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Biomedical subjects

H Xu

Publications and source records attributed to H Xu.

At least 541 records · Page 30Linked to original sources
PubMed1996

Probes for narcotic receptor-mediated phenomena. 21. Novel derivatives of 3-(1,2,3,4,5,11-hexahydro-3-methyl-2,6-methano-6H-azocino[4,5-b]indol- 6-yl)-phenols with improved delta opioid receptor selectivity.

Derivatives of racemic and optically pure levorotatory 3-(1,2,3,4,5,11-hexahydro-3-methyl-2,6-methano-6H-azocino[4,5-b]in dol-6-yl)phenols containing methoxy substituents in the C10', C9', and C8' positions (compounds 9-11, respectively) were synthesized and characterized by spectroscopic and X-ray methods. The binding affinities for the mu, delta and kappa 1 opioid receptors and activity in the guinea pig ileum (GPI) and mouse vas deferens (MVD) functional bioassays were determined for these compounds. A methoxy substituent in the C8' position decreases the binding affinity for both the mu and delta receptors, while a C10' methoxy substituent has little effect on either binding affinity. Interestingly, a methoxy group at the C9' position in the levorotatory series provides compound (-)-10 which exhibits both enhanced in vitro affinity and selectivity for the delta opioid receptor relative to the unsubstituted derivative (-)-8 and is the most selective (mu/delta IC50 ratio 17.9, kappa 1/delta IC50 ratio 314) and highest affinity (IC50 3.7 nM) delta receptor ligand for this novel class of compounds. The results of the GPI and MVD bioassays are more dramatic and indicate that (-)-10 is an agonist for the delta receptor (IC50 49.0 nM) with substantial selectivity for the delta versus the mu receptor borne out by a GPI/MVD IC50 ratio of > 612.

Analgesics↗
PubMed1996

Loss of deoxcytidine kinase expression and tetraploidization of HL60 cells following long-term culture in 1,25-dihydroxyvitamin D3.

Development of drug resistance is a major problem in attempts to control the growth of neoplastic cell populations. The resistance can he either inherent or acquired by an exposure to a chemotherapeutic drug. The available models for study of these phenomena have not led to major improvements in the therapy for human cancers. Therefore, in order to develop a new model for such studies, we have exposed human myeloid leukemia cells HL60 to increasing concentrations of 1,25-dihydroxyvitamin D3 (1,25D3) and characterized the emerging new phenotypes of these cells over a period of 4 years. During the stepwise development of resistance only cells which did not adhere to the flask walls were passaged. Beginning at 30 nM 1,25D3 the sublines became resistant to the differentiation-inducing and growth-retarding properties of 1,25D3 even at 400 nM. Also, their growth rates in 1,25D3-free media increased. In addition, beginning at 40 nM 1,25D3 the sublines acquired resistance to 5-beta-D-arabinocytosine (araC) due to the lack of expression of the deoxycytidine kinase gene. The araC-resistant sublines were also near-tetraploid, as judged by their DNA content. When grown in 1,25D3-free long-term culture the phenotype was essentially stable. The development of cross-resistance to araC during growth in the presence of an unrelated compound (i.e., 1,25D3) shows that in some instances an apparently inherent drug resistance may in fact he due to a metabolic defect resulting from an exposure to another agent.

Autoradiography↗
PubMed1996

Metabolism of Alzheimer beta-amyloid precursor protein: regulation by protein kinase A in intact cells and in a cell-free system.

Various compounds that affect signal transduction regulate the relative utilization of alternative processing pathways for the beta-amyloid precursor protein (beta APP) in intact cells, increasing the production of nonamyloidogenic soluble beta APP (s beta APP) and decreasing that of amyloidogenic beta-amyloid peptide. In a recent study directed toward elucidating the mechanisms underlying phorbol ester-stimulated s beta APP secretion from cells, it was demonstrated that protein kinase C increases the formation from the trans-Golgi network (TGN) of beta APP-containing secretory vesicles. Here we present evidence that forskolin increases s beta APP production from intact PC12 cells, and protein kinase A stimulates formation from the TGN of beta APP-containing vesicles. Although protein kinase A and protein kinase C converge at the level of formation from the TGN of beta APP-containing vesicles, additional evidence indicates that the regulatory mechanisms involved are distinct.

Alzheimer Disease↗
PubMed1996

T cell populations primed by hapten sensitization in contact sensitivity are distinguished by polarized patterns of cytokine production: interferon gamma-producing (Tc1) effector CD8+ T cells and interleukin (Il) 4/Il-10-producing (Th2) negative regulatory CD4+ T cells.

Contact hypersensitivity (CHS) is a T cell-mediated response to hapten sensitization of the epidermis. The roles of CD4+ and CD8+ T cells in CHS have remained unclear, however, as studies to define either subset as the T cells mediating CHS have provided conflicting results. The goal of this study was to correlate the in vivo function of CD4+ and CD8+ T cells in CHS with the cytokines produced by each T cell population. Antibody-mediated depletion of CD4+ T cells before sensitization of BALB/c mice with 2,4-dinitrofluorobenzene (DNFB) or oxazolone (Ox) resulted in increased and prolonged CHS responses, indicating CD4+ T cells as negative regulators of the response. Depletion of CD8+ T cells resulted in low or abrogated responses, indicating CD8+ T cells as the effector cells in CHS. Sensitization with DNFB or Ox induced lymph node cell populations of CD8+ T cells producing interferon (IFN)-gamma and no interleukin (Il) 4 or Il-10, and CD4+ T cells producing Il-4 and Il-10 and no or little detectable IFN-gamma. The polarized patterns of cytokine production were stimulated by culture of hapten-primed lymph node cells either on anti-T cell receptor antibody-coated wells or with semipurified Langerhans cells isolated from hapten-sensitized mice. Stimulation of cytokine production during culture of hapten-primed CD4+ or CD8+ T cells with Langerhans cells was hapten specific and restricted to class II or class I major histocompatibility complex, respectively. The induction of the CD4+ and CD8+ T cells producing the polarized patterns of cytokines was not restricted to BALB/c mice, as cells from Ox sensitized C57B1/6 and B10.D2 mice produced the same patterns. Collectively, these results expose the induction of two polarized and functionally opposing populations of T cells by hapten sensitization to induce CHS: IFN-gamma-producing effector CD8+ T cells and Il-4/Il-10-producing CD4+ T cells that negatively regulate the response.

Animals↗
PubMed1996

Short course single agent therapy with an LFA-3-IgG1 fusion protein prolongs primate cardiac allograft survival.

The interaction of T cell costimulatory molecules with their ligands is required for optimal T cell activation. Interference with such interactions can induce antigen unresponsiveness and delay xeno- and allograft rejection. We have previously shown that LFA3TIP, a soluble human lymphocyte function-associated antigen (LFA)-3 construct, binds CD2 and inhibits responses of human T cells in vitro. This study reports the first use of a human fusion protein, LFA3TIP, to significantly prolong primate cardiac allograft survival. Based on our observations that LFA3TIP inhibits baboon allogeneic mixed lymphocyte reactions, we gave baboon recipients of heterotopic cardiac allografts injections of LFA3TIP, 3 mg/kg i.v., for 12 consecutive days, starting 2 days before transplantation. This regimen delayed graft rejection from an average of 10.6 +/- 2.3 days for human IgG-treated controls (n = 5) to an average of 18.0 +/- 5.3 days for LFA3TIP-injected animals (n = 7; P < or = 0.01). Grafts from LFA3TIP-treated animals showed markedly diminished coronary endothelialitis as compared with control animals. LFA3TIP reached peak serum levels of approximately 100 micrograms/ml after 7-9 injections and persisted in the 10-micrograms/ml range for 1 to 2 weeks after the final injection. Despite these blood levels, circulating antibodies to LFA3TIP were not detected in the serum. No renal or hepatic toxicity was noted. The possible mechanism by which LFA3TIP acts to inhibit graft rejection is discussed; success in prolonging graft survival when LFA3TIP is used as a single-agent therapy suggests great potential for this novel therapeutic agent.

Animals↗
PubMed1996

Prospective trial of combined hyperfractionated radiotherapy and bronchial arterial infusion of chemotherapy for locally advanced nonsmall cell lung cancer.

PURPOSE: This article is a prospective trial of hyperfractional radiotherapy with bronchial arterial infusion of anticancer drugs to treat locally advanced bronchogenic cancer. The treatment results, the complications of bronchial arterial infusion, the failure patterns, the relationship of technical aspects of delivery of radiotherapy, and the protocol of anticancer drugs are presented. METHODS AND MATERIALS: One hundred and twenty-six patients with locally advanced bronchogenic cancer, treated from January 1988 to January 1990, were divided randomly into four groups in our hospital. Group 1: combination of hyperfractional radiotherapy with bronchial arterial infusion of anticancer drugs (30 cases); Group 2: combination of conventional radiotherapy with bronchial arterial infusion of anticancer (33 cases); Group 3: combination of systemic chemotherapy and split-course radiotherapy (33 cases); Group 4: conventional radiotherapy only (30 cases). RESULTS: All the patients were followed for 3 years. The 1-year survival rates for Groups 1, 2, 3, and 4 are 80, 63.6, 48.5, and 30%, respectively. The 2-year survival rates for Groups 1, 2, 3, and 4 are 23.3, 15.15, 9.1, and 6.6%, respectively. The 3-year survival rates for Groups 1, 2, 3, and 4 are 10, 3.3, 0, and 0%, respectively. CONCLUSION: This study demonstrated that the combination of hyperfractional radiotherapy with bronchial arterial infusion anticancer drugs can be performed safely and effectively for locally advanced bronchogenic carcinoma.

Adenocarcinoma↗
PubMed1996

Exposure to heat shock affects thermosensitivity of the locust flight system.

The natural habitat of the migratory locust, Locusta migratoria, is likely to result in locusts being heat stressed during their normal adult life. It is known that locusts exhibit a heat-shock response: exposure to 45 degrees C for 3 h induces thermotolerance and the expression of heat-shock proteins. We investigated the effects of exposure to heat-shock conditions on the thermosensitivity of flight rhythm generation in tethered, intact animals and in deafferented preparations. Heat shock had no effect on wingbeat frequency measured at the start of flight sequences, nor did it affect the postimaginal maturation of this parameter. During sustained flight, heat shock slowed the characteristic asymptotic reduction of wingbeat frequency. Wingbeat frequency of heat-shocked animals was less sensitive to temperature in the range 24 degrees to 47 degrees C than that of control animals, and the upper temperature limit, above which flight rhythms could not be produced, was 6 degrees to 7 degrees C higher in heat-shocked animals. These results were mirrored in the response of deafferented preparations, indicating that modifications in the properties of the flight neuromuscular system were involved in mediating the response of the intact animal. We propose that exposure to heat shock had the adaptive consequences of reducing thermosensitivity of the neural circuits in the flight system and allowing them to operate at higher temperatures.

Adaptation, Physiological↗
PubMed1996

Diversion of CD4+ T cell development from regulatory T helper to effector T helper cells alters the contact hypersensitivity response.

Cutaneous sensitization to reactive haptens and subsequent challenge results in a T cell-mediated response, contact hypersensitivity (CHS). Recent results from this laboratory have indicated that hapten sensitization induces two populations of reactive T cells: CD8+ T cells producing interferon (IFN)-gamma which mediate the response and CD4+ T cells producing interleukin (IL)-4 and IL-10 which negatively regulate the magnitude and duration of the response. Since CD4+ T cell development to either IFN-gamma-(Th1) or IL-4/IL-10-(Th2)-producing cells is dependent upon the cytokine environment during antigen priming, we hypothesized that CD4+ T cell induction in a Th1-promoting environment would not only alter the CD4+ T cell cytokine-producing phenotype but also the course of the CHS response. Administration of the Th1-promoting cytokine IL-12 during hapten sensitization resulted in a CHS response of greater magnitude following challenge and extended the duration of the response. In hapten-sensitized mice depleted of CD8+ T cells, treatment with IL-12 induced effector CD4+ T cells. Histological examination of challenged ear tissue from these mice indicated minimal edema and an acute mononuclear cell infiltration more typical of classical delayed-type hypersensitivity than CHS. Hapten-primed CD4+ T cells from IL-12 treated, sensitized mice produced IFN-gamma, but not IL-4 in response to T cell receptor-mediated stimulation. Use of neutralizing anti-IFN-gamma antibody indicated that IL-12 not only directly promoted Th1 development but also indirectly inhibited Th2 development through stimulation of IFN-gamma production at the time of hapten sensitization. Overall, these results demonstrate that diversion of CD4+ T cell development to Th1 effector cells rather than to Th2 cells alters the efferent nature of CHS and removes a primary regulatory mechanism of the immune response.

Animals↗
PubMed1996

Transmembrane Ca2+ gradient is essential for high anion transport activity of human erythrocytes.

The role of a transmembrane Ca2+ gradient in anion transport by Band 3 of human resealed erythrocyte ghosts has been studied. The results show that a transmembrane Ca2+ gradient is essential for the conformation of erythrocyte Band 3 with higher anion transport activity. The dissipation of the transmembrane Ca2+ gradient by the ionophore A23187 inhibits the anion transport activity. The extent of this inhibition approaches 90% as the Ca2+ concentration on both sides of the ghost membrane is increased to 1.0 mM and half-maximum inhibitions is observed at 0.25 mM Ca2+. Addition of ATP (0.4 mM) to the resealing medium can partly reestablish the transmembrane Ca2+ gradient by activation of Ca(2+)-ATPase and alleviate the inhibition to some extent. N-ethylmaleimide, an inhibitor of erythrocyte Ca(2+)-ATPase, prevents such restoration. Electron micrographs reveal that numerous larger intramembranous particle can be observed on the P-faces of freeze-fractured resealed ghosts in the absence of a transmembrane Ca2+ gradient.

Anion Exchange Protein 1, Erythrocyte↗
PubMed1996

Immunoregulation of lupus-like NZB/W F1 mice by anti-murine IL-1 alpha, IL-6 antibodies.

Anti-murine IL-1 alpha, IL-6 antibodies were intra-peritoneally injected to the lupus-like NZB/W F1 mice of 4 months with the dosage of 10 micrograms per day for three days and then per month for three months. The mice were killed at the age of 11 months. The results showed that the treatment of the dosage could not absolutely prevent lupus nephritis--it could alleviate proteinuria, obviously reduce the levels of serum IL-1 alpha and inhibit the secretion of IL-1 alpha by celiac macrophage. As to the level of IL-6 and TNF-alpha no significant change was observed.

Animals↗
PubMed1996

CD14 mediate endotoxin induction of nitric oxide synthase in cultured brain glial cells.

Here we show that lipopolysaccharide (LPS) induction of glial inducible nitric oxide synthase (iNOS) requires membrane (m) and soluble (s) forms of CD14. In glial cell cultures, an anti-rat CD14 monoclonal antibody detected CD14 protein in whole cells and cell lysates, and reduced LPS-dependent iNOS expression. Glial cells and normal brain tissue expressed CD14 mRNA, as revealed by isolation of a rat CD14 clone (rCD14) from an astrocyte cDNA library and RT-PCR analysis. Finally, serum the ED(50) of LPS required for glial iNOS expression, and antibodies against sCD14 blocked the potentiating effect of serum.

Amino Acid Sequence↗
PubMed1996

9-(4-Hydroxybutyl)-N2-phenylguanine (HBPG), a thymidine kinase inhibitor, suppresses herpes virus reactivation in mice.

In cells of the nervous system, which have little or no cellular thymidine kinase, the pharmacologic inhibition of viral thymidine kinase may prevent the reactivation of herpes virus, which requires phosphorylated thymidine for replication. We tested a newly synthesized inhibitor of viral thymidine kinase, 9-(4-hydroxybutyl)-N2-phenylguanine (HBPG) for its capacity to suppress the reactivation of herpes simplex virus type 1 (HSV-1) in vivo. Mice, latently infected with McKrae strain HSV-1, were treated with intraperitoneal injections of HBPG in a corn oil vehicle (200 mg/kg every 3 h for a total of ten doses), and subjected to hyperthermic stress to stimulate viral reactivation immediately before the third treatment. Three h after the last treatment, the mice were sacrificed, and the presence of infectious virus was determined by culture of ocular surface swabs and trigeminal ganglionic homogenates. Additionally, viral DNA in ganglionic extracts was analyzed by quantitative PCR. Controls included latently infected, stressed animals receiving injections of corn oil vehicle only, and latently infected, drug- and vehicle-treated, unstressed animals. HBPG had a statistically significant inhibitory effect on hyperthermia-induced viral reactivation. Homogenates of trigeminal ganglia and ocular surface swabs from HBPG-treated animals were less likely to contain infectious virus than those of infected, vehicle-treated, stressed controls (P < 0.005, ANOVA). Unstressed controls showed no reactivation. Quantitation of viral DNA in ganglionic extracts demonstrated a 100-fold reduction in the amount of viral DNA in the ganglia of HBPG-treated animals, compared with vehicle-treated controls (P < 0.05, ANOVA). The results indicate that HBPG has an inhibitory effect when given systemically for the suppression of herpes virus reactivation in mice.

Animals↗
PubMed1996

Predicting age at menopause.

This article reviews methodologic and clinical aspects of predicting age at menopause. Lifetable methods or logistic models applied to a perimenopausal population represent the most feasible and the least biased methods for estimating the probability of menopause by age. Information is emerging about risk factors besides age which influence risk for an earlier menopause and include a variety of medical, demographic, environmental, and genetic factors. The concept of menopause as a consequence of depleted oocytes suggests that the estimated number of ovulatory cycles might also be a useful predictor. Using these variables in a logistic model yields estimated probabilities of menopause for various risk profiles. Smokers who have accumulated more than 10 pack-years, women estimated to have had more than 300 ovulatory cycles, women with a history of depression, women who have lost one ovary at an early age, and women who have a family history of early menopause have earlier menopause and the greatest shift in the cumulative probability of menopause occurs in women with multiple risk factors.

Adult↗
PubMed1996

In vitro evaluation of neonatal human immunity against the pig.

The critical shortage of organ donors has greatly limited the number of clinical allotransplantations. This is particularly true for neonatal patients, for whom xenotransplantation could provide an alternative therapeutic option to allotransplantation. The role of neonatal infant immunity in xenotransplantation is not, however, clearly understood. We examined both the proliferative responses of human neonatal lymphocytes to pig aortic endothelial cells and serum levels of neonatal natural antipig xenoantibody. Neonatal human lymphocytes and serum were isolated from umbilical cord blood. Adult human lymphocytes and serum were used as controls. A one-way xenogeneic mixed lymphocyte-endothelial cell reaction was performed, and lymphocyte proliferation was measured by tritiated thymidine uptake. Neonatal human lymphocytes recognized and proliferated in response to pig aortic endothelial cells (mean 63,926 +/- 26,054 counts per minute). The level of xenogeneic mixed lymphocyte-endothelial cell reaction of neonatal lymphocytes was significantly lower (p < 0.004) than that of adult human lymphocytes (mean 122,444 +/- 33,132 counts per minute). An enzyme-linked immunosorbent assay was performed to determine the binding of natural immunoglobulin M and G antibodies to pig endothelial cells. Whole-cell enzyme-linked immunosorbent assay demonstrated neonatal human serum to contain very low binding levels of natural antipig immunoglobulin M xenoantibody compared with adult serum. Like adult serum, neonatal human serum contained natural antipig immunoglobulin G xenoantibody. Neonatal serum was not cytotoxic to pig endothelial cells, suggesting that immunoglobulin G was not the predominant xenoreactive antibody. To assess whether neonatal pig endothelial cells also expressed xenoantigens, adult and neonatal cultured pig endothelial cells were examined by enzyme-linked immunosorbent assay with adult human serum. Adult human natural immunoglobulin M xenoantibody recognized not only adult pig endothelial cell xenoantigens but also neonatal pig endothelial cell xenoantigens. The binding levels of adult natural antipig immunoglobulin M xenoantibodies to adult and neonatal pig endothelial cells were similar, suggesting that neonatal pig aortic endothelial cells express xenoantigens. The findings of low binding levels of cytotoxic antipig immunoglobulin M xenoantibody and low levels of lymphocyte xenoreactivity to pig endothelial cells in human neonates suggests that pig organs may eventually be a suitable source of xenografts for human neonates.

Adult↗
PubMed1996

Effect of 9-(4-hydroxybutyl)-N2-phenylguanine (HBPG), a thymidine kinase inhibitor, on clinical recurrences of ocular herpetic keratitis in squirrel monkeys.

9-(4-Hydroxybutyl)-N2-phenylguanine (HBPG) is a new viral thymidine kinase inhibitor that we tested for the ability to prevent recurrences of herpetic keratitis. Eighteen squirrel monkeys (Saimiri scuireus) were infected in both corneas with the Rodanus strain of herpes simplex virus type 1 (HSV-1). All corneas showed typical dendritic keratitis 3 days after infection, followed by spontaneous healing. On day 21, the monkeys were randomized into two coded groups and ocular examinations were begun. One group received intraperitoneal (i.p.) injections of HBPG, 150 mg/kg, in a corn oil suspension every 8 h, and the other group received i.p. injections of the corn oil vehicle only. On day 22, recurrences were induced by reducing the temperature of the room in the late afternoon so that a low of 18 degrees C was achieved during the night. After the morning treatment, room temperature was raised to the normal ambient temperature (24-27 degrees C), and treatment was discontinued. Treatment was reinstituted on day 27, the room temperature was lowered again on day 28, and treatment was again discontinued as before. Third and fourth cycles of treatment and cold stress were begun on days 34 and 69. Ocular examinations were continued until day 73, at which point the code was broken. We found that the HBPG treatment significantly reduced the number of corneas with recurrences during the treatment periods, compared with recurrences in untreated, cold-stressed animals (P = 0.01).

Animals↗
PubMed1996

Low molecular weight IgM in healthy adults: influence of HLA.

Circulating LMW IgM was detected in a group of 100 healthy adults, but in very low or trace concentrations. A significant correlation was observed between total IgM and LMW IgM (r = 0.81, p < 0.01), which suggests that the presence of LMW IgM may be due to the "overspill" of LMW IgM during IgM synthesis and secretion. Significantly higher levels of LMW IgM and total IgM were found in females as compared with males. Furthermore, a weak association between A1, B8, DR3 and elevated IgM was also found. However the precise significance of this association is unclear.

Adolescent↗
PubMed1996

Msx3: a novel murine homologue of the Drosophila msh homeobox gene restricted to the dorsal embryonic central nervous system.

We have isolated Msx3, the third member of the murine Msx homeobox gene family which is homologous to the msh gene of Drosophila. The Msx3 cDNA encodes a protein of 204 amino acids which has striking regions of homology in addition to the homeodomain when compared to the other Msx family members. Msx3 maps to the distal end of mouse chromosome 7, thus it is unlinked to either Msx1 or Msx2. RNA in situ analysis of Msx3 gene expression during early development revealed that it is restricted to the dorsal portion of the neural tube with a rostral boundary in the rostral rhombencephalon. This sole expression domain for Msx3 overlaps with both Msx1 and Msx2 at early stages, but in older embryos, Msx3 expression becomes restricted to the ventricular zone of the dorsal neural tube, whereas Msx1 and Msx2 become localized to the non-neuronal roof plate region. The absence of detectable levels of Msx3 expression outside this restricted dorsal region of the developing central nervous system (CNS) is in marked contrast to Msx1 and Msx2, which have extensive expression domains in other embryonic tissues, particularly craniofacial structures and the limbs. By analogy with the expression of msh/Msx genes in other organisms, it is likely that one of the ancestral functions of the msh/Msx gene family is in patterning of the CNS.

Age Factors↗