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Biomedical subjects

L Xu

Publications and source records attributed to L Xu.

At least 433 records · Page 24Linked to original sources
PubMed1998

Activation of the cardiac calcium release channel (ryanodine receptor) by poly-S-nitrosylation.

Several ion channels are reportedly redox responsive, but the molecular basis for the changes in activity is not known. The mechanism of nitric oxide action on the cardiac calcium release channel (ryanodine receptor) (CRC) in canines was explored. This tetrameric channel contains approximately 84 free thiols and is S-nitrosylated in vivo. S-Nitrosylation of up to 12 sites (3 per CRC subunit) led to progressive channel activation that was reversed by denitrosylation. In contrast, oxidation of 20 to 24 thiols per CRC (5 or 6 per subunit) had no effect on channel function. Oxidation of additional thiols (or of another class of thiols) produced irreversible activation. The CRC thus appears to be regulated by poly-S-nitrosylation (multiple covalent attachments), whereas oxidation can lead to loss of control. These results reveal that ion channels can differentiate nitrosative from oxidative signals and indicate that the CRC is regulated by posttranslational chemical modification(s) of sulfurs.

Animals↗
PubMed1998

Discovery and evaluation of a series of 3-acylindole imidazopyridine platelet-activating factor antagonists.

Studies conducted with the goal of discovering a second-generation platelet-activating factor (PAF) antagonist have identified a novel class of potent and orally active antagonists which have high aqueous solubility and long duration of action in animal models. The compounds arose from the combination of the lipophilic indole portion of Abbott's first-generation PAF antagonist ABT-299 (2) with the methylimidazopyridine heterocycle moiety of British Biotechnology's BB-882 (1) and possess the positive attributes of both of these clinical candidates. Structure-activity relationship (SAR) studies indicated that modification of the indole and benzoyl spacer of lead compound 7b gave analogues that were more potent, longer-lived, and bioavailable and resulted in the identification of 1-(N, N-dimethylcarbamoyl)-4-ethynyl-3-[3-fluoro-4-[(1H-2-methylimidazo[4,5-c] pyrid-1-yl)methyl]benzoyl]indole hydrochloride (ABT-491, 22 m.HCl) which has been evaluated extensively and is currently in clinical development.

Animals↗
PubMed1998

Contrasting behavior of pentafluorophenoxyacetone and pentafluorobenzyloxyacetone in electron impact and electron capture mass spectrometry.

Towards the goal of finding new ketone electrophores suitable as molecular labels for electrophoric release tags, pentafluorophenoxyacetone (1) and pentafluorobenzyloxyacetone (2) were prepared. Both ketones were evaluated by electron capture (EC) and electron impact (EI) modes of mass spectrometry (MS). By EC-MS, 1 nearly gave a single ion (as desired), whereas 2 gave many ions. This behavior was completely reversed in EI-MS. To account for certain ion fragments in the EC mass spectrum of 2, an anion radical McLafferty-type rearrangement and loss of a carbene neutral were postulated. Electron impact of 1 gave an abundant ion at m/z 117 (C5F3+), which was suggested to be a diyne cation.

Acetone↗
PubMed1998

Increased renal and vascular cytosolic phospholipase A2 activity in rats with cirrhosis and ascites.

Indirect evidence suggests that the renal and vascular production of prostaglandins is increased in cirrhosis with ascites. However, the activity of the enzymes regulating the prostaglandin pathway has not been investigated in cirrhosis. The aim of the current study was to determine the activity of phospholipase A2 (PLA2), the key enzyme in the regulation of prostaglandin synthesis, in kidney and vascular tissue obtained from rats with carbon tetrachloride-induced cirrhosis and ascites (n = 9) and control rats (n = 6). PLA2 activity was assayed in vitro using [14C]arachidonyl-phosphatidylcholine (PC) and [14C]arachidonyl-phosphatidylethanolamine (PE) as substrates in the presence of Ca2+. Kidneys from cirrhotic rats had significantly higher PLA2 activity compared with control rats, with both PC and PE (35 +/- 5 and 40 +/- 6 vs. 21 +/- 2 and 26 +/- 3 pmol/mg/min, respectively; P < .05 for both). PLA2 activity was increased in the renal cortex as well as in the renal medulla. Fractionation of the kidney extracts by Mono-Q anion-exchange chromatography showed that the elution position of PLA2 activity corresponded to the cytosolic PLA2 isoform (cPLA2). Increased amounts of cPLA2 protein were found in kidney extracts immunoblotted with an anti-cPLA2 antibody However, reverse-transcriptase polymerase chain reaction (RT-PCR) analysis did not detect any difference in cPLA2 mRNA. PLA2 activity was also higher in aortic tissue from cirrhotic rats than in controls (PC 38 +/- 5 vs. 26 +/- 1 and PE 66 +/- 8 vs. 41 +/- 3 pmol/mg/min; P < .05 for both). Incubation of renal and aortic extracts from cirrhotic rats with anti-cPLA2 antibody reduced PLA2 activity by 64% and 88%, respectively. In conclusion, PLA2 activity is increased in kidneys and vascular tissue from cirrhotic rats with ascites. This can be accounted for by an induction of cPLA2, which would mediate, at least in part, the increased renal and vascular production of prostaglandins in cirrhosis.

Animals↗
PubMed1998

Molecular basis for persistent hepatitis B virus infection in the liver after clearance of serum hepatitis B surface antigen.

Hepatitis B virus (HBV) DNA has been detected by polymerase chain reaction (PCR) in the liver of patients with resolved chronic HBV infection and sustained clearance of hepatitis B surface antigen (HBsAg) from serum. However, it is unknown whether the virus is transcriptionally active at this time or if the covalently closed circular (CCC) replicative intermediate of HBV DNA can still be detected. Therefore, hepatic nucleic acid extracts from seven patients who had cleared serum HBsAg were assessed by (PCR) for either reverse-transcribed HBV RNA, or an intact direct repeat region of the HBV genome indicative of the CCC replicative intermediate of HBV DNA. HBV transcripts were detected in four of seven patients in the study group, whereas an intact direct repeat region of the HBV genome was detected in three. Evidence for viral transcription and replication was more frequently detected in patients who had recently cleared serum HBsAg, but HBV RNA was also detected in one patient 5 years after HBsAg clearance, and an intact direct repeat region of HBV DNA was detected in another subject at nearly 4 years after resolution of disease. Therefore, hepatic HBV transcription may be associated with replicative intermediates of persistent HBV DNA in patients who have cleared HBsAg from serum, suggesting that, on occasion, HBV may not be in a latent state but undergoing low-level replication.

Antigens, Viral↗
PubMed1998

Influence of dioxin and metal-contaminated sediment on phase I and II biotransformation enzymes in silver crucian carp.

Several biochemical responses were measured in silver crucian carp (Carassius auratus gibelio) after exposure to sediments obtained from contaminated Ya-Er Lake, No. 1 pond, and an unpolluted reference site, Honglian Lake. After 1 week of exposure, a significant induction of the phase I biotransformation enzyme (ethoxylresorufin-o-deethylase, EROD) was found (83-fold of control), whereas the phase II biotransformation enzyme (glutathione S-transferase, GST) exhibited a slight, but significant induction (1.4-fold of control) after 4 weeks of exposure. The level of cellular glutathione in the liver was also slightly elevated after 4 weeks of exposure. The delayed response of GST to the contaminants indicates that the phase I and phase II biotransformation enzymes are regulated differently in fish. The results suggest that EROD is a sensitive bioindicator to assess the toxicity of dioxin-contamined sediment in the laboratory.

Animals↗
PubMed1998

Glutathione S-transferase activity in aquatic macrophytes with emphasis on habitat dependence.

Glutathione S-transferase activity of both the microsomal and soluble fractions was determined in a variety of aquatic macrophytes. The examined enzyme extract was prepared from a combination of leaves and shoots. Four different model substrates were used. The highest conjugation rate was obtained for 1-iodo-2,4-dinitrobenzene, followed by 1-chloro-2,4-dinitrobenzene, p-nitrobenzoyl chloride, and 1,2-dichloro-4-nitrobenzene. Comparison of several samples of Nuphar lutea L. from two different lake areas revealed increased glutathione S-transferase activity in plants from the site contaminated with polyaromatic hydrocarbons.

Environment↗
PubMed1998

Cervical ripening in the third trimester of pregnancy with intravaginal misoprostol: a double-blind, randomized, placebo-controlled study.

To evaluate the safety and efficacy of intravaginal misoprostol for cervical ripening in the third trimester, a randomized, double-blind, placebo-controlled trial was conducted in 85 patients indicated for induction of labor and with unfavorable cervices. They were randomly assigned to receive either intravaginal misoprostol (100 mg) or placebo placed in the posterior vaginal fornix. The Bishop score, fetal heart rate and Doppler blood flow velocity waveforms were measured before and 12 h after drug administration. Placenta and decidu were histopathologically observed in some cases. Among 85 patients enrolled, 43 received misoprostol and 42 received placebo. Whereas the mean initial Bishop scores were not significantly different between the two groups, the mean Bishop score in misoprostol group was significantly better than those in placebo group. The mean change in Bishop score was also significantly different (4.4 for misoprostol versus 1.0 for placebo, P < 0.01). The prevalence of spontaneous onset of labor within 12 h after drug insertion in misoprostol group (67.4%, 29/43) was significantly higher than that in placebo group (14.3%, 6/42), P < 0.01. The average Doppler velocity systolic to diastolic (S/D) ratios of umbilical artery, middle cranial artery, renal artery were not significantly different before and 12 h after drug insertion between both groups. There was no significant difference in frequency of abnormal fetal heart rate tracings or fetal distress and in the mean Apgar scores between the two groups. Except the presence of vasodilation in villi vessels in the misoprostol group, the placental and decidual histopathological changes had no significantly difference between two groups. It is concluded that intravaginal misoprostol may be an effective and safe cervical ripening agent in the third trimester of pregnancy.

Administration, Intravaginal↗
PubMed1998

Successful detection of active osteoclasts in situ by systemic administration of an osteoclast-specific monoclonal antibody.

Cell-surface proteins preferentially expressed on osteoclasts are thought to play important roles in the functional modulation of the osteoclasts. Recently, we found a novel cell-surface antigen designated Kat1-antigen (Kat1-Ag) specifically expressed on rat osteoclasts. It would be useful to regulate the functional activity of the osteoclasts directly via an osteoclast-specific antigen expressed on the cell surface of the osteoclasts. In order to establish the basis of such an application, in the present study we established a method for the direct detection of osteoclasts in situ by a systemic administration of the anti-Kat1-Ag monoclonal antibody (mAb Kat1) to rats, and we successfully detected functional osteoclasts in situ. Prior to performing in vivo experiments, we examined the reactivity of the mAb Kat1 to the isolated rat osteoclasts. Approximately 40-80% of the osteoclasts were reactive with mAb Kat1, suggesting that this mAb recognizes osteoclasts in a specific differentiation or functional state. Calcitonin treatment of osteoclast-like cells formed in vitro from bone marrow cells resulted in a conversion of Kat1-positive osteoclast-like cells into Kat1-negative multinucleated cells, showing the positive correlation between the Kat1-Ag expression and the potential bone-resorbing activity of osteoclasts. Administration of this lineage-specific mAb to the peritoneal cavity of newborn rats resulted in a successful recruitment of mAb Kat1 to the newly formed osteoclasts and functional osteoclasts in a highly specific manner. Detailed analysis by immunoelectron microscopy revealed that this mAb specifically bound to the basolateral side of the active osteoclasts, which were identified by their typical ruffled border and clear zone, whereas the mAb did not react to postfunctional osteoclasts. These findings demonstrate a high potential utility of mAb Kat1 in osteoclast-targeted regulation of bone remodeling.

Animals↗
PubMed1998

Regulation of cardiac muscle Ca2+ release channel by sarcoplasmic reticulum lumenal Ca2+.

The cardiac muscle sarcoplasmic reticulum Ca2+ release channel (ryanodine receptor) is a ligand-gated channel that is activated by micromolar cytoplasmic Ca2+ concentrations and inactivated by millimolar cytoplasmic Ca2+ concentrations. The effects of sarcoplasmic reticulum lumenal Ca2+ on the purified release channel were examined in single channel measurements using the planar lipid bilayer method. In the presence of caffeine and nanomolar cytosolic Ca2+ concentrations, lumenal-to-cytosolic Ca2+ fluxes >/=0.25 pA activated the channel. At the maximally activating cytosolic Ca2+ concentration of 4 microM, lumenal Ca2+ fluxes of 8 pA and greater caused a decline in channel activity. Lumenal Ca2+ fluxes primarily increased channel activity by increasing the duration of mean open times. Addition of the fast Ca2+-complexing buffer 1,2-bis(2-aminophenoxy)ethanetetraacetic acid (BAPTA) to the cytosolic side of the bilayer increased lumenal Ca2+-activated channel activities, suggesting that it lowered Ca2+ concentrations at cytosolic Ca2+-inactivating sites. Regulation of channel activities by lumenal Ca2+ could be also observed in the absence of caffeine and in the presence of 5 mM MgATP. These results suggest that lumenal Ca2+ can regulate cardiac Ca2+ release channel activity by passing through the open channel and binding to the channel's cytosolic Ca2+ activation and inactivation sites.

Adenosine Triphosphate↗
PubMed1998

Position 120-123, a potential active site of trichosanthin.

Trichosanthin (TCS) is a type-I ribosome-inactivating protein (RIP) with wide spectrum of biological and pharmacological activities. In the present study, a potential site on the TCS molecule (position 120-123) is identified which may be important for the biological activities of TCS. By using site-directed mutagenesis, position 120-123 of TCS was either deleted or changed from Lys-Ile-Arg-Glu (hydrophilic) to Ser-Ala-Gly-Gly (hydrophobic). Deletion of these residues rendered a TCS molecule completely deprived of ribosome inactivating activity, while hydrophobic replacement caused 4000-fold decrease in ribosome inactivating activity. The abortifacient activity of these two mutants was retained with decreased potency. This implies that position 120-123 of the native TCS molecule plays a critical role in maintaining its biological activity.

Abortifacient Agents, Nonsteroidal↗
PubMed1998

Topography of the osteoarthritic thumb carpometacarpal joint and its variations with regard to gender, age, site, and osteoarthritic stage.

The articular topography of 46 osteoarthritic thumb carpometacarpal joints was quantitatively analyzed, as well as variations with regard to gender, age, site, and anatomic osteoarthritic stage. It was found that for osteoarthritic thumb carpometacarpal joints, (1) the opposing articular surfaces of elder and severely degenerated joints are more congruent than those of middle-aged and minimally or moderately degenerated joints, although the articular contact area is not significantly different when accounting for thinning of the cartilage layer with age or disease; (2) significant changes in joint topography due to osteoarthritis only occur in severely degenerated joints; (3) joints in women are less congruent, have smaller contact areas, and are likely to experience higher contact stresses than joints in men for similar activities of daily living that involve similar joint loads; and (4) osteoarthritic changes are less severe on the dorsoulnar aspect of the trapezium and the dorsal aspect of the metacarpal, which are known to be low load-bearing regions.

Adult↗
PubMed1998

Stress analysis of the human temporomandibular joint.

Stress analysis of the human temporomandibular joint (TMJ) consisting of mandibular disc, condyle and fossa-eminence complex during normal sagittal jaw closure was performed using non-linear finite element analysis (FEA). The geometry of the TMJ was obtained from magnetic resonance imaging (MRI). The tissue proportion was measured from a cadaver TMJ. Contact surfaces were defined to represent the interaction between the mandibular disc and the condyle, and between the mandibular disc and the fossa-eminence complex so that finite sliding was allowed between contact bodies. Stresses in the TMJ components (disc, condyle and fossa-eminence complex), and forces in capsular ligaments were obtained. The results demonstrated that, with the given condylar displacement, the stress in the condyle was dominantly compressive and in the fossa-eminence complex was dominantly tensile. The cancellous bone was shielded by the shell shaped cortical bone from the external loading. The results illustrate the stress distributions in the TMJ during a normal jaw closure.

Computer Simulation↗
PubMed1998

Immunization for Ebola virus infection.

Infection by Ebola virus causes rapidly progressive, often fatal, symptoms of fever, hemorrhage and hypotension. Previous attempts to elicit protective immunity for this disease have not met with success. We report here that protection against the lethal effects of Ebola virus can be achieved in an animal model by immunizing with plasmids encoding viral proteins. We analyzed immune responses to the viral nucleoprotein (NP) and the secreted or transmembrane forms of the glycoprotein (sGP or GP) and their ability to protect against infection in a guinea pig infection model analogous to the human disease. Protection was achieved and correlated with antibody titer and antigen-specific T-cell responses to sGP or GP. Immunity to Ebola virus can therefore be developed through genetic vaccination and may facilitate efforts to limit the spread of this disease.

Animals↗
PubMed1998

Gene transfer into human umbilical cord blood-derived CD34+ cells by particle-mediated gene transfer.

Delivery of genes into hematopoietic progenitor cells offers an attractive means for the introduction of corrective or protective genes into cells of both the myeloid and lymphoid lineage. Previously, investigators have often used murine retroviral vectors for gene delivery which require cells to be cycling for efficient delivery. We describe a nonviral method of gene delivery using particle-mediated gene transfer to obviate many disadvantages of viral vectors related to safety, production costs and the need for cell cycle proliferation. Using a CMV-CAT reporter plasmid, we show transfection of highly purified CD34+ cells isolated from umbilical cord blood. Effective gene transfer was shown in unstimulated and in growth-stimulated cells. Following transfection with a neomycin resistance gene, differentiation into cells of the myeloid lineage was observed, assayed by CFU-GM in the presence of G-418. Both unstimulated and stimulated cells gave rise to CFU-GM in the presence of G-418, indicating that stable expression of the neomycin resistance gene was maintained in early progenitors. These results demonstrate that particle-mediated gene transfer into human hematopoietic cells from umbilical cord blood can be achieved without affecting their CFU-GM differentiation potential. This gene transfer method offers an alternative approach to gene therapy studies involving human hematopoietic progenitor cells.

Anti-Bacterial Agents↗
PubMed1998

Potentiation of murine astrocyte antioxidant defence by bcl-2: protection in part reflects elevated glutathione levels.

Overexpression of the proto-oncogene bcl-2 has been shown to protect a variety of cell types from oxidative and non-oxidative injury, blocking apoptotic and necrotic types of cell death. Retroviral vectors were used to stably overexpress bcl-2 in primary murine astrocyte cultures with more than 95% efficiency. Compared to beta-galactosidase-expressing and uninfected control cells, bcl-2 overexpressing astrocytes suffered < 40% injury after 24 h glucose deprivation, while controls were essentially completely injured. After exposure to 0.2 mM hydrogen peroxide, the bcl-2 overexpressing astrocytes suffered < 40% the injury seen in controls. In contrast, when the cultures were injured by combined oxygen-glucose deprivation, no difference in the extent or time course of injury was found between cells overexpressing bcl-2 and those expressing beta-galactosidase. To investigate one possible mechanism of bcl-2 protection, we measured the levels of glutathione and three antioxidant enzymes. Astrocytes overexpressing bcl-2 had elevated glutathione levels (130-200%), increased superoxide dismutase (170%) and glutathione peroxidase (140%) activities compared with beta-galactosidase-expressing controls. Bcl-2 overexpressing astrocytes suffered less lipid peroxidation after glucose deprivation, as assessed by cis-parinaric acid fluorescence, and demonstrated more rapid removal of hydrogen peroxide from the medium. When glutathione levels were decreased 80% by pretreatment with buthionine sulfoximine, the extent of protection from glucose deprivation of bcl-2 overexpressing cells was decreased by about half. Increased antioxidant defence contributes to protection from glucose deprivation in bcl-2 overexpressing astrocytes.

Animals↗