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Biomedical subjects

Lin Wang

Publications and source records attributed to Lin Wang.

At least 127 records · Page 7Linked to original sources
PubMed2005

Doxycycline attenuates and delays toxicity of the oculopharyngeal muscular dystrophy mutation in transgenic mice.

The muscular dystrophies are a heterogeneous group of disorders for which there are currently no cures. Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant late-onset, progressive disease that generally presents in the fifth or sixth decade with dysphagia, ptosis and proximal limb weakness. OPMD is caused by the abnormal expansion of a (GCG)n trinucleotide repeat in the coding region of the poly-(A) binding protein nuclear 1 (PABPN1) gene. In unaffected individuals, (GCG)6 codes for the first six alanines in a homopolymeric stretch of ten alanines. In most individuals with OPMD this (GCG)6 repeat is expanded to (GCG)8-13, leading to a stretch of 12-17 alanines in mutant PABPN1. PABPN1 with an expanded polyalanine tract forms aggregates consisting of tubular filaments within the nuclei of skeletal muscle fibers. We have developed a transgenic mouse model of OPMD that manifests progressive muscle weakness accompanied by intranuclear aggregates and TUNEL-stained nuclei in skeletal muscle fibers. The onset and severity of these abnormalities were substantially delayed and attenuated by doxycycline treatment, which may exert its therapeutic effect by reducing aggregates and by distinct antiapoptotic properties. Doxycycline may represent a safe and feasible therapeutic for this disease.

Animals↗
PubMed2005

Effective antitumour mono- and combination therapy by gene delivery of angiostatin-like molecule and interleukin-12 in a murine hepatoma model.

METHODS: We applied an experimental approach employing two recombinant adenoviral vectors (Ad) that express interleukin-12 (IL-12) and angiostatin-like molecule (K1-3) respectively to a subcutaneous hepatoma model in mice. RESULTS: Injection of AdK1-3 into tumour nodules established by subcutaneous (s.c.) implantation of Hepa129 hepatoma cells in C3H mice resulted in a significant dose-dependent reduction in tumour growth by 57% in the high dosage group (5x10(9) plaque-forming units [pfu], n=8) 10 days after treatment initiation. Similar antitumoural effects were found for the intratumoural mono-therapy with IL-12 (2.5x10(9) pfu, n=8) resulting in 60% tumour inhibition at the same time point. The survival rate was significantly (p=0.009) improved in the IL-12 but not in the K1-3 treatment group. A combination therapy of AdK1-3 and AdIL-12 was also effective, but did not further improve antitumour efficacy compared with the monotherapy. CONCLUSION: In conclusion, both mono- and combination therapy of K1-3 and IL-12 significantly inhibited tumour progression in this experimental tumour model. The co-administration of both compounds did not result in additive antitumour effects. We hypothesise that the lack of additive antitumour effects of the combination treatment might be attributed to partially counteracting antitumour effects and further studies are needed to illustrate the interference of tumour angiogenesis and tumour inflammation in this tumour model.

Adenoviridae↗
PubMed2005

Altered T helper 1 reaction but not increase of virus load in patients with dengue hemorrhagic fever.

To investigate whether dengue-2 patients with and without dengue hemorrhagic fever had different virus load, immune mediators, or T helper (Th) reaction, we simultaneously measured virus load, immune mediators and the Th1/Th2 transcription factors T-bet/GATA-3 mRNA expression in a large outbreak of dengue-2 infections in Southern Taiwan. Results showed that virus load was not significantly different between patients with and without dengue hemorrhagic fever. Patients with dengue fever had higher IFN-gamma levels, but patients with dengue hemorrhagic fever had significantly higher IL-10 levels. Further studies showed that patients with dengue hemorrhagic fever had a significantly lower T-bet than those with dengue fever, but GATA-3 mRNA expression in peripheral blood leukocytes was not significant difference between both groups. In conclusion, altered Th1 reaction as reflected by lower T-bet mRNA expression associated with higher IL-10 levels might be involved in the pathogenesis of dengue hemorrhagic fever.

Adult↗
PubMed2005

Collagen alpha1(I) gene (COL1A1) is repressed by RFX family.

Collagen type I is composed of three polypeptide chains transcribed from two separate genes (COL1A1 and COL1A2) with different promoters requiring coordinate regulation. Our recent publications, centering on COL1A2 regulation, demonstrate that methylation in the first exon of COL1A2 at a regulatory factor for X box (RFX) site (at -1 to +20) occurs in human cancer cells and correlates with increased RFX1 binding and decreased collagen transcription (Sengupta, P. K., Erhlich, M., and Smith, B. D. (1999) J. Biol. Chem. 274, 36649-36655; Sengupta, S., Smith, E. M., Kim, K., Murnane, M. J., and Smith, B. D. (2003) Cancer Res. 63, 1789-1797). In normal cells, RFX5 complex along with major histocompatibility class II transactivator (CIITA) is induced by interferon-gamma to occupy this site and repress collagen transcription (Xu, Y., Wang, L., Buttice, G., Sengupta, P. K., and Smith, B. D. (2004) J. Biol. Chem. 279, 41319-41332). In this paper, we demonstrate that COL1A1 has an RFX consensus binding site surrounding the transcription start site (-11 to +10) that contains three methylation sites rather than one in the COL1A2 gene RFX binding site. RFX1 interacts weakly with the unmethylated COL1A1 site, and binds with higher affinity to the methylated site. RFX1 represses the unmethylated COL1A1 less efficiently than COL1A2. COL1A1 promoter activity is sensitive to DNA methylation and the COL1A1 gene is methylated in human cancer cells with coordinately decreased collagen expression. The DNA methylation inhibitor, 5-aza-2'-deoxycytidine (aza-dC) increases collagen gene expression with time in human cancer cells. On the other hand, RFX5 interacts with both collagen type I genes with a similar binding affinity and represses both promoters equally in transient transfections. Two dominant negative forms of RFX5 activate both collagen genes coordinately. Finally, CIITA RNA interference experiments indicate that CIITA induction is required for interferon gamma-mediated repression of both collagen type I genes.

Animals↗
PubMed2005

SNPHunter: a bioinformatic software for single nucleotide polymorphism data acquisition and management.

BACKGROUND: Single nucleotide polymorphisms (SNPs) provide an important tool in pinpointing susceptibility genes for complex diseases and in unveiling human molecular evolution. Selection and retrieval of an optimal SNP set from publicly available databases have emerged as the foremost bottlenecks in designing large-scale linkage disequilibrium studies, particularly in case-control settings. RESULTS: We describe the architectural structure and implementations of a novel software program, SNPHunter, which allows for both ad hoc-mode and batch-mode SNP search, automatic SNP filtering, and retrieval of SNP data, including physical position, function class, flanking sequences at user-defined lengths, and heterozygosity from NCBI dbSNP. The SNP data extracted from dbSNP via SNPHunter can be exported and saved in plain text format for further down-stream analyses. As an illustration, we applied SNPHunter for selecting SNPs for 10 major candidate genes for type 2 diabetes, including CAPN10, FABP4, IL6, NOS3, PPARG, TNF, UCP2, CRP, ESR1, and AR. CONCLUSION: SNPHunter constitutes an efficient and user-friendly tool for SNP screening, selection, and acquisition. The executable and user's manual are available at http://www.hsph.harvard.edu/ppg/software.htm

Algorithms↗
PubMed2005

Transient oscillations induced by delayed growth response in the chemostat.

In this paper, in order to try to account for the transient oscillations observed in chemostat experiments, we consider a model of single species growth in a chemostat that involves delayed growth response. The time delay models the lag involved in the nutrient conversion process. Both monotone response functions and nonmonotone response functions are considered. The nonmonotone response function models the inhibitory effects of growth response of certain nutrients when concentrations are too high. By applying local and global Hopf bifurcation theorems, we prove that the model has unstable periodic solutions that bifurcate from unstable nonnegative equilibria as the parameter measuring the delay passes through certain critical values and that these local periodic solutions can persist, even if the delay parameter moves far from the critical (local) bifurcation values. When there are two positive equilibria, then positive periodic solutions can exist. When there is a unique positive equilibrium, the model does not have positive periodic oscillations and the unique positive equilibrium is globally asymptotically stable. However, the model can have periodic solutions that change sign. Although these solutions are not biologically meaningful, provided the initial data starts close enough to the unstable manifold of one of these periodic solutions they may still help to account for the transient oscillations that have been frequently observed in chemostat experiments. Numerical simulations are provided to illustrate that the model has varying degrees of transient oscillatory behaviour that can be controlled by the choice of the initial data.

Biological Clocks↗
PubMed2005

Schistosoma japonicum migration through mouse skin compared histologically and immunologically with S. mansoni.

The migration of Schistosoma japonicum and S. mansoni through mouse skin epidermis and dermis was compared by immunofluorescence techniques from 4 to 22 h after infection. At all times, the percentage of parasites detected in the dermis was significantly higher for S. japonicum than for S. mansoni. Thus, S. japonicum migrates more rapidly very early after infection. This agrees with the quicker migration observed previously by this species for later times. Both species expressed antigens related to the cercarial glycocalyx on the parasite body and antigenically detectable elastase in the acetabular glands, at least until 22 h after infection. Bot sets of antigens were also left as "traces" in cercarial migration channels in the skin as well as in skin tissue in the absence of detectable worms or migration channels. The data further substantiate differences between schistosome species in the speed of migration, and suggest that glycocalyx-related antigens and cercarial elastase continue to be expressed for at least 1 day after infection.

Animals↗
PubMed2005

Monolayer-multilayer transitions in a lung surfactant model: IR reflection-absorption spectroscopy and atomic force microscopy.

A hydrophobic pulmonary surfactant protein, SP-C, has been implicated in surface-associated activities thought to facilitate the work of breathing. Model surfactant films composed of lipids and SP-C display a reversible transition from a monolayer to surface-associated multilayers upon compression and expansion at the air/water (A/W) interface. The molecular-level mechanics of this process are not yet fully understood. The current work uses atomic force microscopy on Langmuir-Blodgett films to verify the formation of multilayers in a dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylglycerol, cholesterol, and SP-C model system. Isotherms of SP-C-containing films are consistent with exclusion and essentially complete respreading during compression and expansion, respectively. Multilayer formation was not detected in the absence of SP-C. Most notable are the results from IR reflection-absorption spectroscopy (IRRAS) conducted at the A/W interface, where the position and intensity of the Amide I band of SP-C reveal that the predominantly helical structure changes its orientation in monolayers versus multilayers. IRRAS measurements indicate that the helix tilt angle changed from approximately 80 degrees in monolayers to a transmembrane orientation in multilayers. The results constitute the first quantitative measure of helix orientation in mixed monolayer/multilamellar domains at the A/W interface and provide insight into the molecular mechanism for SP-C-facilitated respreading of surfactant.

Lipid Bilayers↗
PubMed2005

Endoproteolytic cleavage of FE65 converts the adaptor protein to a potent suppressor of the sAPPalpha pathway in primates.

Adaptor protein FE65 (APBB1) specifically binds to the intracellular tail of the type I transmembrane protein, beta-amyloid precursor protein (APP). The formation of this complex may be important for modulation of the processing and function of APP. APP is proteolytically cleaved at multiple sites. The cleavages and their regulation are of central importance in the pathogenesis of dementias of the Alzheimer type. In cell cultures and perhaps in vivo, secretion of the alpha-cleaved APP ectodomain (sAPPalpha) is the major pathway in the most cells. Regulation of the process may require extracellular/intracellular cues. Neither extracellular ligands nor intracellular mediators have been identified, however. Here, we show novel evidence that the major isoform of FE65 (97-kDa FE65, p97FE65) can be converted to a 65-kDa N-terminally truncated C-terminal fragment (p65FE65) via endoproteolysis. The cleavage region locates immediately after an acidic residue cluster but before the three major protein-protein binding domains. The cleavage activity is particularly high in human and non-human primate cells and low in rodent cells; the activity appears to be triggered/enhanced by high cell density, presumably via cell-cell/cell-substrate contact cues. As a result, p65FE65 exhibits extraordinarily high affinity for APP (up to 40-fold higher than p97FE65) and potent suppression (up to 90%) of secretion of sAPPalpha. Strong p65FE65-APP binding is required for the suppression. The results suggest that p65FE65 may be an intracellular mediator in a signaling cascade regulating alpha-secretion of APP, particularly in primates.

Aged↗
PubMed2005

Candidate gene association studies of genes involved in neuronal cholinergic transmission in Alzheimer's disease suggests choline acetyltransferase as a candidate deserving further study.

Consistent deficits in the cholinergic system are evident in the brains of Alzheimer's Disease (AD) patients, including reductions in the activities of acetylcholine, acetylcholinesterase (AChE), and choline acetyltransferase (ChAT), increased butyrylcholinesterase (BChE) activity, and a selective loss of nicotinic acetylcholine receptors (nAChRs). Accordingly, we have analyzed polymorphisms in the genes encoding AChE, ChAT, BChE, and several of the subunit genes from neuronal nAChRs, for genetic associations with late-onset AD. A significant association for disease was detected for a non-coding polymorphism in ChAT (allele chi(1) (2) = 12.84, P = 0.0003; genotype chi(2) (2) = 11.89, P = 0.0026). Although replication analysis did not confirm the significance of this finding when the replication samples were considered alone (allele chi(1) (2) = 1.02, P = 0.32; genotype chi(2) (2) = 1.101, P = 0.58) the trends were in the correct direction and a significant association remained when the two sample sets were pooled (allele chi(1) (2) = 12.37, P = 0.0004; genotype chi(2) (2) = 11.61, P = 0.003). Previous studies have reported significant disease associations for both the K-variant of BChE and the coding ChAT rs3810950 polymorphism with AD. Replication analyses of these two loci failed to detect any significant association for disease in our case-control samples.

Aged↗
PubMed2005

Sex difference in the repolarization currents of rabbit ventricular cells.

The current difference between male and female rabbit ventricular myocytes was investigated for elucidating the mechanism of longer QT interval and higher incidence of drug-associated torsade de pointes in female rabbits than in male rabbits. Whole cell patch clamp technique was used to record APD, Ito, IK,tail, IK1 and ICa,L of myocytes from left ventricular apex. There was no difference in the membrane capacitance between male and female rabbit myocytes. APD90 was longer in female rabbits (560.4+/-26.5 ms, n=15) than in male ones (489.0+/-20.7 ms, n = 14), P<0. 05. In female rabbit myocytes, IKtail, Ito, IK1 and ICa,L were 0.71+/-0.05 pA/pF (n=17), 8.28+/-1.03 pA/pF (n=18), 24.5+/-3.6 pA/pF (n=12) and 9.0+/-2.3 pA/pF (n=15) respectively. In male rabbit myocytes, they were 0.84+/-0.07 pA/pF (n=18), 8.60+/-1.20 pA/pF (n=18), 25.9+/-4.5 pA/pF (n=14) and 9.3+2.6 pA/pF (n=16) respectively. IK,tail in female rabbits was significantly lower than that of male rabbits (P<0.05), but there was no difference in Ito,IK1 and ICa.L between male rabbits and female rabbits (P>0.05). The lower IK.tail of female rabbit myocytes may contribute to the longer repolarization and the higher incidence of drug-associated torsade de pointes.

Action Potentials↗
PubMed2005

Effect of lidocaine and amiodarone on transmural heterogeneity of ventricular repolarization in isolated rabbit hearts model of sustained global ischemia.

To study the effect of of lidocaine and amiodarone on the transmural heterogeneity of ventricular repolarization in isolated rabbit hearts model of sustained global ischemia and to explore the mechanisms underlying the antiarrhythmic activity of lidocaine and amiodarone, rabbits were randomly divided into 4 groups: control group, ischemia group, lidocaine group and amiodarone group. By the monophasic action potential (MAP) recording technique, MAPs of epicardium, mid-myocardium and endocardium were simultaneously recorded across the left ventricular free wall in rabbit hearts perfused by low-flow ischemia (2.5 mL/min) in Langendorff method to study the transmural dispersion of repolarization (TDR) and arrhythmic induced by ischemia. Our results showed that TDR of three myocardial layers in ischemia group were significantly lengthened after ischemia. TDR was increased from 17.5 +/- 3.9 ms to 31.2 +/- 4.6 ms at the time that concided with the onset of sustained ventricle arrhythmic. Amiodarone could decrease TDR, but lidocaine could increase TDR at initial ischemia, and no significant difference was found at other ischemia time points. 5 cases had ventriclar arrhythmia in ischemia group (62.5%), but no case in lidocaine group (P < 0.01) and only 1 case in amiodarone group had ventrilar arrhythmia (P < 0.01). No significant difference was found between amiodarone group and lidocaine group. It is concluded that TDR of of three myocardial layers increases significantly at ischemia and it is closely associated with development of ventricular arrhythmia, and amiodarone could decrease TDR, but lidocaine could increase TDR at initial ischemia and has no effects at other ischemia time points.

Action Potentials↗
PubMed2005

Value of echocardiography for evaluation of the flow-dependent epicardial coronary vasodilation in vivo.

To assess the value of echocardiography for detection of the flow-dependent epicardial coronary vasodilation, the changes in internal diameter of the left anterior descending coronary arteries (LAD) induced by reactive hyperemia were studied by echocardiography in 12 health anesthetized open-chest dogs. Reactive hyperemia was induced by brief occlusion of the left anterior descending coronary artery for 30 s followed by rapid release. The two- dimensional images of the left anterior descending coronary artery before and after reactive hyperemia with and without intracoronary infusion of N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase (NOS) were investigated. The internal diameter of LAD was measured and its percent change induced by reactive hyperemia was calculated. Our results showed that the internal diameter of LAD was 2.23 +/- 0.19 mm before intracoronary infusion of L-NAME (baseline). The internal diameter of LAD significantly increased to 2.52 +/- 0.24 mm (P < 0.01) after reactive hyperemia at baseline, and the percent change in internal diameter of LAD was (13.10 +/- 3.59)%. The internal diameter of LAD before and after reactive hyperemia under the condition of intracoronary infusion of L-NAME was not different from that before reactive hyperemia at baseline. The percent change in internal diameter of LAD was (1.07 +/- 2.97)%, and it was significantly lower than that at baseline (P < 0.001). We are led to conclude that the change in internal diameter of LAD responding to reactive hyperemia was detected sensitively by echocardiography, and this change was associated with endothelium-derived nitric oxide.

Animals↗
PubMed2005

Changes of monophasic action potential duration and effective refractory period of three layers myocardium of canine during acute ischemia in vivo.

The effect of acute ischemia on the electrophysiological characteristics of the three layers myocardium of canine in vivo was investigated. Twelve canines were divided into two groups randomly: acute ischemia (AI) group and sham operation (SO) group. By using the monophasic action potential (MAP) technique, MAP and effective refractory period (ERP) of the three layers myocardium were measured by specially designed plunge needle electrodes and the transmural dispersion of repolarization (TDR) and transmural dispersion of ERP (TDE) were analyzed. The results showed that in the AI group, MAP duration (MAPD) was shortened from 201.67 +/- 21.42 ms to 169.50 +/- 13.81 ms (P < 0.05), but ERP prolonged to varying degrees and TDE increased during ischemia. In the SO group, MAPD and ERP did not change almost. Among of the three layers myocardium of canine, MAPD was coincident in two groups. It was concluded that during acute ischemia, MAPD was shortened sharply, but there was no significant difference among of the three layers myocardium. The prolonged ERP was concomitant with increased TDE during acute ischemia, which may play an important role in the occurrence of arrhythmias induced by acute ischemia. These findings may have important implications in arrhythmogenesis.

Action Potentials↗
PubMed2005

Expression of telomerase subunits in gastric cancer.

To detect the expression of telomerase subunits (human telomerase reverse transcriptase, human telomerase associated protein 1 and human telomerase RNA) in gastric cancer and to examine the role that different telomerase subunits play in the gastric carcinogenesis, reverse transcription-polymerase chain reaction (RT-PCR) was used to detect telomerase subunits messenger RNA in 24 samples of gastric cancer and corresponding non-cancerous tissue. The results showed that the positive rate of hTERT mRNA from gastric cancer and corresponding non-cancerous tissues was 100% and 25%, respectively. The former was significantly higher than the latter (chi2 = 26.4, P < 0.01). The positive rate of hTEP1 mRNA from gastric cancer and corresponding non-cancerous tissues was 100% and 91.7%, respectively and no significant difference was found between them (chi2 = 2.1, P > 0.05). The positive rates of hTR for gastric cancer and corresponding non-cancerous tissues were both 100% and no significant difference existed between them. It is concluded that in contrast to hTEP1 and hTR, the up-regulation of hTERT mRNA expression may play a more important role in the development of gastric cancer.

Adult↗
PubMed2005

Identification of natural compounds with antiviral activities against SARS-associated coronavirus.

More than 200 Chinese medicinal herb extracts were screened for antiviral activities against Severe Acute Respiratory Syndrome-associated coronavirus (SARS-CoV) using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt (MTS) assay for virus-induced cytopathic effect (CPE). Four of these extracts showed moderate to potent antiviral activities against SARS-CoV with 50% effective concentration (EC50) ranging from 2.4 +/- 0.2 to 88.2 +/- 7.7 microg/ml. Out of the four, Lycoris radiata was most potent. To identify the active component, L. radiata extract was subjected to further fractionation, purification, and CPE/MTS assays. This process led to the identification of a single substance lycorine as an anti-SARS-CoV component with an EC50 value of 15.7 +/- 1.2 nM. This compound has a CC50 value of 14980.0 +/- 912.0 nM in cytotoxicity assay and a selective index (SI) greater than 900. The results suggested that four herbal extracts and the compound lycorine are candidates for the development of new anti-SARS-CoV drugs in the treatment of SARS.

Amaryllidaceae Alkaloids↗
PubMed2005

CD 39-associated high ATPase activity contribute to the loss of P 2 X 7-mediated calcium response in LCL cells.

The P 2 X 7 nucleotide receptor is an adenosine 5'-triphosphate (ATP)-gated ion channel, which induces cation channel opening imparting significant permeability to Ca(2+), and is widely expressed in cells of hematopoietic origin. Our previous report showed that P 2 X 7-mediated calcium response was absent in three Epstein-Barr virus (EBV)-positive and P 2 X 7 positive cell lines. In this report, we detected the cell surface ATPase activity, which contributes to the hydrolysis of extracellular ATP, and the expression of CD 39, which is the main source of ATPase on hematopoietic cells, in these cell lines. Then, we tried to restore the P 2 X 7-mediated calcium response in LCL-H and J 6-1 cells by either increasing the concentration of agonist or suppressing the ATPase activity by betagammaMeATP, a synthetic poorly metabolizable ATP analogue. The results showed that LCL-H and J 6-1 cells had higher levels of ATPase activity and CD 39 expression. The treatment of 300 microM betagammaMeATP efficiently inhibited the ATPase activity on LCL-H and J 6-1 cells. Both elevation of agonist concentration (10mM ATP or 1mM BzATP) and pretreatment with 300 microM betagammaMeATP followed by stimulation with normal concentration of agonists (1mM ATP or 0.1mM BzATP) could cause P 2 X 7-mediated calcium response in LCL-H but neither in J 6-1 cells. These results suggested that multiple mechanisms contributed to the loss of the P 2 X 7-mediated calcium response. CD 39-associated high ATPase activity contributed to the loss of the P 2 X 7-mediated calcium response in LCL-H cells, while additional mechanism(s) existed in J 6-1 cells.

Adenosine Triphosphatases↗