Publications by authors named "Pinpin Lin"

111 Publications

Proximity to petrochemical industrial parks and risk of chronic glomerulonephritis.

Environ Res 2022 Jan 10;208:112700. Epub 2022 Jan 10.

National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan; Environmental and Occupational Medicine, College of Medicine, National Taiwan University and National Taiwan University Hospital, Taipei, Taiwan; Institute of Environmental and Occupational Health Sciences, College of Public Health, National Taiwan University, Taiwan. Electronic address:

This study determined whether individuals residing near petrochemical industrial parks (PIPs) have a higher risk of chronic glomerulonephritis (CGN). We performed population-based 1:4 case-control study by using Taiwan's National Health Insurance Research Database from 2000 to 2016. The subjects were aged 20-65 years, residing in western Taiwan, and did not have a history of any renal or urinary system disease in 2000. The case cohort included those who had at least three outpatient visits or one hospitalization between 2001 and 2016 with codes for CGN as per International Classification of Diseases (ICD)-Ninth and Tenth Revisions. Controls were randomly sampled age-, sex-, and urbanization-matched individuals without renal and urinary system diseases. Petrochemical exposure was evaluated by the distance to the nearest PIP of the residential township, and petrochemical exposure probability was examined considering the monthly prevailing wind direction. Conditional logistic regression was used to determine the association between petrochemical exposure and CGN risk. A total of 320,935 subjects were included in the final analysis (64,187 cases and 256,748 controls). After adjustment for potential confounders, living in townships within a 3-km radius of PIPs was associated with a higher risk of CGN (adjusted odds ratio [aOR] = 1.32, 95% confidence interval [CI] = 1.28-1.37). Compared with townships more than 20 km away from PIPs, those within 10 km of PIPs were associated with significantly increased risks of CGN in a dose-dependent manner. When prevailing wind was considered, townships with high exposure probability were associated with a significantly increased risk of CGN. We found that those residing near PIPs or with high petrochemical exposure probability had a higher risk of CGN. These findings highlight the need for monitoring environmental nephrotoxic substances and the renal health of residents living near PIPs.
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http://dx.doi.org/10.1016/j.envres.2022.112700DOI Listing
January 2022

A machine learning-driven approach for prioritizing food contact chemicals of carcinogenic concern based on complementary in silico methods.

Food Chem Toxicol 2022 Jan 1;160:112802. Epub 2022 Jan 1.

Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County, 35053, Taiwan; Graduate Institute of Data Science, College of Management, Taipei Medical University, Taipei, 106, Taiwan; Doctoral Degree Program in Toxicology, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan. Electronic address:

Carcinogenicity is one of the most critical endpoints for the risk assessment of food contact chemicals (FCCs). However, the carcinogenicity of FCCs remains insufficiently investigated. To fill the data gap, the application of standard experimental methods for identifying chemicals of carcinogenic concerns from a large set of FCCs is impractical due to their resource-intensive nature. In contrast, computational methods provide an efficient way to quickly screen chemicals with carcinogenic potential for subsequent experimental validation. Since every model was developed based on a limited number of training samples, the use of single models for carcinogenicity assessment may not cover the complex mechanisms of carcinogenesis. This study proposed a novel machine learning-based weight-of-evidence (WoE) model for prioritizing chemical carcinogenesis. The WoE model can nonlinearly integrate complementary computational methods of structural alerts, quantitative structure-activity relationship models and in silico toxicogenomics models into a WoE-score. Compared to the best single method, the WoE model gained 8% and 19.7% improvement in the area under the receiver operating characteristic curve (AUC) value and chemical coverage, respectively. The prioritization of 1623 FCCs concludes 44 chemicals of high carcinogenic concern. The machine learning-based WoE approach provides a fast and comprehensive way for prioritizing chemicals of carcinogenic concern.
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http://dx.doi.org/10.1016/j.fct.2021.112802DOI Listing
January 2022

Dietary Exposure of the Taiwan Population to Mercury Content in Various Seafood Assessed by a Total Diet Study.

Int J Environ Res Public Health 2021 11 21;18(22). Epub 2021 Nov 21.

Department of Food Science, National Taiwan Ocean University, Keelung City 20224, Taiwan.

This paper examines the health risks of exposure to methylmercury (MeHg) through the consumption of mercury-contaminated seafood in Taiwan, based on the total diet study (TDS) method. Samples of seafood ( = 140) were purchased at fishing harbors or supermarkets and classified into seven categories (pelagic fish, inshore fish, farmed fish, shellfish, cephalopods, crustaceans, and algae). For each sample, we analyzed raw and cooked versions and compared the concentration difference. Total mercury (THg) was detected at the highest rate and in the highest concentrations in pelagic fish, followed by inshore fish and other farmed fish. The average concentration of THg was higher after cooking. In a 75th percentile scenario, the hazard indices for children aged 1 to 3 years and children aged 4 to 6 years were higher than 100% of the provisional tolerable weekly intake. Taking into consideration the risk assessment results, MeHg concentrations, and the nutritional composition of fish, we have provided weekly consumption advisories for children aged 1 to 3 years, children aged 4 to 6 years, and childbearing women aged 19 to 49 years. The weekly consumption advisories for childbearing women are 35 g/week of pelagic fish and 245 g/week of inshore fish based on the risk results from MeHg and the potential benefits from eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) intake.
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http://dx.doi.org/10.3390/ijerph182212227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619390PMC
November 2021

Conditioned Media of Adipose-Derived Stem Cells Suppresses Sidestream Cigarette Smoke Extract Induced Cell Death and Epithelial-Mesenchymal Transition in Lung Epithelial Cells.

Int J Mol Sci 2021 Nov 8;22(21). Epub 2021 Nov 8.

Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Zhunan 35053, Taiwan.

The role of the epithelial-mesenchymal transition (EMT) in lung epithelial cells is increasingly being recognized as a key stage in the development of COPD, fibrosis, and lung cancers, which are all highly associated with cigarette smoking and with exposure to second-hand smoke. Using the exposure of human lung cancer epithelial A549 cells and non-cancerous Beas-2B cells to sidestream cigarette smoke extract (CSE) as a model, we studied the protective effects of adipose-derived stem cell-conditioned medium (ADSC-CM) against CSE-induced cell death and EMT. CSE dose-dependently induced cell death, decreased epithelial markers, and increased the expression of mesenchymal markers. Upstream regulator analysis of differentially expressed genes after CSE exposure revealed similar pathways as those observed in typical EMT induced by TGF-β1. CSE-induced cell death was clearly attenuated by ADSC-CM but not by other control media, such as a pass-through fraction of ADSC-CM or A549-CM. ADSC-CM effectively inhibited CSE-induced EMT and was able to reverse the gradual loss of epithelial marker expression associated with TGF-β1 treatment. CSE or TGF-β1 enhanced the speed of A549 migration by 2- to 3-fold, and ADSC-CM was effective in blocking the cell migration induced by either agent. Future work will build on the results of this in vitro study by defining the molecular mechanisms through which ADSC-CM protects lung epithelial cells from EMT induced by toxicants in second-hand smoke.
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http://dx.doi.org/10.3390/ijms222112069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8584490PMC
November 2021

Ambient Particulate Matter Induces Vascular Smooth Muscle Cell Phenotypic Changes via NOX1/ROS/NF-κB Dependent and Independent Pathways: Protective Effects of Polyphenols.

Antioxidants (Basel) 2021 May 14;10(5). Epub 2021 May 14.

National Institute of Environmental Health Sciences, National Health Research Institutes, Zhunan 53053, Taiwan.

Epidemiological studies have demonstrated an association between ambient particulate matter (PM) exposure and vascular diseases. Here, we observed that treatment with ambient PM increased cell migration ability in vascular smooth muscle cells (VSMCs) and pulmonary arterial SMCs (PASMCs). These results suggest that VSMCs and PASMCs transitioned from a differentiated to a synthetic phenotype after PM exposure. Furthermore, treatment with PM increased intracellular reactive oxygen species (ROS), activated the NF-κB signaling pathway, and increased the expression of proinflammatory cytokines in VSMCs. Using specific inhibitors, we demonstrated that PM increased the migration ability of VSMCs via the nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase 1 (NOX1)/ROS-dependent NF-κB signaling pathway, which also partially involved in the induction of proinflammatory cytokines. Finally, we investigated whether nature polyphenolic compounds prevent PM-induced migration and proinflammatory cytokines secretion in VSMCs. Curcumin, resveratrol, and gallic acid prevented PM-induced migration via the ROS-dependent NF-κB signaling pathway. However, honokiol did not prevent PM-induced migration or activation of the ROS-dependent NF-κB signaling pathway. On the other hand, all polyphenols prevented PM-induced cytokines secretion. These data indicated that polyphenols prevented PM-induced migration and cytokine secretion via blocking the ROS-dependent NF-κB signaling pathway in VSMCs. However, other mechanisms may also contribute to PM-induced cytokine secretion.
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http://dx.doi.org/10.3390/antiox10050782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156007PMC
May 2021

Study Protocol for radiation exposure and cancer risk assessment- The Taiwan Nuclear Power Plants and Epidemiology Cohort Study (TNPECS).

J Epidemiol 2021 May 29. Epub 2021 May 29.

National Institute of Environmental Health Sciences, National Health Research Institutes.

Background: This cohort was established to evaluate whether 38-year radiation exposure (since the start of nuclear reactor operations) is related to cancer risk in residents near three near nuclear power plants (NPPs).

Methods: This cohort study enrolled all residents who lived near (within 8 km) of any of the three NPPs in Taiwan from 1978 to 2016 (n=214,502; person-years=4,660,189). The control population (n=257,475; person-years=6,282,390) from three towns comprised all residents having lived far (more than 15 km) from all three NPPs. Radiation exposure will be assessed by computer programs GASPAR-II and LADTAP-II by following methodologies provided in the USNRC regulatory guides. We calculated the cumulative individual tissue organ equivalent dose and cumulative effective dose for each resident. This study presents the number of new cancer cases and prevalence in the residence-nearest NPP group and control group in the 38-year research observation period.

Conclusions: TNPECS provides a valuable platform for research and opens unique possibilities for testing whether radiation exposure since the start of operations of nuclear reactors will affect health across the life course. The release of radioactive nuclear species caused by the operation of NPPs caused residents to have an effective dose between 10 and 10 mSv / year. The mean of cumulative medical radiation exposure dose between the residence-nearest NPP group and the control group is not different (7.69±18.39 mSv and 7.61±19.17 mSv, p=0.114).
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http://dx.doi.org/10.2188/jea.JE20210020DOI Listing
May 2021

Maternal proximity to petrochemical industrial parks and risk of premature rupture of membranes.

Environ Res 2021 03 29;194:110688. Epub 2020 Dec 29.

Environmental and Occupational Medicine, College of Medicine, National Taiwan University and National Taiwan University Hospital, Taipei, Taiwan; National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan; Institute of Environmental and Occupational Health Sciences, College of Public Health, National Taiwan University, Taipei, Taiwan. Electronic address:

Background: Living near petrochemical industries has been reported to increase the risks of adverse birth outcomes, such as low birth weight and preterm delivery. However, evidence regarding the role of petrochemical exposure in pregnancy complications remains limited. This study evaluated the association between maternal proximity to petrochemical industrial parks (PIPs) during pregnancy and the occurrence of premature rupture of membranes (PROM).

Methods: We performed a population-based 1:3 case-control study by using the 2004-2014 Taiwanese Birth Certificate Database. Birth records reported as stillbirth or bearing congenital anomalies were excluded. Cases were newborns reported to have PROM, whereas controls were randomly sampled from those without any pregnancy complications by matching birth year and urbanization index of the residential township. The proximity to PIPs was evaluated by calculating the distance to the nearest PIP of the maternal residential township during pregnancy. Furthermore, petrochemical exposure opportunity, accounting for monthly prevailing wind direction, was quantified during the entire gestational period. We applied conditional logistic regression models to evaluate the associations.

Results: In total, 29371 PROM cases were reported during the study period, with a corresponding 88113 healthy controls sampled. The results revealed that living within a 3-km radius of PIPs during pregnancy would increase the risk of PROM (odds ratio [OR] = 1.76, 95% CI: 1.66-1.87). Furthermore, compared with the lowest exposed group, those with high petrochemical exposure opportunity had a significantly increased risk of PROM occurrence (OR = 1.69-1.75). The adverse effects remained robust in the subgroup analysis for both term- and preterm-PROM.

Conclusions: The results of the present work provide evidence that living near PIPs during pregnancy would increase the risk of PROM, and additional studies are warranted to confirm our findings.
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http://dx.doi.org/10.1016/j.envres.2020.110688DOI Listing
March 2021

Primary Amine Modified Gold Nanodots Regulate Macrophage Function and Antioxidant Response: Potential Therapeutics Targeting of Nrf2.

Int J Nanomedicine 2020 29;15:8411-8426. Epub 2020 Oct 29.

National Institute of Environmental Health Sciences, National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan.

Background: Gold nanoparticles with high biocompatibility and immunomodulatory properties have potential applications in the development of new diagnostic and therapeutic strategies for nanomedicine. Nanoparticles targeting macrophages can manipulate or control immunological diseases. This study assessed the activity of dendrimer-encapsulated gold nanodots (AuNDs) with three surface modifications [ie, outfacing groups with primary amine (AuNDs-NH2), hydroxyl (AuNDs-OH), and quaternary ammonium ions (AuNDs-CH3)] regulated macrophage function and antioxidant response through Nrf2-dependent pathway.

Methods: AuNDs were prepared and characterized. Intracellular distribution of AuNDs in human macrophages was observed through confocal microscopy. The activity of AuNDs was evaluated using macrophage functions and antioxidant response in the human macrophage cell line THP-1.

Results: AuNDs-NH2 and AuNDs-CH3, but not AuNDs-OH, drove the obvious Nrf2-antioxidant response element pathway in THP-1 cells. Of the three, AuNDs-NH2 considerably increased mRNA levels and antioxidant activities of heme oxygenase 1 and NAD(P)H quinone dehydrogenase 1 in THP-1 cells. IL-6 mRNA and protein expression was mediated through Nrf2 activation in AuNDs-NH2-treated macrophages. Furthermore, Nrf2 activation by AuNDs-NH2 increased the phagocytic ability of THP-1 macrophages.

Conclusion: AuNDs-NH2 had immunomodulatory activities in macrophages. The findings of the present work suggested that AuNDs have potential effects against chronic inflammatory diseases via the Nrf2 pathway.
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http://dx.doi.org/10.2147/IJN.S268203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605661PMC
November 2020

Prediction of human fetal-maternal blood concentration ratio of chemicals.

PeerJ 2020 21;8:e9562. Epub 2020 Jul 21.

National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli County, Taiwan.

Background: The measurement of human fetal-maternal blood concentration ratio (logFM) of chemicals is critical for the risk assessment of chemical-induced developmental toxicity. While a few in vitro and ex vivo experimental methods were developed for predicting logFM of chemicals, the obtained experimental results are not able to directly predict in vivo outcomes.

Methods: A total of 55 chemicals with logFM values representing in vivo fetal-maternal blood ratio were divided into training and test datasets. An interpretable linear regression model was developed along with feature selection methods. Cross-validation on training dataset and prediction on independent test dataset were conducted to validate the prediction model.

Results: This study presents the first valid quantitative structure-activity relationship model following the Organisation for Economic Co-operation and Development (OECD) guidelines based on multiple linear regression for predicting in vivo logFM values. The autocorrelation descriptor AATSC1c and information content descriptor ZMIC1 were identified as informative features for predicting logFM. After the adjustment of the applicability domain, the developed model performs well with correlation coefficients of 0.875, 0.850 and 0.847 for model fitting, leave-one-out cross-validation and independent test, respectively. The model is expected to be useful for assessing human transplacental exposure.
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http://dx.doi.org/10.7717/peerj.9562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380269PMC
July 2020

Curation of cancer hallmark-based genes and pathways for in silico characterization of chemical carcinogenesis.

Database (Oxford) 2020 01;2020

National Institute of Environmental Health Sciences, National Health Research Institutes, 35 Keyan Road, Miaoli County 35053, Taiwan.

Exposure to toxic substances in the environment is one of the most important causes of cancer. However, the time-consuming process for the identification and characterization of carcinogens is not applicable to a huge amount of testing chemicals. The data gaps make the carcinogenic risk uncontrollable. An efficient and effective way of prioritizing chemicals of carcinogenic concern with interpretable mechanism information is highly desirable. This study presents a curation work for genes and pathways associated with 11 hallmarks of cancer (HOCs) reported by the Halifax Project. To demonstrate the usefulness of the curated HOC data, the interacting HOC genes and affected HOC pathways of chemicals of the three carcinogen lists from IARC, NTP and EPA were analyzed using the in silico toxicogenomics ChemDIS system. Results showed that a higher number of affected HOCs were observed for known carcinogens than the other chemicals. The curated HOC data is expected to be useful for prioritizing chemicals of carcinogenic concern. Database URL: The HOC database is available at https://github.com/hocdb-KMU-TMU/hocdb and the website of Database journal as Supplementary Data.
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http://dx.doi.org/10.1093/database/baaa045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294774PMC
January 2020

Exposure to Zinc Oxide Nanoparticles Disrupts Endothelial Tight and Adherens Junctions and Induces Pulmonary Inflammatory Cell Infiltration.

Int J Mol Sci 2020 May 13;21(10). Epub 2020 May 13.

Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 35053, Taiwan.

Zinc oxide nanoparticles (ZnONPs) are frequently encountered nanomaterials in our daily lives. Despite the benefits of ZnONPs in a variety of applications, many studies have shown potential health hazards of exposure to ZnONPs. We have shown that oropharyngeal aspiration of ZnONPs in mice increases lung inflammation. However, the detailed mechanisms underlying pulmonary inflammatory cell infiltration remain to be elucidated. Endothelium functions as a barrier between the blood stream and the blood vessel wall. Endothelial barrier dysfunction may increase infiltration of immune cells into the vessel wall and underlying tissues. This current study examined the effects of ZnONPs exposure on endothelial barriers. ZnONPs exposure increased leukocyte infiltration in the mouse lungs. In endothelial cells, ZnONPs reduced the continuity of tight junction proteins claudin-5 and zonula occludens-1 (ZO-1) at the cell junctions. ZnONPs induced adherens junction protein VE-cadherin internalization from membrane to cytosol and dissociation with β-catenin, leading to reduced and diffused staining of VE-cadherin and β-catenin at cell junctions. Our results demonstrated that ZnONPs disrupted both tight and adherens junctions, compromising the integrity and stability of the junction network, leading to inflammatory cell infiltration. Thus, ZnONPs exposure in many different settings should be carefully evaluated for vascular effects and subsequent health impacts.
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http://dx.doi.org/10.3390/ijms21103437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279309PMC
May 2020

Identification of ambient fine particulate matter components related to vascular dysfunction by analyzing spatiotemporal variations.

Sci Total Environ 2020 Jun 10;719:137243. Epub 2020 Feb 10.

National Institute of Environmental Health Sciences, National Health Research Institutes, Zhunan, Taiwan. Electronic address:

Exposure to ambient fine particulate matter (PM) has been associated with vascular diseases in epidemiological studies. We have demonstrated previously that exposure to ambient PM caused pulmonary vascular remodeling in mice and increased vascular smooth muscle cells (VSMCs) viability. Here, we further demonstrated that exposure of mice to ambient PM increased urinary 8‑hydroxy‑2'‑deoxyguanosine (8-OHdG) and cytokines concentrations in the broncheoalveolar lavage. The objective of the present study was to identify the PM components related to vascular dysfunction. Exposure to PM collected from various areas and seasons in Taiwan significantly increased viability, oxidative stress, and inflammatory cytokines secretion in VSMCs. The mass concentrations of benz[a]anthracene (BaA), benzo[e]pyrene (BeP), perylene, dibenzo[a,e]pyrene, molybdenum, zinc (Zn), vanadium (V), and nickel in the PM were significantly associated with increased viability of VSMCs. These components, except BaA and BeP, also were significantly associated with chemokine (CC motif) ligand 5 (CCL5) concentrations in the VSMCs. The effects of V and Zn on cell viability and CCL5 expression, respectively, were verified. In addition, the mass concentrations of sulfate and manganese (Mn) in PM were significantly correlated with increased oxidative stress; this correlation was also confirmed. After extraction, the inorganic fraction of PM increased cell viability and oxidative stress, but the organic fraction of PM increased only cell viability, which was inhibited by an aryl hydrocarbon receptor antagonist. These data suggest that controlling the emission of Zn, V, Mn, sulfate, and PAHs may prevent the occurrence of PM-induced vascular diseases.
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http://dx.doi.org/10.1016/j.scitotenv.2020.137243DOI Listing
June 2020

Leveraging complementary computational models for prioritizing chemicals of developmental and reproductive toxicity concern: an example of food contact materials.

Arch Toxicol 2020 02 2;94(2):485-494. Epub 2020 Jan 2.

National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli County, 35053, Taiwan.

The evaluation of developmental and reproductive toxicity of food contact materials (FCMs) is an important task for food safety. Since traditional experiments are both time-consuming and labor-intensive, only a small number of FCMs have sufficient toxicological data for evaluating their effects on human health. While computational methods such as structural alerts and quantitative structure-activity relationships can serve as first-line tools for the identification of chemicals of high toxicity concern, models with binary outputs and unsatisfied accuracy and coverage prevent the use of computational methods for prioritizing chemicals of high concern. This study proposed a genetic algorithm-based method to develop a weight-of-evidence (WoE) model leveraging complementary methods of structural alerts, quantitative structure-activity relationships and in silico toxicogenomics models for chemical prioritization. The WoE model was applied to evaluate 623 food contact chemicals and identify 26 chemicals of high toxicity concern, where 13 chemicals have been reported to be developmental or reproductive toxic and further experiments are suggested for the remaining 13 chemicals without toxicity data related to developmental and reproductive effects. The proposed WoE model is potentially useful for prioritizing chemicals of high toxicity concern and the methodology may be applied to toxicities other than developmental and reproductive toxicity.
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http://dx.doi.org/10.1007/s00204-019-02641-0DOI Listing
February 2020

Vanadium Derivative Exposure Promotes Functional Alterations of VSMCs and Consequent Atherosclerosis via ROS/p38/NF-κB-Mediated IL-6 Production.

Int J Mol Sci 2019 Dec 4;20(24). Epub 2019 Dec 4.

Cellular and System Medicine, National Health Research Institutes, Zhunan 35053, Taiwan.

Vanadium is a transition metal widely distributed in the Earth's crust, and is a major contaminant in fossil fuels. Its pathological effect and regulation in atherosclerosis remain unclear. We found that intranasal administration of the vanadium derivative NaVO significantly increased plasma and urinary vanadium levels and induced arterial lipid accumulation and atherosclerotic lesions in apolipoprotein E-deficient knockout mice () murine aorta compared to those in vehicle-exposed mice. This was accompanied by an increase in plasma reactive oxygen species (ROS) and interleukin 6 (IL-6) levels and a decrease in the vascular smooth muscle cell (VSMC) differentiation marker protein SM22α in the atherosclerotic lesions. Furthermore, exposure to NaVO or VOSO induced cytosolic ROS generation and IL-6 production in VSMCs and promoted VSMC synthetic differentiation, migration, and proliferation. The anti-oxidant -acetylcysteine (NAC) not only suppresses IL-6 production and VSMC pathological responses including migration and proliferation but also prevents atherosclerosis in mice. Inhibition experiments with NAC and pharmacological inhibitors demonstrated that NaVO-induced IL-6 production is signaled by ROS-triggered p38-mediated NF-κB-dependent pathways. Neutralizing anti-IL-6 antibodies impaired NaVO-mediated VSMC migration and proliferation. We concluded that NaVO exposure activates the ROS-triggering p38 signaling to selectively induce NF-κB-mediated IL-6 production. These signaling pathways induce VSMC synthetic differentiation, migration, and proliferation, leading to lipid accumulation and atherosclerosis.
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http://dx.doi.org/10.3390/ijms20246115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940940PMC
December 2019

Persistent elevation of blood pressure by ambient coarse particulate matter after recovery from pulmonary inflammation in mice.

Environ Toxicol 2019 Jul 27;34(7):814-824. Epub 2019 Mar 27.

National Institute of Environmental Health Sciences, National Health Research Institutes, Zhunan, 350 Taiwan.

Exposure to ambient particulate matter (PM) is associated with hypertension and cardiovascular diseases. Recently, we reported that exposure to fine and coarse PM caused pulmonary inflammation and pulmonary small arterial remodeling in mice, and osteopontin (OPN) level was elevated following PM exposure. However, in the present study, cotreatment with 5-methoxytryptophan for 4 weeks partially reduced coarse PM-induced pulmonary inflammation without reducing pulmonary OPN secretion or recovery from pulmonary arterial remodeling in mice. Persistent vascular dysfunction may lead to vascular remodeling. Therefore, we further compared the relationship between coarse PM-induced inflammation and vascular dysfunction by exposing mice to PM before and after cessation of PM exposure. Oropharyngeal aspiration of PM for 8 weeks induced pulmonary inflammation and pulmonary small artery remodeling in mice, as well as increased serum C-reactive protein and OPN concentrations and systolic blood pressure (SBP). After the cessation of PM exposure for another 8 weeks, lung inflammation had recovered and vascular remodeling had partially recovered. Elevation of OPN, metalloproteinases (MMPs), and cytokines in bronchioalveolar lavage were significantly reduced. However, PM-induced systemic responses did not recover after the cessation of PM exposure. Notably, not only serum OPN and SBP remained significantly elevated; also, serum endothelin-1, MMP-9, and keratinocyte-derived chemokine concentrations were significantly increased after cessation of PM exposure for another 8 weeks. These data suggested that systemic inflammation and systemic vascular dysfunction might be important in PM-induced elevation of SBP. Furthermore, SBP elevation was persistent after cessation of PM exposure for 8 weeks.
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http://dx.doi.org/10.1002/tox.22749DOI Listing
July 2019

Type 2 diabetes occurrence and mercury exposure - From the National Nutrition and Health Survey in Taiwan.

Environ Int 2019 05 27;126:260-267. Epub 2019 Feb 27.

National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan; Department of Public Health, China Medical University, Taichung, Taiwan; Department of Public Health, National Defense Medical Center, Taipei, Taiwan; Department of Safety, Health, and Environmental Engineering, National United University, Miaoli, Taiwan. Electronic address:

Background: The global prevalence of type 2 diabetes continues to increase in both developed and developing countries. Environmental exposure to mercury may be an important and modifiable risk factor for type 2 diabetes. However, the epidemiological results are controversial.

Objectives: This study aimed to examine the association between blood mercury levels and prevalence of type 2 diabetes.

Methods: A total of 646 adult participants were selected from the National Nutrition and Health Survey in Taiwan (NAHSIT) 2005-2008. The participants were interviewed using structured questionnaires to record data on basic demographics, socioeconomic status, lifestyle, medical history, and 24-h dietary recall. Specimens of blood and urine were collected at the health examination. Type 2 diabetes was defined as a fasting blood glucose level ≥ 126 mg/dL or intake of hypoglycemic medications. The mercury concentration in red blood cells (RBC-Hg) was quantified by cold vapor atomic absorption spectrometry.

Results: Participants with type 2 diabetes had a significantly higher RBC-Hg than those without type 2 diabetes. A significant association between the RBC-Hg and prevalence of type 2 diabetes was observed [odds ratio (OR): 1.64; 95% confidence intervals: 1.14-2.35] after potential confounders were well considered, including age, sex, body mass index (BMI), hypertension, total cholesterol, saltwater fish consumption, geographical strata, seasonality and hemoglobin (Hb) level.

Conclusion: Our findings showed that elevated RBC-Hg is significantly associated with type 2 diabetes prevalence. Future research, particularly for longitudinal cohort studies with suitable specimens, needs to be performed to verify our findings.
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http://dx.doi.org/10.1016/j.envint.2019.02.038DOI Listing
May 2019

Lung Tumorigenesis Alters the Expression of Slit2-exon15 Splicing Variants in Tumor Microenvironment.

Cancers (Basel) 2019 Feb 1;11(2). Epub 2019 Feb 1.

Divisions of Medical Oncology and Pulmonary Medicine, Chung Shan Medical University Hospital, Taichung 40201, Taiwan.

Slit2 expression is downregulated in various cancers, including lung cancer. We identified two Slit2 splicing variants at exon15-Slit2-WT and Slit2-ΔE15. In the RT-PCR analyses, the Slit2-WT isoform was predominantly expressed in all the lung cancer specimens and in their normal lung counterparts, whereas Slit2-ΔE15 was equivalently or predominantly expressed in 41% of the pneumothorax specimens. A kRas transgenic mice system was used to study the effects of tumorigenesis on the expressions of the Slit2-exon15 isoforms. The results revealed that a kRas-induced lung tumor increased the Slit2-WT/Slit2-ΔE15 ratio and total Slit2 expression level. However, the lung tumors generated via a tail vein injection of lung cancer cells decreased the Slit2-WT/Slit2-ΔE15 ratio and total Slit2 expression level. Interestingly, the lipopolysaccharide (LPS)-induced lung inflammation also decreased the Slit2-WT/Slit2-ΔE15 ratio. Since Slit2 functions as an anti-inflammatory factor, the expression of Slit2 increases in kRas lungs, which indicates that Slit2 suppresses immunity during tumorigenesis. However, an injection of lung cancer cells via the tail vein and the LPS-induced lung inflammation both decreased the Slit2 expression. The increased Slit2 in the tumor microenvironment was mostly Slit2-WT, which lacks growth inhibitory activity. Thus, the results of our study suggested that the upregulation of Slit2-WT, but not Slit2-ΔE15, in a cancer microenvironment is an important factor in suppressing immunity while not interfering with cancer growth.
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http://dx.doi.org/10.3390/cancers11020166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406468PMC
February 2019

Identification of osteopontin as a biomarker of human exposure to fine particulate matter.

Environ Pollut 2019 Feb 25;245:975-985. Epub 2018 Nov 25.

National Institute of Environmental Health Sciences, National Health Research Institutes, Zhunan, Taiwan, ROC. Electronic address:

Ambient particulate matter (PM) exposure is associated with pulmonary and cardiovascular diseases; however, there is scant research linking data on animal and human cells. The objective of this study was to investigate these associations. Vascular remodeling plays a crucial role in both pulmonary and cardiovascular diseases. Therefore, we conducted a transcriptomic analysis using vascular smooth muscle cells (VSMCs) to identify potential regulators or markers of PM exposure. We demonstrated that fine and coarse PM increased VSMC proliferation in mice. We conducted a genome-wide cDNA microarray analysis, followed by a pathway analysis of VSMCs treated with coarse PM for durations of 24, 48, and 72 h. Sixteen genes were discovered to be time-dependently upregulated and involved in VSMC proliferation. Osteopontin (OPN) is indicated as one of the regulators of these upregulated genes. Both fine and coarse PM from industrial and urban areas significantly increased OPN expression in VSMCs and macrophages. Moreover, oropharyngeal instillation of fine and coarse PM for 8 weeks increased the VSMCs in the pulmonary arteries of mice. OPN level was consistently increased in the lung tissues, bronchoalveolar lavage fluid, and serum of mice. Moreover, we analyzed the plasma OPN levels of 72 healthy participants recruited from the studied metropolitan area. Each participant wore a personal PM sampler to assess their PM exposure over a 24 h period. Our results indicate that personal exposure to fine PM is positively correlated with plasma OPN level in young adults. The data obtained in this study suggest that exposure to fine and coarse PM may cause pulmonary vascular lesions in humans and that OPN level may be a biomarker of PM exposure in humans.
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http://dx.doi.org/10.1016/j.envpol.2018.11.071DOI Listing
February 2019

Prioritization of pesticides in crops with a semi-quantitative risk ranking method for Taiwan postmarket monitoring program.

J Food Drug Anal 2019 01 3;27(1):347-354. Epub 2018 Jul 3.

National Institute of Environmental Health Sciences, National Health Research Institutes, Taiwan. Electronic address:

A risk-based prioritization of chemical hazards in monitoring programs allows regulatory agencies to focus on the most potentially concerned items involving human health risk. In this study, a risk-based matrix, with a scoring method using multiple factors for severity and probability of exposure, was employed to identify the pesticides presented in crops that may pose the greatest risk to human health. Both the probability of exposure and the severity were assessed for 91 pesticides detected in a Taiwanese postmarketing monitoring program. Probability of exposure was evaluated based on the probability of consumption and evidence of pesticide residues in crops. Severity was assessed based on the nature of the hazard (i.e., the description of toxic effects), and the acceptable daily intake (ADI) reported by available toxicological reports. This study showed that the nature of the hazard and probability of consumption had the strongest contribution to risk score. Dithiocarbamates, endosulfan, and carbofuran were identified as the pesticides with the highest concern for human health risks in Taiwan. These pesticides should be monitored more frequently than others in crops during the postmarketing monitoring program. However, some uncertainties shall be noted or improved when this methodology is applied for risk prioritization in the future.
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http://dx.doi.org/10.1016/j.jfda.2018.06.009DOI Listing
January 2019

Novel STAT3 Inhibitor LDOC1 Targets Phospho-JAK2 for Degradation by Interacting with LNX1 and Regulates the Aggressiveness of Lung Cancer.

Cancers (Basel) 2019 Jan 9;11(1). Epub 2019 Jan 9.

National Institute of Environmental Health Science, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 35053, Taiwan.

Meta-analysis revealed that () increased methylation more in people with lung tumors than in those who were healthy and never smoked. Quantitative methylation-specific PCR revealed that cigarette smoke condensate (CSC) exposure drives promoter hypermethylation and silence in human bronchial cells. Immunohistochemistry studies showed that downregulation is associated with poor survival of patients with lung cancer. Loss and gain of LDOC1 functions enhanced and attenuated aggressive phenotypes in lung adenocarcinoma A549 and non⁻small cell lung carcinoma H1299 cell lines, respectively. We found that LDOC1 deficiency led to reinforcing a reciprocal loop of IL-6/JAK2/STAT3, through which LDOC1 mediates the cancer progression. LDOC1 knockdown considerably augmented tumorigenesis and the phosphorylation of JAK2 and STAT3 in vivo. Results from immunoprecipitation and immunofluorescent confocal microscopy indicated that LDOC1 negatively regulates JAK2 activity by forming multiple protein complexes with pJAK2 and E3 ubiquitin-protein ligase LNX1, and in turn, LDOC1 targets pJAK2 to cause ubiquitin-dependent proteasomal degradation. LDOC1 deficiency attenuates the interactions between LNX1 and pJAK2, leading to ineffective ubiquitination of pJAK2, which activates STAT3. Overall, our results elucidated a crucial role of LDOC1 in lung cancer and revealed how LDOC1 acts as a bridge between tobacco exposure and the IL-6/JAK2/STAT3 loop in this human malignancy.
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http://dx.doi.org/10.3390/cancers11010063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356782PMC
January 2019

Probabilistic Integrated Human Mixture Risk Assessment of Multiple Metals Through Seafood Consumption.

Risk Anal 2019 02 3;39(2):426-438. Epub 2018 Sep 3.

Institute of Food Safety and Health Risk Assessment, National Yang-Ming University, Taipei, Taiwan.

Inorganic arsenic (iAs), cadmium (Cd), lead (Pb), and methylmercury (MeHg) are toxic metals that cause substantial health concern and are present in various seafood items. This study linked probabilistic risk assessment to the interactive hazard index (HI ) approach to assess the human mixture risk posed by the dietary intake of iAs, Cd, Pb, and MeHg from seafood for different age populations, and joint toxic actions and toxic interactions among metals were also considered in the assessment. We found that, in combination, an iAs-Cd-Pb-MeHg mixture synergistically causes neurological toxicity. Furthermore, an iAs-Cd-Pb mixture antagonistically causes renal and hematological effects and additively causes cardiovascular effect. Our results demonstrated that if toxic interactions are not considered, the health risk may be overestimated or underestimated. The 50th percentile HI estimates in all age populations for neurological, renal, cardiovascular, and hematological effects were lower than 1; however, the 97.5th percentile HI estimates might exceed 1. In particular, toddlers and preschoolers had the highest neurological risk, with 0.16 and 0.19 probabilities, respectively, of neurological HI exceeding 1. Saltwater fish consumption was the principal contributor to the health risk. We suggest that regular monitoring of metal levels in seafood, more precise dietary surveys, further toxicological data, and risk-benefit analysis of seafood consumption are warranted to improve the accuracy of human mixture risk assessment and determine optimal consumption.
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http://dx.doi.org/10.1111/risa.13183DOI Listing
February 2019

ChemDIS-Mixture: an online tool for analyzing potential interaction effects of chemical mixtures.

Sci Rep 2018 07 3;8(1):10047. Epub 2018 Jul 3.

National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli County, 35053, Taiwan.

The assessment of bioactivity and toxicity for mixtures remains a challenging work. Although several computational models have been developed to accelerate the evaluation of chemical-chemical interaction, a specific biological endpoint should be defined before applying the models that usually relies on clinical and experimental data. The development of computational methods is desirable for identifying potential biological endpoints of mixture interactions. To facilitate the identification of potential effects of mixture interactions, a novel online system named ChemDIS-Mixture is proposed to analyze the shared target proteins, and common enriched functions, pathways, and diseases affected by multiple chemicals. Venn diagram tools have been implemented for easy analysis and visualization of interaction targets and effects. Case studies have been provided to demonstrate the capability of ChemDIS-Mixture for identifying potential effects of mixture interactions in clinical studies. ChemDIS-Mixture provides useful functions for the identification of potential effects of coexposure to multiple chemicals. ChemDIS-Mixture is freely accessible at http://cwtung.kmu.edu.tw/chemdis/mixture .
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http://dx.doi.org/10.1038/s41598-018-28361-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030136PMC
July 2018

Risk assessment of methylmercury based on internal exposure and fish and seafood consumption estimates in Taiwanese children.

Int J Hyg Environ Health 2018 05 15;221(4):697-703. Epub 2018 Mar 15.

National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli, Taiwan. Electronic address:

Fish and seafood consumption is a major source of human exposure to methylmercury (MeHg). This study evaluated the potential health risk of MeHg in Taiwanese children from fish and seafood consumption using a toxicokinetic model, hazard quotients and hazard indices (HIs). Two biomonitoring programs provided an important resource for blood specimens for assessing MeHg exposure in human populations. For internal exposures, total mercury (THg) was measured as a biomarker of MeHg in whole blood (WB) and red blood cells using inductively coupled plasma mass spectrometry and cold-vapor atomic absorption spectroscopy, respectively. The THg concentrations were used to estimate MeHg concentrations. Consumption of fish and seafood was assessed using the National Food Consumption database in Taiwan, while mercury concentrations in edible fish and seafood were collected from published studies in Taiwan. Our results indicated that 1) the highest median THg (representing estimated MeHg) daily intakes were found to decrease with increasing age in children consuming saltwater fish for age groups 0-3, 4-6, 7-12, and 13-18 years: 0.03 > 0.02 > 0.017 > 0.007 (μg kg-BW day); 2) HI greater than one, based on WB-THg, was found in 28% of 4-6-year-old children and 3) internal exposure estimates based on WB-THg, though slightly higher, were comparable to those based on fish and seafood consumption. The results support the use of dietary intake estimates as surrogates for internal blood MeHg levels in Taiwanese children to assess their exposure.
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http://dx.doi.org/10.1016/j.ijheh.2018.03.002DOI Listing
May 2018

Development of an in Vitro-Based Risk Assessment Framework for Predicting Ambient Particulate Matter-Bound Polycyclic Aromatic Hydrocarbon-Activated Toxicity Pathways.

Environ Sci Technol 2017 Dec 1;51(24):14262-14272. Epub 2017 Dec 1.

National Institute of Environmental Health Sciences, National Health Research Institutes , Zhunan, Taiwan 35053, ROC.

Polycyclic aromatic hydrocarbons (PAHs) are widely distributed throughout the atmosphere as mixtures attached to ambient particulate matter (PM). PAHs usually elicit similar toxicological pathways but do so with varying levels of efficacy. In this study, we utilized high-throughput screening (HTS) in vitro data of PAHs to predict health risks associated with coarse and fine PM. PM samples with 22 PAH compounds obtained from residential areas close to industrial parks in central Taiwan were analyzed. On the basis of the PM-bound PAH concentrations and their activities reported in HTS assays, we developed a probabilistic model for estimating cumulative exposure of humans to PAHs. Activity-to-exposure ratio (AER) values were calculated to compare relative risks of activating the aryl hydrocarbon receptor (AhR), nuclear factor erythroid 2-related factor 2 (Nrf2), and tumor suppressor gene (p53) when children or adults were exposed to fine or coarse PM in different seasons. On the basis of AER values, the risk of fine PM exposure was relatively higher than the risk of exposure to coarse PM in pathway activation. Children as a susceptible population had a risk of the activating AhR pathway greater than that of adults. Particularly higher risks were observed in winter than in summer. Among three pathways, AhR was the most sensitive one activated by exposure to PAHs. In addition, the activation of the AhR, Nrf2, and p53 pathways was compared by in vitro reporter assays with and without the pre-extraction of PAHs from PM. Our proposed novel approach accounts for mixture toxicities in characterizing in vitro pathway-based risks via inhalation exposure to ambient PAHs.
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http://dx.doi.org/10.1021/acs.est.7b02002DOI Listing
December 2017

Interleukin-24 as a target cytokine of environmental aryl hydrocarbon receptor agonist exposure in the lung.

Toxicol Appl Pharmacol 2017 06 27;324:1-11. Epub 2017 Mar 27.

National Institute of Environmental Health Sciences, National Health Research Institutes, Zhunan, Taiwan. Electronic address:

Exposure to environmental aryl hydrocarbon receptor (AhR) agonists, such as halogenated aromatic hydrocarbons and polycyclic aromatic hydrocarbons (PAHs), has great impacts on the development of various lung diseases. As emerging molecular targets for AhR agonists, cytokines may contribute to the inflammatory or immunotoxic effects of environmental AhR agonists. However, general cytokine expression may not specifically indicate environmental AhR agonist exposure. By comparing cytokine and chemokine expression profiles in human lung adenocarcinoma cell line CL5 treated with AhR agonists and the non-AhR agonist polychlorinated biphenyl (PCB) 39, we identified a target cytokine of environmental AhR agonist exposure of in the lungs. Thirteen cytokine and chemokine genes were altered in the AhR agonists-treated cells, but none were altered in the PCB39-treated cells. Interleukin (IL)-24 was the most highly induced gene among AhR-modulated cytokines. Cotreatment with AhR antagonist completely prevented IL-24 induction by AhR agonists in the CL5 cells. Knockdown AhR expression with short-hairpin RNA (shRNA) significantly reduced benzo[a]pyrene (BaP)-induced IL-24 mRNA levels. We further confirmed that gene transcription, but not mRNA stability, was involved in IL-24 upregulation by BaP. Particulate matter (PM) in the ambient air contains some PAHs and is reported to activate AhR. Oropharyngeal aspiration of PM significantly increased IL-24 levels in lung epithelia and in bronchoalveolar lavage fluid of mice 4weeks after treatment. Thus, our data suggests that IL-24 is a pulmonary exposure target cytokine of environmental AhR agonists.
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http://dx.doi.org/10.1016/j.taap.2017.03.019DOI Listing
June 2017

Involvement of the cytokine-IDO1-AhR loop in zinc oxide nanoparticle-induced acute pulmonary inflammation.

Nanotoxicology 2017 04 3;11(3):360-370. Epub 2017 Apr 3.

a National Health Research Institutes, National Institute of Environmental Health Sciences , Zhunan , Taiwan.

Zinc oxide nanoparticles (ZnONPs) are widely used in our daily life, such as in sunscreens and electronic nanodevices. However, pulmonary exposure to ZnONPs causes acute pulmonary inflammation, which is considered as an initial event for various respiratory diseases. Thus, elucidation of the underlying cellular mechanisms of ZnONPs can help us in predicting their potential effects in respiratory diseases. In this study, we observed that ZnONPs increased proinflammatory cytokines, accompanied with an increased expression of aryl hydrocarbon receptor (AhR) and its downstream target cytochrome P450 1A1 (CYP1A1) in macrophages in vitro and in mouse lung epithelia in vivo. Moreover, zinc nitrate, but not silica or titanium dioxide nanoparticles (NPs), had similar effects on macrophages, indicating that the zinc element or ion released from ZnONPs is likely responsible for the activation of the AhR pathway. Cotreatment with an AhR antagonist or AhR knockout reduced ZnONPs-induced cytokine secretion in macrophages or mice, respectively. Furthermore, kynurenine (KYN), an endogenous AhR agonist and a tryptophan metabolite catalyzed by indoleamine 2,3-dioxygenase (IDO), was increased in the serums of mice that aspirated ZnONPs. Consistently, ZnONPs increased IDO1 expression in lung cells in vitro and in vivo. Finally, AhR knockout reduced ZnONPs-induced pulmonary inflammation, cytokine secretion and KYN production in mice, suggesting that AhR activation is involved in ZnONPs-induced cytokine secretion and pulmonary inflammation. In summary, we demonstrated that the pulmonary exposure of ZnONPs stimulated the cytokine-IDO1-AhR loop in the lungs, which has been implied to play roles in immune dysfunctions.
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http://dx.doi.org/10.1080/17435390.2017.1306129DOI Listing
April 2017

A histone deacetylase inhibitor enhances expression of genes inhibiting Wnt pathway and augments activity of DNA demethylation reagent against nonsmall-cell lung cancer.

Int J Cancer 2017 05 14;140(10):2375-2386. Epub 2017 Mar 14.

Institute of Basic Medical Sciences, National Cheng Kung University, Tainan, Taiwan, ROC.

Development of new inhibitors targeting histone deacetylases (HDACs) with improved efficacy for solid tumor therapy is urgently needed. Here, we report the development of a novel HDAC inhibitor TMU-35435 and verify it as a single agent and in combination treatment with DNA demethylation reagent 5-aza-2'-deoxycytidine (5-aza-dC) in lung cancer preclinical models. TMU-35435 exerted cancer-specific cytotoxicity via mitochondria-mediated apoptosis. Expression microarrays revealed a unique TMU-35435-induced gene networks enriched in biological processes, including "negative regulation of cell proliferation" and "Wnt receptor signaling pathway" compared to FDA-approved HDAC inhibitor SAHA. TMU-35435 inhibited tumor growth with good pharmacokinetic properties and safety features in lung orthotopic and subcutaneously implanted xenograft models. TMU-35435 and 5-aza-dC showed synergistic antitumor effects through reactivation of tumor suppressor genes and those genes encoding negative regulators of Wnt signaling pathway in vitro and in vivo. Some genes showed additive inhibition of DNA methylation upon TMU-35435 and 5-aza-dC combined treatment. Our findings suggested that TMU-35435 is a potential HDAC inhibitor for lung cancer treatment as a single agent and in combination with 5-aza-dC.
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http://dx.doi.org/10.1002/ijc.30664DOI Listing
May 2017

Targeted lipidomics profiling of acute arsenic exposure in mice serum by on-line solid-phase extraction stable-isotope dilution liquid chromatography-tandem mass spectrometry.

Arch Toxicol 2017 Sep 16;91(9):3079-3091. Epub 2017 Feb 16.

Department of Chemistry, Fu Jen Catholic University, No. 510 Zhongzheng Rd. Xinzhuang Dist, New Taipei City, 24205, Taiwan.

Lipidomics is the area of study dedicated to the comprehensive analysis and characterization of the functions and metabolism of lipids in biological samples. One of the most comprehensively studied classes of lipids is polyunsaturated fatty acids (PUFAs). Eicosanoids are a series of bioactive lipid mediators that are metabolized from PUFAs and generated majorly from the precursor arachidonic acid. This study identified the profiles of target eicosanoids after acute exposure to arsenic. The principle objective was to determine and validate 10 eicosanoids in mouse serum using on-line solid-phase extraction integrated with liquid chromatography-electrospray tandem mass spectrometry. Intra-day and inter-day repeatability was 82.4-119.2 and 86.7-124.4%, respectively. The limit of detection and limit of quantification were from 0.003 to 0.288 ng/mL and from 0.009 to 0.962 ng/mL, respectively. The levels of 7 of the 10 eicosanoids-namely 8-isoPGF, PGF, PGE, 13(s)-HODE, 15(s)-HETE, 12(s)-HETE, and 5(s)-HETE-in mouse serum significantly and dose-dependently increased after arsenic exposure compared with the levels in the vehicle control group. To our knowledge, this is the first study to quantify eicosanoids in mouse serum. This approach provides simple sample preparation, small sample volumes, and a precise and accurate method for determining changes in the profile of these eicosanoids in mouse serum after acute exposure to arsenic.
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http://dx.doi.org/10.1007/s00204-017-1937-6DOI Listing
September 2017

Case Study III: The Construction of a Nanotoxicity Database - The MOD-ENP-TOX Experience.

Adv Exp Med Biol 2017 ;947:325-344

Center for Environment and Health, KU Leuven, Leuven, Belgium.

The amount of experimental studies on the toxicity of nanomaterials is growing fast. Interpretation and comparison of these studies is a complex issue due to the high amount of variables possibly determining the toxicity of nanomaterials.Qualitative databases providing a structured combination, integration and quality evaluation of the existing data could reveal insights that cannot be seen from different studies alone. A few database initiatives are under development but in practice very little data is publicly available and collaboration between physicists, toxicologists, computer scientists and modellers is needed to further develop databases, standards and analysis tools.In this case study the process of building a database on the in vitro toxicity of amorphous silica nanoparticles (NPs) is described in detail. Experimental data were systematically collected from peer reviewed papers, manually curated and stored in a standardised format. The result is a database in ISA-Tab-Nano including 68 peer reviewed papers on the toxicity of 148 amorphous silica NPs. Both the physicochemical characterization of the particles and their biological effect (described in 230 in vitro assays) were stored in the database. A scoring system was elaborated in order to evaluate the reliability of the stored data.
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http://dx.doi.org/10.1007/978-3-319-47754-1_11DOI Listing
October 2017

Combination of the novel histone deacetylase inhibitor YCW1 and radiation induces autophagic cell death through the downregulation of BNIP3 in triple-negative breast cancer cells in vitro and in an orthotopic mouse model.

Mol Cancer 2016 06 10;15(1):46. Epub 2016 Jun 10.

Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, Taiwan, 704.

Background: Triple-negative breast cancer (TNBC) is the most aggressive and invasive of the breast cancer subtypes. TNBC is a challenging disease that lacks targets for treatment. Histone deacetylase inhibitors (HDACi) are a group of targeted anticancer agents that enhance radiosensitivity. Bcl-2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) is a member of the Bcl-2 subfamily. BNIP3 is not found in normal breast tissue but is up-regulated in breast cancer. In the present study, we investigated the anti-cancer effects of a newly developed HDACi, YCW1, combined with ionizing radiation (IR) in TNBC in vitro and in an orthotopic mouse model. Furthermore, we examined the relationship between autophagy and BNIP3.

Methods: Trypan blue exclusion was used to investigate the viability of 4 T1 (a mouse TNBC cell line) and MDA-MB-231 cells (a human TNBC cell line) following combined YCW1 and IR treatment. Flow cytometry was used to determine apoptosis and autophagy. The expression levels of BNIP3, endoplasmic reticulum (ER) stress- and autophagic-related proteins were measured using western blot analysis. An orthotopic mouse model was used to investigate the in vivo effects of YCW1 and IR alone and in combination. Tumor volumes were monitored using a bioluminescence-based IVIS Imaging System 200.

Results: We found that YCW1 significantly enhanced toxicity in 4 T1 cells compared with suberoylanilide hydroxamic acid (SAHA), which was the first HDACi approved by the Food and Drug Administration for clinical use in cancer patients. The combined treatment of YCW1 and IR enhanced cytotoxicity by inducing ER stress and increasing autophagy induction. Additionally, the combined treatment caused autophagic flux and autophagic cell death. Furthermore, the expression level of BNIP3 was significantly decreased in cells following combined treatment. The downregulation of BNIP3 led to a significant increase in autophagy and cytotoxicity. The combined anti-tumor effects of YCW1 and IR were also observed in an orthotopic mouse model; combination therapy resulted in a significant increase in autophagy and decreased tumor tissue expression of BNIP3 in the tumor tissue.

Conclusions: These data support the possibility of using a combination of HDACi and IR in the treatment of TNBC. Moreover, BNIP3 may be a potential target protein for TNBC treatment.
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http://dx.doi.org/10.1186/s12943-016-0531-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4902929PMC
June 2016
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