.

3T3 Cells↗
PubMed1999

Suppression of coronary vasculitis in a murine model of Kawasaki disease using an angiogenesis inhibitor.

Coronary arteritis can be induced in C57BL/6 mice with a single intraperitoneal (ip) injection of Lactobacillus casei cell fragments. Histologic sections resemble the vasculitis and aneurysms observed in the medium-sized coronary arteries of children with Kawasaki disease. Since endothelial cells could play an important role in the development of vasculitis, a recently described angiogenesis inhibitor that is not an immunosuppressive agent, AGM-1470 (derived from Aspergillus fumigatus), was used to evaluate its therapeutic potential in this model. A total of 32 mice were administered 0.5 mg of sterile L. casei preparation ip on day 0 and randomized to either a treatment (AGM-1470, 27mg/kg sc alternate days) or a control (vehicle only) protocol. Hearts were harvested on day 14 (early disease) or at the end of the study on day 28 (established disease). Histologic sections were scored blindly for vasculitis. Day 14 sections from both protocols manifested only minimal disease, indicating that the vasculitis had not yet matured. By day 28, the AGM-1470 group had significantly less coronary vasculitis than the control group (0.7 vs 2.6, p < 0.005, respectively). These studies suggest that endothelial cells may play an active role in this pathologic process and that angiogenesis inhibitors, such as AGM-1470, could be useful tools for the treatment and understanding of vasculitis.

Animals↗
PubMed1999

Involvement of calcineurin in angiotensin II-induced cardiomyocyte hypertrophy and cardiac fibroblast hyperplasia of rats.

A rapidly emerging body of literature implicates a pivotal role for the Ca2+-calmodulin-dependent phosphatase, calcineurin, as a cellular target for a variety of Ca2+-dependent signaling pathways culminating in cardiac hypertrophy. The aim of the present study was to test whether calcineurin is involved in the signal transduction of angiotensin II (AngII)-induced cardiac myocyte hypertrophy and fibroblast hyperplasia. Firstly, we observed that calcineurin activity was significantly increased in AngII-stimulated cardiac myocytes as well as fibroblasts, but was markedly inhibited by Losartan (50 micromol/l), H7 (50 micromol/l), and Fura-2/AM (5 micromol/l). It is indicated that AngII-induced activation of calcineurin is through an ATI receptor, may be dependent on the sustained increases of [Ca2+]i, and be regulated by protein kinase C. In a second experiment, we found that cyclosporin (0.1-10micromol/l), a specific inhibitor of calcineurin, decreased the protein synthesis rate in AngII-stimulated cardiomyocytes and the DNA synthesis rate in AngII-treated fibroblasts in a dose-dependent manner. In the latter experiment, calcineurin inhibition reduced the mRNA level of the atrial natriuretic factor gene. These results indicate that calcineurin is involved in the signal transduction of AngII-induced cardiomyocyte hypertrophy and fibroblast hyperplasia.

Angiotensin II↗
PubMed1999

Factors limiting contrast sensitivity in experimentally amblyopic macaque monkeys.

Contrast detection is impaired in amblyopes. To understand the contrast processing deficit in amblyopia, we studied the effects of masking noise on contrast threshold in amblyopic macaque monkeys. Amblyopia developed as a result of either experimentally induced strabismus or anisometropia. We used random spatiotemporal broadband noise of varying contrast power to mask the detection of sinusoidal grating patches. We compared masking in the amblyopic and non-amblyopic eyes. From the masking functions, we calculated equivalent noise contrast (the noise power at which detection threshold was elevated by square root of 2) and signal-to-noise ratio (the ratio of threshold contrast to noise contrast at high noise power). The relation between contrast threshold and masking noise level was similar for amblyopic and non-amblyopic eyes. Although in most cases there was some elevation in equivalent noise for amblyopic compared to fellow eyes, signal-to-noise ratio showed greater variation with the extent of amblyopia. These results support the idea that the contrast detection deficit in amblyopia is a cortical deficit.

Amblyopia↗
PubMed1999

For discussion: live attenuated vaccines for group B meningococcus.

Current attempts at preventing infections caused by group B Neisseria meningitidis are largely directed on generating immune responses to outer membrane proteins or the lipopolysaccharide of this organism. We suggest an alternative approach: the use of a live, attenuated strain of Neisseria meningitidis which could be delivered mucosally to elicit both local and systemic immune responses.

Bacterial Vaccines↗
PubMed1999

Identification of S-(n-butylcarbamoyl)glutathione, a reactive carbamoylating metabolite of tolbutamide in the rat, and evaluation of its inhibitory effects on glutathione reductase in vitro.

Tolbutamide (TOLB), a widely used hypoglycemic agent in the therapy of non-insulin-dependent diabetes mellitus, has been reported to be teratogenic and/or embryotoxic in several animal species and humans. It has been proposed that the teratogenic effects of TOLB are linked to drug-mediated depletion of glutathione (GSH) through inhibition of the enzyme glutathione reductase (GR), although the mechanism by which this inhibition occurs remains unknown. In the study presented here, rats were injected with TOLB (200 mg/kg ip), and bile was collected for analysis by liquid chromatography/tandem mass spectrometry (LC/MS/MS). This led to the identification of S-(n-butylcarbamoyl)glutathione (SBuG), a reactive GSH conjugate derived from n-butyl isocyanate, as a minor metabolite of TOLB in bile. Upon incubation of SBuG (0.25-1.0 mM) with GR from either yeast or bovine intestinal mucosa in the presence of NADPH (0.20 mM), enzyme activity was lost in a time- and concentration-dependent manner. No inhibition was observed when NADPH was omitted from incubations, or when the natural substrate for the enzyme, glutathione disulfide (GSSG, 0.05 mM), was added. TOLB itself did not inhibit GR over the concentration range of 0.8-2.0 mM. It is concluded that metabolic activation of TOLB in vivo leads to the generation of reactive intermediates (n-butyl isocyanate and SBuG) which carbamoylate and thereby inhibit GR. At critical periods of organogenesis, the resulting perturbation of GSH homeostasis in exposed tissues may play a key role in the teratogenic and/or embryotoxic effects of TOLB.

Animals↗
PubMed1999

Modulatory effects of alveolar macrophages on CD4+ T-cell IL-5 responses correlate with IL-1beta, IL-6, and IL-12 production.

Increasing evidence suggests that the pattern of T-cell cytokine production can be modulated by antigen presenting cell (APC)-derived factors during the cell interactions. Recently, it has been shown that alveolar macrophages (AMs) from atopic asthmatics (AA) but not atopic nonasthmatics (AN) enhance interleukin (IL)-5 production by CD4+ T-cells. The present study compared AM production of IL-1beta, IL-6, and IL-12, as well as their associated functional capacity to influence IL-5 production by allergen-specific CD4+ T-cells in 10 AA, 10 AN, and nine nonatopic control subjects (C). AMs from AA showed a relatively high production of IL-1beta and IL-6 (p<0.05) and a relatively low secretion of IL-12 compared to C, whereas AMs from AN and C behaved similarly. This study confirmed previous findings that co-culture with AMs augments IL-5 production from allergen-stimulated CD4+ T-cells only in AA and not in nonasthmatics even if they are atopic. On the other hand, stimulation with allergen alone did not enhance IL-5 production by CD4+ T-cells in either AA nor AN. AM-induced changes in CD4+ T-cell IL-5 production upon allergen stimulation significantly correlated with their ability to produce IL-1beta (r=0.59, p<0.01), IL-6 (r=0.56, p<0.01), and inversely with IL-12 (r=-64, p=0.002) in all atopic subjects, and even more closely with the ratio of IL-12/IL-1beta (r=-0.75, p<0.001) and IL-12/IL-6 production (r=-0.81, p<0.001) in these subjects. These findings suggest that the role of alveolar macrophages from atopic asthmatics in enhancing interleukin-5 production by allergen-specific CD4+ T-cells is due, at least partly, to their aberrant production of interleukin-1beta, interleukin-6, and particularly of interleukin-12.

Adult↗
PubMed1999

Metabolic interactions between mibefradil and HMG-CoA reductase inhibitors: an in vitro investigation with human liver preparations.

AIMS: To determine the effects of mibefradil on the nletabolism in human liver microsomal preparations of the HMG-CoA reductase inhibitors simvastatin, lovastatin, atorvastatin, cerivastatin and fluvastatin. METHODS: Metabolism of the above five statins (0.5, 5 or 10 microM), as well as of specific CYP3A4/5 and CYP2C8/9 marker substrates, was examined in human liver microsomal preparations in the presence and absence of mibefradil (0.1-50 microM). RESULTS: Mibefradil inhibited, in a concentration-dependent fashion, the metabolism of the four statins (simvastatin, lovastatin, atorvastatin and cerivastatin) known to be substrates for CYP3A. The potency of inhibition was such that the IC50 values (<1 microM) for inhibition of all of the CYP3A substrates fell within the therapeutic plasma concentrations of mibefradil, and was comparable with that of ketoconazole. However, the inhibition by mibefradil, unlike that of ketoconazole, was at least in part mechanism-based. Based on the kinetics of its inhibition of hepatic testosterone 6beta-hydroxylase activity, mibefradil was judged to be a powerful mechanism-based inhibitor of CYP3A4/5, with values for Kinactivation, Ki and partition ratio (moles of mibefradil metabolized per moles of enzyme inactivated) of 0.4 min(-1), 2.3 microM and 1.7, respectively. In contrast to the results with substrates of CYP3A, metabolism of fluvastatin, a substrate of CYP2C8/9, and the hydroxylation of tolbutamide, a functional probe for CYP2C8/9, were not inhibited by mibefradil. CONCLUSION: Mibefradil, at therapeutically relevant concentrations, strongly suppressed the metabolism in human liver microsomes of simvastatin, lovastatin, atorvastatin and cerivastatin through its inhibitory effects on CYP3A4/5, while the effects of mibefradil on fluvastatin, a substrate for CYP2C8/9, were minimal in this system. Since mibefradil is a potent mechanism-based inhibitor of CYP3A4/5, it is anticipated that clinically significant drug-drug interactions will likely ensue when mibefradil is coadministered with agents which are cleared primarily by CYP3A-mediated pathways.

Aryl Hydrocarbon Hydroxylases↗
PubMed1999

Growth inhibition of psoriatic keratinocytes by quinazoline tyrosine kinase inhibitors.

Psoriasis is characterized by hyperproliferation of keratinocytes associated with an inflammatory infiltrate in the epidermis. Among factors which may be related to hyperplasia of psoriatic keratinocytes is the persistent autocrine stimulation of the epidermal growth factor receptor (EGFR) by transforming growth factor-alpha. Owing to the pivotal role of the EGFR in driving the growth of human psoriatic keratinocytes, we examined two selective inhibitors of EGFR kinase activity: 4-(3-bromophenylamino)-6, 7-dimethoxyquinazoline (AG1517/SU5271) and 4-(3-chlorophenylamino)-6, 7-dimethoxyquinazoline (AG1478) on psoriatic keratinocytes. SU5271 potently inhibits ligand-induced autophosphorylation of EGFR, and downstream signal transduction events, including DNA replication and cell cycle progression. SU5271, at micromolar concentrations, inhibited the proliferation of keratinocytes isolated from psoriatic lesions in excellent correlation with its EGFR kinase inhibitory activity in these cells. Biologically active concentrations of SU5271 penetrated human cadaver skin, suggesting that this compound is a strong candidate as an antipsoriatic agent.

Animals↗
PubMed1999

Expression of caspase and BCL-2 apoptotic family members in mouse preimplantation embryos.

Apoptosis, as determined by blastomere and DNA fragmentation, occurs in many preimplantation mouse embryos. To investigate which genes contribute to apoptosis in preimplantation embryos, we used the reverse transcription-polymerase chain reaction to assess mRNA levels for seven genes in the caspase family and seven genes in the BCL-2 family. All caspase mRNAs were detectable in oocytes, while expression in preimplantation embryos varied in a stage-specific manner. An assay for group II caspase enzymatic activity showed that although transcripts for these caspases could not be detected in zygotes, proteolytic activity could be detected in polar bodies, fragmented zygotes, and zygotes treated with staurosporine. This suggests that maternal caspases are inherited during oogenesis. Transcripts for some members of the BCL-2 family could be detected at every stage of preimplantation development. Transcripts for other members were rarely detected. When BCL-2 and BAX protein levels were assessed using immunofluorescence, both proteins were detected in zygotes and in blastocysts. When fragmented blastocysts were compared to normal blastocysts, levels of BCL-2 immunofluorescence tended to be lower in fragmented blastocysts. This result supports a model in which the ratio of BCL-2 to BAX is altered in apoptotic embryos.

Animals↗
PubMed1999

Transcriptional and posttranscriptional regulation of beta(2)-adrenergic receptor gene in rat liver during sepsis.

Changes in beta(2)-adrenergic receptor (beta(2)-AR) gene expression in the rat liver during different phases of sepsis were studied. Sepsis was induced by cecal ligation and puncture (CLP). Septic rats exhibit two metabolically distinct phases: an initial hyperglycemic (9 h after CLP; early sepsis) followed by a hypoglycemic phase (18 h after CLP; late sepsis). The [(3)H]dihydroalprenolol binding studies show that the density of beta(2)-AR was decreased by 12 and 35% during the early and late phases of sepsis, respectively. Western blot analyses depict that the beta(2)-AR protein level was reduced by 37 and 72% during early and late sepsis, respectively. The reverse transcription polymerase chain reaction and Southern blot analyses reveal that the steady-state level of beta(2)-AR mRNA was decreased by 37% during early phase and 77% during late phase of sepsis. Nuclear run-off assays show that the rate of transcription of beta(2)-AR mRNA was reduced by 36% during early sepsis and 64% during late sepsis. The stability assays indicate that the half-life of beta(2)-AR mRNA was shortened by 21 and 50% during the early and late phases of sepsis, respectively, indicating that the rate of degradation of beta(2)-AR mRNA was progressively enhanced during sepsis. These findings demonstrate that the beta(2)-AR gene was underexpressed in the liver during the progression of sepsis, and, furthermore, the underexpression of the beta(2)-AR gene was the result of a reduction in the rate of transcription coupled with an enhancement in the rate of degradation of beta(2)-AR gene transcripts. Thus our findings that the transcriptional and posttranscriptional regulation of beta(2)-AR gene associated with decreases in beta(2)-AR number and its protein expression may provide a molecular mechanistic explanation for the development of hypoglycemia during the late stage of sepsis.

Animals↗
PubMed1999

Prediction of antidepressant effects of sleep deprivation by metabolic rates in the ventral anterior cingulate and medial prefrontal cortex.

OBJECTIVE: Sleep deprivation has been shown to have an antidepressant benefit in a subgroup of depressed patients. Functional imaging studies by the authors and others have suggested that patients with elevated metabolic rates in the anterior cingulate gyrus at baseline are more likely to respond to either sleep deprivation or antidepressant medications than patients with normal metabolic rates. The authors extend their earlier work in a larger group of patients and explore additional brain areas with statistical probability mapping. METHOD: Thirty-six patients with unipolar depression and 26 normal volunteers were studied with positron emission tomography before and after sleep deprivation. Response to sleep deprivation was defined as a 40% or larger decrease in total scores on the Hamilton Depression Rating Scale. RESULTS: One-third of the depressed patients had a significant response to sleep deprivation. Responders had higher relative metabolic rates in the medial prefrontal cortex, ventral anterior cingulate, and posterior subcallosal gyrus at baseline than depressed patients who did not respond to sleep deprivation and normal volunteers. Lower Hamilton depression scores correlated significantly with lower metabolic rates in the left medial prefrontal cortex. After sleep deprivation, significant decreases in metabolic rates occurred in the medial prefrontal cortex and frontal pole in the patients who responded positively to sleep deprivation. CONCLUSIONS: High pretreatment metabolic rates and decreases in metabolic rates after treatment in the medial prefrontal cortex may characterize a subgroup of depressed patients who improve following sleep deprivation and, perhaps, other antidepressant treatments.

Adolescent↗
PubMed1999

Pathogen virulence genes--implications for vaccines and drug therapy.

The emergence and spread of bacteria resistant to antimicrobial drugs is a major public health problem with a growing number of infections becoming virtually untreatable. There is a need to develop interventions both to prevent and to treat diseases caused by multi-resistant microbes. We review some recently developed methods (including whole genome nucleotide sequencing projects) to study bacterial pathogenesis, and discuss how knowledge gained from understanding the molecular mechanisms of disease can be applied to combat the threat of infectious diseases.

Animals↗
PubMed1999

2-pyridylthioureas: novel nonpeptide somatostatin agonists with SST4 selectivity.

Somatostatin [somatotropin release-inhibiting factor (SRIF)] is a cyclic tetradecapeptide that is a potent inhibitor of growth hormone (GH) secretion from the anterior pituitary. In addition to the inhibitory effects on GH-release, SRIF-14 and SRIF-28, a 28-amino acid form of SRIF extended from the N-terminal end, inhibit the release of a variety of other peptides including glucagon, insulin, and gastrin, and both peptides act as neurotransmitters and neuromodulators in the central nervous system and the periphery. SRIF exerts its potent inhibitory effects following binding to high affinity SRIF receptors (ssts) that have been identified on target tissues. The recent cloning of five ssts has confirmed that the effects of SRIF are mediated by a family of G protein-coupled receptors (sst1-5). Based on structural and pharmacological properties sst2, sst3, and sst5 belong to the SRIF1 receptor subclass, and the sst1 and sst4 subtypes comprise the SRIF2 subclass. The major difference between these two subclasses is that SRIF1 receptors bind octapeptide and hexapeptide SRIF-14 analogs with high affinity, while SRIF2 receptors bind these analogs with drastically reduced affinity. A screening program was initiated to identify a lead nonpeptide with affinity for sst1-5 receptors. The search focused on a scaffold with the following attachments: (1) a heteroaromatic nucleus to mimic the Trp8 residue, (2) a nonheteroaromatic nucleus to mimic Phe7, and (3) a primary amine or other basic group to mimic the Lys9 residue of SRIF-14. Using these criteria, a novel thiourea (NNC 26-9100, 17) was discovered as a structural lead. The key fragments in this compound are a heteroaromatic moiety (pyridine), an aromatic group, and a basic imidazole group connected through a thiourea scaffold. Compound 17 exhibited a Ki = 6 nM at sst4 receptors with a 100-fold sst4/sst2 selectivity and was shown to be a full agonist at this receptor subtype. This article will review the literature on the design and development of nonpeptide somatostatin receptor ligands and the therapeutic potential of these agents. Furthermore, our work on the development of 2-pyridylthioureas as sst4 receptor agonists will be described.

Animals↗
PubMed1999

Role of a potent inhibitory monoclonal antibody to cytochrome P-450 3A4 in assessment of human drug metabolism.

Cytochrome P-450 (CYP) 3A4 is an inordinately important CYP enzyme that catalyzes the metabolism of a vast array of clinically used drugs. Microsomal proteins of Spodoptera frugiperda (Sf21) insect cells infected with recombinant baculoviruses encoding CYP3A4 cDNA were used to immunize mice and to develop a monoclonal antibody (mAb(3A4a)) specific to CYP3A4 through the use of hybridoma technology. The mAb is both a potent inhibitor and a strong binder of CYP3A4. One and 5 microl (0.5 and 2.5 microM IgG(2a)) of the mAb mouse ascites in 1-ml incubation containing 20 pmol of CYP3A4 strongly inhibited the testosterone 6beta-hydroxylation by 95 and 99%, respectively, and, to a lesser extent, cross-inhibited CYP3A5 and CYP3A7 activity. mAb(3A4a) exhibited no cross-reactivity with any of the other recombinant human CYP isoforms (CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1) in the course of CYP reaction phenotyping and Western immunoblot analyses. The potency of mAb-induced inhibition is insensitive to substrate concentration in human liver microsomes. Therefore, mAb(3A4a) was used to assess the quantitative role of CYP3A4/5 to the metabolism of testosterone and diazepam in five human liver microsomes. The results showed that CYP3A4 and CYP3A5 contribute >95% to both testosterone 6beta-hydroxylation and diazepam 3-hydroxylation and 52 to 73% to diazepam N-demethylation, respectively. In addition, mAb(3A4a) significantly inhibited testosterone 6beta-hydroxylase activity in rhesus monkey liver microsomes to a degree equal to that observed with CYP3A4 in human liver microsomes. By comparison, no inhibition of testosterone 6beta-hydroxylase activity was observed in the presence of dog, rat, and mouse liver microsomes. The selectivity of ketoconazole, a chemical inhibitor of CYP3A4, was probed with mAb(3A4a) and was shown to be highly concentration dependent in the diazepam N-demethylation by human liver microsomes. The results demonstrate that inhibitory and immunoblotting mAb(3A4a) can offer a precise and useful tool for quantitative identification of CYP3A4/5 in the metabolism of drugs in clinical use and drugs in development.

Adult↗
PubMed1998

GABA(B) receptors function as a heteromeric assembly of the subunits GABA(B)R1 and GABA(B)R2.

The principal inhibitory neurotransmitter GABA (gamma-aminobutyric acid) exerts its effects through two ligand-gated channels, GABA(A) and GABA(C) receptors, and a third receptor, GABA(B) , which acts through G proteins to regulate potassium and calcium channels. Cells heterologously expressing the cloned DNA encoding the GABA(B)R1 protein exhibit high-affinity antagonist-binding sites, but they produce little of the functional activity expected from studies of endogenous GABA(B) receptors in the brain. Here we describe a new member of the GABA(B) polypeptide family, GABA(B)R2, that shows sequence homology to GABA(B)R1. Neither GABA(B)R1 nor GABA(B)R2, when expressed individually, activates GIRK-type potassium channels; however, the combination of GABA(B)R1 and GABA(B)R2 confers robust stimulation of channel activity. Both genes are co-expressed in individual neurons, and both proteins co-localize in transfected cells. Moreover, immunoprecipitation experiments indicate that the two polypeptides associate with each other, probably as heterodimers. Several G-protein-coupled receptors (GPCRs) exist as high-molecular-weight species, consistent with the formation of dimers by these receptors, but the relevance of these species for the functioning of GPCRs has not been established. We have now shown that co-expression of two GPCR structures, GABA(B)R1 and GABA(B)R2, belonging to the same subfamily is essential for signal transduction by GABA(B) receptors.

Amino Acid Sequence↗
PubMed1998

A method of basal forebrain anatomical standardization for functional image analysis.

Functional as well as structural assessment of the basal forebrain has mostly focused on the dorsal caudate and putamen in axial slices where they are easily outlined or their centers located with stereotaxic methods. The more ventral extent of the basal forebrain, where the irregular form and indistinct boundaries of the nucleus accumbens and substantia innominata are difficult to trace and where the brain's ventral surface may contribute partial volume artifacts to measurement, has been less studied. We present a method based on coronal sections, landmarks placed on clearly visible anchor points, and the computational technique of thin-plate spline warping which allows the alignment of groups of individuals to common coordinates for pixel-by-pixel statistical mapping. The reliability of the landmarks across independent raters yields a median absolute difference of 1.3-1.6 mm. The validity of the method is confirmed by variance maps which reveal significant decreases in variance over spindle and bounding box alignment.

Adult↗