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Biomedical subjects

Q Li

Publications and source records attributed to Q Li.

At least 343 records · Page 19Linked to original sources
PubMed1999

Enantiospecific synthesis of 3-fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-1,2,3,4-tetrahydroisoquinolines as selective inhibitors of phenylethanolamine N-methyltransferase versus the alpha(2)-adrenoceptor.

An enantiospecific method was developed for the synthesis of 3-fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-7-substituted-1,2,3,4-tetrahydroisoquinolines (THIQs) from phenylalanine. Biochemical evaluation of the enantiomers of these compounds at both PNMT and the alpha(2)-adrenoceptor indicates that both sites display similar stereoselectivity. Overall the R-enantiomer was usually the more potent enantiomer at both PNMT and the alpha(2)-adrenoceptor for these 3-fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-THIQs. The one exception is 3-hydroxymethyl-7-nitro-THIQ (9), which was found to display the opposite stereoselectivity at the alpha(2)-adrenoceptor. A comparison of the PNMT inhibitory potency of the enantiomers of these 3-fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-THIQs indicates that all of the 3-substituted-THIQs displayed similar inhibitory potency for PNMT. However, the nature of the 3-substituent was found to have a major effect on the alpha(2)-adrenoceptor affinity of these compounds with the 3-hydroxymethyl- and 3-fluoromethyl-THIQs having the highest affinity and THIQs containing the 3-chloromethyl moiety the least. Compounds R-3-fluoromethyl-7-cyano-THIQ (R-12) and R-3-fluoromethyl-7-N-(4-chlorophenyl)aminosulfonyl-THIQ (R-13) and both enantiomers of 3-chloromethyl-7-nitro-THIQ (R- and S-30) are the most selective inhibitors in this study and display selectivities (alpha(2)-adrenoceptor K(i)/PNMT K(i)) greater than 200. These compounds give important insight into the steric and stereochemical preferences of both PNMT and the alpha(2)-adrenoceptor, which should assist in the development of new PNMT inhibitors.

Adrenergic alpha-Antagonists↗
PubMed1999

Structural analysis and mapping of DNase I hypersensitivity of HS5 of the beta-globin locus control region.

The beta-globin locus control region (LCR) is a cis regulatory element that is located in the 5' part of the locus and confers high-level erythroid lineage-specific and position-independent expression of the globin genes. The LCR is composed of five DNase I hypersensitive sites (HSs), four of which are formed in erythroid cells. The function of the 5'-most site, HS5, remains unknown. To gain insights into its function, mouse HS5 was cloned and sequenced. Comparison of the HS5 sequences of mouse, human, and galago revealed two extensively conserved regions, designated HS5A and HS5B. DNase I hypersensitivity mapping revealed that two hypersensitive sites are located within the HS5A region (designated HS5A(major) and HS5A(minor)), and two are located within the HS5B region (HS5B(major), HS5B(minor)). The positions of each of these HSs colocalize with either GATA-1 or Ap1/NF-E2 motifs, suggesting that these protein binding sites are implicated in the formation of HS5. Gel retardation assays indicated that the Ap1/NF-E2 motifs identified in murine HS5A and HS5B interact with NF-E2 or similar proteins. Studies of primary murine cells showed that HS5 is formed in all hemopoietic tissues tested (fetal liver, adult thymus, and spleen), indicating that this HS is not erythroid lineage specific. HS5 was detected in murine brain but not in murine kidney or adult liver, suggesting that this site is not ubiquitous. The presence of GATA-1 and NF-E2 motifs (which are common features of the DNase I hypersensitive sites of the LCR) suggests that the HS5 is organized in a manner similar to that of the other HSs. Taken together, our results suggest that HS5 is an inherent component of the beta-globin locus control region.

Animals↗
PubMed1999

Metal-ion affinity and specificity in EF-hand proteins: coordination geometry and domain plasticity in parvalbumin.

BACKGROUND: The EF-hand family is a large set of Ca(2+)-binding proteins that contain characteristic helix-loop-helix binding motifs that are highly conserved in sequence. Members of this family include parvalbumin and many prominent regulatory proteins such as calmodulin and troponin C. EF-hand proteins are involved in a variety of physiological processes including cell-cycle regulation, second messenger production, muscle contraction, microtubule organization and vision. RESULTS: We have determined the structures of parvalbumin mutants designed to explore the role of the last coordinating residue of the Ca(2+)-binding loop. An E101D substitution has been made in the parvalbumin EF site. The substitution decreases the Ca(2+)-binding affinity 100-fold and increases the Mg(2+)-binding affinity 10-fold. Both the Ca(2+)- and Mg(2+)-bound structures have been determined, and a structural basis has been proposed for the metal-ion-binding properties. CONCLUSIONS: The E101D mutation does not affect the Mg(2+) coordination geometry of the binding loop, but it does pull the F helix 1.1 A towards the loop. The E101D-Ca(2+) structure reveals that this mutant cannot obtain the sevenfold coordination preferred by Ca(2+), presumably because of strain limits imposed by tertiary structure. Analysis of these results relative to previously reported structural information supports a model wherein the characteristics of the last coordinating residue and the plasticity of the Ca(2+)-binding loop delimit the allowable geometries for the coordinating sphere.

Animals↗
PubMed1999

p300 stimulates transcription instigated by ligand-bound thyroid hormone receptor at a step subsequent to chromatin disruption.

We investigate the role of the transcriptional coactivator p300 in gene activation by thyroid hormone receptor (TR) on addition of ligand. The ligand-bound TR targets chromatin disruption independently of gene activation. Exogenous p300 facilitates transcription from a disrupted chromatin template, but does not itself disrupt chromatin in the presence or absence of ligand-bound receptor. Nevertheless, the acetyltransferase activity of p300 is required to facilitate transcription from a disrupted chromatin template. Expression of E1A prevents aspects of chromatin remodeling and transcriptional activation dependent on TR and p300. E1A selectively inhibits the acetylation of non-histone substrates. E1A does not prevent the assembly of a DNase I-hypersensitive site induced by TR, but does inhibit topological alterations and the loss of canonical nucleosome arrays dependent on the addition of ligand. Mutants of E1A incompetent for interaction with p300 partially inhibit chromatin disruption but still allow nuclear receptors to activate transcription. We conclude that p300 has no essential role in chromatin disruption, but makes use of acetyltransferase activity to stimulate transcription at a subsequent step.

Acetyltransferases↗
PubMed1999

Synthesis and antimicrobial activity of 4H-4-oxoquinolizine derivatives: consequences of structural modification at the C-8 position.

The antibacterial 4H-4-oxoquinolizines were introduced recently to overcome bacterial resistance to fluoroquinolones. They exhibit potent antibacterial activity against Gram-positive, Gram-negative, and anaerobic organisms and are highly active against some quinolone-resistant bacteria including quinolone-resistant MRSA. Preliminary studies indicated that oxoquinolizines possess distinct activity and toxicity profiles as compared with their parent quinolones. In order to develop a potent antibacterial agent with the desired spectrum of activity, good tolerability, and balanced pharmacokinetic profile, we synthesized and evaluated a series of oxoquinolizines with various substituents at the C-8 position. Most compounds tested in this study demonstrated better activity against Gram-positive bacteria than ciprofloxacin and exhibited good susceptibility against ciprofloxacin- and methicillin-resistant S. aureus. While maintaining potent in vitro activity, several compounds showed improved in vivo efficacy over ABT-719 as indicated by the mouse protection test. As an example, the oral ED(50) values for the cis-3-amino-4-methylpiperidine analogue 3ss against S. aureus NCTC 10649M, S. pneumoniae ATCC 6303, and E. coli JUHL were 0. 8, 2.0, and 1.4 mg/kg, compared to 3.0, 10.0, and 8.3 mg/kg for ABT-719. The current study revealed that the steric and electronic environment, conformation, and absolute stereochemistry of the C-8 group are very important to the antibacterial profiles. Structural modifications of the C-8 group provide a useful means to improve the antibacterial activities, physicochemical properties, and pharmacokinetic profiles. Manipulation of the C-8 group also allows us to generate analogues with the desired spectrum of activity, such as analogues that are selective against respiratory pathogens.

Animals↗
PubMed1999

Analysis of beta-N-oxalyl-L-alpha,beta-diaminopropionic acid and homoarginine in Lathyrus sativus by capillary zone electrophoresis.

A simple capillary zone electrophoresis (CZE) method has been developed for the simultaneous quantitative determination of beta-N-oxalyl-L-alpha,beta-diaminopropionic acid (beta-ODAP) and homoarginine in Lathyrus sativus (LS; grass pea). A new Na2B4O7-Na2SO4 run buffer was used and the pH was 9.20, contents of beta-ODAP and homoarginine in crude extracts of LS plant material were determined with this method, the RSDs of peak areas of beta-ODAP and homoarginine were 2.62% and 3.61%, respectively. It was found that the equilibrium concentration ratio of alpha- and beta-ODAP decreased from 34.5/65.5 to 28.6/71.4 when the pH of the solution increased from pH 3.0 to pH 11.0.

Amino Acids, Diamino↗
PubMed1999

Evidence for quantum critical behavior in the optimally doped cuprate Bi(2)Sr(2)CaCu(2)O(8+delta)

The photoemission line shapes of the optimally doped cuprate Bi(2)Sr(2)CaCu(2)O(8+delta) were studied in the direction of a node in the superconducting order parameter by means of very high resolution photoemission spectroscopy. The peak width or inverse lifetime of the excitation displays a linear temperature dependence, independent of binding energy, for small energies, and a linear energy dependence, independent of temperature, for large binding energies. This behavior is unaffected by the superconducting transition, which is an indication that the nodal states play no role in the superconductivity. Temperature-dependent scaling suggests that the system displays quantum critical behavior.

Journal Article↗
PubMed1999

Acute immunotoxicity of p-chloronitrobenzene in mice: II. Effect of p-chloronitrobenzene on the immunophenotype of murine splenocytes determined by flow cytometry.

To evaluate the immunotoxicity of p-chloronitrobenzene (p-CNB), we investigated its effect on the immunophenotype of murine splenocytes. BDF1 male mice were randomly divided into exposed and control groups: the exposed group received p-CNB at 300 mg/kg dissolved in olive oil, while the control group received only olive oil, by a single intraperitoneal (i.p.) or subcutaneous (s.c.) injection. On days 3, 5, 7, and 10 after the injection, splenocytes were harvested from both groups, and the following cell phenotypes were quantified by flow cytometry: (1) B cells (CD45R/B220); (2) T cells (CD3e); (3) T-cell subsets (CD4 and CD8a); (4) natural killer (NK) cells (NK-1.1); (5) macrophages (CD11b; Mac-1); (6) nucleated erythrocytes (Ter-119); and (7) dead cells with propidium iodide (PI). The percentages and numbers of B, T, subsets of T (CD4 and CD8), and NK cells in the exposed mice significantly decreased as compared with the respective control. On the other hand, macrophages (Mac-1+ cells), nucleated erythrocytes (Ter-119+ cells), and dead cells in the exposed mice markedly increased as compared with the respective control after i.p. injection of p-CNB. The above findings indicate that p-CNB has an immunotoxic effect on mice.

Animals↗
PubMed1999

Synthesis and biochemical evaluation of 3-fluoromethyl-1,2,3, 4-tetrahydroisoquinolines as selective inhibitors of phenylethanolamine N-methyltransferase versus the alpha(2)-adrenoceptor.

A series of 3-fluoromethyl-1,2,3,4-tetrahydroisoquinolines (3-fluoromethyl-THIQs) was proposed, and their phenylethanolamine N-methyltransferase (PNMT) and alpha(2)-adrenoceptor affinities were predicted through the use of comparative molecular field analysis (CoMFA) models. These compounds were synthesized and evaluated for affinity at PNMT and the alpha(2)-adrenoceptor. It was discovered that these compounds are some of the most selective inhibitors of PNMT versus the alpha(2)-adrenoceptor known. To determine the ability of these compounds to penetrate the blood-brain barrier (BBB), a series of THIQs possessing a variety of calculated partition coefficients (Clog P) were assayed using an in vitro BBB model. This study found a good correlation between lipophilicity (Clog P) and BBB permeability, which indicated that THIQs possessing Clog P values of at least 0.13-0.57 should have some penetration into the brain. Two compounds [3-fluoromethyl-7-N-(4-chlorophenyl)aminosulfonyl-THIQ (18) and 3-fluoromethyl-7-cyano-THIQ (20)] possess calculated partition coefficients greater than 0.57 and display selectivities (alpha(2)-adrenoceptor K(i)/PNMT K(i)) greater than 200 and thus represent promising leads in the development of highly selective inhibitors of PNMT with the ability to penetrate the BBB.

Adrenal Glands↗
PubMed1999

Synthesis and evaluation of 3-trifluoromethyl-7-substituted-1,2,3, 4-tetrahydroisoquinolines as selective inhibitors of phenylethanolamine N-methyltransferase versus the alpha(2)-adrenoceptor.

A series of 3-trifluoromethyl-1,2,3,4-tetrahydroisoquinolines was synthesized and evaluated as inhibitors of phenylethanolamine N-methyltransferase (PNMT) and as inhibitors of the binding of clonidine at the alpha(2)-adrenoceptor. These compounds were found to be selective inhibitors of PNMT due to their decreased affinity for the alpha(2)-adrenoceptor, which was attributed to steric bulk intolerance around the 3-position of 1,2,3,4-tetrahydroisoquinoline (THIQ) at the alpha(2)-adrenoceptor and to the decreased pK(a) of the THIQ amine due to the 3-trifluoromethyl moiety. Overall, these compounds displayed less affinity for PNMT compared to previously studied THIQ-type inhibitors, except for 16 which was found to have good affinity for PNMT (PNMT K(i) = 0.52 microM). Compounds 14 and 16 proved to be the most selective inhibitors in this small series of compounds and are some of the most selective inhibitors of PNMT known (14, selectivity alpha(2) K(i)/PNMT K(i) = 700; 16, selectivity alpha(2) K(i)/PNMT K(i) > 1900). Compounds 14 and 16 are also quite lipophilic due to the 3-trifluoromethyl moiety and represent promising new leads for the development of new highly selective inhibitors of PNMT, which should be sufficiently lipophilic to penetrate the blood-brain barrier.

Adrenergic alpha-Agonists↗
PubMed1999

DNA damage by copper(II) complexes: coordination-structural dependence of reactivities.

A variety of copper complexes with different structural features have been shown to bind double-helical DNA with binding constants of 10(4)-10(7) M-1 and to promote double-strand DNA damage upon reductant/H2O2 activation. The interaction of the Cu complex with DNA results in hyperchromism and shifts to longer wavelengths of the strongest transitions in the Cu complexes, as well as striking hypochromism or hyperchromism of DNA absorption at 260 nm. In the presence of DMPO as the spin trap, the solution of each copper complex exhibits typical four-line ESR spectra of the hydroxyl radical by adding 2-mercaptoethanol and H2O2 to the solution. Quantitation by 2-deoxy-D-ribose shows that the competence of hydroxyl radical generation by the copper complexes upon reductant and H2O2 activation decreases in order, that is, Cu(HTCD)(2+)-Cu(Im)4Cl2-Cu(IDB) (NO3)2 > Cu(IDB)Cl2 > Cu(IDBt)Cl2. The copper complex-mediated hydroxyl radical, a powerful oxidant that attacks the adjacent DNA, is responsible for the DNA oxidative damage. The lambda DNA damage chemistry illustrates that the competence and selectivity of double-strand lambda DNA damage by the copper complexes are dependent on their geometric structures and types of ligands. The decreasing order of the DNA damage capacity by the present complexes is Cu(Im)4Cl2-Cu(IDB)-(NO3)2 > Cu(HTCD)2+ > Cu(IDBt)Cl2 > Cu(IDB)Cl2.

Animals↗
PubMed1999

Activation of the 9E3/cCAF chemokine by phorbol esters occurs via multiple signal transduction pathways that converge to MEK1/ERK2 and activate the Elk1 transcription factor.

Using primary fibroblasts in culture, we have investigated the signal transduction mechanisms by which phorbol esters, a class of tumor promoters, activate the 9E3 gene and its chemokine product the chicken chemotactic and angiogenic factor. This gene is highly stimulated by phorbol 12,13-dibutyrate (PDBu) via three pathways: (i) a small contribution through protein kinase C (the commonly recognized pathway for these tumor promoters), (ii) a contribution involving tyrosine kinases, and (iii) a larger contribution via pathways that can be interrupted by dexamethasone. All three of these pathways converge into the mitogen-activated protein kinases, MEK1/ERK2. Using a luciferase reporter system, we show that although both the AP-1 and PDRIIkB (a NFkappaB-like factor in chickens) response elements are capable of activation in these normal cells, regions of the 9E3 promoter containing them are unresponsive to PDBu stimulation. In contrast, we show for the first time that activation by PDBu occurs through a segment of the promoter containing Elk1 response elements; deletion and mutation of these elements abrogates 9E3/chicken chemotactic and angiogenic factor expression. Electrophoretic mobility shift assays and functional studies using PathDetect systems show that stimulation of the cells by phorbol esters leads to activation of the Elk1 transcription factor, which binds to its element in the 9E3 promoter.

Animals↗
PubMed1999

Methylation and silencing of the Thrombospondin-1 promoter in human cancer.

Neovascularization is a common feature of many human cancers, but relatively few molecular defects have been demonstrated in genes regulating angiogenesis. Decreased expression of Thrombospondin-1 (THBS1), a P53 and Rb regulated angiogenesis inhibitor, has been observed in some human tumors, including glioblastoma multiforme (GBM). To study whether methylation-associated inactivation is involved in down-regulating THBS1 expression in cancer, we analysed the methylation status of THBS1 in several cell lines and primary tumors. Three cell lines (RKO, CEM and RAJI) were completely methylated at several CpG sites within the THBS1 5' CpG island, and had no detectable expression by RT-PCR. THBS1 expression was readily reactivated using the methylation-inhibitor 5-deoxy-azacytidine in all three lines. Furthermore, THBS1 methylation was present in 33% (14/42) of primary GBMs. Thus, de novo methylation may serve as a potential way to inactivate THBS1 expression in human neoplasms.

Brain Neoplasms↗
PubMed1999

Tradescantia bioassays for the determination of genotoxicity of water in the Panlong River, Kunming, People's Republic of China.

The Panlong river passes through Kunming City and receives a large quantity of municipal sewage and wastewater from industrial effluent. Along the river, 20 sites were selected to collect water samples to assess the genotoxicity using two Tradescantia assays, the micronucleus (Trad-MCN) and the stamen-hair-mutation (Trad-SHM) assays. The lowest frequencies in the Trad-MCN assay and the Trad-SHM assay are 3.19 MCN/100 tetrads and 1.32 M/1000 stamen hairs, respectively. In the water samples obtained from the Songhua Reservoir, the MCN frequencies and mutation rates are not statistically significantly different from the data found for the negative control (2.49 MCN/100 tetrads and 0.71 M/1000 stamen hairs). Among the other water samples, 19 in Trad-MCN assay and 17 in Trad-SHM assay show significantly higher genotoxicity than the control. The highest genotoxicity was in samples No. 19 for the MCN assay (8.73 MCN/100 cells), over three times higher than the negative control, and in sample No. 11 for the SHM assay (4.30 M/1000), six times higher than the negative control, and were about the same as for the positive control (10.0 mg/l NaN3, 9.28 MCN/100 tetrads and 7.44 SHM/1000 stamen hairs), respectively. The peak frequencies for the Trad-MCN assays were observed in the water samples obtained from the sites that were near industrial and municipal wastewater that ran into the river as effluent. In general, the frequency of MCN and SHM mutations increased where the river passed through Kunming. The Trad-MCN assay seemed more sensitive than that of the Trad-SHM assay in detecting genotoxicity of the river water pollution.

Biological Assay↗
PubMed1999

Surface Characterization of NH4PAA-Stabilized Zirconia Suspensions.

Ammonium polyacrylate (NH4PAA) stabilized yttria-doped (3 mol%) tetragonal zirconia (Y-TZP) aqueous suspensions were prepared. Surface chemistry of the suspension was investigated by a variety of techniques. Isotherm adsorption of dispersants on ZrO2 particles demonstrated an optimum coverage of 0.25 mg/g at pH 10. The isoelectric point (IEP) of ZrO2 suspensions was shifted to low pH regions with the presence of NH4PAA. Scanning auger microscopy (SAM) and FTIR and UV spectrophotometry were employed to determine the surface properties of ZrO2 suspensions, which confirmed that the surface Zr-O bonds were affected by the adsorbed polymers. Atomic force microscopy (AFM) analysis indicated that the interactions between particles were evidently influenced by polymer dispersants. Copyright 1999 Academic Press.

Journal Article↗
PubMed1999

Enhanced antitumor effects of bone marrow transplantation in combination with fibroblast-mediated IL-2 and IL-3 gene therapy.

BACKGROUND: Bone marrow transplantation (BMT) and gene therapy are potent approaches to the recovery of bone marrow depression and induction of antitumor immunity after chemotherapy for the treatment of malignancies. In the present study, enhanced antitumor effect of BMT in combination with fibroblast-mediated interleukin (IL)-2 and IL-3 gene therapy was observed in tumor-bearing mice after chemotherapy. METHODS: BALB/c mice were inoculated s.c. with J558L plasmacytoma cells and injected i.p. with cyclophosphamide 300 mg/kg 3 days later. 24 hours after chemotherapy syngeneic bone marrow cells in combination with NIH3T3 fibroblast cells engineered to produce IL-2 (NIH3T3-IL-2) and/or NIH3T3 cells engineered to produce IL-3 (NIH3T3-IL-3) were implanted into the tumor-bearing mice. RESULTS: BMT in combination with implantation of either NIH3T3-IL-2 or NIH3T3-IL-3 cells exerted significant inhibition on the growth of J558L tumors and prolonged the survival period of the tumor-bearing mice as compared with the treatments with Hanks solution, BMT alone, or BMT plus implantation of NIH3T3 cells transduced with Neo gene. Synergistic antitumor effect was observed in mice after combined BMT and cytokine gene therapy. The cytotoxicities of natural killer cells, cytotoxic T lymphocytes, and macrophages in mice increased markedly after the combined treatment. Recovery of CFU-GM, CFU-MK and CFU-E formation in mice after combined therapy was accelerated obviously in mice after combined therapy. CONCLUSIONS: BMT in combination with fibroblast-mediated IL-2 and IL-3 gene therapy elicited augmented antitumor effects synergistically in tumor-bearing mice after chemotherapy mainly through induction of antitumor immune response and accelerated recovery of hematopoiesis.

3T3 Cells↗
PubMed1999

IKK1-deficient mice exhibit abnormal development of skin and skeleton.

IkappaB kinases (IKKs) IKK1 and IKK2 are two putative IkappaBalpha kinases involved in NF-kappaB activation. To examine the in vivo functions of IKK1, we generated IKK1-deficient mice. The mutant mice are perinatally lethal and exhibit a wide range of developmental defects. Newborn mutant mice have shiny, taut, and sticky skin without whiskers. Histological analysis shows thicker epidermis, which is unable to differentiate. Limbs and tail are wrapped inside the skin and do not extend properly out of the body trunk. Skeleton staining reveals a cleft secondary palate, split sternebra 6, and deformed incisors. NF-kappaB activation mediated by TNFalpha and IL-1 is diminished in IKK1-deficient mouse embryonic fibroblast (MEF) cells. The IKK complex in the absence of IKK1 is capable of phosphorylating IkappaBalpha and IkappaBbeta in vitro. Our results support a role for IKK1 in NF-kappaB activation and uncover its involvement in skin and skeleton development. We conclude further that the two related kinases IKK1 and IKK2 have distinct functions and can not be substituted for each other's functions.

Animals↗