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Biomedical subjects

Z Li

Publications and source records attributed to Z Li.

At least 181 records · Page 10Linked to original sources
PubMed2001

Influence of human p16(INK4) and p21(CIP1) on the in vitro activity of recombinant Plasmodium falciparum cyclin-dependent protein kinases.

The regulatory mechanisms of most cyclin dependent protein kinases (CDKs) are well understood and are highly conserved in eukaryotes. CDKs from the malaria parasite, Plasmodium falciparum, appear to be regulated in a similar manner with regard to cyclin binding and phosphorylation. In order to further understand their regulatory mechanisms, we examined two classes of cyclin dependent kinase inhibitors (CDIs) to inhibit a panel of plasmodial CDKs. We find that Pfmrk and PfPK5 are inhibited by heterologous p21(CIP1) with varying degrees of inhibition. In contrast, PfPK6, a kinase with sequence features characteristic of both a CDK and MAP kinase, is unaffected by this CDI. Furthermore, the CDK4/6 specific CDI, p16(INK4), fails to inhibit these plasmodial CDKs. Taken together, these results suggest that plasmodial CDKs may be regulated by the binding of inhibitory proteins in vivo.

Animals↗
PubMed2001

A method to assess the proportion of treatment effect explained by a surrogate endpoint.

Randomized clinical trials are the standard for evaluating new drugs, devices and procedures. Traditional clinical trials entail not only considerable expense, but require considerable time to complete. The use of surrogate endpoints constitutes an effort to control cost and completion time for clinical trials. We propose a method to quantify the proportion of treatment effect explained by a surrogate endpoint based on a general model setting which includes the commonly used linear, logistic and Cox regression models. The interpretation of this quantitative measure is facilitated by graphical displays. To reduce the variability associated with the estimate, a meta-analytic approach is proposed based on random effects models. An example using real clinical trial data is given to illustrate the proposed procedures.

Biometry↗
PubMed2001

Inhibition of JNK activation through NF-kappaB target genes.

The proinflammatory cytokine tumour necrosis factor-alpha (TNF-alpha) regulates immune responses, inflammation and programmed cell death (apoptosis). The ultimate fate of a cell exposed to TNF-alpha is determined by signal integration between its different effectors, including IkappaB kinase (IKK), c-Jun N-terminal protein kinase (JNK) and caspases. Activation of caspases is required for apoptotic cell death, whereas IKK activation inhibits apoptosis through the transcription factor NF-kappaB, whose target genes include caspase inhibitors. JNK activates the transcription factor c-Jun/AP-1, as well as other targets. However, the role of JNK activation in apoptosis induced by TNF-alpha is less clear. It is unknown whether any crosstalk occurs between IKK and JNK, and, if so, how it affects TNF-alpha-induced apoptosis. We investigated this using murine embryonic fibroblasts that are deficient in either the IKKbeta catalytic subunit of the IKK complex or the RelA/p65 subunit of NF-kappaB. Here we show that in addition to inhibiting caspases, the IKK/NF-kappaB pathway negatively modulates TNF-alpha-mediated JNK activation, partly through NF-kappaB-induced X-chromosome-linked inhibitor of apoptosis (XIAP). This negative crosstalk, which is specific to TNF-alpha signalling and does not affect JNK activation by interleukin-1 (IL-1), contributes to inhibition of apoptosis.

Animals↗
PubMed2001

Potassium silver tin selenide, K(2)Ag(2)Sn(2)Se(6).

The title compound was synthesized by a reactive salt reaction at 773 K over a period of 5 d. It has a one-dimensional chain structure consisting of K(+) cations and one-dimensional [Ag(2)Sn(2)Se(6)](2-) anions. The chain is constructed by edge-sharing bitetrahedral [Sn(2)Se(6)] units connected in a 1:2 ratio via linear Ag(+) ions.

Journal Article↗
PubMed2001

Design and synthesis of a novel class of histone deacetylase inhibitors.

Histone deacetylase inhibitors (HDACs) have emerged as a novel class of antiproliferative agents. Utilizing structure-based design, the synthesis of a series of sulfonamide hydroxamic acids is described. Further optimization of this series by substitution of the terminal aromatic ring yielded HDAC inhibitors with good in vitro and in vivo activities.

Cell Division↗
PubMed2001

Design and synthesis of Pfmrk inhibitors as potential antimalarial agents.

The synthesis and inhibitory activities of 10 potential inhibitors of Pfmrk, a Plasmodium falciparum cyclin-dependent protein kinase, are described. The most potent inhibitor is a 3-phenyl-quinolinone compound with an IC(50) value of 18 microM. It is the first compound reported to inhibit Pfmrk at the micro molar range.

Animals↗
PubMed2001

Reconstruction of SEA-B7.1 double signals on human hepatocellular carcinoma cells and analysis of its immunological effect.

Since transfection of established tumors with immunostimulatory genes, such as superantigens (SAg), a family of bacterial and viral proteins with strong immunostimulatory properties, can elicit antitumor immunity, direct transfection of tumors with genes of staphylococcal enterotoxin A (SEA) could probably set up a new way of immunological pathway. In our study, human hepatocellular carcinoma (HCC) cell lines stably transduced with SEA and B7.1/SEA fused genes, HHCCSEA and HHCCBS, were obtained by using the method of retroviral mediated gene transduction. The results showed that human HCC cells could express SEA gene. Although a tiny quantity of expression was detected, a robust immune response was promoted. The cytotoxicity of CTL on HHCCBS was the same as that on HHCCSEA. But the K(m) value of the reaction of the former was lower than that of HHCCSEA. Furthermore, the activity assay of T cells by ELISPOT demonstrated that HHCCBS could elicit more CTL activity than HHCCSEA and HHCCB7.1. It suggested that the affinity of T cells to HHCCBS was higher and the maxim velocity of reaction could be attained at an early stage of the reaction. Transduced HCC cells were also analyzed for HLA expression, and it was found that a majority of the cells expressed HLA-I molecules but no HLA-DR molecules. After blocking the HLA-I molecules by HLA-I mAb, the cytotoxicity of T lymphocytes dropped remarkably. The results suggested that SEA were mainly presented by HLA-I molecules, and that B7.1 and SEA could have synergistic action at the early stage of the reaction, but the relationship between them in the consequent process needs to be clarified.

Carcinoma, Hepatocellular↗
PubMed2001

Development of a two-part transcription probe to determine the completeness of temporal and spatial compartmentalization of gene expression during bacterial development.

We have developed a two-part test, using the Bacillus subtilis sacB/SacY transcription antitermination system, to evaluate the completeness of temporal and spatial compartmentalization of gene expression during bacterial cell development. Transcription of sacY(1-55) (encoding a constitutively active form of the antiterminator, SacY) is directed by one promoter, whereas transcription of sacB'-'lacZ (the target of SacY action) is directed by the same or another promoter. To obtain beta-galactosidase activity, SacY(1-55) needs to be present when sacB'-'lacZ is being transcribed. We tested the system by analyzing the spatial compartmentalization of the activities of RNA polymerase final sigma factors, which are tightly regulated during sporulation of B. subtilis: final sigma(F) and then final sigma(G) in the prespore, final sigma(E) and then final sigma(K) in the mother cell. We have confirmed that the activities of final sigma(F) and final sigma(E) are spatially compartmentalized. We have demonstrated that there is also sharp temporal compartmentalization, with little or no overlap in the activities of final sigma(F) and final sigma(G) or of final sigma(E) and final sigma(K). In contrast, we found no compartmentalization of the activity of the main vegetative factor, final sigma(A), which continued to be active alongside all of the sporulation-specific final sigma factors. We also found no temporal compartmentalization of expression of loci that are activated during the development of competent cells of B. subtilis, a developmental program distinct from spore formation. A possible mechanism to explain the temporal compartmentalization of final sigma(F) and final sigma(G) activities is that the anti-sigma factor SpoIIAB transfers from final sigma(G) to final sigma(F).

Bacillus subtilis↗
PubMed2001

Photochemically enhanced binding of small molecules to the tumor necrosis factor receptor-1 inhibits the binding of TNF-alpha.

The binding of tumor necrosis factor alpha (TNF-alpha) to the type-1 TNF receptor (TNFRc1) plays an important role in inflammation. Despite the clinical success of biologics (antibodies, soluble receptors) for treating TNF-based autoimmune conditions, no potent small molecule antagonists have been developed. Our screening of chemical libraries revealed that N-alkyl 5-arylidene-2-thioxo-1,3-thiazolidin-4-ones were antagonists of this protein-protein interaction. After chemical optimization, we discovered IW927, which potently disrupted the binding of TNF-alpha to TNFRc1 (IC(50) = 50 nM) and also blocked TNF-stimulated phosphorylation of Ikappa-B in Ramos cells (IC(50) = 600 nM). This compound did not bind detectably to the related cytokine receptors TNFRc2 or CD40, and did not display any cytotoxicity at concentrations as high as 100 microM. Detailed evaluation of this and related molecules revealed that compounds in this class are "photochemically enhanced" inhibitors, in that they bind reversibly to the TNFRc1 with weak affinity (ca. 40-100 microM) and then covalently modify the receptor via a photochemical reaction. We obtained a crystal structure of IV703 (a close analog of IW927) bound to the TNFRc1. This structure clearly revealed that one of the aromatic rings of the inhibitor was covalently linked to the receptor through the main-chain nitrogen of Ala-62, a residue that has already been implicated in the binding of TNF-alpha to the TNFRc1. When combined with the fact that our inhibitors are reversible binders in light-excluded conditions, the results of the crystallography provide the basis for the rational design of nonphotoreactive inhibitors of the TNF-alpha-TNFRc1 interaction.

Antigens, CD↗
PubMed2001

The effect of IQGAP1 on Xenopus embryonic ectoderm requires Cdc42.

IQGAP1 contains a number of protein recognition motifs through which it binds to targets. Several in vitro studies have documented that IQGAP1 interacts directly with calmodulin, actin, E-cadherin, beta-catenin, and the small GTPases Cdc42 and Rac. Nevertheless, direct demonstration of in vivo function of mammalian IQGAP1 is limited. Using a novel assay to evaluate in vivo function of IQGAP1, we document here that microinjection of IQGAP1 into early Xenopus embryos generates superficial ectoderm lesions at late blastula stages. This activity was retained by the mutated variants of IQGAP1 in which the calponin homology domain or the WW domain was deleted. By contrast, deletion of the IQ (IQGAP1-DeltaIQ), Ras-GAP-related (IQGAP1-DeltaGRD), or C-terminal (IQGAP1-DeltaC) domains abrogated the effect of IQGAP1 on the embryos. None of the latter mutants bound Cdc42, suggesting that the binding of Cdc42 by IQGAP1 is critical for its function. Moreover, overexpression of IQGAP1, but not IQGAP1-DeltaGRD, significantly increased the amount of active Cdc42 in embryonic cells. Co-injection of wild type IQGAP1 with dominant negative Cdc42, but not the dominant negative forms of Rac or Rho, blocked the effect of IQGAP1 on embryonic ectoderm. Together these data indicate that the activity of IQGAP1 in embryonic ectoderm requires Cdc42 function.

Animals↗
PubMed2001

The metal ion binding properties of calreticulin modulate its conformational flexibility and thermal stability.

Calreticulin (CRT) is a soluble chaperone involved in the conformational maturation of glycoproteins in the endoplasmic reticulum. Using biochemical and biophysical techniques including circular dichroism, proteolysis, and analytical ultracentrifugation, we have determined the effects of calcium and zinc ions on the structural properties of human CRT. Circular dichroism analysis has shown that the binding of calcium and zinc ions to CRT induces no significant changes in the secondary structure of the protein but affects in very distinct ways the local tertiary packing of these elements. More specifically, these studies have revealed that CRT adopts a more rigid and thermally stable structure upon binding calcium ions and a more loosely packed and thermally destabilized structure upon binding zinc ions. Consistent with these results, proteolysis experiments demonstrated that the intrinsic conformational flexibility of CRT can be modulated toward either a decrease or an increase in susceptibility to cleavage by chymotrypsin upon binding calcium or zinc ions, respectively. Results from sedimentation analysis indicated that the global three-dimensional structure of CRT is essentially unchanged upon binding calcium ions. In marked contrast, CRT self-associates reversibly to form dimers upon binding zinc ions. Collectively, our results provide evidence that calcium and zinc ions induce strikingly different changes in the biochemical and structural properties of CRT.

Binding Sites↗
PubMed2001

Synergistic effect of cationic surfactants on perchloroethylene degradation by zero-valent iron.

Zero-valent iron (ZVI) as a permeable barrier material for degradation of chlorinated organic compounds has been extensively studied recently. One of the focal areas in ZVI studies is to increase the contaminant reduction rate. In this research, batch tests were performed to evaluate the synergistic effect of sorbed cationic surfactants on degradation of perchloroethylene (PCE). Sorption of cationic surfactants on ZVI was a function of hydrophobic chain length of the surfactanttail group. Minimal counterion sorption indicated that the sorbed surfactant molecules form a patchy monolayer on ZVI. Both PCE and trichloroethylene (TCE) degradation by ZVI with and without sorbed surfactant followed pseudo-first-order reaction kinetics. In general, the PCE degradation rate increases as the chain length of sorbed surfactant increases. Compared to unmodified ZVI, both apparent rate constants of PCE degradation and TCE accumulation increased by an order of magnitude when ZVI was modified by hexadecyltrimethylammonium. The rate of PCE degradation by ZVI modified to lower surfactant loading was relatively higher than that by ZVI modified to higher surfactant loading. It was speculated that longer chain length will result in better admicelle formations, and thus, promote PCE partition and increase PCE surface concentration or surface admicelle catalysis, while low surfactant loading makes significant amounts of surface reduction sites still available. The PCE reduction rate constants were not affected by solution ionic strength, but high initial solution pH, buffered by sodium carbonate and sodium bicarbonate, significantly reduced the PCE degradation rate.

Cations↗
PubMed2001

Folic acid supplements during pregnancy and risk of miscarriage.

BACKGROUND: Although taking supplements that contain 400 microg of folic acid before and during early pregnancy reduces a woman's risk for having a baby with a neural-tube defect (NTD), the effects of such supplements on other pregnancy outcomes remain unclear. We examined whether the use of such supplements affects the occurrence of miscarriage. METHODS: Participants were women in China who had taken part in a recent folic acid campaign to prevent NTDs and who had registered in this campaign before they became pregnant for the first time. We examined the risk for miscarriage among women who had confirmed pregnancies and who had or had not taken pills containing only 400 microg of folic acid before and during early pregnancy. RESULTS: The overall rate of miscarriage was 9.1% (2155/23806). The rates of miscarriage among women who had and had not taken folic acid pills before and during the first trimester were 9.0% and 9.3%, respectively (risk ratio 0.97 [95% CI 0.84-1.12]). The distributions of gestational age at pregnancy diagnosis and at miscarriage were similar for both groups of women. INTERPRETATION: In this population-based study of a cohort of women whose use of folic acid supplements while pregnant had been previously documented and who had been pregnant for the first time, we found no evidence that daily consumption of 400 microg of folic acid before and during early pregnancy influenced their risk for miscarriage.

Abortion, Spontaneous↗
PubMed2001

Visualizing postendocytic traffic of synaptic vesicles at hippocampal synapses.

We have investigated mechanisms in postendocytic processing of synaptic vesicles at hippocampal synapses, using synaptobrevin/vesicle-associated membrane protein (VAMP) tagged with variants of the green fluorescent protein. Following exocytosis, VAMP is retrieved at synaptic and adjoining axonal regions. Retrieved VAMP-containing vesicles return to synaptic vesicle clusters at a rate slower than endocytosis. Vesicles containing a different protein, synaptophysin, recluster at a similar rate, suggesting common vesicular intermediates for the two proteins. Activity prolongs the time taken by endocytosed vesicles to return to synapses. Exogenous calcium buffers slow endocytosis but have no additional effect on the time course of reclustering. In contrast, the protein kinase inhibitor staurosporine does not affect endocytosis but slows reclustering. Finally, since VAMP can move freely on surface membranes, sustained synaptic activity leads to mixing of this vesicular component between adjacent synapses.

Animals↗
PubMed2001

A mitogen-activated protein kinase-dependent signaling pathway in the activation of platelet integrin alpha IIbbeta3.

We have recently shown that the platelet integrin alpha(IIb)beta(3) is activated by von Willebrand factor (vWF) binding to its platelet receptor, glycoprotein Ib-IX (GPIb-IX), via the protein kinase G (PKG) signaling pathway. Here we show that GPIb-IX-mediated activation of integrin alpha(IIb)beta(3) is inhibited by dominant negative mutants of Raf-1 and MEK1 in a reconstituted integrin activation model in Chinese hamster ovary (CHO) cells and that the integrin-dependent platelet aggregation induced by either vWF or low dose thrombin is inhibited by MEK inhibitors PD98059 and U0126. Thus, mitogen-activated protein kinase (MAPK) pathway is important in GPIb-IX-dependent activation of platelet integrin alpha(IIb)beta(3). Furthermore, vWF binding to GPIb-IX induces phosphorylation of Thr-202/Tyr-204 of extracellular signal-regulated kinase 2 (ERK2). GPIb-IX-induced ERK2 phosphorylation is inhibited by PKG inhibitors and enhanced by overexpression of recombinant PKG. PKG activators also induce ERK phosphorylation, indicating that activation of MAPK pathway is downstream from PKG. Thus, our data delineate a novel integrin activation pathway in which ligand binding to GPIb-IX activates PKG that stimulates MAPK pathway, leading to integrin activation.

Animals↗