Publications (25)83.51 Total impact
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Article: Thrombin-induced NF-κB activation and IL-8/CXCL8 release is mediated by c-Src-dependent Shc, Raf-1, and ERK pathways in lung epithelial cells.
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ABSTRACT: In addition to its functions in thrombosis and hemostasis, thrombin also plays an important role in lung inflammation. Our previous report showed that thrombin activates the protein kinase C (PKC)α/c-Src and Gβγ/Rac1/PI3K/Akt signaling pathways to induce IκB kinase α/β (IKKα/β) activation, NF-κB transactivation, and IL-8/CXCL8 expressions in human lung epithelial cells (ECs). In this study, we further investigated the mechanism of c-Src-dependent Shc, Raf-1, and extracellular signal-regulated kinase (ERK) signaling pathways involved in thrombin-induced NF-κB activation and IL-8/CXCL8 release. Thrombin-induced increases in IL-8/CXCL8 release and κB-luciferase activity were inhibited by the Shc small interfering RNA (siRNA), p66Shc siRNA, GW 5074 (a Raf-1 inhibitor), and PD98059 (a mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor). Treatment of A549 cells with thrombin increased p66Shc and p46/p52Shc phosphorylation at Tyr239/240 and Tyr317, which was inhibited by cell transfection with the dominant negative mutant of c-Src (c-Src DN). Thrombin caused time-dependent phosphorylation of Raf-1 and ERK, which was attenuated by the c-Src DN. Thrombin-induced IKKα/β phosphorylation was inhibited by GW 5074 and PD98059. Treatment of cells with thrombin induced Gβγ, c-Src, and p66Shc complex formation in a time-dependent manner. Taken together, these results show for the first time that thrombin activates Shc, Raf-1, and ERK through Gβγ, c-Src, and Shc complex formation to induce IKKα/β phosphorylation, NF-κB activation, and IL-8/CXCL8 release in human lung ECs.Cellular signalling 01/2013; · 4.09 Impact Factor -
Article: Plasma long pentraxin 3 (PTX3) concentration is a novel marker of disease activity in patients with community-acquired pneumonia.
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ABSTRACT: Abstract Background: Long pentraxin 3 (PTX3) is an acute-phase protein secreted by various cells, including leukocytes and endothelial cells. Like C-reactive protein (CRP), it belongs to the pentraxin superfamily. The aim of this study was to investigate the differential changes in plasma levels of PTX3 between before and after antibiotic treatment in hospitalized adult patients with community-acquired pneumonia (CAP). Methods: Plasma PTX3 levels were measured in 61 adult patients with CAP and 60 healthy controls using a commercial enzyme-linked immunosorbent assay (ELISA). Upon initial hospitalization, APACHE II, CURB-65, and pneumonia severity index (PSI) scores were determined to assess CAP severity in patients. Results: The results showed a decline in the number of white blood cells (WBCs) and neutrophils, and decreases in the concentrations of CRP and PTX3 observed after antibiotic treatment. The plasma concentration of PTX3, but not CRP, was correlated with the severity of CAP based on the PSI (r=0.290, p=0.023), CURB-65 (r=0.312, p=0.015), and APACHE II scores (r=0.427, p=0.001). The PTX3 level also exhibited a significant correlation with the length of hospital stay (r=0.500, p<0.0001). Conclusions: PTX3 may be able to play a role in the diagnosis and clinical assessment of the severity of CAP, which could potentially guide the development of treatment strategies.Clinical Chemistry and Laboratory Medicine 11/2012; · 2.15 Impact Factor -
Article: Thrombin-induced CCN2 expression in human lung fibroblasts requires the c-Src/JAK2/STAT3 pathway.
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ABSTRACT: Thrombin is a multifunctional serine protease and an important fibrotic mediator that induces CCN2 expression. We previously showed that thrombin induces CCN2 expression via an ASK1-dependent JNK/AP-1 pathway in human lung fibroblasts. In this study, we further investigated the roles of c-Src, JAK2, and STAT3 in thrombin-induced CCN2 expression. Thrombin-induced CCN2 expression and CCN2-Luc activity were attenuated by a JAK inhibitor (AG490) and JAK2DN, STAT3DN, and the STAT decoy ODN. Moreover, transfection of cells with a CCN2-mtSTAT-Luc construct inhibited thrombin-induced CCN2-Luc activity. Treatment of cells with thrombin caused JAK2 phosphorylation at Tyr1007/1008 and STAT3 phosphorylation at Tyr705 in time-dependent manners. Thrombin-induced STAT3 phosphorylation was inhibited by AG490 and JAK2DN. Thrombin-induced STAT3 binding to the CCN2 promoter was analyzed by a DNA-binding affinity pull-down assay. In addition, thrombin-induced CCN2 expression and CCN2-Luc activity were inhibited by c-SrcDN and PP2 (an Src inhibitor). Transfection of cells with c-SrcDN also inhibited thrombin-induced JAK2 and STAT3 phosphorylation. Taken together, these results indicate that thrombin might activate c-Src to induce JAK2 activation, which in turn, causes STAT3 activation, and finally induces CCN2 expression in human lung fibroblasts.Journal of leukocyte biology 10/2012; · 4.99 Impact Factor -
Article: Osthole inhibits the invasive ability of human lung adenocarcinoma cells via suppression of NF-κB-mediated matrix metalloproteinase-9 expression.
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ABSTRACT: The induction of matrix metalloproteinase (MMP)-9 is particularly important for the invasiveness of various cancer cells. Osthole, a natural coumarin derivative extracted from traditional Chinese medicines, is known to inhibit the proliferation of a variety of tumor cells, but the effect of osthole on the invasiveness of tumor cells is largely unknown. This study determines whether and by what mechanism osthole inhibits invasion in CL1-5 human lung adenocarcinoma cells. Herein, we found that osthole effectively inhibited the migratory and invasive abilities of CL1-5 cells. A zymographic assay showed that osthole inhibited the proteolytic activity of MMP-9 in CL1-5 cells. Inhibition of migration, invasion, and MMP2 and/or MMP-9 proteolytic activities was also observed in other lung adenocarcinoma cell lines (H1299 and A549). We further found that osthole inhibited MMP-9 expression at the messenger RNA and protein levels. Moreover, a chromatin immunoprecipitation assay showed that osthole inhibited the transcriptional activity of MMP-9 by suppressing the DNA binding activity of nuclear factor (NF)-κB in the MMP-9 promoter. Using reporter assays with point-mutated promoter constructs further confirmed that the inhibitory effect of osthole requires an NF-κB binding site on the MMP-9 promoter. Western blot and immunofluorescence assays demonstrated that osthole inhibited NF-κB activity by inhibiting IκB-α degradation and NF-κB p65 nuclear translocation. In conclusion, we demonstrated that osthole inhibits NF-κB-mediated MMP-9 expression, resulting in suppression of lung cancer cell invasion and migration, and osthole might be a potential agent for preventing the invasion and metastasis of lung cancer.Toxicology and Applied Pharmacology 04/2012; 261(1):105-15. · 4.45 Impact Factor -
Article: Molecular detection of rifabutin-susceptible Mycobacterium tuberculosis.
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ABSTRACT: Rapid assays are still needed to detect rifabutin (RFB) susceptibility for proper tuberculosis treatment. To assess the use of the GenoType MTBDRplus assay and subsequent rpoB gene sequencing on detection of RFB susceptibility, we analyzed 800 multidrug-resistant Mycobacterium tuberculosis isolates, and 13% (104/800) were RFB susceptible. Of the 104 RFB-susceptible isolates, 71 (68.3%) isolates were rapidly identified using two molecular assays, while the remaining isolates could be determined using conventional drug-susceptibility testing according to the clinician's decision.Journal of clinical microbiology 03/2012; 50(6):2085-8. · 4.16 Impact Factor -
Article: Association of Mycobacterium tuberculosis genotypes and clinical and epidemiological features - a multi-center study in Taiwan.
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ABSTRACT: Genotypes of Mycobacterium tuberculosis (MTB) are related to the geographic origin of the patients and population migration. The relationship between genotypes of MTB and clinical presentations has mainly focused on transmission of multi-drug resistant MTB strain in population. This study aimed to investigate the molecular epidemiology and dynamic change of MTB genotypes in Taiwan, and their association with clinical presentation among patients with pulmonary tuberculosis. A multi-center, two-year study which enrolled 516 patients with 516 MTB isolates was conducted, including: (1) 254 isolates from northern Taiwan; (2) 38 isolates from mid-western Taiwan; (3) 211 isolates from southern Taiwan; and (4) 13 isolates from the east coast of Taiwan. The isolates were genotyped with spoligotyping and standardized 12-loci-MIRU-VNTR method. The results showed Beijing/Beijing-like family was the major genotype of MTB in the northern (58%), eastern (53%), and southern (33%) regions. The second most widely spread lineage were the EAI-Manila (20% in the west and south) and Haarlem family (13-27% in the south, west, and east). According to the cluster analysis of 12-MIRU-VNTR genotypes, there were differences in distribution of MTB genotype between the northern and southern regions, and a temporal relationship between isolation year and 12-MIRU-VNTR genotype especially in loci 26 and 39 might exist. Furthermore, some patients with cavity lesions on chest films were associated with a cluster of Beijing family MTB strains, which can be defined by cluster analysis of 12-MIRU-VNTR genotype. However, the results of 12-loci-MIRU-VNTR genotyping in a longitudinal study should be interpreted with caution due to its short term instability. Further investigations of different molecular methodologies are necessary.Infection, genetics and evolution: journal of molecular epidemiology and evolutionary genetics in infectious diseases 01/2012; 12(1):28-37. · 3.22 Impact Factor -
Article: Improved consistency in dosing anti-tuberculosis drugs in taipei, taiwan.
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ABSTRACT: It was reported that 35.5% of tuberculosis (TB) cases reported in 2003 in Taipei City had no recorded pre-treatment body weight and that among those who had, inconsistent dosing of anti-TB drugs was frequent. Taiwan Centers for Disease Control (CDC) have taken actions to strengthen dosing of anti-TB drugs among general practitioners. Prescribing practices of anti-TB drugs in Taipei City in 2007-2010 were investigated to assess whether interventions on dosing were effective. Lists of all notified culture positive TB cases in 2007-2010 were obtained from National TB Registry at Taiwan CDC. A medical audit of TB case management files was performed to collect pretreatment body weight and regimens prescribed at commencement of treatment. Dosages prescribed were compared with dosages recommended. The proportion of patients with recorded pre-treatment body weight was 64.5% in 2003, which increased to 96.5% in 2007-2010 (p<0.001). The proportion of patients treated with consistent dosing of a 3-drug fixed-dose combination (FDC) increased from 73.9% in 2003 to 87.7% in 2007-2010 (p<0.001), and that for 2-drug FDC from 76.0% to 86.1% (p = 0.024), for rifampicin (RMP) from 62.8% to 85.5% (p<0.001), and for isoniazid from 87.8% to 95.3% (p<0.001). In 2007-2010, among 2917 patients treated with either FDCs or RMP in single-drug preparation, the dosage of RMP was adequate (8-12 mg/kg) in 2571(88.1%) patients, too high in 282(9.7%), too low in 64(2.2%). In multinomial logistic regression models, factors significantly associated with adequate dosage of RMP were body weight and preparations of RMP. Patients weighting <40kg (relative risk ratio (rrr) 6010.5, 95% CI 781.1-46249.7) and patients weighting 40-49 kg (rrr 1495.3, 95% CI 200.6-11144.6) were more likely to receive higher-than-recommended dose of RMP. Prescribing practice in the treatment of TB in Taipei City has remarkably improved after health authorities implemented a series of interventions.PLoS ONE 01/2012; 7(8):e44133. · 4.09 Impact Factor -
Article: Thrombin induces inducible nitric oxide synthase expression via the MAPK, MSK1, and NF-κB signaling pathways in alveolar macrophages.
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ABSTRACT: In this study, we investigated the roles of mitogen activated protein kinase (MAPK), mitogen stress-activated protein kinase 1 (MSK1), and nuclear factor-κB (NF-κB) signaling pathways in thrombin-induced inducible nitric oxide synthase (iNOS) expression in alveolar macrophages (NR8383). Treatment of NR8383 cells with thrombin caused an increase in iNOS expression in a concentration- and time-dependent manner. Treatment of NR8383 cells with SB203580 (4-(4-Fluorophenyl)-2-[4-(methylsulfinyl)phenyl]-5-(4-pyridyl)-1H-imidazole, a p38 MAPK inhibitor), PD98059 (2'-amino-3'-methoxyflavone, a MAPK kinase (MEK) inhibitor), and SP600125 (anthra[1-9-cd]pyrazol-6(2H)-one, a JNK inhibitor) all inhibited thrombin-induced iNOS expression. Stimulation of cells with thrombin caused an increase in p38 MAPK, ERK, and JNK phosphorylation. Treatment of cells with Ro 31-8220 (an MSK1 inhibitor) and MSK1 small interfering RNA (MSK1 siRNA) both inhibited thrombin-induced iNOS expression. Thrombin caused time-dependent activation of MSK1 Ser531 phosphorylation, which was inhibited by SB203580 and PD98059, but not by SP600125. Treatment of cells with pyrrolidine dithiocarbamate (PDTC, an NF-κB inhibitor) inhibited thrombin-induced iNOS expression in a concentration-dependent manner. Treatment of NR8383 cells with thrombin induced κB-luciferase activity and p65 Ser276 phosphorylation. Thrombin-induced increases in p65 Ser276 phosphorylation and κB-luciferase activity were inhibited by SB203580, PD98059, Ro 31-8220, and MSK1 siRNA. Taken together, these results suggest that the signaling pathways of MAPK, MSK1, and NF-κB play important roles in thrombin-induced iNOS expression in alveolar macrophages.European journal of pharmacology 12/2011; 672(1-3):180-7. · 2.59 Impact Factor -
Article: Initial presentations predict mortality in pulmonary tuberculosis patients--a prospective observational study.
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ABSTRACT: Despite effective anti-TB treatments, tuberculosis remains a serious threat to public health and is associated with high mortality. Old age and multiple co-morbidities are known risk factors for death. The association of clinical presentations with mortality in pulmonary tuberculosis patients remains an issue of controversy. This prospective observational study enrolled newly diagnosed, culture-proven pulmonary tuberculosis patients from five medical centers and one regional hospital, which were referral hospitals of TB patients. Radiographic findings and clinical symptoms were determined at the time of diagnosis. Patients who died for any reason during the course of anti-TB treatment were defined as mortality cases and death that occurred within 30 days of initiating treatment was defined as early mortality. Clinical factors associated with overall mortality and early mortality were investigated. A total of 992 patients were enrolled and 195 (19.7%) died. Nearly one-third (62/195, 31.8%) of the deaths occurred before or within 30 days of treatment initiation. Older age (RR = 1.04, 95%CI: 1.03-1.05), malignancy (RR = 2.42, 95%CI: 1.77-3.31), renal insufficiency (RR = 1.77, 95%CI: 1.12-2.80), presence of chronic cough (RR = 0.63, 95%CI: 0.47-0.84), fever (RR = 1.45, 95%CI: 1.09-1.94), and anorexia (RR = 1.49, 95%CI: 1.07-2.06) were independently associated with overall mortality. Kaplan-Meier survival analysis demonstrated significantly higher mortality in patients present with fever (p<0.001), anorexia (p = 0.005), and without chronic cough (p<0.001). Among patients of mortality, those with respiratory symptoms of chronic cough (RR = 0.56, 95%CI: 0.33-0.98) and dyspnea (HR = 0.51, 95%CI: 0.27-0.98) were less likely to experience early mortality. The radiological features were comparable between survivors and non-survivors. In addition to demographic characteristics, clinical presentations including the presence of fever, anorexia, and the absence of chronic cough, were also independent predictors for on-treatment mortality in pulmonary tuberculosis patients.PLoS ONE 01/2011; 6(9):e23715. · 4.09 Impact Factor -
Article: Evaluation of the rapid MGIT TBc identification test for culture confirmation of Mycobacterium tuberculosis complex strain detection.
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ABSTRACT: A culture confirmation test for the detection of Mycobacterium tuberculosis complex strains that uses a lateral-flow immunochromatographic assay to detect the MPB64 antigen, the MGIT TBc identification (TBc ID) test, has been developed. We evaluated the performance of the TBc ID test in the detection of the M. tuberculosis complex in 222 primary-positive liquid cultures. We compared these results to those of nucleic acid-based identification and conventional biochemical tests. The validity of the TBc ID test was determined, and all of the nontuberculous mycobacteria (NTM) and Nocardia species tested were found to be negative. The detection limit of the TBc ID test was 5 × 10(5) CFU/ml, and for IS6110 real-time PCR it was 5 CFU/ml. All of the M. tuberculosis and M. africanum cultures were found to be positive, while M. bovis and M. bovis BCG cultures were negative. With the exception of 1 contaminated culture, the 221 culture-positive isolates contained 171 (77.5%) M. tuberculosis isolates, 39 (17.6%) NTM species, and 11 (5.0%) unidentified species. Two culture-positive isolates harbored a 63-bp deletion at position 196 of the mpb64 gene. The sensitivity, specificity, positive predictive values, and negative predictive values of the TBc ID test were 98.8, 100, 100, and 95.1%, respectively. Furthermore, the approximate turnaround time for real-time PCR was 4 h (including buffer and sample preparation), while for the TBc ID test it was less than 1 h. We suggest an algorithm for the primary identification of M. tuberculosis in liquid culture using the TBc ID test as an alternative to conventional subculture followed by identification using biochemical methods.Journal of clinical microbiology 12/2010; 49(3):802-7. · 4.16 Impact Factor -
Article: Hepatitis associated with prothionamide for treatment of multidrug-resistant tuberculosis.
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ABSTRACT: Timely and intensive monitoring for, and management of, adverse effects caused by anti-tuberculosis drugs are essential components of control programs for multidrug-resistant tuberculosis (MDR-TB). This retrospective case series was conducted in northern Taiwan from January 2007 to December 2008 at Taipei Medical University-Wan Fang Hospital, a 750-bed tertiary-care center and MDR-TB referral center. Hepatitis associated with prothionamide was defined as the recurrence of hepatitis after a second prothionamide treatment re-challenge. In total, 47 patients with MDR-TB enrolled in the Directly Observed Therapy, Short Course-Plus Program were identified during the study period, and 44 (93.6%) were treated with prothionamide. Seven of these 44 patients (15.9%) developed hepatitis after being treated with prothionamide concurrent with other anti-tuberculosis agents. Hepatitis associated with prothionamide occurred in three of these seven patients (6.8%). In these three patients, hepatitis developed following treatment with prothionamide for 28 days, 39 days or 45 days. Hepatitis developed rapidly after re-challenge with prothionamide at 4 days, 4 days and 3 days, respectively. Liver function returned to the normal range after cessation of prothionamide treatment for 19 days, 27 days or 28 days. Close monitoring of liver function was necessary in MDR-TB patients who received prothionamide treatment.Journal of the Formosan Medical Association 12/2010; 109(12):923-7. · 1.13 Impact Factor -
Article: Mixed infection with Beijing and non-Beijing strains in pulmonary tuberculosis in Taiwan: prevalence, risk factors, and dominant strain.
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ABSTRACT: Patients with pulmonary tuberculosis (TB) can be simultaneously infected with different strains of Mycobacterium tuberculosis (mixed infection). We investigated the prevalence and risk factors of mixed infection by Beijing and non-Beijing strains in pulmonary TB patients in Taiwan. We developed a quantitative PCR method to simultaneously detect the presence of Beijing and non-Beijing strains. A total of 868 pretreatment samples (from 868 patients), including 563 sputum samples smear-positive for acid-fast bacilli and 305 liquid medium samples culture-positive for mycobacteria, were tested. Medical records of patients with culture-confirmed pulmonary TB were reviewed. The detection limit of our quantitative PCR method was five copies of target sequences. With mycobacterial culture result as the reference standard, the sensitivity and specificity of our quantitative PCR method were 95% and 98%, respectively. M. tuberculosis strains were isolated in 466 samples, of which 231 (49.6%) were infected with a Beijing strain. Another 14 patients (3.0%) had mixed infection, with the Beijing strain being the dominant strain in 13 (93%). Age <25 years with pulmonary cavities was associated with mixed infection. In patients infected with non-Beijing strains, the bacterial load of non-Beijing strains was lower among those with mixed infection than among those without. Our quantitative PCR method was accurate in detecting Beijing and non-Beijing strains in smear-positive sputum and culture-positive liquid medium samples. Mixed infection was present in pulmonary TB patients (3.0%), especially in those aged <25 years with pulmonary cavities. Beijing strains seem to be more dominant than non-Beijing strains in patients with mixed infection.Clinical Microbiology and Infection 10/2010; 17(8):1239-45. · 4.54 Impact Factor -
Article: Diverse cell morphology and intracellular calcium dynamics in pulmonary vein cardiomyocytes.
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ABSTRACT: Pulmonary veins (PVs) contain cardiomyocytes with a complex cellular morphology and high arrhythmogenesis. Ca(2+) regulation and Ca(2+) sparks play a pivotal role in the electrical activity of cardiomyocytes. The purpose of this study was to investigate whether the cell morphology can determine the PV electrical activity and Ca(2+) homeostasis. Through confocal microscopy with fluo-3 Ca(2+) fluorescence, Ca(2+) sparks and Ca(2+) transients were evaluated in isolated single rabbit left atria (LA) and PV cardiomyocytes according to the cell morphology (rod, rod-spindle and spindle/bifurcated). Twenty-two (20%) rod, 49 (43%) rod-spindle and 41 (37%) spindle/bifurcated cardiomyocytes were identified in the LA (n = 29) and PV (n = 83) cardiomyocytes. The PV cardiomyocytes with pacemaker activity had a higher incidence of spindle/bifurcated morphology than LA and PV cardiomyocytes without pacemaker activity. As compared to those in the rod or rod-spindle cardiomyocytes, spindle/bifurcated cardiomyocytes had a larger Ca(2+) transient amplitude and higher frequency of the Ca(2+) sparks with larger amplitude and longer duration. In contrast, rod-spindle and rod cardiomyocytes had similar Ca(2+) transients and Ca(2+) sparks. The cell length correlated well with the amplitude of the Ca(2+) transient and Ca(2+) spark duration with a linear regression. In conclusion, cell morphology and cell length play a potential role in the Ca(2+) homeostasis and Ca(2+) spark. The large Ca(2+) transients and high frequency of Ca(2+) sparks in spindle/bifurcated cardiomyocytes may cause a high arrhythmogenesis in the PV cardiomyocytes with pacemaker activity.Heart and Vessels 10/2010; 26(1):101-10. · 2.05 Impact Factor -
Article: Use of high-dose inhaled corticosteroids is associated with pulmonary tuberculosis in patients with chronic obstructive pulmonary disease.
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ABSTRACT: The use of high-dose inhaled corticosteroids (ICS) in patients with chronic obstructive pulmonary disease (COPD) has recently been shown to increase the incidence of pneumonia. However, to our knowledge, the impact of high-dose ICS on pulmonary tuberculosis (TB) has never been investigated. To study that impact, we conducted a retrospective study including patients aged more than 40 years old with irreversible airflow limitation between August 2000 and July 2008 in a medical center in Taiwan. Of the 36,684 patients who underwent pulmonary function testing, we included 554 patients. Among them, patients using high-dose ICS (equivalent to >500 microg/d of fluticasone) were more likely to have more severe COPD and receive oral corticosteroids than those using medium-dose, low-dose, or no ICS. Sixteen (3%) patients developed active pulmonary TB within a follow-up of 25,544 person-months. Multivariate Cox regression analysis revealed that the use of high-dose ICS, the use of 10 mg or more of prednisolone per day, and prior pulmonary TB were independent risk factors for the development of active pulmonary TB. Chest radiography and sputum smear/culture for Mycobacterium tuberculosis should be performed before initiating high-dose ICS and regularly thereafter.Medicine 01/2010; 89(1):53-61. · 4.35 Impact Factor -
Article: Luteolin, a non-selective competitive inhibitor of phosphodiesterases 1-5, displaced [3H]-rolipram from high-affinity rolipram binding sites and reversed xylazine/ketamine-induced anesthesia.
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ABSTRACT: The aim of the present study was to investigate the mode of action of luteolin on phisphodiesterase (PDE) 1-5, and the possible adverse effects, such as nausea, vomiting, and gastric hypersecretion, determined by replacing [(3)H]-rolipram binding and reversing xylazine/ketamine-induced anesthesia. The reversing effect was reported to occur through a presynaptic alpha(2)-adrenoceptor inhibition and trigger vomiting in ferrets. In contrast, clonidine, an alpha(2)-adrenoceptor agonist, prevented emesis induced by PDE4 inhibitors in ferrets. According to the Lineweaver-Burk analysis, luteolin (3-30 microM) competitively inhibited PDE1-5 activities, with K(i) values of 15.0, 6.4, 13.9, 11.1, and 9.5 microM, respectively, which did not significantly differ from each other. The equilibrium dissociation constant (K(d)) and maximal density (B(max)) for [(3)H]-rolipram binding at high-affinity rolipram binding sites of guinea pig brain cell membranes were 10.1 nM and 3.7 p mol/g of tissue, respectively. The EC(50) (PDE4(H)) values of luteolin and Ro 20-1724, a selective PDE4 inhibitor, for displacing 2 nM [(3)H]-rolipram binding were 11.2 microM and 45.6 nM, respectively. The therapeutic (PDE4(H)/PDE4(L)) ratios of luteolin and Ro 20-1724 were calculated to be 0.6, and 0.004, respectively. Both luteolin (10-30 micromol/kg, s.c.) and Ro 20-1724 (0.1-1 micromol/kg, s.c.) significantly reversed the xylazine/ketamine-induced anesthesia in mice. Although luteolin non-selectively and competitively inhibited PDE1-5, only PDE4 inhibition contributed to a reversing effect. In conclusion, because of the low therapeutic (PDE4(H)/PDE4(L)) ratio of luteolin, the gastrointestinal adverse effects such as nausea, vomiting and gastric hypersecretion should be carefully monitored, whenever luteolin is used for treating allergies, asthma or chronic obstructive pulmonary disease.European journal of pharmacology 10/2009; 627(1-3):269-75. · 2.59 Impact Factor -
Article: Thrombin-induced connective tissue growth factor expression in human lung fibroblasts requires the ASK1/JNK/AP-1 pathway.
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ABSTRACT: Thrombin plays an important role in lung inflammatory diseases. Thrombin can induce connective tissue growth factor (CTGF) expression in lung fibroblasts. However, little is known about the signaling pathway in thrombin-induced CTGF expression. In this study, we investigated the role of apoptosis signal-regulating kinase 1 (ASK1) in thrombin-induced CTGF expression in human lung fibroblasts. Thrombin caused a concentration- and time-dependent increase in CTGF expression in WI-38 cells and primary lung fibroblasts. Thrombin-induced CTGF expression and CTGF-luciferase activity were inhibited by a protease-activated receptor 1 antagonist (SCH79797), the dominant-negative mutants (DNs) of ASK1 and JNK1/2, and an AP-1 inhibitor (curcumin). Thrombin caused ASK1 Ser(967) dephosphorylation, the dissociation of ASK1 and 14-3-3, and a subsequent increase in ASK1 activity. Thrombin induced increases in JNK phosphorylation and kinase activity, which were attenuated by ASK1DN. Furthermore, SCH79797 diminished the thrombin-induced ASK1 and JNK activities. Thrombin-induced CTGF-luciferase activity was predominately controlled by the sequence -747 to -184 bp upstream of the transcription start site of the human CTGF promoter and was attenuated by transfection with the deleted AP-1 binding site construct. Thrombin caused increases in c-Jun phosphorylation, the formation of an AP-1-specific DNA-protein complex, and the recruitment of c-Jun to the CTGF promoter. Furthermore, thrombin-mediated AP-1 activation was inhibited by ASK1DN, JNK1/2DN, and SP600125. These results suggest for the first time that thrombin, acting through protease-activated receptor 1, activates the ASK1/JNK signaling pathway, which in turn initiates c-Jun/AP-1 activation and recruitment of c-Jun to the CTGF promoter and ultimately induces CTGF expression in human lung fibroblasts.The Journal of Immunology 07/2009; 182(12):7916-27. · 5.79 Impact Factor -
Article: NAT2 fast acetylator genotypes are associated with an increased risk for lung cancer with wildtype epidermal growth factor receptors in Taiwan.
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ABSTRACT: Identifying the risk factors responsible for lung cancer especially for nonsmokers is critical for both its prevention and treatment. Studies have linked the polymorphisms in N-acetyltransferases (NAT2), a key enzyme for metabolism of hydrocarbons, with lung cancer in Asian female nonsmokers. Since a high percentage of lung adenocarcinoma in Asian female nonsmokers contains activating hotspot mutations in epidermal growth factor receptors (EGFR), we hypothesized that NAT2 polymorphisms might represent a risk factor in lung cancer with EGFR mutations. We studied NAT polymorphisms in 117 nonsmall cell lung cancer (NSCLC) patients and in 119 healthy controls and EGFR hotspot mutations in exons 18-21 in 100 of the 117 patients using polymerase chain reactions. NAT2 fast acetylator genotypes were significantly associated with patients with lung cancer (P = 0.04, odds ratio (OR): 1.90, 95% confidence interval (CI): 1.02-3.57). Further analyses revealed that NAT2 fast acetylator genotypes were significantly associated with NSCLC with wildtype EGFR (P = 0.008, OR: 3.16, 95% CI: 1.31-7.63), but not with those with EGFR mutations (P = 0.40). Therefore, NAT2 fast acetylator genotypes are a potential risk factor especially for lung cancer with wildtype EGFR.Lung Cancer 09/2008; 64(1):9-12. · 3.43 Impact Factor -
Article: Extensively drug-resistant tuberculosis, Taiwan.
Emerging Infectious Diseases 06/2008; 14(5):849-50. · 6.79 Impact Factor -
Article: Tuberculosis among foreign-born persons in Taiwan, 2002-2005.
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ABSTRACT: The foreign-born population has been growing in Taiwan. Most foreign-born persons come from countries with a high burden of tuberculosis (TB). Monitoring the trend and characteristics of TB in this population is essential for TB control in Taiwan. Information about foreign-born persons residing in Taiwan and data of all foreign-born TB cases notified during 2002-2005 were obtained from the national authorities and analyzed. A total of 2,444 foreign-born TB cases were notified during 2002-2005, which accounted for 3.6% of all notified TB cases during that period in Taiwan. The proportion of foreign-born TB cases was constant, without any significant yearly variation. The average annual TB notification rate in the foreign-born population was higher than that in the Taiwan-born population (94.0/100,000 vs. 72.0/100,000). There were significant differences in age, sex and regional distribution between foreign-born and Taiwan-born TB cases (p < 0.001). Foreign-born cases were predominantly female (65.4%) and aged 25-44 years (70.9%), whereas the majority of cases among the Taiwan-born population were male (69.4%) and aged > or = 65 years (49.6%). Most foreign-born TB patients (62.7%) lived in northern Taiwan but only about one-third (36.1%) of Taiwan-born TB cases were notified from that region. Among foreign-born TB cases whose original countries were recorded, the majority came from Mainland China and Vietnam, which accounted for 73.0% of all cases, followed by the Philippines (7.4%), Thailand (7.3%) and Indonesia (6.0%). Foreign-born TB patients have different profiles and a higher case rate compared to Taiwan-born patients. Monitoring the epidemiologic trend of TB among foreign-born persons, especially those who come from high TB-burden countries, is essential in the fight against TB in Taiwan.Journal of the Formosan Medical Association 05/2008; 107(5):389-95. · 1.13 Impact Factor -
Article: Age transition of tuberculosis patients in Taiwan, 1957-2001.
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ABSTRACT: The incidence of tuberculosis (TB) has been falling in many developed countries; however, there is a trend of an increasing proportion of TB among the elderly. The aim of this study was to evaluate the age transition of patients with TB in Taiwan from 1957 to 2001. Data on the number of TB cases and patient age were collected from the National Tuberculosis Registry for three different 5-year periods: 1957-1961, 1977-1981, and 1997-2001. The distribution of TB cases in these three different periods was analyzed. The age distributions of TB patients were different among the 1957-61 (n = 26,000), 1977-81 (n = 31,363) and 1997-2001 (n = 71,447) groups. During the 1957-61 period, the most common age group was 25-44 years (50.9%). During 1977-81, the most common age group was 45-64 years (44.9%). In 1997-2001, the most common age group had shifted to people aged 65 years or older (43.7%). For the whole period from 1957 to 2001, after adjusting for age shifts in the general population, the proportion of TB patients had significantly increased in persons 65 years or older, slightly increased in persons aged 0-14 years, and decreased in the 15-24, 25-44, and 45-64-year-old age groups. For the period 1977-2001, age-specific registered case rates increased with age. The age of TB patients in Taiwan showed a rising trend from 1957 to 2001. A high index of suspicion and prompt investigation of elderly patients with signs and symptoms characteristic of TB may allow earlier diagnosis and treatment.Journal of the Formosan Medical Association 02/2006; 105(1):25-30. · 1.13 Impact Factor
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Institutions
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2012
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Centers for Disease Control - Taiwan
- Research and Diagnostic Center
Taipei, Taipei, Taiwan -
Taipei Veterans General Hospital
- Department of Chest Medicine
Taipei, Taipei, Taiwan
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2002–2012
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Taipei Medical University
- • Graduate Institute of Clinical Medicine
- • Graduate Institute of Medical Sciences
Taipei, Taipei, Taiwan
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2004–2010
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Wan Fang Hospital
Taipei, Taipei, Taiwan
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