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Biomedical subjects

B Lu

Publications and source records attributed to B Lu.

At least 37 records · Page 2Linked to original sources
PubMed2004

The relationship between full field electroretinogram and perimetry-like visual thresholds in RCS rats during photoreceptor degeneration and rescue by cell transplants.

Dark-adapted full field electroretinogram (ERG) and visual receptive field thresholds (recorded from the superior colliculus) were correlated in a model of retinal degeneration, the Royal College of Surgeons rat. In both untreated and retinal pigment epithelium cell transplanted rats, optimal correlation was between b-wave amplitude and preserved visual field area with thresholds under a defined level. The work shows that the magnitude of the b-wave can be used to predict the computed area and degree of visual field preservation recorded in the central nervous system. These observations validate using ERG to assess residual visual function and the effect of transplantation.

Animals↗
PubMed2004

Preservation of vision following cell-based therapies in a model of retinal degenerative disease.

This study examines whether subretinal transplantation of a human retinal pigment epithelial cell line (ARPE19) or human Schwann cells early in the course of degeneration can limit the loss of visual acuity that normally occurs in dystrophic Royal College of Surgeons (RCS) rats as they age. The acuity of both transplanted groups was significantly better than controls at all ages tested, though the rescue profile of each cell type was unique. These data indicate that the transplantation of cells with very different phenotypes can be used to limit the deterioration of spatial vision in an animal model of retinal degenerative disease.

Animals↗
PubMed2004

Transcriptional targeting of adenoviral vector through the CXCR4 tumor-specific promoter.

Adenoviral vectors are considered to be good gene delivery vectors for cancer gene therapy due to their wide host tissue range and cell cycle-independent infectivity. However, the disadvantages include the lack of specificity for cancer cells and the high liver accumulation in vivo. The human CXCR4 gene is expressed at high levels in many types of cancers, but is repressed in the liver. We explored the CXCR4 promoter as a candidate to restrict adenoviral transgene expression to tumor cells with a low expression in host tissues. The luciferase activities in multiple cancer cell lines infected with recombinant adenovirus reAdGL3BCXCR4 or the control vector reAdGL3BCMV revealed that the CXCR4 promoter exhibited relatively high transcriptional activity in a breast cancer cell line, MDA-MB-361, and two ovarian cancer cell lines, OVCAR-3 and SKOV3. ip1, 65% (P=0.0087), 16.7% (P=0.1) and 20% (P=0.0079) compared to that of the CMV promoter, respectively, and low expression, 4.9 and 0.1%, respectively, in both normal cell lines HFBC and HMEC. In addition, CXCR4 had a low expression of luciferase (0.32%) compared to that of the CMV promoter in mouse liver in vivo. The data also revealed that the CXCR4 promoter was a stronger tumor-specific promoter (TSP) than the Cox-2M promoter in primary melanomas obtained from two patients. The CXCR4 promoter is shown to have a 'tumor-on' and 'liver-off' status in vitro and in vivo, and CXCR4 may prove to be a good candidate TSP for cancer gene therapy approaches for melanoma and breast cancers.

Adenoviridae↗
PubMed2004

Prevention of angiogenesis by naked DNA IL-12 gene transfer: angioprevention by immunogene therapy.

IL-12 is thought to induce a cytokine cascade with antiangiogenic effects mediated by IFN-gamma and angiostatic CXCR3 chemokine ligands. Naked DNA intramuscular injection of an expression vector plasmid producing IL-12 resulted in significant, well-tolerated elevation of serum IL-12 levels. Injection of the IL-12 plasmid at least 2 days, and up to 20 days, before subcutaneous injection of matrigel with angiogenic factors resulted in strong prevention of angiogenesis in both C57/bl and nude mice. A single injection of the IL-12 plasmid contemporarily with the matrigel or 2 days after resulted in partial, statistically not significant, inhibition. Control plasmid injection did not affect either angiogenesis or angiogenesis inhibition by IL-12 protein in vivo. Angiogenesis inhibition was observed in NK cell-depleted C57/bl and nude mice as well as in IFN-gamma(-/-) and CXCR3(-/-) knockout mice, indicating that NK- and/or T-cell-initiated IFN-gamma-chemokine cascades were not involved in the angiogenesis inhibition observed in vivo. Finally, IL-12 plasmid DNA gene transfer significantly prevented the growth and vascularization of highly angiogenic KS-Imm Kaposi's sarcoma and TS/A murine mammary carcinoma tumors in nude and/or syngeneic mice. These data suggest that a preventive gene therapy approach using antiangiogenic cytokines can effectively inhibit tumor angiogenesis and KS, representing an example of angioimmunoprevention.

Animals↗
PubMed2004

Obesity and inequities in health in the developing world.

OBJECTIVE: To update the social distribution of women's obesity in the developing world and, in particular, to identify the specific level of economic development at which, if any, women's obesity in the developing world starts to fuel inequities in health. DESIGN: Multilevel logistic regression analyses applied to anthropometric and socioeconomic data collected by nationally representative cross-sectional surveys conducted from 1992 to 2000 in 37 developing countries within a wide range of world regions and stages of economic development (gross national product (GNP) from 190 to 4440 US dollars per capita). SUBJECTS: : In total, 148 579 nonpregnant women aged 20-49 y. MEASUREMENTS: Body mass index to assess obesity status; quartiles of years of education to assess woman's socioeconomic status (SES), and GNP per capita to assess country's stage of economic development. RESULTS: Belonging to the lower SES group confers strong protection against obesity in low-income economies, but it is a systematic risk factor for the disease in upper-middle income developing economies. A multilevel logistic model-including an interaction term between the country's GNP and each woman's SES-indicates that obesity starts to fuel health inequities in the developing world when the GNP reaches a value of about 2500 US dollars per capita. CONCLUSIONS: For most upper-middle income economies and part of the lower-middle income economies, obesity among adult women is already a relevant booster of health inequities and, in the absence of concerted national public actions to prevent obesity, economic growth will greatly expand the list of developing countries where this situation occurs.

Adult↗
PubMed2004

The use of gene therapy in cancer research and treatment.

Gene therapy involves identifying a gene of interest and then manipulating the expression of this gene through a variety of techniques. Here we specifically address gene therapy's role in cancer research. This paper will encompass thoroughly investigated techniques such as cancer vaccines and suicide gene therapy and the latest advancements in and applications of these techniques. It will also cover newer techniques such as Antisense Oligonucleotides and small interfering RNAs and how these technologies are being developed and used. The use of gene therapy continues to expand in cancer research and has an integral role in the advancement of cancer treatment.

Gene Expression Regulation, Neoplastic↗
PubMed2003

Lung-targeting microspheres of carboplatin.

Carboplatin (CPt) was incorporated in the gelatin microspheres by the method of emulsion and the drug content determined spectrophotometrically. The arithmetic mean diameter of the microspheres was 13.20 microm with 98% of the microspheres ranging from 5.0 to 28.6 microm. The average carboplatin content was 23.76% and the yield of the microspheres 85.12%. The microspheres were stable for three months when stored at 37 degrees C/RH 75%, showing insignificant change in appearance and drug content. The in vitro release profile of the microspheres could be described by a biexponential equation, and the release t(1/2) was 49.7 min and 92.04% released in 10h; while for the original drug, CPt, under the same conditions, 92.15% released in the first half an hour. Very high lung-targeting efficiency in vivo was proved by the results of targeting parameters. The S-180 lung neoplasm models were established by i.v. cancer cells in mice and the number of pulmonary nodules examined for evaluation of the treatment effect. The results of therapeutic tests showed that the antitumour effects were increased by injection of the microspheres compared with the injection of CPt solution: half of the dose in the microspheres showed comparable effect to the original drug.

Animals↗
PubMed2003

Putative functional characteristics of human estrogen receptor-beta isoforms.

Estrogen receptors (ERalpha and ERbeta) are clearly multifaceted in terms of structure and function. Several relatively abundant ERbeta isoforms have been identified, which can be differentially expressed in various tIssues. In order to provide insight into the possible role of the ERbeta family in breast tIssue a study of the putative functions of the human (h) ERbeta1, hERbeta2 and hERbeta5 isoforms was undertaken. Only hERbeta1 was found to bind ligand, which induced conformational changes as determined by protease digestion assays. All ERbeta isoforms could bind to and bend DNA although the relative efficiency with which they bound DNA differed with hERalpha>hERbeta1>hERbeta2>>hERbeta5. All ERbeta isoforms inhibited ERalpha transcriptional activity on an estrogen-response element (ERE)-reporter gene. The relative activities were hERbeta1>hERbeta2>hERbeta5; however, only hERbeta1 had transcriptional activity of its own. Both LY117018-hERalpha and LY117018-hERbeta1 complexes alone could activate transcription on a TGF-beta3-CAT gene. Although hERbeta2 and hERbeta5 had no activity alone, they inhibited ERalpha but not hERbeta1 transcriptional activity of transforming growth factor (TGF)-beta3-CAT. In marked contrast to activity on an ERE-CAT reporter gene, hERbeta1 did not modulate ERalpha transcriptional activity on a TGF-beta3-CAT reporter gene. These data support promoter-specific differential activities of hERbeta isoforms with respect to models of ERalpha regulated gene expression, and suggest that they may have a role in differentially modulating estrogen action.

Base Sequence↗
PubMed2002

Transplantation of EGF-responsive neurospheres from GFP transgenic mice into the eyes of rd mice.

The isolation of stem cells from various regions of the central nervous system has raised the possibility of using them as a donor cell source for cell transplantation, where they offer great promise for repair of the diseased brain, spinal cord, and retina. Here, we have studied the migration, integration, and differentiation of EGF-responsive neurospheres isolated from the brains of green fluorescent protein transgenic mice and transplanted into the eyes of mature rd mice, a model of retinitis pigmentosa. While grafts of freshly isolated postnatal day 8 retina expressed many markers characteristic of mature retina (e.g. rhodopsin, protein kinase C), very few of the grafted cells migrated into host retina. EGF-responsive neurospheres, conversely, readily migrated into and integrated with the remaining host retina, but showed a very limited ability to differentiate into mature retinal neurons. While the progenitor cells used here show remarkable ability to integrate with host retina and develop some attributes of retinal cells, the failure to fully differentiate into retinal cells suggests that they already express some level of terminal commitment that precludes using them to replace lost photoreceptors.

Animals↗
PubMed2002

Protective effects of neurokinin-1 receptor during colitis in mice: role of the epidermal growth factor receptor.

1. The role of substance P and its high affinity neurokinin-1 receptor in colitis has not been fully elucidated. We assessed the participation of neurokinin-1 receptor in colitis using the 2,4,6,-trinitrobenzensulphonic acid and dextran sulphate-induced animal models of colitis and genetically-engineered, neurokinin-1 receptor-deficient mice. 2. Clinical signs, macroscopic and histologic damage associated with 2,4,6,-trinitrobenzensulphonic acid (12 days) and dextran sulphate (5 days) colitis were more severe in neurokinin-1 deficient than in wild-type mice, while immunoreactivities for epidermal growth factor and its receptor were similar in the colon of both mice strains before and after colitis. 3. Substance P, dose-dependently induced intestinal fibroblast proliferation and enhanced epidermal growth factor-induced proliferation in intestinal fibroblasts isolated from wild-type, but not from neurokinin-1 receptor deficient mice. 4. Substance P-induced intestinal fibroblast proliferation required the presence of epidermal growth factor receptor with kinase activity. Furthermore, substance P induced epidermal growth factor tyrosine phosphorylation and activation in normal intestinal fibroblasts. 5. Our results indicate that in mice lacking the neurokinin - 1 receptor, substance P plays a protective role in prolonged experimental colitis.

Animals↗
PubMed2001

A quantitative method to measure telomerase activity by bioluminescence connected with telomeric repeat amplification protocol.

Telomerase is expected to be a new biomarker for cancer diagnosis. The telomeric repeat amplification protocol (TRAP) is a sensitive method to detect telomerase activity. However, TRAP and its modified protocols are not always suitable for measuring telomerase activity of a large number of clinical samples to diagnosis cancer because these methods generally require a time-consuming detection step such as gel electrophoresis. To improve the procedure for mass diagnosis, we applied bioluminescence to replace the detection step. Telomerase activity is measured by evaluating the amount of inorganic pyrophosphate generated in PCR amplification of telomerase elongation product, with use of the sensitive enzymatic luminometric inorganic pyrophosphate detection assay (ELIDA). TRAP connected with ELIDA (TRAP-ELIDA) can quantitatively detect telomerase activity within linearity from 2 to 1000 cell equivalents. The ELIDA signals accorded with results of TRAP-SYBR green staining, and the results of ELIDA were significantly correlated to those of TRAP connected with an enzyme-linked immunosorbent assay (TRAP-ELISA) (r(2) = 0.992, P < 0.001). TRAP-ELIDA is a simple and sensitive method to quantify telomerase activity without time-consuming gel electrophoresis. Because TRAP-ELIDA measures telomerase activity with a luminometer, it could be applied to a large number of clinical samples at the same time.

Adenosine Triphosphate↗
PubMed2001

Macrophage inflammatory protein-1alpha uses a novel receptor for primitive hemopoietic cell inhibition.

Macrophage inflammatory protein-1alpha (MIP-1alpha) is a member of the chemokine family of proinflammatory mediators. In addition to its inflammatory roles, MIP-1alpha has been shown to be active as an inhibitor of primitive hemopoietic cell proliferation. Indeed, a dysfunction in this inhibitory process has been postulated to contribute to leukemogenesis. Research has been aimed at characterizing the receptor involved in cellular inhibition by MIP-1alpha. This study demonstrates that of all the beta-chemokines tested, only MIP-1alpha is capable of inhibiting primitive hemopoietic cell proliferation. Because no MIP-1alpha-specific receptors have been identified, this suggests that inhibition is mediated by an uncharacterized receptor. Further evidence for the involvement of a novel receptor in this process is the equivalent potencies of MIP-1alphaS and MIP-1alphaP variants of human MIP-1alpha and the fact that primitive cells from bone marrow derived from individual MIP-1alpha receptor null mice display a full response to MIP-1alpha inhibition.

Animals↗
PubMed2001

Ca(2+) binding protein frequenin mediates GDNF-induced potentiation of Ca(2+) channels and transmitter release.

Molecular mechanisms underlying long-term neurotrophic regulation of synaptic transmission and plasticity are unknown. We report here that long-term treatment of neuromuscular synapses with glial cell line-derived neurotrophic factor (GDNF) potentiates spontaneous and evoked transmitter release, in ways very similar to presynaptic expression of the Ca(2+) binding protein frequenin. GDNF enhances the expression of frequenin in motoneurons, and inhibition of frequenin expression or activity prevents the synaptic action of GDNF. GDNF also facilitates Ca(2+) influx into the nerve terminals during evoked transmission by enhancing Ca(2+) currents. The effect of GDNF on Ca(2+) currents is blocked by inhibition of frequenin expression, occluded by overexpression of frequenin, and is selective to N-type Ca(2+) channels. These results identify an important molecular target that mediates the long-term, synaptic action of a neurotrophic factor.

Animals↗
PubMed2001

Protein synthesis-dependent and -independent regulation of hippocampal synapses by brain-derived neurotrophic factor.

A fundamental difference between short-term and long-term forms of synaptic plasticity is the dependence on transcription and translation of new genes. Using organotypic cultures of hippocampal slices, we have investigated whether the modulation of synapses by brain-derived neurotrophic factor (BDNF) also requires protein synthesis. Long-term treatment of hippocampal slice cultures with BDNF increased the number of docked vesicles, but not that of reserve pool vesicles, at CA1 excitatory synapses. BDNF also increased the levels of the vesicle proteins synaptophysin, synaptobrevin, and synaptotagmin, without affecting the presynaptic membrane proteins syntaxin and SNAP-25, or the vesicle-binding protein synapsin-I. The increase in synaptophysin and synaptobrevin expression was moderate (2-fold) and occurred within 6 h after BDNF application. In contrast, synaptotagmin expression took 24 h to reach maximum levels (5-fold). The delayed increase in synaptotagmin was blocked by protein synthesis inhibitors, while the early increase in synaptophysin and synaptobrevin was not. Moreover, the BDNF-induced increase of synaptotagmin was blocked by inhibiting the cAMP/protein kinase A (PKA) pathway. However, BDNF did not activate PKA, and application of a PKA activator did not mimic the BDNF effect. Taken together, these results suggest a novel, protein synthesis-dependent form of BDNF modulation that requires cAMP gating.

Animals↗
PubMed2001

Enhanced sensitivity of insulin-resistant adipocytes to vanadate is associated with oxidative stress and decreased reduction of vanadate (+5) to vanadyl (+4).

Vanadate (sodium orthovanadate), an inhibitor of phosphotyrosine phosphatases (PTPs), mimics many of the metabolic actions of insulin in vitro and in vivo. The potential of vanadate to stimulate glucose transport independent of the early steps in insulin signaling prompted us to test its effectiveness in an in vitro model of insulin resistance. In primary rat adipocytes cultured for 18 h in the presence of high glucose (15 mm) and insulin (10(-7) m), sensitivity to insulin-stimulated glucose transport was decreased. In contrast, there was a paradoxical enhanced sensitivity to vanadate of the insulin-resistant cells (EC(50) for control, 325 +/- 7.5 microm; EC(50) for insulin-resistant, 171 +/- 32 microm; p < 0.002). Enhanced sensitivity was also present for vanadate stimulation of insulin receptor kinase activity and autophosphorylation and Akt/protein kinase B Ser-473 phosphorylation consistent with more effective PTP inhibition in the resistant cells. Investigation of this phenomenon revealed that 1) depletion of GSH with buthionine sulfoximine reproduced the enhanced sensitivity to vanadate while preincubation of resistant cells with N-acetylcysteine (NAC) prevented it, 2) intracellular GSH was decreased in resistant cells and normalized by NAC, 3) exposure to high glucose and insulin induced an increase in reactive oxygen species, which was prevented by NAC, 4) EPR (electron paramagnetic resonance) spectroscopy showed a decreased amount of vanadyl (+4) in resistant and buthionine sulfoximine-treated cells, which correlated with decreased GSH and increased vanadate sensitivity, while total vanadium uptake was not altered, and 5) inhibition of recombinant PTP1B in vitro was more sensitive to vanadate (+5) than vanadyl (+4). In conclusion, the paradoxical increased sensitivity to vanadate in hyperglycemia-induced insulin resistant adipocytes is due to oxidative stress and decreased reduction of vanadate (+5) to vanadyl (+4). Thus, sensitivity of PTP inhibition and glucose transport to vanadate is regulated by cellular redox state.

Acetylcysteine↗
PubMed2001

Metabolic regulation of brain Abeta by neprilysin.

Amyloid beta peptide (Abeta), the pathogenic agent of Alzheimer's disease (AD), is a physiological metabolite in the brain. We examined the role of neprilysin, a candidate Abeta-degrading peptidase, in the metabolism using neprilysin gene-disrupted mice. Neprilysin deficiency resulted in defects both in the degradation of exogenously administered Abeta and in the metabolic suppression of the endogenous Abeta levels in a gene dose-dependent manner. The regional levels of Abeta in the neprilysin-deficient mouse brain were in the distinct order of hippocampus, cortex, thalamus/striatum, and cerebellum, where hippocampus has the highest level and cerebellum the lowest, correlating with the vulnerability to Abeta deposition in brains of humans with AD. Our observations suggest that even partial down-regulation of neprilysin activity, which could be caused by aging, can contribute to AD development by promoting Abeta accumulation.

Aging↗
PubMed2001

Replacement of segmental bone defects using porous bioceramic cylinders: a biomechanical and X-ray diffraction study.

A porous ceramic material [hydroxyapatitetricalcium phosphate (HA-TCP)] was implanted in the femora of 30 dogs to investigate the possibility of using this material to repair segmental bone defects. A bone segment, 1.5 cm in length, was removed from the diaphysis of one femur in each dog to create the defect. Cylinders of corresponding size were inserted into the defects. The animals were divided into three groups with recovery times of 2 months, 4 months, and 6 months, respectively. The implants were harvested and subjected to biomechanic tests (bending strength) and X-ray diffraction analysis. The bending strengths of the implant construct increased gradually over time postoperatively. The values of strength for the three different time groups had significant variations (p < 0.05). The X-ray diffraction analysis indicated that the peaks of the TCP included in the cylinders decreased in intensity after implantation and tended to be similar to those of natural bone by 6 months after operation. Conversely, the peaks for the HA had fewer changes compared with preimplantation values. Based on the results of this experiment it was concluded that the porous HA-TCP ceramic cylinders have potential for repair of segmental bone defects if assisted by adequate stabilizing fixtures during the early postoperative period.

Animals↗