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X S He

Publications and source records attributed to X S He.

30 records · Page 2Linked to original sources
PubMed1993

Synthesis and biological evaluation of 1-[1-(2-benzo[b]thienyl)cyclohexyl]piperidine homologues at dopamine-uptake and phencyclidine- and sigma-binding sites.

Piperidine and cyclohexyl ring homologues of the high-affinity dopamine (DA) uptake inhibitor 1-[1-(2-benzo[b]thienyl)cyclohexyl]piperidine (BTCP, 3) were each prepared in four steps from the appropriate cycloalkanones. These compounds were tested for their ability to displace [3H]BTCP and [3H]cocaine and to inhibit [3H]DA uptake in rat striatal homogenates. The ratios IC50([3H]cocaine)/IC50([3H]BTCP) ranged from 62 for BTCP to 1.5 for 1-[2-(benzo[b]thienyl)-cyclopentylamine (17); cocaine gave a ratio of 0.6. This indicates that BTCP is the most selective of all the compounds tested for sites labeled by [3H]BTCP whereas cocaine is most selective for sites labeled by [3H]cocaine. The wide differences in the relative abilities of these compounds to displace [3H]BTCP and [3H]cocaine suggests that these two radioligands are labeling different sites on the transporter. In general, the compounds structurally related to BTCP exhibited greater selectivity for sites labeled by [3H]BTCP. However, several of the BTCP-related derivatives showed greater (compared with BTCP and cocaine) ability to displace [3H]cocaine. Most notably, 1-[1-(2-benzo[b]thienyl)cyclohexyl]pyrrolidine (7) exhibited a 3.4-fold greater affinity for these sites compared with BTCP and a 9-fold greater affinity at these sites than cocaine. Most of the BTCP homologues displayed greater ability to inhibit [3H]DA uptake in rat forebrain synaptosomes than cocaine. BTCP and 7 were the most potent of all the compounds tested in terms of their ability to inhibit uptake of [3H]DA. IC50 ratios for [3H]cocaine binding/[3H]DA uptake ranged from 0.47 for 1-[1-(2-benzo[b]thienyl)cyclopentyl]homopiperidine (11) to 8.8 for 1-(2-benzo[b]thienyl)cyclohexylamine (4). The importance of this ratio remains unclear in terms of identification of potential cocaine antagonists. As for BTCP, all of the compounds tested showed Ki values > 10,000 nM for displacement of [3H]TCP from rat brain homogenates. These compounds were able to displace the highly selective sigma receptor probe [3H]-(+)-pentazocine from guinea pig brain homogenates with Ki values ranging from 125 to 9170 nM. The significance of their sigma-binding activity in light of their dopaminergic properties is unclear. The diverse binding properties of these compounds at the DA-uptake site and their spectrum of inhibitory activities for [3H]DA uptake identifies them as a useful base for the development of subtype selective probes at this site. These compounds will allow further study of the structure and function of the "cocaine" receptor as well as the development of potential cocaine antagonists.

Animals↗
PubMed1993

Synthesis and binding characteristics of potential SPECT imaging agents for sigma-1 and sigma-2 binding sites.

2-, 3-, and 4-idophenyl derivatives of the high-affinity sigma ligand N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (1) were synthesized in two to four steps starting from N-methyl-2-(1-pyrrolidinyl)ethylamine. These compounds were evaluated for their capacity to label both sigma 1 and sigma 2 subtypes in vitro. sigma-1 binding affinity was determined by measuring competition with [3H]-(+)-pentazocine binding to guinea pig brain membranes while sigma 2 binding was evaluated through competition with [3H]DTG binding to rat liver membranes in the presence of excess dextrallorphan. The binding data revealed that N-[2-(3-iodophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (2) and N-[2-(4-iodophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine (3) displayed almost identical binding affinity at sigma 1 sites to the parent compound 1. This suggests that the 3- or 4-iodo group can effectively substitute for the 3,4-dichloro substituents of 1. In this series of compounds, Ki's at the sigma 1 site varied from 2.0 nM for N-(4-iodobenzyl)-N-methyl-2-(1-pyrrolidinyl)ethylamine (6) to 26.6 nM for N-(2-iodobenzyl)-N-methyl-2-(1-pyrrolidinyl)ethylamine (4). Ki's for sigma 2 site ranged from 8.1 nM for 1 to 220 nM for N-(3-bromobenzyl)-N-methyl-2-(1-pyrrolidinyl)ethylamine (11) while the sigma 2/sigma 1 ratio varied from 1.8 for 4 to 25 for 11. Comparing halogen substitution, the trend Cl = I > Br > F was observed for binding affinity at sigma 1 sites; no such trend was observed at sigma 2 sites. On the basis of the binding data, compounds 2 and 3 were selected for labeling with 123I. Thus, treatment of the corresponding 3- and 4-(tributylstannyl) intermediates (7 and 8) with Na123I in the presence of excess CH3CO3H furnished [123I]-2 and [123I]-3 in up to 70% radiochemical yield. Preliminary in vitro binding with [123I]-3 indicated up to 97% specific binding with guinea pig brain membranes.

Animals↗
PubMed1993

Pressure propagation in pulsatile flow through random microvascular networks.

A microvascular network with random dimensions of vessels is built on the basis of statistical analysis of conjunctival beds reported in the literature. Our objective is to develop a direct method of evaluating the statistics of the pulsatile hydrodynamic field starting from a priori statistics which mimic the large-scale heterogeneity of the network. The model consists of a symmetric diverging-converging dentritic network of ten levels of vessels, each level described by a truncated Gaussian distribution of vessel diameters and lengths. In each vascular segment, the pressure distribution is given by a diffusion equation with random parameters, while the blood flow rate depends linearly on the pressure gradient. The results are presented in terms of the mean value and standard deviation of the pressure and flow rate waveforms at two positions along the network. It is shown that the assumed statistical variation of vessel lengths results in flow rate deviations as high as 50 percent of the mean, while the corresponding effect of vessel diameter variation is much smaller. For a given pressure drop, the statistical variation of lengths increases the mean flow while the effect on the mean pressure distribution is negligible.

Blood Pressure↗
PubMed1992

Synthesis and biological evaluation of conformationally restricted 2-(1-pyrrolidinyl)-N-[2-(3,4-dichlorophenyl)ethyl]-N-methylethylenediam ines as sigma receptor ligands. 1. Pyrrolidine, piperidine, homopiperidine, and tetrahydroisoquinoline classes.

The synthesis and sigma receptor affinity of a series of conformationally restricted derivatives of 2-(1-pyrrolidinyl)-N-[2-(3,4-dichlorophenyl)ethyl]-N-methylethylenedi amine (1) is described. The pyrrolidinyl (or N,N-dialkyl),ethylenediamine,N-alkyl, and phenylethyl portions of this sigma receptor pharmacophore were restricted by its incorporation into 1,2-cyclohexanediamine-, pyrrolidine-, piperidine-, homopiperidine-, and tetrahydroisoquinoline-containing ligands. The sigma receptor binding affinities of these compounds were determined using [3H](+)-pentazocine in guinea pig brain homogenates. The synthesis of all but one class was achieved by acylation and alane reduction of the appropriate diamine precursors whose synthesis is also reported. sigma receptor affinities ranged from 1.34 nM for 6,7-dichloro-2-[2-(1-pyrrolidinyl)ethyl]tetrahydroisoquinoline (12) to 455 nM for (1R,2R)-trans-N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2- (1-pyrrolidinyl)cyclohexylamine [(-)-4]. In this displacement assay, (+)-pentazocine exhibited a Ki of 3.1 nM while DTG and haloperidol showed Ki values of 27.7 and 3.7 nM, respectively. The conformationally free parent compound 1 exhibited a Ki value of 2.1 nM. Comparison of both the sigma receptor affinities and nitrogen atom geometry of the compounds revealed that a gauche relation of the nitrogen atoms of cis-1,2-cyclohexanediamines is not imperative for high affinity as we had previously thought. It is highly likely that nitrogen lone pair orientations and steric factors on the aliphatic portions of these ligands play a major role in the sigma receptor binding of this pharmacophore.

Animals↗
PubMed1991

Expression of a full-length nonstructural protein NS1 of bluetongue virus serotype 17 in Escherichia coli.

The relative abundance of the nonstructural protein NS1 in bluetongue virus (BTV)-infected cells, the existence of NS1 in the BTV particles and the highly conserved NS1 gene among BTV serotypes indicate the diagnostic potential of using NS1 in detecting BTV infections. In this study a NS1 gene was expressed with the T7 RNA polymerase expression system to produce a full-length NS1 protein. Sheep anti-NS1 antibodies were raised with the E. coli-produced NS1 and used to show that the NS1 proteins of the five BTV serotypes in the Unites States were immunologically indistinguishable.

Animals↗
PubMed1991

Localization of a new promoter, P5, in the sigA operon of Bacillus subtilis and its regulation in some spo mutant strains.

The sigA operon of Bacillus subtilis is transcribed from at least two SigA and two SigH promoters. Primer extension and promoter probe analyses have localized a fifth promoter, P5, that is active only at later sporulation stages (T3 to T5). Mutations in the genes for the sigma factors SigG, SigK, SigH, and SigE do not block transcription from P5. The expression from P5 is blocked or severely reduced in spo0A, spo0B, spo0E, and spo0K mutants.

Bacillus subtilis↗
PubMed1990

[A novel type of phase variation regarding integrated and free states of plasmid pFDX163 in Bacillus stearothermophilus CU21].

pFDX1 is a recombinant plasmid which carries a foreign gene xylE. By selecting for kanamycin-resistant mutants of Bacillus stearothermophilus CU21(pFDX1) at higher temperature, a variant strain CU21-163 was obtained. This strain harbors a mutant plasmid pFDX163, which was formed by insertion of a 2.0kb H-fragment from the CU21 genome onto the plasmid pFDX1. pFDX163 was supposed to be integrated into the CU21 chromosome via homologous recombination of H-fragments. The CU21-163 strain consists of two cell types, i.e. y-cell and w-cell. The expression level of xylE gene in the former is higher than that in the latter. The progeny of a y-cell always contains some w-cells, while that of a w-cell contains y-cells. This is supposed to be due to a phase variation of CU21-163. Analysis on the amount of free and integrated plasmid DNA in different DNA samples of CU21-163 cells allows us to draw the conclusion that there are both free and integrated plasmids in the y-cells, whereas only integrated ones in the w-cells.

Blotting, Southern↗
PubMed1990

[Expression of xylE gene in Bacillus stearothermophilus].

Using the gene expression vector pFDC11 for Bacillus stearothermophilus CU21, a recombinant plasmid pFDX1 was constructed, which carries the Pseudomonas-derived xylE gene coding for Catechol 2,3-dioxygenase (CatO2ase). CatO2ase activity can be detected from CU21 (pFDX1) cells grown at 48 degrees C. This result indicates that the promoterless xylE gene can be expressed in a thermophilic host under the direction of a promoter from a thermophilic bacterium. By selecting Kmr mutants at elevated growth temperature, a segregant CU21-161 was obtained, the xylE gene expression of which at 55 degrees C and 60 degrees C was much higher than that of the parental strain. A method for CatO2ase assay with suspension of intact cells was also reported in this paper.

Catechol 2,3-Dioxygenase↗
PubMed1989

[A low copy number mutant of pUC-derived plasmid].

A low copy number mutant of ColE1-like plasmid of Escherichia coli was reported in this paper. The recombinant plasmid pPGVT3 derived from the vector pUC4 was unstable in the E. coli host strain DF2145. No transformant could be obtained at 40 degrees C when DF2145 was transformed with pPGVT3. By in vitro mutagenesis of pPGVT3 plasmid DNA with hydroxylamine which induces point mutations, a mutant plasmid pPGVT3HA was obtained, which was stable in DE2145. The mutation site was localized within the pUC moiety of pPGVT3HA. The copy number of the mutated pUC vector and its derivatives were found to be reduced. The effect of low copy number mutation on the stability of the recombinant plasmids was discussed.

Escherichia coli↗
PubMedDate not supplied

Xenobiotic considerations for the development of autoimmune liver diseases: bad genes and bad luck.

The etiologic origins of autoimmune disease remain an enigma. Although considerable information on the mechanisms of immunopathology has been acquired, in part from murine models, such mechanisms have yet to be substantiated in human autoimmune disease. This absence of validation is especially true for organ-specific diseases like those affecting the liver. In this review we focus on the putative role of xenobiotics as inducing agents for autoimmune liver pathology. In particular, we discuss the autoantibody immune response, the humoral hallmark of autoimmune disease, as well as cellular immune responses. We believe that exposure to environmental factors, namely xenobiotics, is the initiating straw that breaks the camel's back, leading to the loss of tolerance to self proteins in genetically susceptible hosts. The end result is a perpetuating process that is determined by the governing features of the genetics of the host and by exposure to the inciting environmental agent. Interestingly, the liver, an organ that plays a major role in immune tolerance, can itself become the target of autoreactivity and immune destruction.

Antibody Formation↗