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Liping Wang

Publications and source records attributed to Liping Wang.

At least 37 records · Page 2Linked to original sources
PubMed2006

VEGF C2578A polymorphism does not contribute to amyotrophic lateral sclerosis susceptibility in sporadic Chinese patients.

A linkage and association of the VEGF (vascular endothelial growth factor) C2578A polymorphism and amyotrophic lateral sclerosis (ALS) has been found in some studies. We analysed the C2578A polymorphism in sporadic ALS patients from a Chinese population. The polymorphism was analysed in 115 patients and 200 healthy individuals by amplifying across position 2705 to 2494 of the promoter region of the VEGF gene. It was found that the frequency of the allele A was 24% in ALS patients and 28% in healthy individuals (p = 0.264). Comparing the background of this polymorphism in healthy individuals between Chinese and Caucasians, significant decreases were found in the frequencies of the A/A genotype and allele A (p(s)<0.001). We concluded that VEGF C2578A polymorphism did not confer a susceptibility to sporadic Chinese ALS patients, which was in disagreement with that reported previously in Caucasian populations and might be ascribed to the different genetic background between Chinese and Caucasians.

Adult↗
PubMed2006

Regulation of growth plate chondrocytes by 1,25-dihydroxyvitamin D3 requires caveolae and caveolin-1.

UNLABELLED: We examined the role of caveolae and caveolin-1 in the mechanism of 1alpha,25(OH)(2)D(3) action in growth plate chondrocytes. We found that caveolae are required for rapid 1alpha,25(OH)(2)D(3)-dependent PKC signaling, and caveolin-1 must be present based on studies using chondrocytes from Cav-1(-/-) mice. INTRODUCTION: 1,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)] regulates endochondral ossification in part through membrane-associated mechanisms, including protein kinase C (PKC) signaling activated by a membrane-associated 1alpha,25(OH)(2)D(3)-binding protein, ERp60. We tested the hypothesis that caveolae are required for 1alpha,25(OH)(2)D(3) action and play an important role in regulating chondrocyte biology and growth plate physiology. MATERIALS AND METHODS: Rat costochondral chondrocytes were examined for caveolae by transmission electron microscopy of cultured cells and of cells in situ. Western blots and confocal microscopy were used to detect caveolae proteins including caveolin-1 (Cav-1) and 1alpha,25(OH)(2)D(3) receptors. Caveolae cholesterol was depleted with beta-cyclodextrin (CD) and effects of 1alpha,25(OH)(2)D(3) on PKC, DNA synthesis, alkaline phosphatase, and proteoglycan production determined. Chondrocytes from Cav-1(-/-) and C57BL/6 wildtype mice were also treated with 1alpha,25(OH)(2)D(3). Epiphyses and costochondral junctions of 8-week-old male Cav-1(-/-) and wildtype mice (N = 8) were compared by histomorphometry and microCT. Data were analyzed by ANOVA and Bonferroni for posthoc comparisons. RESULTS: Growth zone chondrocytes had caveolae and Cav-1, -2, and -3. Resting zone chondrocytes, which do not exhibit a rapid 1alpha,25(OH)(2)D(3)-dependent increase in PKC activity, also had these caveolins, but caveolae were larger and fewer in number. ERp60 but not VDR co-localized with Cav-1 in plasma membranes and in lipid rafts. CD-treatment blocked 1alpha,25(OH)(2)D(3) effects on all parameters tested. The Cav-1(-/-) cells did not respond to 1alpha,25(OH)(2)D(3), although 1alpha,25(OH)(2)D(3) increased PKC, alkaline phosphatase, and [(35)S]-sulfate incorporation in wildtype C57BL/6 cells. Histology and microCT showed that Cav-1(-/-) growth plates were longer and had more hypertrophic cells in each column. Growth plate changes were reflected in the metaphysis. CONCLUSIONS: The membrane-mediated effects of 1alpha,25(OH)(2)D(3) require caveolae and Cav-1, and Cav-1 deficiency results in altered growth plate physiology.

Animals↗
PubMed2006

[Voice change and acoustic character of essential voice tremor].

OBJECTIVE: To discuss the voice change and acoustic character of essential voice tremor. METHOD: Observations and acoustic studies were performed about clinical manifestations and voice of 18 patients with essential voice tremor. RESULT: In 18 patients with essential voice tremor, female accounts for 72% (13/18 cases). The mean age at tremor onset was 57 years old . And 8900 of them had no neurologic abnormalities. The clinical manifestation includes voice tremor, dysphonia, even frequent voice interruption. The laryngeal body happens to regular tremor in automatically. Bilateral vocal cords, ventricular cords and arytenoid cartilages also tremble regularly open and closed, together with the tremor of voice-producing organs(soft palate, tongue and lateral pharyngeal wall). The frequency of voice tremor is 4-6 Hz. The acoustic analysis characteristics of voice is the obvious increasing of Shimmer, presenting the specific change of the parameters such as soft phonation index (SPI), degree of voiceless (DUV), degree of voice breaks (DVB), FO tremor intensity index (FTRI) and Amplitude Tremor Intensity Index (ATRI). CONCLUSION: The voice change of essential voice tremor is a kind of regular tremor with low frequency. For the severe patients, it shows dysphonia and frequent voice interruption.

Acoustics↗
PubMed2005

Plasma membrane requirements for 1alpha,25(OH)2D3 dependent PKC signaling in chondrocytes and osteoblasts.

1,25-Dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)] acts on chondrocytes and osteoblasts through traditional nuclear Vitamin D receptor (VDR) mechanisms as well as through rapid actions on plasma membranes that initiate intracellular signaling pathways. We have investigated the mechanisms involved in activation of protein kinase C (PKC) and downstream biological responses that depend on the latter pathway. These studies show that PKC activation depends on presence of a membrane receptor ERp60 and rapid increases in phospholipase A(2) (PLA(2)) activity. Cells that are responsive to 1alpha,25(OH)(2)D(3) express PLA(2) activating protein (PLAA), suggesting a link between ERp60 and PLA(2). Increased PLA(2) results in increased arachidonic acid release and formation of lysophospholipid, which then activates phospholipase C beta (PLCbeta), leading to rapid formation of inositol-trisphosphate (IP3) and diacylglycerol (DAG). PLA(2), PLC, and DAG are all associated with lipid rafts including caveolae in many cells, suggesting that the caveolar environment may be an important mediator of PKC activation by 1alpha,25(OH)(2)D(3). Here, we use the VDR(-/-) mouse costochondral cartilage growth plate to examine the expression of ERp60 and PLAA in vivo in 1alpha,25(OH)(2)D(3)-responsive hypertrophic chondrocytes (growth zone cells) and in resting zone cells that do not respond to this Vitamin D metabolite in vitro. In addition, we determined if intact lipid rafts are required for the response of rat costochondral cartilage growth zone cells to 1alpha,25(OH)(2)D(3). The results show that ERp60 and PLAA are localized to 1alpha,25(OH)(2)D(3)-responsive growth zone cells and metaphyseal osteoblasts, even in VDR(-/-) mice. Disruption of lipid rafts using beta-cyclodextrin blocks the activation of PKC by 1alpha,25(OH)(2)D(3) and reduces the ability of 1alpha,25(OH)(2)D(3) to regulate [(35)S]-sulfate incorporation.

Animals↗
PubMed2005

Structure-guided synthesis of tamoxifen analogs with improved selectivity for the orphan ERRgamma.

The design and synthesis of 4-hydroxytamoxifen (4-OHT) derivatives are described. The binding affinities of these compounds toward the orphan estrogen-related receptor gamma and the classical estrogen receptor alpha demonstrate that analogs bearing hydroxyalkyl groups display improved binding selectivity profiles compared with that of 4-OHT. An X-ray crystal structure of one of the designed compounds bound to ERRgamma LBD confirms the molecular basis of the selectivity.

Binding Sites↗
PubMed2005

Loop entropy and cytochrome c stability.

The loop entropy model proposes that loop closure in a protein becomes entropically more costly as the length of the loop increases. A model protein, cytochrome c, is composed of four loops connecting five helices surrounding a heme-containing core. To test the loop entropy model a series of mutant proteins are constructed with (Gly)n or (Thr)n segments (n = 4-20) inserted between Gly23 and Gly24 of omega loop A of a pseudo wild-type reference protein. Scanning calorimetry shows that protein stability decreases as n increases in the (Gly)n or (Thr)n segment. The dependence of stability on loop length is analyzed with the loop entropy model. Fitting to the model gives a quantitative description of stability differences for the mutant proteins, but with a smaller power-dependence of the probability of loop closure (c-value) than expected from polymer theory. A possible explanation for the discrepancy is that thermodynamically unfavorable loop entropy is partially offset by interactions between the inserted homopolymer and flanking heteropolymer portions of the unfolded protein. The interactions may involve molecular crowding that favors coalescence of the heteropolymer at the insert site and thus closure of the homopolymer loops, possibly as an aspect of the folding code. This may allow use of loop insert mutants to assess the strength of the heteropolymer-encoded folding signals that facilitate loop closure at the insert site.

Amino Acid Sequence↗
PubMed2005

Heterogeneity of engrafted bone-lining cells after systemic and local transplantation.

The outcome of various osteoprogenitor-cell transplantation protocols was assessed using Col1a1-GFP reporter transgenic mice. The model requires the recipient mice to undergo lethal total body irradiation (TBI) followed by rescue with whole bone marrow. When the mice are rescued with total bone marrow from a Col1a1-GFP transgenic mouse, green fluorescence protein (GFP)-positive donor cells can be observed on most endosteal and trabecular bone surfaces. Although the cells express an osteoblast-restricted GFP, they fail to progress to osteocytes, do not form a mineralized matrix, and do not generate bone nodules in vitro. However when calvarial progenitor cells derived from the same transgenic mice are injected into the bone marrow space, osteogenesis by the donor cells is observed. Using different GFP colors that distinguish the donor and recipient osteoblasts, commingling of the 2 cells types is observed along the mineralizing osteoblast surface as well as within the osteocyte population of the endosteal bone. Despite the ability of the injected progenitor cells to produce bone within the injected bone, they lack the ability to form mineralized bone nodules when explanted to primary osteoblast culture. These reagents and imaging protocols will be useful in evaluating other cells having a better progenitor potential than calvarial-derived stromal cells.

Animals↗
PubMed2005

Functional expression of the ecto-ATPase NTPDase2 and of nucleotide receptors by neuronal progenitor cells in the adult murine hippocampus.

An astrocyte-like cell population corresponding to residual radial glia represents the neuronal progenitors of the adult mammalian hippocampus. We show that radial glia-like cells of the dentate gyrus express surface-located ATP-hydrolyzing activity and are immunopositive for NTPDase2. This enzyme hydrolyzes extracellular nucleoside triphosphates such as ATP and UTP to their nucleoside diphosphates and is thus involved in the control of signaling via P2 receptors. NTPDase2 is expressed from embryonic day 17 onward. In the hippocampus, the embryonic pattern of NTPDase2 expression mirrors that of the dentate migration of neuroblasts. Double-immunolabeling revealed that NTPDase2 is associated with subpopulations of glial fibrillary acidic protein-, nestin- and doublecortin-positive radial cells. It is absent from mature granule cells or S100-positive astrocytes. NTPDase2-positive cells proliferate. Furthermore, after mitosis, progenitor cells preferentially reveal an NTPDase2-positive phenotype. Patch-clamp analysis demonstrates functional nucleotide receptors in progenitor cells expressing nestin promotor-driven green fluorescent protein. Our results identify the ecto-nucleotidase NTPDase2 and functional P2X receptors at hippocampal progenitor cells. We infer that signaling pathways via extracellular nucleotides may play a role in the control of hippocampal neurogenesis.

Adenosine Triphosphatases↗
PubMed2005

Novel 4-amino-furo[2,3-d]pyrimidines as Tie-2 and VEGFR2 dual inhibitors.

A novel class of furo[2,3-d]pyrimidines has been discovered as potent dual inhibitors of Tie-2 and VEGFR2 receptor tyrosine kinases (TK) and a diarylurea moiety at 5-position shows remarkably enhanced activity against both enzymes. One of the most active compounds, 4-amino-3-(4-((2-fluoro-5-(trifluoromethyl)phenyl)amino-carbonylamino)phenyl)-2-(4-methoxyphenyl)furo[2,3-d]pyrimidine (7k) is <3 nM on both TK receptors and the activity is rationalized based on the X-ray crystal structure.

3T3 Cells↗
PubMed2005

Discovery and evaluation of 2-anilino-5-aryloxazoles as a novel class of VEGFR2 kinase inhibitors.

A series of derivatives of 2-anilino-5-phenyloxazole (5) has been identified as inhibitors of VEGFR2 kinase. Herein we describe the structure-activity relationship (SAR) of this novel template. Optimization of both aryl rings led to very potent inhibitors at both the enzymatic and cellular levels. Oxazole 39 had excellent solubility and good oral PK when dosed as the bis-mesylate salt and demonstrated moderate in vivo efficacy against HT29 human colon tumor xenografts. X-ray crystallography confirmed the proposed binding mode, and comparison of oxazoles 39 and 46 revealed interesting differences in orientation of 2-pyridyl and 3-pyridyl rings, respectively, attached at the meta position of the 5-phenyl ring.

Adenosine Triphosphate↗
PubMed2005

(2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.

A novel series of beta-amino amides incorporating fused heterocycles, i.e., triazolopiperazines, were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (1) is a potent, orally active DPP-IV inhibitor (IC(50) = 18 nM) with excellent selectivity over other proline-selective peptidases, oral bioavailability in preclinical species, and in vivo efficacy in animal models. MK-0431, the phosphate salt of compound 1, was selected for development as a potential new treatment for type 2 diabetes.

Administration, Oral↗
PubMed2005

A rare Cu/Zn superoxide dismutase mutation causing familial amyotrophic lateral sclerosis with variable age of onset and incomplete penetrance in China.

More than 100 mutations in the Cu/Zn superoxide dismutase (SOD) gene have been found, accounting for about 20% of familial ALS (FALS). However, few have been identified in Chinese patients with FALS. We present a five-generation Chinese family with FALS with a rare mutation in exon 4 of the Cu/Zn SOD gene codon position 105, converting serine to leucine. Forty-seven family members including the proband were examined clinically; two affected persons had EMG and nerve conduction studies. Genomic DNA was extracted from peripheral blood leukocytes of the family members after informed consent. All five exons of the Cu/Zn SOD gene were amplified by polymerase chain reaction (PCR) and DNA sequencing was performed on purified products. Exon 4 of the Cu/Zn SOD gene was amplified from genomic DNA isolated from not only the family members but also from 50 unrelated healthy Chinese control subjects. A rare S105L mutation, which is heterozygous with C by T at position 1,125 of the coding sequence in exon 4 of the Cu/Zn SOD gene, was found in the proband and her affected elder brother. The clinical phenotype within the FALS patients in this family is relatively variable. The age at onset ranged from 32 to 65 years, with initial symptoms in either the upper or lower extremities in different family members. Two subjects aged 72 and 60 years remained asymptomatic until their death from other causes, although their offspring carrying the same mutation have already developed clinical evidence of the disease. The S105L mutation was identified in another seven asymptomatic family members, aged 7 to 59 years. It is concluded that the S105L mutation in exon 4 of the Cu/Zn SOD gene is pathogenic. The phenotype is characterized by relatively variable clinical symptoms, with incomplete penetrance.

Adolescent↗
PubMed2005

Functional mimicry of a human immunodeficiency virus type 1 coreceptor by a neutralizing monoclonal antibody.

Interaction of the human immunodeficiency virus type 1 (HIV-1) gp120 envelope glycoprotein with the primary receptor, CD4, promotes binding to a chemokine receptor, either CCR5 or CXCR4. The chemokine receptor-binding site on gp120 elicits CD4-induced (CD4i) antibodies in some HIV-1-infected individuals. Like CCR5 itself, the CD4i antibody 412d exhibits a preference for CCR5-using HIV-1 strains and utilizes sulfated tyrosines to achieve binding to gp120. Here, we show that 412d binding requires the gp120 beta19 strand and the base of the V3 loop, elements that are important for the binding of the CCR5 N terminus. Two gp120 residues in the V3 loop base determined 412d preference for CCR5-using HIV-1 strains. A chimeric molecule in which the 412d heavy-chain third complementarity-determining loop sequence replaces the CCR5 N terminus functioned as an efficient second receptor, selectively supporting the entry of CCR5-using HIV-1 strains. Sulfation of N-terminal tyrosines contributed to the function of this chimeric receptor. These results emphasize the close mimicry of the CCR5 N terminus by the gp120-interactive region of a naturally elicited CD4i antibody.

Amino Acid Sequence↗
PubMed2004

Bioprocessing strategies to improve heterologous protein production in filamentous fungal fermentations.

Filamentous fungi have long been used for the production of metabolites and enzymes. With developments in genetic engineering and molecular biology, filamentous fungi have also achieved increased attention as hosts for recombinant DNA. However, the production levels of non-fungal proteins are usually low. Despite the achievements obtained using molecular tools, the heterologous protein loss caused by extracellular fungal protease degradation persists. This review provides an overview of the potential bioprocessing strategies that can be applied to inhibit protease activity thereby enhancing heterologous protein production.

Bioreactors↗
PubMed2004

Neutralization sensitivity of a simian-human immunodeficiency virus (SHIV-HXBc2P 3.2N) isolated from an infected rhesus macaque with neurological disease.

Simian-human immunodeficiency virus (SHIV) chimerae, after in vivo passage in monkeys, can induce acquired immunodeficiency syndrome (AIDS)-like illness and death. A monkey infected with the molecularly cloned, pathogenic SHIV-HXBc2P 3.2 exhibited multifocal granulomatous pneumonia as well as progressive neurological impairment characterized by tremors and pelvic limb weakness. SHIV-HXBc2P 3.2N was isolated from brain tissue explants and characterized. Viruses with the envelope glycoproteins of SHIV-HXBc2P 3.2N exhibited increased sensitivity to soluble CD4 and several neutralizing antibodies compared with viruses with the parental SHIV-HXBc2P 3.2 envelope glycoproteins. By contrast, viruses with SHIV-HXBc2P 3.2 and SHIV-HXBc2P 3.2N envelope glycoproteins were neutralized equivalently by 2G12 and 2F5 antibodies, which are rarely elicited in HIV-1-infected humans. A constellation of changes involving both gp120 and gp41 envelope glycoproteins was responsible for the difference in susceptibility to neutralization by most antibodies. Surprisingly, the gain of an N-linked glycosylation site in the gp41 ectodomain contributed greatly to neutralization sensitivity. Thus, the environment of the central nervous system, particularly in the context of immunodeficiency, allows the evolution of immunodeficiency viruses with greater susceptibility to neutralization by antibodies.

Amino Acid Sequence↗
PubMed2004

Small-molecule inhibitors of HIV-1 entry block receptor-induced conformational changes in the viral envelope glycoproteins.

When interacting with the CD4 receptor, the HIV gp120 envelope glycoprotein undergoes conformational changes that allow binding to the chemokine receptor. Receptor binding is proposed to lead to conformational changes in the gp41 transmembrane envelope glycoprotein involving the creation and/or exposure of a coiled coil consisting of three heptad repeat (HR) sequences. The subsequent interaction of the HR2 region of gp41 with this coiled coil results in the assembly of a six-helix bundle that promotes the fusion of the viral and target cell membranes. Here we show that CD4 binding to gp120 induces the formation and/or exposure of the gp41 HR1 coiled coil in a process that does not involve gp120 shedding and that depends on the proteolytic maturation of the gp160 envelope glycoprotein precursor. Importantly, BMS-806 and related HIV-1 entry inhibitors bind gp120 and block the CD4 induction of HR1 exposure without significantly affecting CD4 binding. Moreover, these compounds do not disrupt gp120-chemokine receptor binding or the HR1-HR2 interaction within gp41. These studies thus define a receptor-induced conformational rearrangement of gp120-gp41 that is important for both CD4-dependent and CD4-independent HIV-1 entry and is susceptible to inhibition by low-molecular-weight compounds.

Cell Line↗