Biomedical subjects

A Zhang

Publications and source records attributed to A Zhang.

At least 145 records · Page 8Linked to original sources

PubMed1995

Human obesity: from lipid abnormalities to lipid oxidation.

The obese state has been recognized to accentuate the known risk factors for atherosclerotic disease as dyslipidemia, hypertension, glucose intolerance and insulin resistance. Among other risk factors, obesity is characterized by a series of lipid disturbances, such as hypercholesterolemia, high fasting (and postprandial) triglyceride levels, low HDL cholesterol, high apolipoprotein B, high small dense lipoprotein particles and alterations of serum and tissue LPL-activity. Although obesity is associated with such cluster of lipid abnormalities, these factors do not explain the complete process of atherogenesis in the obese subject. Other risk factors belonging to the polymetabolic syndrome-cluster, insulin resistance, hypertension, fibrinogen, add substantial but not full explanation to the atherothrombotic process. Over the last decade, a series of excellent studies have provided the background for a more indepth mechanism of atherosclerosis; the role of lipid peroxidation in particular has been one of the focuses of this current research. There exists a lot of evidence suggesting a major role for oxidized LDL and VLDL particles in the pathogenesis of atherosclerosis. Although obesity is characterized by dyslipidemia, less is known about the oxidation capacity of lipoproteins in obese subjects. We measured the oxidizability in vitro in 21 premenopausal women and compared them to 18 age-matched controls. The oxidizability of the non-HDL fraction is evaluated by measuring the fluorescence and thiobarbituric acid reactive substances (TBARS: MDA nM/mg non-HDL) at different time intervals of incubation. TBARS formation increased linearly with the increase of lipids both in non-obese and obese subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Apolipoproteins B↗

PubMed1994

Design and construction of rhinovirus chimeras incorporating immunogens from polio, influenza, and human immunodeficiency viruses.

This paper describes the design and construction of chimeric human rhinoviruses that contain immunogenic regions from other pathogens as part of their surface coat proteins. Segments encoding the poliovirus 3 Sabin VP1 and VP2 proteins, the influenza hemagglutinin (HA) glycoprotein, and the human immunodeficiency virus gp120 surface and gp41 transmembrane glycoproteins were inserted into a full-length clone of human rhinovirus 14 (HRV14) at regions corresponding to neutralizing immunogenic sites IA (NIm-IA) and II (NIm-II). Of 12 chimeric constructs described, 3 produced viable virus. An HRV14 chimeric virus containing five amino acids of influenza HA (corresponding to 300 A2 of solvent-accessible surface area) had wild-type HRV14 growth characteristics and was neutralized by four of four anti-influenza HA antisera with reciprocal neutralizing titers ranging from 180 to 330. However, antisera raised in two guinea pigs against the HRV14:influenza HA chimera did not show significant neutralization of relevant strains of influenza. These results are the first to demonstrate the feasibility of making viable chimeras of human rhinoviruses displaying heterologous immunogens.

Amino Acid Sequence↗

PubMed1994

A rapid and simple method for measuring the susceptibility of low-density-lipoprotein and very-low-density-lipoprotein to copper-catalyzed oxidation.

Much evidence has accumulated to suggest a role for the oxidation of low-density-lipoprotein (LDL) and very low-density-lipoprotein (VLDL) in the pathogenesis of atherosclerosis. The susceptibility of lipoprotein to copper-catalyzed oxidation is often used to evaluate its oxidizability. A method was developed which isolates the non-high-density lipoprotein (non-HDL) fraction and removes EDTA by a dextran-magnesium precipitation method. The oxidizability of this fraction is evaluated by monitoring the fluorescence and measuring thiobarbituric acid reactive substances (TBARS) at different intervals of incubation. Those parameters reflect apolipoprotein B (apo B) modification and lipid degradation during LDL and VLDL oxidation. Our assay is sensitive enough to study factors which can influence the oxidizability of LDL and VLDL. The method is simple, rapid and can be easily conducted in a routine laboratory.

Catalysis↗

PubMed1994

Use of random systematic mutagenesis to generate viable human rhinovirus 14 chimeras displaying human immunodeficiency virus type 1 V3 loop sequences.

Random systematic mutagenesis was used to generate a library of human rhinovirus 14 chimeras that each display a segment from the V3 loop of human immunodeficiency virus type 1. The sequence XXIGPGRAXX, where X could be any of the 20 amino acids, was inserted at the neutralizing immunogenic site II of human rhinovirus 14 between VP2 residues 159 and 160. Twenty-five unique chimeric viruses were isolated, and the identity of their randomized residues was determined. A nonrandom amino acid distribution that may reflect structural requirements for viability was observed at the randomized positions. Fifteen of 25 chimeras were neutralized by one or more of a panel of four anti-human immunodeficiency virus type 1 V3 loop antibody preparations, indicating that antigenicity had been successfully transplanted. Libraries of chimeric viruses produced by using the techniques described may be a source of vaccines and other immunotherapeutic reagents. The random systematic mutagenesis methodology described should be generally useful for the rapid transplantation of foreign sequences into viral coat and other proteins to produce libraries containing members with the desired properties.

Amino Acid Sequence↗

PubMed1994

Role of excitatory amino acids in regulation of rat pial microvasculature.

Recently, attention has been drawn to the possibility that excitatory amino acids (EAAs) may play an important role in the pathogenesis of hypoxic-ischemic neuronal injury. Exaggerated release of EAAs and excessive stimulation of N-methyl-D-aspartate (NMDA) receptors and other EAA receptors have been suggested to contribute to neuronal death in ischemia and anoxia. A number of in vitro and in vivo experimental studies have shown that EAA-receptor antagonists exert a protective effect on the brain after cerebral ischemia. Because neurons are in close apposition to small intracerebral vessels, synaptically released EAAs might also regulate small blood vessel function. With the use of quantitative television microscopic observations, in vivo studies were undertaken on pial arterioles of rats. Perivascular administration of cumulative doses (10(-7)-10(-2) M) of L-glycine, L-glutamate, L-aspartate, and NMDA on the pial microvessels resulted in concentration-dependent constriction of pial arterioles (5-30% decreases in diameter) and cerebrovasospasm; the relative order of potency was aspartate > NMDA > glycine > glutamate. High concentrations of EAAs often resulted in rupture of postcapillary venules. No amine or opiate antagonist or cyclooxygenase inhibitor prevented or attenuated the effects of these putative EAAs. EAA-induced constriction and spasm of pial arterioles as well as rupture of venules could, however, be blocked by the noncompetitive NMDA-receptor antagonist MK-801 and by Mg2+. MK-801 also produced a concentration-dependent relaxation on normal pial arterioles. These results are compatible with the idea that a specific NMDA-receptor complex (RC) exists in rat cortical microvessels, which subserves vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗

PubMed1994

Libraries of human rhinovirus-based HIV vaccines generated using random systematic mutagenesis.

Human rhinovirus (HRV), an immunogenic and relatively nonpathogenic virus, has been engineered to display HIV-1 immunogens with the intent of developing a vaccine against AIDS. HIV immunogens from the V3 loop have been placed into the neutralizing immunogenic (NIm) sites on the surface of HRV14 naturally recognized by the immune system. To increase the likelihood of recovering viable chimeras displaying the transplanted HIV-1 V3 loop sequences in conformations that mimic that of HIV, we have used random systematic mutagenesis to produce libraries of chimeric HRV14 in which the transplanted epitope from HIV-1 is flanked by one or more randomized amino acid residues. This allows the HIV epitope to be accommodated into the HRV coat proteins in many conformations, some of which should result in the production of viable, immunogenic hybrids. Using this approach, a library containing the sequence XXIGPGRAXX, where X could be any of the 20 amino acids, was generated. A nonrandom distribution of residues was found at the randomized positions, which may be a reflection of the structural requirements for viability. A subset of chimeras was identified that reacted with neutralizing anti-HIV-1 V3 loop antibody preparations, indicating that the antigenicity of the epitopes had been transplanted. Another chimeric virus library was designed to reflect the natural diversity of the V3 loop by incorporating amino acids at frequencies similar to those found among naturally occurring isolates of HIV-1. Powerful selection techniques utilizing anti-HIV-1 V3 loop neutralizing antibodies are being employed to isolate efficiently antigenic chimeras that could serve as potential vaccine candidates.

AIDS Vaccines↗

PubMed1994

RH-3421, a potent dihydropyrazole insecticide, inhibits depolarization-stimulated rises in free [Ca2+] and 45Ca2+ uptake in mammalian synaptosomes.

The dihydropyrazole RH-3421 inhibits veratridine- and K(+)-induced rises in synaptosomal free Ca2+ with IC50s of 0.2 and 1 microM, respectively. The K(+)-induced rise in free synaptosomal Ca2+, which requires external Ca2+, is also blocked by RH-3421 in the presence of tetrodotoxin. The K(+)-stimulated 45Ca2+ uptake by synaptosomes is unaffected by tetrodotoxin, blocked by cobalt ions and inhibited by RH-3421 both alone (IC50 = 11 microM) and in the presence of tetrodotoxin. RH-3421 does not influence the level of free Ca2+ or basal 45Ca2+ uptake in non-depolarized synaptosomes. The results suggest RH-3421 inhibits voltage-sensitive calcium channels in nerve endings.

Animals↗

PubMed1994

[Characterization and quantification of dermatan sulfate from donkey skin].

Dermatan sulfate (DS), a recently known antithrombotic glycosaminoglycan, was isolated and purified from donkey skin. Physiochemical characteristics of the glycan, including constituent analysis, electrophoretic behaviour, molecular mass, specific lyase degradations, IR and PMR spectra were described, using porcine skin-origin dermatan sulfate as a standard reference. Contents of DS in donkey skin and its gelatinized preparations (Ejiao) were also measured. Results indicate that the presence of DS may explain the long reputed clinical efficacy of donkey skin and Ejiao in treating serious symptoms associated with what has been called endogenous wind in traditional Chinese medicine.

Animals↗

PubMed1994

Cocaine-induced cerebrovasospasm and its possible mechanism of action.

Experiments were designed to study the effects and mechanism of action of cocaine (COC) on cerebrovascular tissues. Acute exposure to COC (10(-9) to 5 x 10(-3) M) induced contractile responses in isolated canine basilar (BA) and middle cerebral arteries in a dose-dependent manner, but not in mesenteric arteries. The presence or absence of intact endothelium did not alter COC concentration-response curves. The sensitivity to COC was higher in BA (ED50 = 7.20 +/- 0.16 x 10(-5) M) than middle cerebral arteries (ED50 = 1.25 +/- 0.12 x 10(-4) M). Similar effects of COC were also noted in BA from piglets (ED50 = 0.99 +/- 0.25 x 10(-4) M) and sheep (ED50 = 1.34 +/- 0.31 x 10(-4) M). A variety of amine antagonists, an opiate antagonist and an N-MDA receptor antagonist failed to interfere with the COC-induced contractions. However, haloperidol, indomethacin, verapamil and excess [Mg++]0 (4.8 x 10(-3) M) as well as removal of [Ca++]0 completely prevented vasospasms induced by COC. Dopamine and COC resulted in very similar concentration-response curves on canine BA. COC stimulation failed to affect vascular release of thromboxane B2, prostaglandins or 6-Keto-prostaglandin F1 alpha. Interestingly, 10(-7) M COC rapidly elevated intracellular free Ca++ concentrations of cultured cerebral vascular muscle cells about 50% over initial resting levels. The data suggest that COC produces cerebrovasospasm, probably by a direct action on cerebral blood vessels via promoting Ca++ influx and/or intracellular Ca++ release in cerebral vascular muscle cells, which may be modulated by Mg++.

Animals↗

PubMed1993

Sex pheromone for the brownbanded cockroach is an unusual dialkyl-substituted alpha-pyrone.

Female brownbanded cockroaches, Supella longipalpa, emit a sex pheromone that attracts males from a distance. This pheromone was isolated and identified as 5-(2,4-dimethylheptanyl)-3-methyl-2H-pyran-2-one (which we refer to as supellapyrone), and its structure was confirmed by synthesis. A racemic blend of the synthetic compound elicited behavioral and electrophysiological responses comparable to the natural pheromone across a range of doses. This compound is not only a very different type of cockroach pheromone but also makes up an additional class of natural products--namely, 3,5-dialkyl-substituted alpha-pyrones.

Journal Article↗

PubMed1993

Ethanol-induced contraction of cerebral arteries in diverse mammals and its mechanism of action.

Acute ethanol exposure (8-570 mM) induced potent contractile responses of rings in both basilar and middle cerebral arteries, from dogs, sheep, piglets and baboons, in a dose-dependent manner. The contractions were reproducible and not tachyphylactic. The middle cerebral arteries were found to be more sensitive to ethanol than the basilar arteries. No known pharmacological antagonist, tested, exerted any effects on ethanol-induced contractions. No differences in responsiveness to ethanol in canine cerebral arteries were found between male and female animals or between the presence and the absence of endothelial cells. Removal of extracellular Ca2+ ([Ca2+]o) partially attenuated ethanol-induced contractions, while withdrawal of extracellular Mg2+ ([Mg2+]o) potentiated such contractions. In the complete absence of [Ca2+]o, caffeine and ethanol induced similar, transient contractions followed by relaxation in K(+)-depolarized cerebral vascular tissue. Ethanol-induced contractions were completely abolished by pretreatment of tissues with caffeine. Our results suggest that: (a) acute ethanol intoxication can induce direct contractions (independent of amine, prostanoid or opioid mediation) of diverse mammalian cerebral vascular tissues, including those from primates; (b) these contractile responses are heterogeneous along the cerebrovascular tree and independent of endothelial cells; (c) in addition to a need for [Ca2+]o, an intracellular release of Ca2+ is needed for ethanol to induce contractions; and (d) hypomagnesemia or Mg deficiency potentiates the contractile effects of ethanol on brain vessels and may be a risk factor for ethanol-related, ischemic stroke events.

Animals↗

PubMed1993

The fish odour syndrome: biochemical, familial, and clinical aspects.

OBJECTIVES: To study the biochemical, familial, and clinical features of the fish odour syndrome among subjects with suspected body malodour. DESIGN: Subjects who responded to a newspaper article were screened for the fish odour syndrome by interview and biochemical tests. Families of subjects with the syndrome were tested if possible. SETTING: St Mary's Hospital, London, and some interviews at subjects' homes. SUBJECTS: 187 subjects (28 males) with suspected body malodour, of whom 156 (19 males) underwent biochemical tests. Five families of six of the subjects with the fish odour syndrome agreed to further tests. MAIN OUTCOME MEASURES: Amounts of trimethylamine and trimethylamine N-oxide in urine collected over 24 hours under normal dietary conditions and for eight hours after oral challenge with 600 mg trimethylamine. RESULTS: The fish odour syndrome was diagnosed in 11 subjects: the percentage of total trimethylamine excreted in their urine samples that was oxidised to trimethylamine N-oxide was < 55% under normal dietary conditions and < 25% after oral challenge with trimethylamine (in normal subjects > 80% of trimethylamine was N-oxidised). Parents of six of the subjects with the syndrome were tested: all showed impaired N-oxidation of excreted trimethylamine (< 80%) after oral challenge, indicating that they were heterozygous carriers of the allele for the syndrome. The syndrome was associated with various psychosocial reactions including clinical depression. CONCLUSIONS: The fish odour syndrome can be inherited in an autosomal recessive fashion. It should be considered as a possible causative factor in patients complaining of body malodour.

Adolescent↗

PubMed1993

Cocaine induces rapid loss of intracellular free Mg2+ in cerebral vascular smooth muscle cells.

Acute exposure of cultured canine cerebral vascular smooth muscle cells to low concentrations of cocaine HCl (10(-9) to (10(-7) M) resulted in significant, rapid (1 min) loss of intracellular free Mg ions ([Mg2+]i); these reductions (12-25%) in [Mg2+]i were reversible upon exposure to normal, Mg(2+)-containing physiological salt solution. These findings help to provide a rational basis for why cocaine can result in cerebrovasospasm and stroke.

Animals↗

PubMed1993

Structure determination of antiviral compound SCH 38057 complexed with human rhinovirus 14.

SCH 38057 (1-[6-(2-chloro-4-methoxyphenoxy)-hexyl]imidazole hydrochloride) is a new, water-soluble antiviral compound that has inhibitory activities against a number of picornavirus infections. The structure of the human rhinovirus 14 (HRV14) complex with SCH 38057 was determined at 3.0 A resolution by single-crystal diffraction techniques using synchrotron X-radiation. SCH 38057 was found to bind at the innermost end of the hydrophobic pocket within the capsid protein VP1, a locus of binding of other antipicornaviral agents; however, the complex differs from previously reported complexes in two important aspects. It leaves a considerable volume near the entrance to the binding pocket unoccupied. In addition, the alterations in the conformation of the VP1 polypeptide are similar to, but more extensive than those observed in HRV14 complexes with other antiviral agents. Although only 9 amino acids of VP1 have close contacts with the SCH 38057 molecule (within 3.6 A), at least 36 amino acids from both VP1 and VP3 have significantly altered conformations (C alpha movement > 0.5 A versus native). The structures of complexes of HRV14 with SCH 38057 and WIN 51711 are compared. Aromatic ring interactions between picornavirus capsid residues and antiviral inhibitors are proposed to be among the major determinants for positioning of these compounds.

Antiviral Agents↗

PubMed1993

Effects of 5-hydroxymethyl-2'-deoxyuridine and 3-aminobenzamide on chromosome aberrations in cultured human lymphocytes.

Effects of 5-hydroxymethyl-2'-deoxyuridine (HmdUrd, a thymidine analog) and 3-aminobenzamide (3AB) on chromosome aberrations in cultured human lymphocytes were studied. The results show that HmdUrd is an effective clastogen in human peripheral lymphocytes. When cells were treated with HmdUrd and 3AB, a synergistic effect on chromatid gaps, breaks and exchanges was found. These findings support the hypotheses that 5-hydroxymethyluracil (HmUra) residues in DNA are formed and then removed by the action of 5-HmUra-DNA glycosylase (Teeber et al., 1984) and that 3AB interferes with the completion of DNA repair following HmUra excision.

Antineoplastic Agents↗

PubMed1993

SCH 38057: a picornavirus capsid-binding molecule with antiviral activity after the initial stage of viral uncoating.

The activity of a new water-soluble molecule, SCH 38057, against picornaviruses is described. SCH 38057 inhibited plaque formation of selected entero- and rhinoviruses in a range of 10.2 to 29.1 microM (50% endpoint) and had a therapeutic index of 10 against poliovirus type 2 (polio 2) in HeLa cells. When administered orally or subcutaneously, SCH 38057 protected mice infected with either coxsackievirus B3 (CVB3) or echovirus-9 from mortality. The molecule provided a low level of protection against thermal inactivation of virus, indicating that SCH 38057 interacts with the picornavirus capsid. Binding studies with [3H]SCH 38057 revealed that the molecule binds to CVB3 and human rhinovirus 14 (HRV14) in a ratio of 29 and 19 molecules per viral particle, respectively. The affinity constant for SCH 38057 binding to CVB3 was 7.0 x 10(-4) M. When added to cultures of infected cells at 3 h after infection, SCH 38057 markedly inhibited viral RNA synthesis. This finding with lack of inhibition of attachment and loss of infectious virus after attachment were interpreted to indicate that, although SCH 38057 binds to the viral capsid, the molecule exerts its antiviral effect after the initial stage of picornavirus uncoating, i.e., after conversion of the 156S infectious viral particle to smaller subviral species.

Animals↗

PubMed1993

Mg2+ and caffeine-induced intracellular Ca2+ release in human vascular endothelial cells.

Interaction of ionized magnesium ([Mg2+]o) and caffeine in regulation of intracellular free calcium concentration ([Ca2+]i) in human aortic endothelial cells was studied using fura-2 and digital imaging microscopy. In 1.2 mM [Mg2+]o, basal [Ca2+]i was 73.7 +/- 22.4 nM, with a heterogeneous distribution within the cells. No significant changes of basal [Ca2+]i were found either when cells were treated with 10 mM caffeine or when [Mg2+]o was lowered from 1.2 mM to 0.3 mM. However, a combined superfusion of the cells with 0.3 mM [Mg2+]o and 10 mM caffeine resulted in a significant elevation of [Ca2+]i to 382.8 +/- 57.1 nM, probably by release of Ca2+ from internal stores, which was attenuated by NiCl2 (1 mM). These results suggest that a Ca(2+)-induced Ca2+ release mechanism is involved in regulation of [Ca2+]i in endothelial cells, which may be either regulated or modulated by Mg2+.

Aorta↗

PubMed1993

Magnesium, hypertensive vascular diseases, atherogenesis, subcellular compartmentation of Ca2+ and Mg2+ and vascular contractility.

Abnormal dietary deficiency in Mg as well as abnormalities in Mg metabolism appear to play important roles as risk factors for ischemic heart disease and acute myocardial infarction, namely in hypertensive vascular disease, diabetic vascular disease, insulin resistance, atherosclerosis and vasospasm. Experimental, epidemiological as well as clinical evidence that supports a role for Mg in these risk factors are reviewed. Extracellular Mg ions ([Mg2+]o) exert important actions upon divalent cation metabolism, transport and intracellular release of [Ca2+]i and intracellular free Mg ([Mg2+]i) in both vascular smooth muscle and endothelial cells. Digital imaging microscopy, using molecular fluorescent probes, clearly indicates that both intracellular free Ca2+ and intracellular free Mg2+ are compartmented in both vascular smooth muscle cells and endothelial cells. [Mg2+]o appears to exert important effects on the precise subcellular location and concentration of both [Ca2+]i and [Mg2+]i. Use of specific ion-selective electrodes for [Mg2+]o has revealed that [Mg2+]o can change more rapidly than heretofore believed in cardiovascular pathophysiologic states. The latter new findings therefore suggest that the ionized level of [Mg2+]o is an important determinant of vascular tone, contractility and reactivity.

Arteriosclerosis↗