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Biomedical subjects

M Liu

Publications and source records attributed to M Liu.

At least 37 records · Page 2Linked to original sources
PubMed2001

Antimalarial alkoxylated and hydroxylated chalcones [corrected]: structure-activity relationship analysis.

Chalcones with 2',3',4'-trimethoxy, 2',4'-dimethoxy, 4'-methoxy, 4'-ethoxy, 2',4'-dihydroxy, and 4'-hydroxy groups on ring B were synthesized and evaluated in vitro against Plasmodium falciparum (K1) in a [3H] hypoxanthine uptake assay. The other ring A was quinoline, pyridine, naphthalene, or phenyl rings with electron-donating or electron-withdrawing substituents of varying lipophilicities. Trimethoxy 6 and 27, dimethoxy 7, 8, 29, and methoxy 31 analogues had good in vitro activities (IC(50) < 5 microM). 3-Quinolinyl ring A derivatives were well represented among the active compounds. Hydroxylated chalcones were less active than the corresponding alkoxylated analogues. When evaluated in vivo, 8 and 208 were comparable to chloroquine in extending the lifespan of infected mice. Multivariate data analysis showed that in vitro activity was mainly determined by the properties of ring B. Quantitative structure-activity relationship models with satisfactory predictive ability were obtained for various B ring chalcones using projections to latent structures. A model with good predictability was proposed for 19 active chalcones. Size and hydrophobicity were identified as critical parameters.

Animals↗
PubMed2001

Lumbar lateral interbody cage with plate augmentation: in vitro biomechanical analysis.

Many studies have concluded that stand alone cages provide limited stabilization to the spine, and this primary stabilization decreases postoperatively due to various factors. A supplemental fixation may, therefore, be needed to improve the stability. Extensive biomechanical analysis was performed in the present study to further evaluate the stabilization achieved by a laterally inserted cage and the role of an anterior lateral supplemental fixation. Eight human cadaver functional spinal units were subjected sequentially to four different test conditions: (1) intact, (2) instrumented laterally with a long cylindrical threaded cage, (3) the same cage supplemented with a lateral fixation plate, the plate being firmly connected to the cage, and (4) removal of the connection between the plate and the cage. Pure moments were applied to each specimen in a quasi static manner, ranging from -7 Nm to 7 Nm in flexion/extension, lateral bending and axial rotation. Three-dimensional segmental motions were simultaneously recorded under each loading condition. Statistical analysis was carried out on the motion parameters, including the range of motion (ROM) and the neutral zone (NZ). Inter-group comparisons were made using the Friedman test and the Wilcoxon test. The results showed that the stand alone lateral cage provided stabilization by increasing segmental stiffness above that of the intact spine. The stiffness increase ratios were: 1.6 in flexion/extension ( P=0.07), 1.3 in lateral bending ( P=0.4) and 1.0 in axial rotation ( P=0.67). A supplemental plate provided significant reinforcement of the stabilization. The stiffness increase ratios relative to the intact spine were: 3.1 in flexion/extension ( P=0.012), 5.0 in lateral bending ( P=0.012) and 2.3 in axial rotation ( P=0.012). After removal of the connection between the cage and the plate, the stiffness ratios were: 2.7 in flexion/extension ( P=0.027), 4.6 in lateral bending ( P=0.027) and 2.1 in axial rotation ( P=0.027). Globally, the cage alone increased the segmental stiffness above that of the intact spine by a factor of 1.1 ( P=0.39), with the supplemental plate, segmental stiffness increased by a factor of 3.1 ( P<0.01), and the unconnected cage/plate increased stiffness by a factor of 3.0 ( P=0.02). Supplementation of the lateral cage with an anterolateral plate was thus shown to provide significant additional stabilization in all directions, which may potentially compensate for the postoperative decrease in segmental stability.

Adult↗
PubMed2001

Structure of ferrofluid dynamics.

The complete magnetodissipative structure of ferrofluid dynamics is derived from general principles, without reference to the angular momentum of the ferromagnetic grains. The results are independent of most microscopic details, and easily interpret two previous experiments. Both the Debye theory and the effective-field theory by Shliomis are shown to be special cases of the new set of equations.

Journal Article↗
PubMed2001

Prostaglandin E1 protects lung transplants from ischemia-reperfusion injury: a shift from pro- to anti-inflammatory cytokines.

INTRODUCTION: Prostaglandin E1 (PGE1) has been demonstrated to reduce ischemia-reperfusion (IR) injury following lung transplantation. However, the cytoprotective mechanisms remain largely unknown. The purpose of this study was to determine whether the mechanism through which PGE1 improves IR injury is related to the level of apoptosis or the release of inflammatory cytokines. METHODS: In a rat single-lung-transplant model, animals were randomly allocated into four groups of five animals each. Group 1 received normal saline (NS) in the preservation solution and during the 2-hr reperfusion period. Group 2 received NS in the preservation solution and PGE1 during the reperfusion period. Group 3 received PGE1 in the preservation solution and NS during the reperfusion period. Group 4 received PGE1 in the preservation solution and during the reperfusion period. RESULTS: The two groups that received PGE1 during the reperfusion period had a significantly higher partial pressure of oxygen (PaO2), lower wet-dry weight ratio, and lower peak airway pressure at the end of the reperfusion period than did the two groups that received NS. In the two groups that received PGE1 during the reperfusion period, we observed significantly higher levels of interleukin (IL)-10 in the transplanted lung tissue and plasma and significantly lower levels of tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and IL-12 in lung tissue. The levels of IL-4 and macrophage inflammatory protein-2 (MIP-2) were not significantly different between groups. The number of apoptotic cells and the expression of Bcl-2 were not significantly different between groups. CONCLUSIONS: PGE1 does not decrease the amount of apoptosis after reperfusion and does not significantly upregulate Bcl-2. We have demonstrated that PGE1 administered during the reperfusion period reduces IR injury and improves lung function through a mechanism that is likely mediated by a shift between pro- and anti-inflammatory cytokine release.

Alprostadil↗
PubMed2001

Identification of a prostate-specific G-protein coupled receptor in prostate cancer.

Membrane receptors coupled to heterotrimeric G-proteins play an essential role in the transmission of signals from the extracellular environment to the cytoplasm of the cell. A wide variety of external stimuli, including neurotransmitters, hormones, phospholipids, photons, odorants, taste ligands, and growth factors, can activate specific members of the G-protein coupled receptors (GPCRs). Besides essential functions in fully differentiated cells and tissues, GPCRs are also involved in embryogenesis, tissue regeneration, cell growth stimulation, and cell proliferation. In this study, we identified a novel prostate-specific G-protein coupled receptor that interacts with Galpha(12) in our yeast two-hybrid assays. The expression of the receptor protein is highly restricted to human prostate tissues using multiple-tissue Northern blot analysis, and tissue expression array. Furthermore, the expression of prostate-specific receptor is increased significantly in prostate tumors in comparison with the matched normal prostate tissues using PCR and Southern blot analysis, suggesting a potential role of this tissue-specific G-protein coupled receptor in prostate cancer development.

Amino Acid Sequence↗
PubMed2001

In vivo transtracheal adenovirus-mediated transfer of human interleukin-10 gene to donor lungs ameliorates ischemia-reperfusion injury and improves early posttransplant graft function in the rat.

We examined the effect of adenovirus-mediated transtracheal transfer of the human interleukin 10 (hIL-10) gene on lung ischemia-reperfusion (IR) injury, which is the insult due to hypothermic preservation plus graft reperfusion, and posttransplant lung function in Lewis rat lungs. Thirty rats were divided into 6 groups (n = 5). Groups 1 and 4 received 5 x 10(9) PFU of Ad5E1RSVhIL-10, groups 2 and 5 received 5 x 10(9) PFU of Ad5BGL2 ("empty" vector), and groups 3 and 6 received 3% sucrose (diluent). After 24 hr of in vivo transfection, lungs were stored at 4 degrees C (cold ischemic time, CIT) for 6 hr (groups 1-3) or 24 hr (groups 4-6) before transplantation. After 2 hr of reperfusion, lung function was assessed by oxygenation (FIO2, 1.0), airway pressure (AwP), and wet-to-dry (W/D) weight ratios. Rat tumor necrosis factor alpha (rTNF-alpha), interferon gamma (IFN-gamma), IL-10, and hIL-10 were measured in graft tissue and recipient plasma by ELISA and detected by immunohistochemistry (IHC). Partial pressure of oxygen (PaO2) levels in the hIL-10 group (6 hr of CIT) were higher than in empty vector and diluent groups (PaO2, 530 +/- 23 vs. 387 +/- 31 and 439 +/- 27 mmHg, respectively, p < 0.05). IL-10 rats after 24 hr of CIT showed higher PaO2 levels (260 +/- 29 mmHg) than empty vector (96 +/- 24 mmHg) or diluent (133 +/- 10 mmHg) lungs (p < 0.05). AwP and W/D ratios were reduced in hIL10 lungs (p < 0.05) compared with the other groups. rTNF-alpha and INF-gamma were reduced in tissue and plasma in groups 1 and 4 (p < 0.05). rIL-10 was reduced in the tissue of hIL-10 lungs (p < 0.05). IHC showed equal distribution of cytokines in tissue and abundant transgene expression in large and small airway epithelium in hIL-10 lungs.

Adenoviridae↗
PubMed2001

Misacylation and editing by Escherichia coli valyl-tRNA synthetase: evidence for two tRNA binding sites.

Valyl-tRNA synthetase (ValRS) has difficulty discriminating between its cognate amino acid, valine, and structurally similar amino acids. To minimize translational errors, the enzyme catalyzes a tRNA-dependent editing reaction that prevents accumulation of misacylated tRNA(Val). Editing occurs with threonine, alanine, serine, and cysteine, as well as with several nonprotein amino acids. The 3'-end of tRNA plays a vital role in promoting the tRNA-dependent editing reaction. Valine tRNA having the universally conserved 3'-terminal adenosine replaced by any other nucleoside does not stimulate the editing activity of ValRS. As a result 3'-end tRNA(Val) mutants, particularly those with 3'-terminal pyrimidines, are stably misacylated with threonine, alanine, serine, and cysteine. Valyl-tRNA synthetase is unable to hydrolytically deacylate misacylated tRNA(Val) terminating in 3'-pyrimidines but does deacylate mischarged tRNA(Val) terminating in adenosine or guanosine. Evidently, a purine at position 76 of tRNA(Val) is essential for translational editing by ValRS. We also observe misacylation of wild-type and 3'-end mutants of tRNA(Val) with isoleucine. Valyl-tRNA synthetase does not edit wild-type tRNA(Val)(A76) mischarged with isoleucine, presumably because isoleucine is only poorly accommodated at the editing site of the enzyme. Misacylated mutant tRNAs as well as 3'-end-truncated tRNA(Val) are mixed noncompetitive inhibitors of the aminoacylation reaction, suggesting that ValRS, a monomeric enzyme, may bind more than one tRNA(Val) molecule. Gel-mobility-shift experiments to characterize the interaction of tRNA(Val) with the enzyme provide evidence for two tRNA binding sites on ValRS.

3' Untranslated Regions↗
PubMed2001

Catalytic acid-base groups in yeast pyruvate decarboxylase. 1. Site-directed mutagenesis and steady-state kinetic studies on the enzyme with the D28A, H114F, H115F, and E477Q substitutions.

The roles of four of the active center groups with potential acid-base properties in the region of pH optimum of pyruvate decarboxylase from Saccharomyces cerevisiae have been studied with the substitutions Asp28Ala, His114Phe, His115Phe, and Glu477Gln, introduced by site-directed mutagenesis methods. The steady-state kinetic constants were determined in the pH range of activity for the enzyme. The substitutions result in large changes in k(cat) and k(cat)/S(0.5) (and related terms), indicating that all four groups have a role in transition state stabilization. Furthermore, these results also imply that all four are involved in some manner in stabilizing the rate-limiting transition state(s) both at low substrate (steps starting with substrate binding and culminating in decarboxylation) and at high substrate concentration (steps beginning with decarboxylation and culminating in product release). With the exception of some modest effects, the shapes of neither the bell-shaped k(cat)/S(0.5)-pH (and related functions) plots nor the k(cat)-pH plots are changed by the substitutions. Yet, the fractional activity still remaining after substitutions virtually rules out any of the four residues as being directly responsible for initiating the catalytic process by ionizing the C2H. There is no effect on the C2 H/D exchange rate exhibited by the D28A and E477Q substitutions. These results strongly imply that the base-induced deprotonation at C2 is carried out by the only remaining base, the iminopyrimidine tautomer of the coenzyme, via intramolecular proton abstraction. The first product is released as CO(2) rather than HCO(3)(-) by both wild-type and E477Q and D28A variants, ruling out several mechanistic alternatives.

Alanine↗
PubMed2001

Regulation of the p21-activated kinase (PAK) by a human Gbeta -like WD-repeat protein, hPIP1.

The family of p21-activated protein kinases (PAKs) is composed of serine-threonine kinases whose activity is regulated by the small guanosine triphosphatases (GTPases) Rac and Cdc42. In mammalian cells, PAKs have been implicated in the regulation of mitogen-activated protein cascades, cellular morphological and cytoskeletal changes, neurite outgrowth, and cell apoptosis. Although the ability of Cdc42 and Rac GTPases to activate PAK is well established, relatively little is known about the negative regulation of PAK or the identity of PAK cellular targets. Here, we describe the identification and characterization of a human PAK-interacting protein, hPIP1. hPIP1 contains G protein beta-like WD repeats and shares sequence homology with the essential fission yeast PAK regulator, Skb15, as well as the essential budding yeast protein, MAK11. Interaction of hPIP1 with PAK1 inhibits the Cdc42/Rac-stimulated kinase activity through the N-terminal regulatory domains of PAK1. Cotransfection of hPIP1 in mammalian cells inhibits PAK-mediated c-Jun N-terminal kinase and nuclear factor kappa B signaling pathways. Our results demonstrate that hPIP1 is a negative regulator of PAK and PAK signaling pathways.

Amino Acid Sequence↗
PubMed2001

Leukocyte-specific adaptor protein Grap2 interacts with hematopoietic progenitor kinase 1 (HPK1) to activate JNK signaling pathway in T lymphocytes.

Immune cell-specific adaptor proteins create various combinations of multiprotein complexes and integrate signals from cell surface receptors to the nucleus, modulating the specificity and selectivity of intracellular signal transduction. Grap2 is a newly identified adaptor protein specifically expressed in lymphoid tissues. This protein shares 40--50% sequence homology in the SH3 and the SH2 domain with Grb2 and Grap. However, the Grap2 protein has a unique 120-amino acid glutamine- and proline-rich domain between the SH2 and C-terminal SH3 domains. The expression of Grap2 is highly restricted to lymphoid organs and T lymphocytes. In order to understand the role of this specific adaptor protein in immune cell signaling and activation, we searched for the Grap2 interacting protein in T lymphocytes. We found that Grap2 interacted with the hematopoietic progenitor kinase 1 (HPK1) in vitro and in Jurkat T cells. The interaction was mediated by the carboxyl-terminal SH3 domain of Grap2 with the second proline-rich motif of HPK1. Coexpression of Grap2 with HPK1 not only increased the kinase activity of HPK1 in the cell, but also had an additive effect on HPK1 mediated JNK activation. Furthermore, over expression of Grap2 and HPK1 induced significant transcriptional activation of c-Jun in the JNK signaling pathway and IL-2 gene reporter activity in stimulated Jurkat T cells. Therefore, our data suggest that the hematopoietic specific proteins Grap2 and HPK1 form a signaling complex to mediate the c-Jun NH(2)-terminal kinase (JNK) signaling pathway in T cells.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Inhibition of angiogenesis and tumor growth by SCH221153, a dual alpha(v)beta3 and alpha(v)beta5 integrin receptor antagonist.

New blood vessel formation is essential for tumor growth and metastatic spread. Integrins alpha(v)beta3 and alpha(v)beta5 are arginine-glycine-aspartic acid-dependent adhesion receptors that play a critical role in angiogenesis. Hence, selective dual alpha(v)beta3 and alpha(v)beta5 antagonists may represent a novel class of angiogenesis and tumor-growth inhibitors. Here, an arginine-glycine-aspartic acid-based peptidomimetic library was screened to identify alpha(v)beta3 antagonists. Selected compounds were then modified to generate potent and selective dual inhibitors of alpha(v)beta3 and alpha(v)beta5 receptors. One of these compounds, SCH 221153, inhibited the binding of echistatin to alpha(v)beta3 (IC50 = 3.2 nM) and alpha(v)beta5 (IC50 = 1.7 nM) with similar potency. Its IC50 values for related alpha(IIb)beta3 and alpha5beta1 receptors were 1294 nM and 421 nM, respectively, indicating that SCH 221153 is highly selective for alpha(v)beta3 and alpha(v)beta5 receptors. In cell-based assays, SCH 221153 inhibited the binding of echistatin to alpha(v)beta3- and alpha(v)beta5-expressing 293 cells and blocked the adhesion of endothelial cells to immobilized vitronectin and fibroblast growth factor 2 (FGF2). SCH 221153, but not the inactive analogue SCH 216687, was effective in inhibiting FGF2 and vascular endothelial growth factor-induced endothelial cell proliferation in vitro with an IC50 equal to 3-10 microM. Angiogenesis induced by FGF2 in the chick chorioallantoic membrane assay was also inhibited by SCH 221153. Finally, SCH 221153 exerted a significant inhibition on tumor growth induced by intradermal or s.c. injection of human melanoma LOX cells in severe combined immunodeficient mice.

Allantois↗
PubMed2001

Phosphorylation and regulation of G-protein-activated phospholipase C-beta 3 by cGMP-dependent protein kinases.

Among the drugs that are known to relax the vascular smooth muscle and regulate other cellular functions, beta-adrenergic agonists and nitric oxide-containing compounds are some of the most effective ones. The mechanisms of these drugs are thought to lower agonist-induced intracellular [Ca(2+)] by increasing intracellular cAMP and cGMP, activating their respective protein kinases. However, the physiological targets of cyclic nucleotide-dependent protein kinases are not clear. The molecular basis for the regulation of intracellular Ca(2+) by signaling pathways coupled to cyclic nucleotides is not well defined. G-protein-activated phospholipase C (PLC-beta) catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphates to generate diacylglycerol and inositol 1,4,5-triphosphate, leading to the activation of protein kinase C and the mobilization of intracellular Ca(2+). In this study, we shown that G-protein-activated PLC enzymes are the potential targets of cGMP-dependent protein kinases (PKG). PKG can directly phosphorylate PLC-beta2 and PLC-beta3 in vitro with purified proteins and in vivo with metabolic labeling. Phosphorylation of PLC-beta leads to the inhibition of G-protein-activated PLC-beta3 activity by 50-70% in COS-7 cell transfection assays. By using phosphopeptide mapping and site-directed mutagenesis, we further identified two key phosphorylation sites for the regulation of PLC-beta3 by PKG (Ser(26) and Ser(1105)). Mutation at these two sites (S26A and S1105A) of PLC-beta3 completely blocked the phosphorylation of PLC-beta3 protein catalyzed by PKG. Furthermore, mutation of these serine residues removed the inhibitory effect of PKG on the activation of the mutant PLC-beta3 proteins by G-protein subunits. Our results suggest a molecular mechanism for the regulation of G-protein-mediated intracellular [Ca(2+)] by the NO-cGMP-dependent signaling pathway.

Animals↗
PubMed2001

N-terminal PDZ domain is required for NHERF dimerization.

NHERF, a 55 kDa PDZ-containing protein, binds receptors and ion transporters to mediate signal transduction at the plasma membrane. Recombinant NHERF demonstrated an apparent size of 150 kDa on gel filtration, which could be reduced to approximately 55 kDa by protein denaturing agents, consistent with the formation of NHERF dimers. Biosensor studies established the time- and concentration-dependent dimerization of NHERF. Overlays of recombinant NHERF fragments suggested that NHERF dimerization was principally mediated by the N-terminal PDZ-I domain. In PS120 cells, reversible protein phosphorylation modulated NHERF dimerization and suggested a role for NHERF dimers in hormonal signaling.

Animals↗
PubMed2001

Genomic characterization, localization, and functional expression of FGL2, the human gene encoding fibroleukin: a novel human procoagulant.

For diseases in which thrombosis plays a pivotal role, such as virus-induced fulminant hepatitis, fetal loss syndrome, and xenograft rejection, the major procoagulant has remained elusive. Here we describe the isolation and functional expression of a distinct human prothrombinase, termed FGL2. The murine fgl2 gene product has been implicated in the pathophysiology of murine fulminant hepatitis. The predicted ORF corresponds to a 439-amino-acid type II integral membrane protein that contains a carboxy-terminal Fibrinogen-related domain. Functional analysis showed that FGL2-encoded protein is indeed a prothrombinase. This enzyme is a serine protease and directly cleaves prothrombin to thrombin. The FGL2 gene is a single-copy gene in the haploid human genome and has two exons separated by a 2195-bp intron expressing two mRNA transcripts of 1.5 and 5.0 kb. The 5'-flanking region contains putative cis-elements including a TATA box, an AP1 site, CEBP sites, Sp1 site, and Ets binding domains. By both radiation hybrid analyses and fluorescence in situ hybridization, human FGL2 was localized to 7q11.23.

Amino Acid Sequence↗
PubMed2001

Invalidation of the Kelvin force in ferrofluids.

Direct and unambiguous experimental evidence for the magnetic force density being of the form MnablaB in a certain geometry-rather than being the Kelvin force MnablaH--is provided for the first time. ( M is the magnetization, H is the field, and B is the flux density.)

Journal Article↗
PubMed2001

Mannitol for acute stroke.

BACKGROUND: Mannitol is an osmotic agent and a free radical scavenger so it might decrease oedema and tissue damage in stroke. OBJECTIVES: To test whether treatment with mannitol reduces short and long-term case fatality and dependency after acute ischaemic stroke or cerebral parenchymal haemorrhage. SEARCH STRATEGY: We searched the Cochrane Stroke Group Specialised Trials Register. In addition to this, supplementary MEDLINE searches were performed. The Chinese Stroke Trials Register was checked and the Latin-American databank LILACS was searched with the search term MANNITOL and its variations in the Portuguese and Spanish languages. A search was performed of Masters and Ph.D. degree theses in the databank of Sao Paulo University, and in abstracts of medical congresses on neurology and neurosurgery from 1965 to 1997 in Brazil. SELECTION CRITERIA: Truly randomised unconfounded clinical trials comparing the effect of mannitol with placebo or open control in patients with acute ischaemic stroke or parenchymal haemorrhage were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected the trials to be included in the review. After reaching an agreement on which trials to include, two of the reviewers extracted data from the trials and performed the data analysis. Accuracy of data extraction was checked by comparing the results. Included trials were tabulated for methodological quality including the method of randomisation and blinding, and stating if CT was performed, if patients were lost to follow-up and if intention-to-treat analysis was performed. Data synthesis and analysis was performed using the Cochrane Review Manager software. MAIN RESULTS: Only one trial fulfilled the inclusion criteria. The number of included patients was small (36 treated and 41 controls) and the follow up was short. Neither beneficial nor harmful effects of mannitol could be proved. Case fatality, the proportion of dependent patients at the end of the follow up and side effects were not reported and were not available from the investigators. The planned outcome analyses and sensitivity analyses could not be performed due to lack of appropriate trials. REVIEWER'S CONCLUSIONS: There is currently not enough evidence to decide whether the routine use of mannitol in acute stroke would result in any beneficial or harmful effect. The routine use of mannitol in all patients with acute stroke is not supported by any evidence from randomised controlled clinical trials. Further trials are needed to confirm or refute the routine use of mannitol in acute stroke.

Acute Disease↗