Chronic exposure to arsenic can generate reactive oxidative species, which can induce certain pro... more Chronic exposure to arsenic can generate reactive oxidative species, which can induce certain proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8). TNF-α, IL-6 and IL-8 have been shown to be involved in the development and progression of various cancers, including bladder cancer. This study aimed to investigate the joint effect of the polymorphism of TNF-α -308 G/A, IL-6 -174 G/C, IL-8 -251 T/A and urinary arsenic profiles on urothelial carcinoma (UC) risk. This study evaluated 300 pathologically-confirmed cases of UC and 594 cancer-free controls. Urinary arsenic species were detected using high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. The polymorphism of TNF-α -308 G/A, IL-6 -174 G/C and IL-8 -251 T/A was determined using polymerase chain reaction-restriction fragment length polymorphism. The joint effects on UC risk were estimated by odds ratios and 95% confidence intervals using unconditional logistic regression. We found that the TNF-α -308 A/A and IL-8 -251 T/T polymorphisms were significantly associated with UC. Moreover, significant dose-response joint effect of TNF-α -308 A/A or IL-8 -251 T/T genotypes and arsenic methylation indices were seen to affect UC risk. The present results also showed a significant increase in UC risk in subjects with the IL-8 -251 T/T genotype for each SD increase in urinary total arsenic and MMA%. In contrast, a significant decrease in UC risk was found in subjects who carried the IL-8 -251 T/T genotype for each SD increase in DMA%.
The goal of the present study was to compare the arsenic methylation capacities in elementary sch... more The goal of the present study was to compare the arsenic methylation capacities in elementary school and junior high school students in an area of Taiwan with low arsenic exposure, and explore the influence of both arsenic methylation capacity and obesity on insulin resistance in these children and adolescents using the HOMA-IR index. We recruited 303 elementary school students and 319 junior high school students in Taipei City from September 2007 to November 2011. Concentrations of inorganic arsenic (arsenite + arsenate), monomethylarsonic acid (MMA(V)) and dimethylarsinic acid (DMA(V)) were determined by a high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. Insulin resistance was determined by HOMA-IR. Elementary school students had significantly lower inorganic arsenic percentage and a higher DMA(V) percentage than junior high school students. It seems that the former had better arsenic methylation capability than the latter. The HOMA-IR value was significantly and positively related to the sum of the urinary inorganic and methylated arsenic (TotalAs) concentrations and also the BMI Z score, with the regression coefficients (β) being 0.058 (p < 0.001) and 0.001 (p = 0.027), respectively. The higher BMI values and higher TotalAs concentration were associated with higher HOMA-IR values in children and adolescents in Taiwan.
Vascular inflammatory process has been suggested to play a key role in the initiation and progres... more Vascular inflammatory process has been suggested to play a key role in the initiation and progression of atherosclerosis, a major complication of diabetes mellitus. Recent studies have shown that brazilin exhibits antihepatotoxic, antiplatelet, cancer preventive, or anti-inflammatory properties. Thus, we investigated whether brazilin suppresses vascular inflammatory process induced by high glucose (HG) in cultured human umbilical vein endothelial cells (HUVEC). HG induced nitrite production, lipid peroxidation, and intracellular reactive oxygen species formation in HUVEC cells, which was reversed by brazilin. Western blot analysis revealed that brazilin markedly inhibited HG-induced phosphorylation of endothelial nitric oxide synthase. Besides, we investigated the effects of brazilin on the MAPK signal transduction pathway because MAPK families are associated with vascular inflammation under stress. Brazilin blocked HG-induced phosphorylation of extracellular signal-regulated kinase and transcription factor NF-B. Furthermore, brazilin concentration-dependently attenuated cell adhesion molecules (ICAM-1 and VCAM-1) expression induced by various concentrations of HG in HUVEC. Taken together, the present data suggested that brazilin could suppress high glucoseinduced vascular inflammatory process, which may be closely related with the inhibition of oxidative stress, CAMs expression, and NF-B activation in HUVEC. Our findings may highlight a new therapeutic intervention for the prevention of vascular diseases.
Antrodia camphorata is a rare Taiwanese medicinal mushroom. Antrodia camphorata extract has been ... more Antrodia camphorata is a rare Taiwanese medicinal mushroom. Antrodia camphorata extract has been reported to exhibit antioxidant, anti-inflammation, antimetastasis, and anticancer activities and plays a role in liver fibrosis, vasorelaxation, and immunomodulation. Critical vascular inflammation leads to vascular dysfunction and cardiovascular diseases, including abdominal aortic aneurysms, hypertension, and atherosclerosis. Platelet activation plays a crucial role in intravascular thrombosis, which is involved in a wide variety of cardiovascular diseases. However, the effect of Antrodia camphorata on platelet activation remains unclear. We examined the effects of Antrodia camphorata on platelet activation. In the present study, Antrodia camphorata treatment (56-224 g/mL) inhibited platelet aggregation induced by collagen, but not U46619, an analogue of thromboxane A 2 , thrombin, and arachidonic acid. Antrodia camphorata inhibited collagen-induced calcium (Ca 2+ ) mobilization and phosphorylation of protein kinase C (PKC) and Akt. In addition, Antrodia camphorata significantly reduced the aggregation and phosphorylation of PKC in phorbol-12, 13-dibutyrate (PDBu) activated platelets. In conclusion, Antrodia camphorata may inhibit platelet activation by inhibiting of Ca 2+ and PKC cascade and the Akt pathway. Our study suggests that Antrodia camphorata may be a potential therapeutic agent for preventing or treating thromboembolic disorders.
Hyperglycaemia, a characteristic feature of diabetes mellitus, induces endothelial dysfunction an... more Hyperglycaemia, a characteristic feature of diabetes mellitus, induces endothelial dysfunction and vascular complications by limiting the proliferative potential of these cells. Here we aimed to investigate the effect of an ethanolic extract of Sanguis draconis (SD), a kind of dragon's blood resin that is obtained from Daemonorops draco (Palmae), on human umbilical vein endothelial cells (HUVEC) under high-glucose (HG) stimulation and its underlying mechanism. Concentration-dependent (0-50 μg/mL) assessment of cell viability showed that SD does not affect cell viability with a similar trend up to 48 h. Remarkably, SD (10-50 μg/mL) significantly attenuated the high-glucose (25 and 50 mM) induced cell toxicity in a concentration-dependent manner. SD inhibited high glucose-induced nitrite (NO) and lipid peroxidation (MDA) production and reactive oxygen species (ROS) formation in HUVEC. Western blot analysis revealed that SD treatments abolished HG-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK 1/2), nuclear transcription factor, κB (NF-κB), VCAM-1, and E-selectin, and it also blocked the breakdown of PARP-116 kDa protein in a dose-dependent manner. Furthermore, we found that SD increased the expression of Bcl-2 and decreased Bax protein expression in HG-stimulated HUVEC. Thus, these results of this study demonstrate for the first time that SD inhibits glucose induced oxidative stress and vascular inflammation in HUVEC by inhibiting the ERK/NF-κB/PARP-1/Bax signaling cascade followed by suppressing the activation of VCAM-1 and E-selectin. These data suggest that SD may have a therapeutic potential in vascular inflammation due to the decreased levels of oxidative stress, apoptosis, and PARP-1 activation.
Cigarette smoking and exposure to environmental tobacco smoke (ETS) are important risk factors fo... more Cigarette smoking and exposure to environmental tobacco smoke (ETS) are important risk factors for many cancers. However, exposure doses have usually not been quantitatively assessed in human studies. In humans 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronate conjugate (defined as total NNAL) are the major metabolites of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a cigarette-specific carcinogen. Although animal studies have shown that exposure to cigarette smoke increases tissue oxidative DNA damage, the relationship between cigarette smoke and 8-hydroxydeoxyguanosine (8-OHdG) is not consistent in human studies. In the present study, we have developed a simple, sensitive, and robust LC-MS/MS method for quantifying total NNAL and 8-OHdG concentrations in human plasma. We quantified total NNAL and 8-OHdG in plasma as well as 8-OHdG in urine of 121 healthy male subjects. Total NNAL levels were significantly higher in ever-smokers than in never-smokers. Furthermore, total NNAL levels in plasma were increased with numbers of cigarettes smoked per day in ever-smokers. It suggests that total NNAL in plasma is a good biomarker for cigarette smoke exposure. After stratifying by smoking status and adjusting for age, ETS exposure and occupation category, total NNAL was associated with plasma and urinary 8-OHdG in never-smokers, but not in ever-smokers. Since total NNAL levels in nonsmokers represented the ETS exposure, it appears that 8-OHdG levels are dose-dependently correlated with their ETS exposure dose. Furthermore, this correlation supports the hypothesis that oxidative DNA damage is one of major adverse effects induced by ETS exposure in humans.
Aim: Our goal was to investigate the relationship between clinical status and the presence of car... more Aim: Our goal was to investigate the relationship between clinical status and the presence of carious or periodontal pathogens among parent-child familial pairs. Clinical practices of risk assessment with consideration of familial pathogen interaction might reduce the need for therapy, improve patient outcomes, and ultimately reduce oral disease burden. Materials and Methods: In this study, we enrolled 30 parent-child pairs, with the children exhibiting complete deciduous dentition or mixed dentition with only permanent first molars. Clinical statuses were evaluated using caries and periodontal disease indicators, including the sum of decay and the number of missing or filled teeth (DMFT) for adults, decay, extraction caused by dental disease, and filled teeth (deft), for children, probing depth, and plaque control record (PCR). Supra-and sub-gingival bacteria were determined based on semi-quantitative measurements of microbial infection by using data from the Dentocult H SM test (caries-related organisms) and the PerioCheck H test (periodontal disease-related organisms). Results: No statistically significant relationship was detected between the prevalence of periodontal pathogens and that of cariogenic pathogens in the oral cavity. However, the clinical status of caries (DMFT) was negatively correlated with the clinical status of periodontal disease (pocket depth) in parents who were infected with dominant periodontal pathogens (r = 20.59, p,0.01). Parents' DMFT scores were positively correlated with children's deft and PCR scores. PCR and deft scores of children appeared to decrease significantly with the parent's pocket depth. Conclusion: The study showed that the quantity of caries pathogens were not significant related to periodontal pathogens, but the caries clinical outcome is negative related with periodontal clinical outcome between familial pairs.
The aim of this study was to assess the cryoprotective effect of static magnetic fields (SMFs) on... more The aim of this study was to assess the cryoprotective effect of static magnetic fields (SMFs) on human erythrocytes during the slow cooling procedure. Human erythrocytes suspended in 20% glycerol were slowly frozen with a 0.4-T or 0.8-T SMF and then moved to a 280uC freezer for 24 hr. The changes in survival rate, morphology, and metabolites of the thawed erythrocytes were examined. To understand possible cryoprotective mechanisms of SMF, membrane fluidity and dehydration stability of SMF-exposed erythrocytes were tested. For each test, sham-exposed erythrocytes were used as controls. Our results showed that freezing coupled with 0.4-T or 0.8-T SMFs significantly increased the relative survival ratios of the frozen-thawed erythrocytes by 10% and 20% (p,0.001), respectively. The SMFs had no effect on erythrocyte morphology and metabolite levels. However, membrane fluidity of the samples exposed to 0.8-T SMF decreased significantly (p,0.05) in the hydrophobic regions. For the dehydration stability experiments, the samples exposed to 0.8-T SMF exhibited significantly lower (p,0.05) hemolysis. These results demonstrate that a 0.8-T SMF decreases membrane fluidity and enhances erythrocyte membrane stability to resist dehydration damage caused by slow cooling procedures.
Cigarette smoking, exposure to secondhand smoke, and arsenic exposure are well known risk factors... more Cigarette smoking, exposure to secondhand smoke, and arsenic exposure are well known risk factors for developing urothelial carcinoma (UC). We investigated the combined effects of cigarette smoking, exposure to secondhand smoke, and the presence of urinary total arsenic on the risk of developing UC. We conducted a hospital-based, case-control study involving 261 UC patients and 672 cancer-free control individuals between September 2002 and May 2009. Individuals who had smoked <100 cigarettes in their lifetime (never smokers) and had a high urinary total arsenic level (≥15.40 μg/g creatinine), and those who had smoked >100 cigarettes in their lifetime (ever smokers) and had a high urinary total arsenic level, had increased risks of developing UC (3.20-fold and 6.45-fold greater), respectively, compared to individuals who were never smokers and had a low urinary total arsenic level. Individuals who had high urinary total arsenic levels and had been exposed to secondhand smoke, and individuals with high urinary arsenic levels who had not been exposed to secondhand smoke, had increased chances (2.71-fold and 5.00-fold greater, respectively) of developing UC, compared to individuals who were not exposed to secondhand smoke and had low urinary total arsenic levels. Ever smokers who had been exposed to secondhand smoke and had a high urinary total arsenic level had the greatest increased risk for developing UC (10.82-fold greater). Individuals in a Taiwanese population who smoked cigarettes, were exposed to secondhand smoke, and a high urinary total arsenic level, had a significant risk for developing UC.
Matrix metalloproteinases (MMPs) play important roles in the invasion and migration of cancer cel... more Matrix metalloproteinases (MMPs) play important roles in the invasion and migration of cancer cells. In melanoma, several signaling pathways are constitutively activated. Among these, the mitogen-activated protein kinase (MAPKs) signaling pathways are activated through multiple signal transduction molecules and appear to play major roles in melanoma progression. Therefore, the inhibition of MAPK signaling might be a crucial role for the treatment of melanoma cancer. We examined the anticancer effect of CME-1, a novel water-soluble polysaccharide fraction, isolated from Cordyceps sinensis mycelia on B16-F10 melanoma cells. B16-F10 cells were exposed to different concentrations of CME-1 (250, 500 and 800 μg/ml) for 24 h in 5% CO² incubator at 37°C. Western blot analysis was performed to detect the expression of MMP-1, p-p38 MAPK, p-ERK1/2, and IkB-α in B16-F10 cells. Cell migration test was performed by wound healing migration assay. CME-1 suppresses cell migration in a concentration-dependent manner. Western blotting analysis revealed that CME-1 led to the reduction on the expression levels of MMP-1 and down regulated the expression of phosphorylated extracellular signal-regulated kinase (ERK1/2 and p38 mitogen-activated protein kinase (p38 MAPK). CME-1 restored the IkB-degradation in B16F10 cells. These results indicate that CME-1 inhibited MMP-1 expressions in B16F10 melanoma cells through either NF-kB or ERK/p38 MAPK down regulation thereby inhibiting B16F10 cell migration. Therefore, we proposed that CME-1 might be developed as a therapeutic potential candidate for the treatment of cancer metastasis.
Few studies investigated the association between chronic arsenic exposure and the mortality of ca... more Few studies investigated the association between chronic arsenic exposure and the mortality of cancers by estimating individual urinary arsenic methylation profiles. Therefore, we compared with the general population in Taiwan to calculate the standardized mortality ratio (SMR) in arseniasis-endemic area of Taiwan from 1996 to 2010 and evaluated the dose-response relationships between environmental arsenic exposure indices or urinary arsenic profiles and the mortality of cause-specific cancer. A cohort of 1563 residents was conducted and collected their urine sample and information regarding arsenic exposure from a questionnaire. All-cause death was identified using the National Death Registry of Taiwan. Urinary arsenic profiles were measured using high performance liquid chromatographyhydride generator-atomic absorption spectrometry. We used Cox proportional hazard models to evaluate the mortality risks. In results, 193 all-site cancer deaths, and 29, 71, 43 deaths respectively for liver, lung and bladder cancers were ascertained. The SMRs were significantly high in arseniasisendemic areas for liver, lung, and bladder cancers. People with high urinary InAs% or low DMA% or low secondary methylation index (SMI) were the most likely to suffer bladder cancer after adjusting other risk factors. Even stopping exposure to arsenic from the artesian well water, the mortality rates of the residents were higher than general population. Finally, urinary InAs%, DMA% and SMI could be the potential biomarkers to predict the mortality risk of bladder cancer.
DNA methylation has been shown to be a promising cancer biomarker. The aim of this study was to e... more DNA methylation has been shown to be a promising cancer biomarker. The aim of this study was to evaluate DNA methylation of three transcription factors, sex-determining region Y-box 1 (SOX1), paired box gene 1 (PAX1), and zinc-finger 582 (ZNF582), in detecting oral squamous cell carcinoma (OSCC). A case-control study was conducted at Taipei Medical University Hospital in Taiwan with 31 cases of various oral cavity squamous cell carcinomas and 40 controls. Questionnaire data assessing environmental exposure, such as alcohol consumption, cigarette smoking, and betel nut chewing, were obtained from each participant. DNA from oral swabs were analyzed for methylation using quantitative methylation polymerase chain reaction with TaqMan probes. Methylation status was determined using a methylation index. Methylation levels of SOX1, PAX1, and ZNF582 were significantly higher in cancer patients (p = 0.02, p = 0.02, and p = 0.03, respectively). Patients with highly methylated SOX1, PAX1, and ZNF582 had an increased cancer risk with odds ratios (ORs) of 16.50 (95 % CI = 2.85-96.65), 60.57 (95 % CI = 5.85-629.94), and 5.07 (95 % CI = 1.08-23.76), respectively. Area under the curve (AUC) values were 0.85, 0.78, and 0.78 for PAX1, SOX1, and ZNF582, respectively. When stratified based on environmental exposure, the AUC of PAX1 methylation (PAX1 (m) ) was 0.94 in environmental exposure-naïve subjects and 0.85 for SOX1 methylation in subjects who chewed betel nut. In general, the sensitivity and specificity of PAX1 (m) were 87 and 80 % for OSCC detection. The sensitivity of PAX1 (m) in subjects who chewed betel nut was 83 %, with a specificity of 75 %. Testing PAX1 DNA methylation using oral swabs is a promising method for oral cancer detection. Combined assessments regarding betel nut consumption and DNA methylation can improve OSCC screening. The double E (environmental and epigenetic) assessment is a potential strategy in OSCC screening.
Using DNA methylation biomarkers in cancer detection is a potential direction in clinical testing... more Using DNA methylation biomarkers in cancer detection is a potential direction in clinical testing. Some methylated genes have been proposed for cervical cancer detection; however, more reliable methylation markers are needed. To identify new hypermethylated genes in the discovery phase, we compared the methylome between a pool of DNA from normal cervical epithelium (n 5 19) and a pool of DNA from cervical cancer tissues (n 5 38) using a methylation bead array. We integrated the differentially methylated genes with public gene expression databases, which resulted in 91 candidate genes. Based on gene expression after demethylation treatment in cell lines, we confirmed 61 genes for further validation. In the validation phase, quantitative MSP and bisulfite pyrosequencing were used to examine their methylation level in an independent set of clinical samples. Fourteen genes, including ADRA1D, AJAP1, COL6A2, EDN3, EPO, HS3ST2, MAGI2, POU4F3, PTGDR, SOX8, SOX17, ST6GAL2, SYT9, and ZNF614, were significantly hypermethylated in CIN31 lesions. The sensitivity, specificity, and accuracy of POU4F3 for detecting CIN31 lesions were 0.88, 0.82, and 0.85, respectively. A bioinformatics function analysis revealed that AJAP1, EDN3, EPO, MAGI2, and SOX17 were potentially implicated in b-catenin signaling, suggesting the epigenetic dysregulation of this signaling pathway during cervical cancer development. The concurrent methylation of multiple genes in cancers and in subsets of precancerous lesions suggests the presence of a driver of methylation phenotype in cervical carcinogenesis. Further validation of these new genes as biomarkers for cervical cancer screening in a larger population-based study is warranted.
Heat acclimation is a physiologically and biochemically adapted process when species transition f... more Heat acclimation is a physiologically and biochemically adapted process when species transition from one environmental temperature to one of the increased temperature. There is very limited epidemiological evidence on the heat-related impacts during exposure to extremely high heat in an occupational environment. This study sought to identify a potential biomarker of heat acclimation and the burden of heat on the body. The aim of this study was to elucidate oxidative DNA damage and heat acclimation through a self-comparison study design in navy boiler tenders, subjects exposed to extremely high heat in an occupational setting. Fifty-eight male soldiers who work in a boiler room were recruited for this study. The subjects were initially assessed with a health examination and body composition assessment before sailing. In order to compare the within-subject differences before and after heat exposure, the index-related heat exposure was collected before and after a routine 5-h work shift and 7-day sailing. Urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG), a useful marker of oxidative DNA damage was the measurement by liquid chromatography/tandem mass spectrometry. The median of the change in urinary 8-OHdG was 0.78 μg/g creatinine, as the urinary 8-OHdG after sailing was significantly higher than before sailing (p < 0.01). The urinary 8-OHdG was significantly decreased in heat-acclimated boiler tenders. Oxidative DNA damage was significantly decreased in heat-acclimated subjects. Urinary 8-OHdG can be used as a biomarker to assess the effect of heat stress as a result of occupational exposure to extremely high heat conditions.
Background Gene polymorphisms in the one-carbon metabolism pathway could contribute to arsenic me... more Background Gene polymorphisms in the one-carbon metabolism pathway could contribute to arsenic methylation capability through plasma folate and homocysteine metabolism, thereby increasing the susceptibility to urothelial carcinoma (UC) risk. Objectives The goal of our study was to evaluate the roles of gene polymorphisms in the one-carbon metabolism pathway in the carcinogenesis of UC. Methods A hospital-based case–controlled study was conducted. The urinary arsenic profile was examined using high-performance liquid chromatography and hydride generator-atomic absorption spectrometry. Folate levels were measured using a competitive immunoassay kit. Genotyping was conducted using polymerase chain reaction-restriction fragment length polymorphism technique. Results Patients with UC had higher urinary total arsenic, inorganic arsenic percentage (InAs%) and monomethylarsenic acid percentage (MMA%), and lower dimethylarsenic acid percentage (DMA%), plasma folate and homocysteine levels than controls. The correlations between folate and DMA%, and folate and homocysteine, were significant according to Pearson’s correlation coefficients. Subjects carrying the 5,10-methylenetetrahydrofolate reductase (MTHFR) CT or TT genotype had a lower DMA% and lower folate levels than those carrying the CC genotype. Participants with the methionine synthase (MS) AA genotype had higher homocysteine levels than those with the AG or GG genotype. However, neither MTHFR nor MS gene polymorphisms were associated with UC risk. Conclusions Environmental factors played a more important role in UC carcinogenesis than MTHFR or MS gene polymorphism.
To elucidate the influence of folate concentration on the association between urinary arsenic pro... more To elucidate the influence of folate concentration on the association between urinary arsenic profiles and urothelial carcinoma (UC) risks in subjects without evident arsenic exposure, 177 UC cases and 488 controls were recruited between September 2002 and May 2004. Urinary arsenic species including inorganic arsenic, monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV) were determined by employing a high performance liquid chromatography-linked hydride generator and atomic absorption spectrometry procedure. After adjustment for suspected risk factors of UC, the higher indicators of urinary total arsenic levels, percentage of inorganic arsenic, percentage of MMAV, and primary methylation index were associated with increased risk of UC. On the other hand, the higher plasma folate levels, urinary percentage of DMAV and secondary methylation index were associated with decreased risk of UC. A dose–response relationship was shown between plasma folate levels or methylation indices of arsenic species and UC risk in the respective quartile strata. The plasma folate was found to interact with urinary arsenic profiles in affecting the UC risk. The results of this study may identify the susceptible subpopulations and provide insight into the carcinogenic mechanisms of arsenic even at low arsenic exposure.
Journal of Toxicology and Environmental Health-part A-current Issues, 2005
The association of 4 genetic polymorphisms, NAD(P)H oxidase, manganese superoxide dismutase (MnSO... more The association of 4 genetic polymorphisms, NAD(P)H oxidase, manganese superoxide dismutase (MnSOD), catalase, and endothelial nitric oxide synthase (e-NOS), was assessed with arsenic-related hypertension risk among 79 hypertensive cases and 213 controls in an arseniasis-hyperendemic area of Taiwan. Overall, MnSOD polymorphism significantly increased the risk of hypertension regardless of arsenic exposure. NADPH oxidase and eNOS polymorphisms were significantly associated with hypertension risk in the high arsenic exposure group; however, catalase polymorphism was not associated with hypertension. Groups were further stratified by triglyceride levels to evaluate whether the cumulative arsenic exposure combined the three polymorphisms together. The adjusted adds ratios (ORs) of at least two risk factors of the cumulative arsenic exposure and MnSOD, NADPH oxidase, and eNOS three-polymorphism combination versus any one risk factor of them were 0.8 (95% CI 0.3-2.3) for individuals with low triglyceride levels (<110 mg/dl) and 2.5 (95% CI 1.0-6.01) for high-triglyceride groups (>110 mg/dl), respectively. These results suggested that the NADPH oxidase, MnSOD, and e-NOS polymorphisms, but not catalase, might play a role in the development of arsenic-related hypertension, especially in subjects with high triglyceride levels.
Chronic exposure to arsenic can generate reactive oxidative species, which can induce certain pro... more Chronic exposure to arsenic can generate reactive oxidative species, which can induce certain proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-8 (IL-8). TNF-α, IL-6 and IL-8 have been shown to be involved in the development and progression of various cancers, including bladder cancer. This study aimed to investigate the joint effect of the polymorphism of TNF-α -308 G/A, IL-6 -174 G/C, IL-8 -251 T/A and urinary arsenic profiles on urothelial carcinoma (UC) risk. This study evaluated 300 pathologically-confirmed cases of UC and 594 cancer-free controls. Urinary arsenic species were detected using high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. The polymorphism of TNF-α -308 G/A, IL-6 -174 G/C and IL-8 -251 T/A was determined using polymerase chain reaction-restriction fragment length polymorphism. The joint effects on UC risk were estimated by odds ratios and 95% confidence intervals using unconditional logistic regression. We found that the TNF-α -308 A/A and IL-8 -251 T/T polymorphisms were significantly associated with UC. Moreover, significant dose-response joint effect of TNF-α -308 A/A or IL-8 -251 T/T genotypes and arsenic methylation indices were seen to affect UC risk. The present results also showed a significant increase in UC risk in subjects with the IL-8 -251 T/T genotype for each SD increase in urinary total arsenic and MMA%. In contrast, a significant decrease in UC risk was found in subjects who carried the IL-8 -251 T/T genotype for each SD increase in DMA%.
The goal of the present study was to compare the arsenic methylation capacities in elementary sch... more The goal of the present study was to compare the arsenic methylation capacities in elementary school and junior high school students in an area of Taiwan with low arsenic exposure, and explore the influence of both arsenic methylation capacity and obesity on insulin resistance in these children and adolescents using the HOMA-IR index. We recruited 303 elementary school students and 319 junior high school students in Taipei City from September 2007 to November 2011. Concentrations of inorganic arsenic (arsenite + arsenate), monomethylarsonic acid (MMA(V)) and dimethylarsinic acid (DMA(V)) were determined by a high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. Insulin resistance was determined by HOMA-IR. Elementary school students had significantly lower inorganic arsenic percentage and a higher DMA(V) percentage than junior high school students. It seems that the former had better arsenic methylation capability than the latter. The HOMA-IR value was significantly and positively related to the sum of the urinary inorganic and methylated arsenic (TotalAs) concentrations and also the BMI Z score, with the regression coefficients (β) being 0.058 (p &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.001) and 0.001 (p = 0.027), respectively. The higher BMI values and higher TotalAs concentration were associated with higher HOMA-IR values in children and adolescents in Taiwan.
Vascular inflammatory process has been suggested to play a key role in the initiation and progres... more Vascular inflammatory process has been suggested to play a key role in the initiation and progression of atherosclerosis, a major complication of diabetes mellitus. Recent studies have shown that brazilin exhibits antihepatotoxic, antiplatelet, cancer preventive, or anti-inflammatory properties. Thus, we investigated whether brazilin suppresses vascular inflammatory process induced by high glucose (HG) in cultured human umbilical vein endothelial cells (HUVEC). HG induced nitrite production, lipid peroxidation, and intracellular reactive oxygen species formation in HUVEC cells, which was reversed by brazilin. Western blot analysis revealed that brazilin markedly inhibited HG-induced phosphorylation of endothelial nitric oxide synthase. Besides, we investigated the effects of brazilin on the MAPK signal transduction pathway because MAPK families are associated with vascular inflammation under stress. Brazilin blocked HG-induced phosphorylation of extracellular signal-regulated kinase and transcription factor NF-B. Furthermore, brazilin concentration-dependently attenuated cell adhesion molecules (ICAM-1 and VCAM-1) expression induced by various concentrations of HG in HUVEC. Taken together, the present data suggested that brazilin could suppress high glucoseinduced vascular inflammatory process, which may be closely related with the inhibition of oxidative stress, CAMs expression, and NF-B activation in HUVEC. Our findings may highlight a new therapeutic intervention for the prevention of vascular diseases.
Antrodia camphorata is a rare Taiwanese medicinal mushroom. Antrodia camphorata extract has been ... more Antrodia camphorata is a rare Taiwanese medicinal mushroom. Antrodia camphorata extract has been reported to exhibit antioxidant, anti-inflammation, antimetastasis, and anticancer activities and plays a role in liver fibrosis, vasorelaxation, and immunomodulation. Critical vascular inflammation leads to vascular dysfunction and cardiovascular diseases, including abdominal aortic aneurysms, hypertension, and atherosclerosis. Platelet activation plays a crucial role in intravascular thrombosis, which is involved in a wide variety of cardiovascular diseases. However, the effect of Antrodia camphorata on platelet activation remains unclear. We examined the effects of Antrodia camphorata on platelet activation. In the present study, Antrodia camphorata treatment (56-224 g/mL) inhibited platelet aggregation induced by collagen, but not U46619, an analogue of thromboxane A 2 , thrombin, and arachidonic acid. Antrodia camphorata inhibited collagen-induced calcium (Ca 2+ ) mobilization and phosphorylation of protein kinase C (PKC) and Akt. In addition, Antrodia camphorata significantly reduced the aggregation and phosphorylation of PKC in phorbol-12, 13-dibutyrate (PDBu) activated platelets. In conclusion, Antrodia camphorata may inhibit platelet activation by inhibiting of Ca 2+ and PKC cascade and the Akt pathway. Our study suggests that Antrodia camphorata may be a potential therapeutic agent for preventing or treating thromboembolic disorders.
Hyperglycaemia, a characteristic feature of diabetes mellitus, induces endothelial dysfunction an... more Hyperglycaemia, a characteristic feature of diabetes mellitus, induces endothelial dysfunction and vascular complications by limiting the proliferative potential of these cells. Here we aimed to investigate the effect of an ethanolic extract of Sanguis draconis (SD), a kind of dragon&amp;amp;amp;amp;amp;amp;#39;s blood resin that is obtained from Daemonorops draco (Palmae), on human umbilical vein endothelial cells (HUVEC) under high-glucose (HG) stimulation and its underlying mechanism. Concentration-dependent (0-50 μg/mL) assessment of cell viability showed that SD does not affect cell viability with a similar trend up to 48 h. Remarkably, SD (10-50 μg/mL) significantly attenuated the high-glucose (25 and 50 mM) induced cell toxicity in a concentration-dependent manner. SD inhibited high glucose-induced nitrite (NO) and lipid peroxidation (MDA) production and reactive oxygen species (ROS) formation in HUVEC. Western blot analysis revealed that SD treatments abolished HG-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK 1/2), nuclear transcription factor, κB (NF-κB), VCAM-1, and E-selectin, and it also blocked the breakdown of PARP-116 kDa protein in a dose-dependent manner. Furthermore, we found that SD increased the expression of Bcl-2 and decreased Bax protein expression in HG-stimulated HUVEC. Thus, these results of this study demonstrate for the first time that SD inhibits glucose induced oxidative stress and vascular inflammation in HUVEC by inhibiting the ERK/NF-κB/PARP-1/Bax signaling cascade followed by suppressing the activation of VCAM-1 and E-selectin. These data suggest that SD may have a therapeutic potential in vascular inflammation due to the decreased levels of oxidative stress, apoptosis, and PARP-1 activation.
Cigarette smoking and exposure to environmental tobacco smoke (ETS) are important risk factors fo... more Cigarette smoking and exposure to environmental tobacco smoke (ETS) are important risk factors for many cancers. However, exposure doses have usually not been quantitatively assessed in human studies. In humans 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and its glucuronate conjugate (defined as total NNAL) are the major metabolites of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, a cigarette-specific carcinogen. Although animal studies have shown that exposure to cigarette smoke increases tissue oxidative DNA damage, the relationship between cigarette smoke and 8-hydroxydeoxyguanosine (8-OHdG) is not consistent in human studies. In the present study, we have developed a simple, sensitive, and robust LC-MS/MS method for quantifying total NNAL and 8-OHdG concentrations in human plasma. We quantified total NNAL and 8-OHdG in plasma as well as 8-OHdG in urine of 121 healthy male subjects. Total NNAL levels were significantly higher in ever-smokers than in never-smokers. Furthermore, total NNAL levels in plasma were increased with numbers of cigarettes smoked per day in ever-smokers. It suggests that total NNAL in plasma is a good biomarker for cigarette smoke exposure. After stratifying by smoking status and adjusting for age, ETS exposure and occupation category, total NNAL was associated with plasma and urinary 8-OHdG in never-smokers, but not in ever-smokers. Since total NNAL levels in nonsmokers represented the ETS exposure, it appears that 8-OHdG levels are dose-dependently correlated with their ETS exposure dose. Furthermore, this correlation supports the hypothesis that oxidative DNA damage is one of major adverse effects induced by ETS exposure in humans.
Aim: Our goal was to investigate the relationship between clinical status and the presence of car... more Aim: Our goal was to investigate the relationship between clinical status and the presence of carious or periodontal pathogens among parent-child familial pairs. Clinical practices of risk assessment with consideration of familial pathogen interaction might reduce the need for therapy, improve patient outcomes, and ultimately reduce oral disease burden. Materials and Methods: In this study, we enrolled 30 parent-child pairs, with the children exhibiting complete deciduous dentition or mixed dentition with only permanent first molars. Clinical statuses were evaluated using caries and periodontal disease indicators, including the sum of decay and the number of missing or filled teeth (DMFT) for adults, decay, extraction caused by dental disease, and filled teeth (deft), for children, probing depth, and plaque control record (PCR). Supra-and sub-gingival bacteria were determined based on semi-quantitative measurements of microbial infection by using data from the Dentocult H SM test (caries-related organisms) and the PerioCheck H test (periodontal disease-related organisms). Results: No statistically significant relationship was detected between the prevalence of periodontal pathogens and that of cariogenic pathogens in the oral cavity. However, the clinical status of caries (DMFT) was negatively correlated with the clinical status of periodontal disease (pocket depth) in parents who were infected with dominant periodontal pathogens (r = 20.59, p,0.01). Parents' DMFT scores were positively correlated with children's deft and PCR scores. PCR and deft scores of children appeared to decrease significantly with the parent's pocket depth. Conclusion: The study showed that the quantity of caries pathogens were not significant related to periodontal pathogens, but the caries clinical outcome is negative related with periodontal clinical outcome between familial pairs.
The aim of this study was to assess the cryoprotective effect of static magnetic fields (SMFs) on... more The aim of this study was to assess the cryoprotective effect of static magnetic fields (SMFs) on human erythrocytes during the slow cooling procedure. Human erythrocytes suspended in 20% glycerol were slowly frozen with a 0.4-T or 0.8-T SMF and then moved to a 280uC freezer for 24 hr. The changes in survival rate, morphology, and metabolites of the thawed erythrocytes were examined. To understand possible cryoprotective mechanisms of SMF, membrane fluidity and dehydration stability of SMF-exposed erythrocytes were tested. For each test, sham-exposed erythrocytes were used as controls. Our results showed that freezing coupled with 0.4-T or 0.8-T SMFs significantly increased the relative survival ratios of the frozen-thawed erythrocytes by 10% and 20% (p,0.001), respectively. The SMFs had no effect on erythrocyte morphology and metabolite levels. However, membrane fluidity of the samples exposed to 0.8-T SMF decreased significantly (p,0.05) in the hydrophobic regions. For the dehydration stability experiments, the samples exposed to 0.8-T SMF exhibited significantly lower (p,0.05) hemolysis. These results demonstrate that a 0.8-T SMF decreases membrane fluidity and enhances erythrocyte membrane stability to resist dehydration damage caused by slow cooling procedures.
Cigarette smoking, exposure to secondhand smoke, and arsenic exposure are well known risk factors... more Cigarette smoking, exposure to secondhand smoke, and arsenic exposure are well known risk factors for developing urothelial carcinoma (UC). We investigated the combined effects of cigarette smoking, exposure to secondhand smoke, and the presence of urinary total arsenic on the risk of developing UC. We conducted a hospital-based, case-control study involving 261 UC patients and 672 cancer-free control individuals between September 2002 and May 2009. Individuals who had smoked &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;100 cigarettes in their lifetime (never smokers) and had a high urinary total arsenic level (≥15.40 μg/g creatinine), and those who had smoked &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;100 cigarettes in their lifetime (ever smokers) and had a high urinary total arsenic level, had increased risks of developing UC (3.20-fold and 6.45-fold greater), respectively, compared to individuals who were never smokers and had a low urinary total arsenic level. Individuals who had high urinary total arsenic levels and had been exposed to secondhand smoke, and individuals with high urinary arsenic levels who had not been exposed to secondhand smoke, had increased chances (2.71-fold and 5.00-fold greater, respectively) of developing UC, compared to individuals who were not exposed to secondhand smoke and had low urinary total arsenic levels. Ever smokers who had been exposed to secondhand smoke and had a high urinary total arsenic level had the greatest increased risk for developing UC (10.82-fold greater). Individuals in a Taiwanese population who smoked cigarettes, were exposed to secondhand smoke, and a high urinary total arsenic level, had a significant risk for developing UC.
Matrix metalloproteinases (MMPs) play important roles in the invasion and migration of cancer cel... more Matrix metalloproteinases (MMPs) play important roles in the invasion and migration of cancer cells. In melanoma, several signaling pathways are constitutively activated. Among these, the mitogen-activated protein kinase (MAPKs) signaling pathways are activated through multiple signal transduction molecules and appear to play major roles in melanoma progression. Therefore, the inhibition of MAPK signaling might be a crucial role for the treatment of melanoma cancer. We examined the anticancer effect of CME-1, a novel water-soluble polysaccharide fraction, isolated from Cordyceps sinensis mycelia on B16-F10 melanoma cells. B16-F10 cells were exposed to different concentrations of CME-1 (250, 500 and 800 μg/ml) for 24 h in 5% CO² incubator at 37°C. Western blot analysis was performed to detect the expression of MMP-1, p-p38 MAPK, p-ERK1/2, and IkB-α in B16-F10 cells. Cell migration test was performed by wound healing migration assay. CME-1 suppresses cell migration in a concentration-dependent manner. Western blotting analysis revealed that CME-1 led to the reduction on the expression levels of MMP-1 and down regulated the expression of phosphorylated extracellular signal-regulated kinase (ERK1/2 and p38 mitogen-activated protein kinase (p38 MAPK). CME-1 restored the IkB-degradation in B16F10 cells. These results indicate that CME-1 inhibited MMP-1 expressions in B16F10 melanoma cells through either NF-kB or ERK/p38 MAPK down regulation thereby inhibiting B16F10 cell migration. Therefore, we proposed that CME-1 might be developed as a therapeutic potential candidate for the treatment of cancer metastasis.
Few studies investigated the association between chronic arsenic exposure and the mortality of ca... more Few studies investigated the association between chronic arsenic exposure and the mortality of cancers by estimating individual urinary arsenic methylation profiles. Therefore, we compared with the general population in Taiwan to calculate the standardized mortality ratio (SMR) in arseniasis-endemic area of Taiwan from 1996 to 2010 and evaluated the dose-response relationships between environmental arsenic exposure indices or urinary arsenic profiles and the mortality of cause-specific cancer. A cohort of 1563 residents was conducted and collected their urine sample and information regarding arsenic exposure from a questionnaire. All-cause death was identified using the National Death Registry of Taiwan. Urinary arsenic profiles were measured using high performance liquid chromatographyhydride generator-atomic absorption spectrometry. We used Cox proportional hazard models to evaluate the mortality risks. In results, 193 all-site cancer deaths, and 29, 71, 43 deaths respectively for liver, lung and bladder cancers were ascertained. The SMRs were significantly high in arseniasisendemic areas for liver, lung, and bladder cancers. People with high urinary InAs% or low DMA% or low secondary methylation index (SMI) were the most likely to suffer bladder cancer after adjusting other risk factors. Even stopping exposure to arsenic from the artesian well water, the mortality rates of the residents were higher than general population. Finally, urinary InAs%, DMA% and SMI could be the potential biomarkers to predict the mortality risk of bladder cancer.
DNA methylation has been shown to be a promising cancer biomarker. The aim of this study was to e... more DNA methylation has been shown to be a promising cancer biomarker. The aim of this study was to evaluate DNA methylation of three transcription factors, sex-determining region Y-box 1 (SOX1), paired box gene 1 (PAX1), and zinc-finger 582 (ZNF582), in detecting oral squamous cell carcinoma (OSCC). A case-control study was conducted at Taipei Medical University Hospital in Taiwan with 31 cases of various oral cavity squamous cell carcinomas and 40 controls. Questionnaire data assessing environmental exposure, such as alcohol consumption, cigarette smoking, and betel nut chewing, were obtained from each participant. DNA from oral swabs were analyzed for methylation using quantitative methylation polymerase chain reaction with TaqMan probes. Methylation status was determined using a methylation index. Methylation levels of SOX1, PAX1, and ZNF582 were significantly higher in cancer patients (p = 0.02, p = 0.02, and p = 0.03, respectively). Patients with highly methylated SOX1, PAX1, and ZNF582 had an increased cancer risk with odds ratios (ORs) of 16.50 (95 % CI = 2.85-96.65), 60.57 (95 % CI = 5.85-629.94), and 5.07 (95 % CI = 1.08-23.76), respectively. Area under the curve (AUC) values were 0.85, 0.78, and 0.78 for PAX1, SOX1, and ZNF582, respectively. When stratified based on environmental exposure, the AUC of PAX1 methylation (PAX1 (m) ) was 0.94 in environmental exposure-naïve subjects and 0.85 for SOX1 methylation in subjects who chewed betel nut. In general, the sensitivity and specificity of PAX1 (m) were 87 and 80 % for OSCC detection. The sensitivity of PAX1 (m) in subjects who chewed betel nut was 83 %, with a specificity of 75 %. Testing PAX1 DNA methylation using oral swabs is a promising method for oral cancer detection. Combined assessments regarding betel nut consumption and DNA methylation can improve OSCC screening. The double E (environmental and epigenetic) assessment is a potential strategy in OSCC screening.
Using DNA methylation biomarkers in cancer detection is a potential direction in clinical testing... more Using DNA methylation biomarkers in cancer detection is a potential direction in clinical testing. Some methylated genes have been proposed for cervical cancer detection; however, more reliable methylation markers are needed. To identify new hypermethylated genes in the discovery phase, we compared the methylome between a pool of DNA from normal cervical epithelium (n 5 19) and a pool of DNA from cervical cancer tissues (n 5 38) using a methylation bead array. We integrated the differentially methylated genes with public gene expression databases, which resulted in 91 candidate genes. Based on gene expression after demethylation treatment in cell lines, we confirmed 61 genes for further validation. In the validation phase, quantitative MSP and bisulfite pyrosequencing were used to examine their methylation level in an independent set of clinical samples. Fourteen genes, including ADRA1D, AJAP1, COL6A2, EDN3, EPO, HS3ST2, MAGI2, POU4F3, PTGDR, SOX8, SOX17, ST6GAL2, SYT9, and ZNF614, were significantly hypermethylated in CIN31 lesions. The sensitivity, specificity, and accuracy of POU4F3 for detecting CIN31 lesions were 0.88, 0.82, and 0.85, respectively. A bioinformatics function analysis revealed that AJAP1, EDN3, EPO, MAGI2, and SOX17 were potentially implicated in b-catenin signaling, suggesting the epigenetic dysregulation of this signaling pathway during cervical cancer development. The concurrent methylation of multiple genes in cancers and in subsets of precancerous lesions suggests the presence of a driver of methylation phenotype in cervical carcinogenesis. Further validation of these new genes as biomarkers for cervical cancer screening in a larger population-based study is warranted.
Heat acclimation is a physiologically and biochemically adapted process when species transition f... more Heat acclimation is a physiologically and biochemically adapted process when species transition from one environmental temperature to one of the increased temperature. There is very limited epidemiological evidence on the heat-related impacts during exposure to extremely high heat in an occupational environment. This study sought to identify a potential biomarker of heat acclimation and the burden of heat on the body. The aim of this study was to elucidate oxidative DNA damage and heat acclimation through a self-comparison study design in navy boiler tenders, subjects exposed to extremely high heat in an occupational setting. Fifty-eight male soldiers who work in a boiler room were recruited for this study. The subjects were initially assessed with a health examination and body composition assessment before sailing. In order to compare the within-subject differences before and after heat exposure, the index-related heat exposure was collected before and after a routine 5-h work shift and 7-day sailing. Urinary 8-hydroxy-2&amp;amp;amp;amp;amp;amp;amp;amp;#39;-deoxyguanosine (8-OHdG), a useful marker of oxidative DNA damage was the measurement by liquid chromatography/tandem mass spectrometry. The median of the change in urinary 8-OHdG was 0.78 μg/g creatinine, as the urinary 8-OHdG after sailing was significantly higher than before sailing (p &amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.01). The urinary 8-OHdG was significantly decreased in heat-acclimated boiler tenders. Oxidative DNA damage was significantly decreased in heat-acclimated subjects. Urinary 8-OHdG can be used as a biomarker to assess the effect of heat stress as a result of occupational exposure to extremely high heat conditions.
Background Gene polymorphisms in the one-carbon metabolism pathway could contribute to arsenic me... more Background Gene polymorphisms in the one-carbon metabolism pathway could contribute to arsenic methylation capability through plasma folate and homocysteine metabolism, thereby increasing the susceptibility to urothelial carcinoma (UC) risk. Objectives The goal of our study was to evaluate the roles of gene polymorphisms in the one-carbon metabolism pathway in the carcinogenesis of UC. Methods A hospital-based case–controlled study was conducted. The urinary arsenic profile was examined using high-performance liquid chromatography and hydride generator-atomic absorption spectrometry. Folate levels were measured using a competitive immunoassay kit. Genotyping was conducted using polymerase chain reaction-restriction fragment length polymorphism technique. Results Patients with UC had higher urinary total arsenic, inorganic arsenic percentage (InAs%) and monomethylarsenic acid percentage (MMA%), and lower dimethylarsenic acid percentage (DMA%), plasma folate and homocysteine levels than controls. The correlations between folate and DMA%, and folate and homocysteine, were significant according to Pearson’s correlation coefficients. Subjects carrying the 5,10-methylenetetrahydrofolate reductase (MTHFR) CT or TT genotype had a lower DMA% and lower folate levels than those carrying the CC genotype. Participants with the methionine synthase (MS) AA genotype had higher homocysteine levels than those with the AG or GG genotype. However, neither MTHFR nor MS gene polymorphisms were associated with UC risk. Conclusions Environmental factors played a more important role in UC carcinogenesis than MTHFR or MS gene polymorphism.
To elucidate the influence of folate concentration on the association between urinary arsenic pro... more To elucidate the influence of folate concentration on the association between urinary arsenic profiles and urothelial carcinoma (UC) risks in subjects without evident arsenic exposure, 177 UC cases and 488 controls were recruited between September 2002 and May 2004. Urinary arsenic species including inorganic arsenic, monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV) were determined by employing a high performance liquid chromatography-linked hydride generator and atomic absorption spectrometry procedure. After adjustment for suspected risk factors of UC, the higher indicators of urinary total arsenic levels, percentage of inorganic arsenic, percentage of MMAV, and primary methylation index were associated with increased risk of UC. On the other hand, the higher plasma folate levels, urinary percentage of DMAV and secondary methylation index were associated with decreased risk of UC. A dose–response relationship was shown between plasma folate levels or methylation indices of arsenic species and UC risk in the respective quartile strata. The plasma folate was found to interact with urinary arsenic profiles in affecting the UC risk. The results of this study may identify the susceptible subpopulations and provide insight into the carcinogenic mechanisms of arsenic even at low arsenic exposure.
Journal of Toxicology and Environmental Health-part A-current Issues, 2005
The association of 4 genetic polymorphisms, NAD(P)H oxidase, manganese superoxide dismutase (MnSO... more The association of 4 genetic polymorphisms, NAD(P)H oxidase, manganese superoxide dismutase (MnSOD), catalase, and endothelial nitric oxide synthase (e-NOS), was assessed with arsenic-related hypertension risk among 79 hypertensive cases and 213 controls in an arseniasis-hyperendemic area of Taiwan. Overall, MnSOD polymorphism significantly increased the risk of hypertension regardless of arsenic exposure. NADPH oxidase and eNOS polymorphisms were significantly associated with hypertension risk in the high arsenic exposure group; however, catalase polymorphism was not associated with hypertension. Groups were further stratified by triglyceride levels to evaluate whether the cumulative arsenic exposure combined the three polymorphisms together. The adjusted adds ratios (ORs) of at least two risk factors of the cumulative arsenic exposure and MnSOD, NADPH oxidase, and eNOS three-polymorphism combination versus any one risk factor of them were 0.8 (95% CI 0.3-2.3) for individuals with low triglyceride levels (<110 mg/dl) and 2.5 (95% CI 1.0-6.01) for high-triglyceride groups (>110 mg/dl), respectively. These results suggested that the NADPH oxidase, MnSOD, and e-NOS polymorphisms, but not catalase, might play a role in the development of arsenic-related hypertension, especially in subjects with high triglyceride levels.
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Papers by Yung-Kai Huang