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Biomedical subjects

S Li

Publications and source records attributed to S Li.

At least 19 recordsLinked to original sources
PubMed2001

Cyclooxygenase-2 mediates the febrile response of mice to interleukin-1beta.

Various lines of evidence have implicated cyclooxygenase (COX)-2 as a modulator of the fever induced by the exogenous pyrogen lipopolysaccharide (LPS). Thus, treatment with specific inhibitors of COX-2 suppresses the febrile response without affecting basal body (core) temperature (T(c)). Furthermore, COX-2 gene-ablated mice are unable to develop a febrile response to intraperitoneal (i.p.) LPS, whereas their COX-1-deficient counterparts produce fevers not different from their wild-type (WT) controls. To extend the apparently critical role of COX-2 for LPS-induced fevers to fevers produced by endogenous pyrogens, we studied the thermal responses of COX-1- and COX-2 congenitally deficient mice to i.p. and intracerebroventricular (i.c.v.) injections of recombinant murine (rm) interleukin (IL)-1beta. We also assessed the effects of one selective COX-1 inhibitor, SC-560, and two selective COX-2 inhibitors, nimesulide (NIM) and dimethylfuranone (DFU), on the febrile responses of WT and COX-1(-/-) mice to LPS and rmIL-1beta, i.p. Finally, we verified the integrity of the animals' responses to PGE2, i.c.v. I.p. and i.c.v. rmIL-1beta induced similar fevers in WT and COX-1 knockout mice, but provoked no rise in the T(c)s of COX-2 null mutants. The fever produced in WT mice by i.p. LPS was not affected by SC-560, but it was attenuated and abolished by NIM and DFU, respectively, while that caused by i.p. rmIL-1beta was converted into a T(c) fall by DFU. There were no differences in the responses to i.c.v. PGE2 among the WT and COX knockout mice. These results, therefore, further support the notion that the production of PGE2 in response to pyrogens is critically dependent on COX-2 expression.

Animals↗
PubMed2001

Effects of flow patterns on endothelial cell migration into a zone of mechanical denudation.

Vascular endothelial cells (ECs) in vivo are subject to different flow conditions due to the variation in vessel geometry. The aim of this study is to elucidate the effects of different flow conditions on EC monolayer migration into a mechanically denuded zone and their underlying mechanisms. Both laminar and disturbed flows significantly enhanced EC migration. EC migration speed was the fastest under laminar flow, which preferentially promoted directional EC migration from the upstream side of the wounded monolayer. C3 exoenzyme (a Rho inhibitor) inhibited EC migration under static and flow conditions, and markedly reduced the effects of flow on EC migration. These results indicate that flow promotes EC migration through the Rho signaling pathway. Genistein (a tyrosine kinase inhibitor) selectively retarded EC migration under disturbed flow, suggesting that tyrosine phosphorylation may play a role in EC migration under disturbed flow. This study has demonstrated that different flow patterns differentially affect EC monolayer migration into the denuded zone involving multiple mechanisms.

ADP Ribose Transferases↗
PubMed2001

Pharmacodynamic-mediated reduction of temozolomide tumor concentrations by the angiogenesis inhibitor TNP-470.

The angiogenic phenotype is associated with increased tumor neovascularization and a state of vascular hyperpermeability to macromolecules. Angiogenesis inhibitors could reverse these processes, resulting in tumor capillaries that have normal membrane permeability. It was proposed that the switch from a hyperpermeable to a normal permeable state could have the untoward effect of decreasing tumor concentrations of anticancer drugs coadministered with angiogenesis inhibitors. The current investigation evaluated a potential drug interaction between the angiogenesis inhibitor O-(N-chloroacetyl-carbamoyl)-fumagillol (TNP-470) and the alkylating agent temozolomide (TMZ), in xenograft models that differentially expressed vascular endothelial growth factor (VEGF), a driving force for angiogenesis. Nude rats bearing either s.c. low VEGF (V-) or high VEGF (V+) or intracerebral V+ gliomas were administered either a multiple-dose regimen of TNP-470 or vehicle control. One day after the last dose of vehicle or TNP-470, a steady-state dosing regimen of TMZ was administered with subsequent collection and high-performance liquid chromatography analysis of plasma and either tumor homogenate or tumor microdialysis steady-state TMZ concentrations, and in some cases [5-(3-methyltriazen-1-yl)imidazole-4-carboximide] MTIC, its active metabolite. Microvessel density (MVD) was quantitated by image analysis using an anti-CD31 method. Statistical analyses of pharmacokinetic and pharmacodynamic end points in the control and TNP-470 treatment groups were completed by nonparametric tests. In both the s.c. and intracerebral V+ models, TNP-470 treatment produced significant reductions in TMZ tumor concentrations and tumor:plasma concentration ratios compared with control, being reduced an average of 25% and 50% in the s.c. and intracerebral tumors, respectively. MTIC concentrations in V+ s.c. tumors also were reduced by 50% in the presence of TNP-470. Consistent with the lower extent of neovascularization in the V- tumors, TMZ and MTIC tumor concentrations were not different in TNP-470 and control treatment groups in s.c. tumors. MVD was reduced by TNP-470 compared with vehicle control in the V+ tumors, but was unaltered in V- tumors, attesting to the use of MVD as a pharmacodynamic end point and the effectiveness of TNP-470 as an angiogenesis inhibitor. Angiogenesis inhibitor's pharmacodynamic actions on tumor angiogenesis can produce a reduction in tumor concentrations of coadministered anticancer agents. It is increasingly important to understand the pharmacokinetic and pharmacodynamic behavior of each class of drug so that optimal dosing regimens can be designed.

Angiogenesis Inhibitors↗
PubMed2001

Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism.

This study investigated whether a polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene (C677T) modifies responses to methotrexate (MTX) in patients undergoing bone marrow transplantation. About 10% to 12% of the population carry the MTHFR TT genotype (enzyme activity, 30% of wild type [CC]). Patients (n = 220) with chronic myelogenous leukemia underwent marrow allografts and were given a short course of MTX. MTX toxicity measures included the oral mucositis index (OMI), speed of engraftment (platelet and granulocyte counts), and bilirubin. Patients with lower MTHFR activity (TT genotype) had 36% higher mean OMI during days 1 to 18 (+5.7, P =.046) and 20% higher OMI between days 6 and 12 (+3.8, P =.27). Platelet counts recovered more slowly among patients with the TT genotype compared to wild type (24% slower recovery to 10 000 platelets/microL, P =.23; 34% slower to 20 000/microL, P =.08). Patients with decreased MTHFR activity appear at risk of higher MTX toxicity. Because of the high prevalence of the TT genotype, these results may have implications for MTX dosage.

Adult↗
PubMed2001

MAP kinase phosphatase-1 gene transcription in rat neuroendocrine cells is modulated by a calcium-sensitive block to elongation in the first exon.

Transcriptional elongation of many eukaryotic, prokaryotic, and viral genes is tightly controlled, which contributes to gene regulation. Here we describe this phenomenon for the MAP kinase phosphatase 1 (MKP-1) immediate early gene. In rat GH4C1 pituitary cells, MKP-1 mRNA is rapidly and transiently induced by the thyrotropin-releasing hormone (TRH) and the epidermal growth factor EGF via transcriptional activation of the gene. Ca(2+) signals are necessary for the induction of MKP-1 in response to TRH but not to EGF. Reporter gene analysis with the newly cloned rat promoter sequence shows only limited induction in response to various stimuli, including TRH or EGF. By nuclear run-on assays we demonstrate that in basal conditions, a strong block to elongation in the first exon regulates the MKP-1 gene and that stimulation with either TRH or EGF overcomes the block. Ca(2+) signals are important to release the MKP-1 elongation block in a manner similar to the c-fos oncogene. These results suggest that a common mechanism of intragenic regulation may be conserved between MKP-1 and c-fos in mammalian cells.

Animals↗
PubMed2001

Detection of analytes by immunoassay using up-converting phosphor technology.

Up-Converting Phosphor Technology (UPT) is based on lanthanide-containing, submicrometer-sized, ceramic particles that can absorb infrared light and emit visible light. Biological matrices do not up-convert; hence, there is no contribution to test background from sample autofluorescence. Up-converting phosphors do not photobleach and are inert to common assay interferants such as hemoglobin. A reader called UPlink has been developed to interrogate lateral flow test strips that utilize UPT labels. The reader contains a miniaturized, 1-W, infrared laser with peak emission at 980 nm. Preliminary assays that use up-converting phosphor labels, including tests for a drugs of abuse panel and Escherichia coli O157:H7, have been developed. In a "sandwich" assay format, 10(3) org/mL E. coli O157:H7 organisms were detectable in a negative control background of 10(9) other organisms per milliliter of culture medium. Coefficients of variation in concentrations tested from 0 to 10(7) org/mL were all < or =10%. In a competitive inhibition assay format, a multiplexed test simultaneously detected amphetamine, methamphetamine, phencyclidine, and opiates in saliva. For all assays, the percent displacement at 10 ng/mL was > or =40% demonstrating performance comparable with lab-based, commercially available EIAs. All assays were complete in 10 min. The development of rapid tests using UPT creates new applications for on-site testing with sensitivity not available using other label technologies.

Amphetamine-Related Disorders↗
PubMed2001

Effect of L-carnitine treatment for valproate-induced hepatotoxicity.

The authors analyzed the association of L-carnitine treatment with hepatic survival in 92 patients with severe, symptomatic, valproate-induced hepatotoxicity. Forty-eight percent of the 42 patients treated with L-carnitine survived, but only 10% of the 50 patients treated solely with aggressive supportive care survived (p < 0.001). Early intervention with IV rather than enteral L-carnitine was associated with the greatest hepatic survival. Specifically, all 10 patients who were diagnosed in <5 days and treated with IV L-carnitine survived. Most patients had features of chronic illness and most children appeared to be malnourished.

Adolescent↗
PubMed2001

Activation of pro-death Bcl-2 family proteins and mitochondria apoptosis pathway in tumor necrosis factor-alpha-induced liver injury.

Tumor necrosis factor-alpha (TNFalpha)-induced cytotoxicity contributes to the pathogenesis in inflammatory and immune responses. Here, we studied the role of pro-death Bcl-2 family proteins and the mitochondria apoptosis pathway in the development of TNFalpha-induced hepatic injury during endotoxemia. After treating mice with lipopolysaccharide or TNFalpha in the presence of d-galactosamine, Bid was cleaved and translocated to mitochondria in hepatocytes. Independently, Bax was also activated by the death receptor engagement and translocated to mitochondria. However, its subsequent insertion into the mitochondrial membrane depends on Bid. Nevertheless, Bid was required, but Bax could be dispensed for the mitochondrial release of cytochrome c from mitochondria, suggesting that Bid could activate additional downstream molecules other than Bax. The lack of this Bid-dependent mitochondria activation and cytochrome c release in the bid-deficient mice was responsible for the significantly delayed effector caspase activation and hepatocyte injury upon endotoxin treatment, culminating in a prolonged survival of the bid-deficient mice. Additional genetic factor(s) could further modify the dependence of TNFalpha toxicity on the mitochondria pathway as the bid-deficient 129/SvJ mice manifested an even higher resistance than the same type of mice in C57BL/6 background. The functional significance of the mitochondria apoptosis pathway was thus elucidated in the TNFalpha-mediated pathogenesis in vivo.

Animals↗
PubMed2001

Carboxy ester hydrolysis promoted by a zinc(II) 2-[bis(2-aminomethyl)amino]ethanol complex: a new model for indirect activation on the serine nucleophile by zinc(II) in zinc enzymes.

A complexation study on the new Zn(II) complexes of asymmetric tripodal ligand 2-[bis(2-aminoethyl)amino]ethanol (L) has revealed that the alcoholic OH group of complex ZnL exhibits remarkable acidity with a very low pK(a) value of 7.7 at 25 degrees C. Both the monomeric complex [ZnH(-0.25)L(H(2)O)](ClO(4))(1.75) (I) and the dimeric alkoxide-coordinating complex [Zn(2)(H(-1)L)(2)](ClO(4))(2) (II) were synthesized, and their structures were determined by X-ray diffraction. The Zn(II)-bound alkoxide, as the reactive nucleophile toward the hydrolysis of esters, has shown a second-order rate constant of 0.13 +/- 0.01 M(-1) s(-1) in 10% (v/v) CH(3)CN at 25 degrees C in 4-nitrophenyl acetate (NA) hydrolysis, which is almost the same as the corresponding value for the very reactive alcohol-dependent [12]aneN(3)-Zn complex. Present work shows for the first time that Zn(II) complexes of the asymmetric tripodal polyamine bearing an ethoxyl pod can also serve as good models of Zn(II)-containing enzymes.

Chelating Agents↗
PubMed2001

Autocrine cell suicide in a Burkitt lymphoma cell line (Daudi) induced by interferon alpha: involvement of tumor necrosis factor as ligand for the CD95 receptor.

The CD95 receptor, a member of the tumor necrosis factor (TNF) receptor superfamily, mediates signals for cell death on specific ligand or antibody engagement. It was hypothesized that interferon alpha (IFN-alpha) induces apoptosis through activation of the CD95-mediated pathway and that CD95 and ligands of the death domain may belong to the group of IFN-stimulated genes. Therefore, the effect of IFN-alpha on CD95-CD95L expression, on the release of TNF-alpha, and on TNF receptor 1 expression in an IFN-sensitive human Burkitt lymphoma cell line (Daudi) was investigated. After 5 days' incubation, apoptosis in 81% of IFN-alpha-treated Daudi cells was preceded by a release of TNF-alpha and an induction of CD95 receptor expression. Although supernatants of IFN-treated Daudi cells induced apoptosis of CD95-sensitive Jurkat cells, CD95L was undetectable on protein or on messenger RNA levels, and the weak initial expression of TNF receptor 1 increased only slightly during IFN treatment. Surprisingly, binding of TNF-alpha to CD95 was observed and confirmed by 3 different techniques-enzyme-linked immunosorbent assay using immobilized CD95:Fc-immunoglobulin G, immunoprecipitation assay using CD95 receptor precipitates of Daudi cells, and binding of sodium iodide 125-TNF-alpha to Daudi cells, which was strongly stimulated by IFN-alpha and inhibited by CD95L, CD95:Fc, unlabeled TNF-alpha, and anti-TNF-alpha antibody. Preincubation of Daudi cells with antagonists of the CD95-mediated pathway resulted in an inhibition of IFN-alpha-mediated cell death. The present investigation shows that IFN-alpha induces autocrine cell suicide of Daudi cells by a cross-talk between the CD95 receptor and TNF-alpha. The CD95 receptor can be considered a third TNF receptor, in addition to p55 and p75.

Antineoplastic Agents↗
PubMed2001

Detection of widespread fluids in the Tibetan crust by magnetotelluric studies.

Magnetotelluric exploration has shown that the middle and lower crust is anomalously conductive across most of the north-to-south width of the Tibetan plateau. The integrated conductivity (conductance) of the Tibetan crust ranges from 3000 to greater than 20,000 siemens. In contrast, stable continental regions typically exhibit conductances from 20 to 1000 siemens, averaging 100 siemens. Such pervasively high conductance suggests that partial melt and/or aqueous fluids are widespread within the Tibetan crust. In southern Tibet, the high-conductivity layer is at a depth of 15 to 20 kilometers and is probably due to partial melt and aqueous fluids in the crust. In northern Tibet, the conductive layer is at 30 to 40 kilometers and is due to partial melting. Zones of fluid may represent weaker areas that could accommodate deformation and lower crustal flow.

Journal Article↗
PubMed2001

FTIR study of horseradish peroxidase in reverse micelles.

Fourier transform infrared (FTIR) method was used to study the secondary structures of horseradish peroxidase (HRP) in aqueous solution and in reverse micelles for the first time. Results indicated that the structure of HRP in sodium bis(2-ethylhexy)sulfosuccinate (AOT) reverse micelles was close to that in aqueous solution. In cetyltrimethylammonium bromide (CTAB) and sodium dodecylfate (SDS) reverse micelles the position of some bands changed. Results indicated that the secondary structure had a close relationship with the surfactant species of the reverse micelles. Among the three types of reverse micelles, the system of AOT reverse micelles was probably the most beneficial reaction media to HRP.

Deuterium Oxide↗
PubMed2001

Effects of azelastine on contractility, action potentials and L-type Ca(2+) current in guinea pig cardiac preparations.

Azelastine is used for symptomatic relief of allergic rhinitis and asthma bronchiale. In vitro studies in smooth muscle cells from guinea pig trachea and ileum demonstrate that the drug blocks L-type Ca(2+) current (I(Ca, L)). However, for safety reasons, it is important to know whether azelastine also affects cardiac I(Ca, L) in therapeutically relevant concentrations. We have therefore studied the effects of azelastine on I(Ca, L) in guinea pig ventricular myocytes using standard whole-cell patch-clamp technique. Force of contraction and action potentials from isolated papillary muscles of the same species were also investigated at physiological temperature (36 degrees C). Azelastine (30 microM) significantly reduced force of contraction, shortened action potential duration, and depressed maximum upstroke velocity. I(Ca, L) was elicited by 200-ms-long clamp steps from -100 to 0 mV (one pulse every 3 s). Azelastine blocked I(Ca, L) reversibly and concentration-dependently with an IC(50) of 20.2+/-1.3 microM and a Hill coefficient of 1.1. At 10 microM, azelastine shifted steady-state inactivation by 5 mV (n=7) to more negative potentials. The time course of I(Ca, L) inactivation could be described by a double exponential function. Azelastine (10 microM) significantly shortened the slow inactivation time constant (tau(s)) from 54.2+/-2.8 ms under control conditions to 38.7+/-2.9 ms (n=16) in the presence of drug. Azelastine also reduced low-voltage-activated Ca(2+) currents with a similar IC(50) value (24 microM, at -35 mV). Since the therapeutic plasma concentrations are in the order of 10-100 nM, we conclude that azelastine does indeed affect also cardiac I(Ca, L), but the concentrations required are at least two orders of magnitude larger than those obtained during drug therapy.

Action Potentials↗
PubMed2001

Artifact-free matrix-assisted laser desorption ionization time-of-flight mass spectra of tert.-butyldimethylsilyl ether derivatives of cyclodextrins used for the synthesis of single-isomer, chiral resolving agents for capillary electrophoresis.

Artifact-free, high-resolution matrix-assisted laser desorption ionization (MALDI) time-of-flight mass spectra have been obtained for the labile, single-isomer, tert.-butyldimethylsilyl ether derivatives of alpha-, beta- and gamma-cyclodextrins by optimizing the MALDI sample preparation method. 2,5-Dihydroxybenzoic acid, a 3:1 mixture of 2,5-dihydroxybenzoic acid and 1-hydroxyisoquinoline, and 2,4,6-trihydroxyacetophenone were investigated as MALDI matrices with methanol and acetonitrile as matrix solvents. Partial-to-complete loss of the tert.-butyldimethylsilyl groups was observed when the commonly used 2,5-dihydroxybenzoic acid was the MALDI matrix and/or methanol was the solvent, both with and without trifluoroacetic acid as additive. Loss of the labile tert.-butyldimethylsilyl groups was avoided with 2,4,6-trihydroxyacetophenone as MALDI matrix and acetonitrile as matrix solvent. Good ion intensities were achieved for the (M+Na)+ and (M+K)+ quasimolecular ions in the positive-ion mode. Minor byproducts were observed in some of the samples and the information was used to aid the optimization of the synthetic work.

Artifacts↗
PubMed2001

Thrombin regulates vascular smooth muscle cell growth and heat shock proteins via the JAK-STAT pathway.

The growth-stimulating effects of thrombin are mediated primarily via activation of a G protein-coupled receptor, PAR-1. Because PAR-1 has no intrinsic tyrosine kinase activity, yet requires tyrosine phosphorylation events to induce mitogenesis, we investigated the role of the Janus tyrosine kinases (JAKs) in thrombin-mediated signaling. JAK2 was activated rapidly in rat vascular smooth muscle cells (VSMC) treated with thrombin, and signal transducers and activators of transcription (STAT1 and STAT3) were phosphorylated and translocated to the nucleus in a JAK2-dependent manner. AG-490, a JAK2-specific inhibitor, and a dominant negative JAK2 mutant inhibited thrombin-induced ERK2 activity and VSMC proliferation suggesting that JAK2 is upstream of the Ras/Raf/MEK/ERK pathway. To elucidate the functional significance of JAK-STAT activation, we studied the effect of thrombin on heat shock protein (Hsp) expression, based upon the following: 1) reports that thrombin stimulates reactive oxygen species production in VSMC; 2) the putative role of Hsps in modulating cellular responses to reactive oxygen species; and 3) the presence of functional STAT1/3-binding sites in Hsp70 and Hsp90beta promoters. Indeed, thrombin up-regulated Hsp70 and Hsp90 protein expression via enhanced binding of STATs to cognate binding sites in the Hsp70 and Hsp90 promoters. Together, these results suggest that JAK-STAT pathway activation is necessary for thrombin-induced VSMC growth and Hsp gene expression.

Animals↗
PubMed2001

Characterization of (123)I-vascular endothelial growth factor-binding sites expressed on human tumour cells: possible implication for tumour scintigraphy.

To explore the possibility of vascular endothelial growth factor (VEGF) receptor scintigraphy of primary tumours and their metastases, we analysed the binding properties of (123)I-labelled VEGF(165) ((123)I-VEGF(165)) and (123)I-VEGF(121) to human umbilical vein endothelial cells (HUVECs), several human tumour cell lines (HMC-1, A431, KU812, U937, HEP-1, HEP-G2, HEP-3B and Raji), a variety of primary human tumours (n = 40) and some adjacent non-neoplastic tissues as well as normal human peripheral blood cells in vitro. Two classes of high-affinity (123)I-VEGF(165)-binding site were found on the cell surface of HUVECs. In contrast, one class of high-affinity binding sites for (123)I-VEGF(165) was found on HMC-1, A431, HEP-1, HEP-G2, HEP-3B and U937 cells as well as many primary tumours. For (123)I-VEGF(121), a single class of high-affinity binding site was found on certain cell lines (HUVEC, HEP-1 and HMC-1) and distinct primary tumours (primary melanomas, ductal breast cancers and ovarian carcinomas as well as meningiomas). Tumour cells expressed significantly higher numbers of VEGF receptors compared with normal peripheral blood cells and adjacent non-neoplastic tissues. Immunohistochemical staining revealed that the VEGF receptor Flk-1 is expressed to a much higher extent within malignant tissues compared with neighbouring non-neoplastic cells. We observed significantly greater specific binding of (123)I-VEGF(165) and (123)I-VEGF(121) to a variety of human tumour cells/tissues compared with the corresponding normal tissues or normal peripheral blood cells. In comparison with (123)I-VEGF(121), (123)I-VEGF(165) bound to a higher number of different tumour cell types with a higher capacity. Thus, (123)I-VEGF(165) may be a potentially useful tracer for in vivo imaging of solid tumours.

Animals↗
PubMed2001

A novel alternative approach for prediction of radiation response of squamous cell carcinoma of head and neck.

Accurate prediction of human tumor response to radiation therapy and concomitant chemoradiation would be an important tool to assist the physician in making recommendations for tumor treatment. Most of the studies that define the molecular markers for prediction of radiation response are based on the observation of gene expression using immunostaining, Northern blot, or Western blot analysis of a single or several genes. The results vary among different studies, and some results are contradictory. However, the studies agree that the change in expression of the tumor-related gene affects the radiation response. In this study, we explored a novel approach to predict the radiation response of human tumor using Atlas human cancer 1.2 cDNA array to analyze the expression profile of 1187 tumor-related genes in radiation-resistant and radiation-sensitive tissues. Sixty tumor-related genes were selected as predictors of radiation response of squamous cell carcinoma of the head and neck. Using the expression intensity of these 60 tumor-related genes, in combination with cluster analysis, we successfully predicted the radiation identity of two tumor samples.

Carcinoma, Squamous Cell↗