Publications by authors named "Ching-Yu Lin"

131 Publications

Lipid changes in extrapulmonary organs and serum of rats after chronic exposure to ambient fine particulate matter.

Sci Total Environ 2021 Aug 10;784:147018. Epub 2021 Apr 10.

Institute of Environmental and Occupational Health Sciences, College of Public Health, National Taiwan University, Taipei, Taiwan; Department of Public Health, College of Public Health, National Taiwan University, Taipei, Taiwan.

Fine particulate matter (PM) is able to pass through the respiratory barrier to enter the circulatory system and can consequently spread to the whole body to cause toxicity. Although our previous studies have revealed significantly altered levels of phosphorylcholine-containing lipids in the lungs of rats after chronic inhalation exposure to PM, the effects of PM on phosphorylcholine-containing lipids in the extrapulmonary organs have not yet been elucidated. In this study, we examined the lipid effects of chronic PM exposure on various organs and serum by using a rat inhalation model followed by a mass spectrometry-based lipidomic approach. Male Sprague-Dawley rats were continuously exposed at the whole body level to nonfiltered and nonconcentrated ambient air from the outside environment of Taipei city for 8 months, while the control rats inhaled filtered air simultaneously. After exposure, serum samples and various organs, including the testis, pancreas, heart, liver, kidney, spleen, and epididymis, were collected for lipid extraction and analysis to examine the changes in phosphorylcholine-containing lipids after exposure. The results from the partial least squares discriminant analysis models demonstrated that the lipid profiles in the PM exposure group were different from those in the control group in the rat testis, pancreas, heart, liver, kidney and serum. The greatest PM-induced lipid effects were observed in the testes. Decreased lyso-phosphatidylcholines (PCs) as well as increased unsaturated diacyl-PCs and sphingomyelins in the testes may be related to maintaining the membrane integrity of spermatozoa, antioxidation, and cell signaling. Additionally, our results showed that decreased PC(16:0/18:1) was observed in both the serum and testes. In conclusion, exposure to chronic environmental concentrations of PM caused lipid perturbation, especially in the testes of rats. This study highlighted the susceptibility of the testes and suggested possible molecular events for future study.
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http://dx.doi.org/10.1016/j.scitotenv.2021.147018DOI Listing
August 2021

Clinical Assay for the Early Detection of Colorectal Cancer Using Mass Spectrometric Wheat Germ Agglutinin Multiple Reaction Monitoring.

Cancers (Basel) 2021 May 2;13(9). Epub 2021 May 2.

Ph.D. Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.

Colorectal cancer (CRC) is currently the third leading cause of cancer-related mortality in the world. U.S. Food and Drug Administration-approved circulating tumor markers, including carcinoembryonic antigen, carbohydrate antigen (CA) 19-9 and CA125 were used as prognostic biomarkers of CRC that attributed to low sensitivity in diagnosis of CRC. Therefore, our purpose is to develop a novel strategy for novel clinical biomarkers for early CRC diagnosis. We used mass spectrometry (MS) methods such as nanoLC-MS/MS, targeted LC-MS/MS, and stable isotope-labeled multiple reaction monitoring (MRM) MS coupled to test machine learning algorithms and logistic regression to analyze plasma samples from patients with early-stage CRC, late-stage CRC, and healthy controls (HCs). On the basis of our methods, 356 peptides were identified, 6 differential expressed peptides were verified, and finally three peptides corresponding wheat germ agglutinin (WGA)-captured proteins were semi-quantitated in 286 plasma samples (80 HCs and 206 CRCs). The novel peptide biomarkers combination of PF4, ITIH4, and APOE achieved sensitivity 84.5%, specificity 97.5% and an AUC of 0.96 in CRC diagnosis. In conclusion, our study demonstrated that WGA-captured plasma PF4, ITIH4, and APOE levels in combination may serve as highly effective early diagnostic biomarkers for patients with CRC.
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http://dx.doi.org/10.3390/cancers13092190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8124906PMC
May 2021

Lipid responses to environmental perfluoroalkyl substance exposure in a Taiwanese Child cohort.

Environ Pollut 2021 Aug 24;283:117007. Epub 2021 Mar 24.

Institute of Environmental and Occupational Health Sciences, College of Public Health, National Taiwan University, Taipei, Taiwan; Department of Public Health, College of Public Health, National Taiwan University, Taipei, Taiwan. Electronic address:

Although recent epidemiologic studies have focused on some of the health effects of perfluoroalkyl substance (PFASs) exposure in humans, the associations between PFASs exposure and the lipidome in children are still unclear. The purpose of this study was to assess lipid changes in children to understand possible molecular events of environmental PFASs exposure and suggest potential health effects. A total of 290 Taiwanese children (8-10 years old) were included in this study. Thirteen PFASs were analyzed in their serum by high-performance liquid chromatography-tandem mass spectrometry (LC-MS). MS-based lipidomic approaches were applied to examine lipid patterns in the serum of children exposed to different levels of PFASs. LC coupling with triple quadrupole MS technology was conducted to analyze phosphorylcholine-containing lipids. Multivariate analyses, such as partial least squares analysis along with univariate analyses, including multiple linear regression, were used to analyze associations between s exposure and unique lipid patterns. Our results showed that different lipid patterns were discovered in children exposed to different levels of specific PFASs, such as PFTrDA, PFOS, and PFDA. These changes in lipid levels may be involved in hepatic lipid metabolism, metabolic disorders, and PFASs-membrane interactions. This study showed that lipidomics is a powerful approach to identify critical PFASs that cause metabolite perturbation in the serum of children and suggest possible adverse health effects of these chemicals in children.
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http://dx.doi.org/10.1016/j.envpol.2021.117007DOI Listing
August 2021

Isotypes of autoantibodies against novel differential 4-hydroxy-2-nonenal-modified peptide adducts in serum is associated with rheumatoid arthritis in Taiwanese women.

BMC Med Inform Decis Mak 2021 02 10;21(1):49. Epub 2021 Feb 10.

Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei, 11031, Taiwan.

Background: Rheumatoid arthritis (RA) is an autoimmune disorder with systemic inflammation and may be induced by oxidative stress that affects an inflamed joint. Our objectives were to examine isotypes of autoantibodies against 4-hydroxy-2-nonenal (HNE) modifications in RA and associate them with increased levels of autoantibodies in RA patients.

Methods: Serum samples from 155 female patients [60 with RA, 35 with osteoarthritis (OA), and 60 healthy controls (HCs)] were obtained. Four novel differential HNE-modified peptide adducts, complement factor H (CFAH), haptoglobin (HPT), immunoglobulin (Ig) kappa chain C region (IGKC), and prothrombin (THRB), were re-analyzed using tandem mass spectrometric (MS/MS) spectra (ProteomeXchange: PXD004546) from RA patients vs. HCs. Further, we determined serum protein levels of CFAH, HPT, IGKC and THRB, HNE-protein adducts, and autoantibodies against unmodified and HNE-modified peptides. Significant correlations and odds ratios (ORs) were calculated.

Results: Levels of HPT in RA patients were greatly higher than the levels in HCs. Levels of HNE-protein adducts and autoantibodies in RA patients were significantly greater than those of HCs. IgM anti-HPT HNE, IgM anti-IGKC, and IgM anti-IGKC HNE may be considered as diagnostic biomarkers for RA. Importantly, elevated levels of IgM anti-HPT HNE, IgM anti-IGKC, and IgG anti-THRB were positively correlated with the disease activity score in 28 joints for C-reactive protein (DAS28-CRP). Further, the ORs of RA development through IgM anti-HPT HNE (OR 5.235, p < 0.001), IgM anti-IGKC (OR 12.655, p < 0.001), and IgG anti-THRB (OR 5.761, p < 0.001) showed an increased risk. Lastly, we incorporated three machine learning models to differentiate RA from HC and OA, and performed feature selection to determine discriminative features. Experimental results showed that our proposed method achieved an area under the receiver operating characteristic curve of 0.92, which demonstrated that our selected autoantibodies combined with machine learning can efficiently detect RA.

Conclusions: This study discovered that some IgG- and IgM-NAAs and anti-HNE M-NAAs may be correlated with inflammation and disease activity in RA. Moreover, our findings suggested that IgM anti-HPT HNE, IgM anti-IGKC, and IgG anti-THRB may play heavy roles in RA development.
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http://dx.doi.org/10.1186/s12911-020-01380-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874460PMC
February 2021

Autophagy Receptor Tollip Facilitates Bacterial Autophagy by Recruiting Galectin-7 in Response to Group A Infection.

Front Cell Infect Microbiol 2020 23;10:583137. Epub 2020 Dec 23.

Department of Microbiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Bacterial autophagy-a type of macroautophagy that is also termed xenophagy-selectively targets intracellular bacteria such as group A (GAS), a ubiquitous pathogen that causes numerous serious diseases, including pharyngitis, skin infections, and invasive life-threatening infections. Although bacterial autophagy is known to eliminate invading bacteria the action of autophagy receptors, the underlying mechanism remains unclear. Herein, we elucidated that Tollip functions as a bacterial-autophagy receptor in addition to participating involved in the intracellular immunity mechanism that defends against bacterial infection. Tollip was recruited to GAS-containing endosomal vacuoles prior to the escape of GAS into the cytosol; additionally, Tollip knockout disrupted the recruitment of other autophagy receptors, such as NBR1, TAX1BP1, and NDP52, to GAS-containing autophagosomes and led to prolonged intracellular survival of GAS. Furthermore, Tollip was found to be required for the recruitment of galectin-1 and -7 to GAS-containing autophagosomes, and immunoprecipitation results indicated that Tollip interacts with galectin-7. Lastly, our data also revealed that galectin-1 and -7 are involved in the restriction of GAS replication in cells. These results demonstrated that Tollip modulates bacterial autophagy by recruiting other autophagy receptors and galectins.
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http://dx.doi.org/10.3389/fcimb.2020.583137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786282PMC
June 2021

Direct and Label-Free Determination of Human Glycated Hemoglobin Levels Using Bacteriorhodopsin as the Biosensor Transducer.

Sensors (Basel) 2020 Dec 18;20(24). Epub 2020 Dec 18.

Department of Family Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 116, Taiwan.

Glycated hemoglobin (HbA1c) levels are an important index for the diagnosis and long-term control of diabetes. This study is the first to use a direct and label-free photoelectric biosensor to determine HbA1c using bacteriorhodopsin-embedded purple membranes (PM) as a transducer. A biotinylated PM (b-PM) coated electrode that is layered with protein A-oriented antibodies against hemoglobin (Hb) readily captures non-glycated Hb (HbA0) and generates less photocurrent. The spectra of bacteriorhodopsin and Hb overlap so the photocurrent is reduced because of the partial absorption of the incident light by the captured Hb molecules. Two HbA0 and HbA1c aptasensors that are prepared by conjugating specific aptamers on b-PM coated electrodes single-step detect HbA0 and HbA1c in 15 min, without cross reactivity, with detection limits of ≤0.1 μg/mL and a dynamic range of 0.1-100 μg/mL. Both aptasensors exhibit high selectivity and long-term stability. For the clinical samples, HbA0 concentrations and HbA1c levels that are measured with aptasensors correlate well with total Hb concentrations and the HbA1c levels that are determined using standard methods (correlation gradient = 0.915 ± 0.004 and 0.981 ± 0.001, respectively). The use of these aptasensors for diabetes care is demonstrated.
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http://dx.doi.org/10.3390/s20247274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7765918PMC
December 2020

Longitudinal change of metabolite profile and its relation to multiple risk factors for the risk of developing hepatitis B-related hepatocellular carcinoma.

Mol Carcinog 2020 11 10;59(11):1269-1279. Epub 2020 Sep 10.

Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.

Despite considerable knowledge of viral pathogenesis, the pathophysiological changes related to the multifactorial, multistep process of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) development remains unclear. Longitudinal metabolomics study can reveal biological process for disease progression. We performed metabolite profiling with longitudinal prediagnostic plasma samples from two nested case-control studies of hepatitis B surface antigen carriers participating in ultrasound screening for HCC, one within a government employee cohort (870 samples from 109 HCC cases and 107 controls) and the other within a hospital-based cohort (266 samples from 63 HCC cases and 114 controls). Of the 34 measured metabolites, tyrosine, isoleucine, and glutamine were consistently associated with HCC. In analyses combining longitudinal data, a high metabolic risk score based on the three amino acids was robustly associated with increased risk of HCC (OR = 3.71, 95% confidence interval: 2.53-5.42), even after adjustment for clinical factors, or when assessed for different times up to ≥8 years before diagnosis. Similar association was observed in an independent, prospective analysis comprising 633 randomly selected individuals of the government employee cohort. More importantly, this metabolite signature was longitudinally influenced by HBV-infection phase and involved in gradual progression to liver fibrosis and cirrhosis. Furthermore, mediation analysis showed that the score mediated substantial proportions of the associations of key viral factors, insulin resistance, and diabetes status with HCC risk. Our results suggest that an amino-acid dysregulation metabotype may play a role in HBV-related HCC development, and may also be linked to common pathways that mediate increased HCC risks.
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http://dx.doi.org/10.1002/mc.23255DOI Listing
November 2020

Urinary concentrations of phthalates in relation to circulating fatty acid profile in National Health and Nutrition Examination Survey, 2003-2004 and 2011-2012.

Environ Pollut 2020 Oct 6;265(Pt B):114714. Epub 2020 Jun 6.

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

Animal studies have suggested that phthalate exposure alters the fatty acid composition of blood plasma. Therefore, we conducted an epidemiological study to examine whether urinary concentrations of phthalates are correlated with circulating fatty acids in the general US population. The 2003-2004 and 2011-2012 National Health and Nutrition Examination Survey were used in this study. Ten urinary phthalate metabolites and 23 fatty acids were measured. Fatty acid patterns were identified using principal component analysis (PCA) with an eigenvalue greater than 1. A two-step analysis was performed. We first performed multivariable linear regressions to evaluate whether urinary phthalate metabolites were related to the PCA-derived components of blood fatty acid levels. Then we performed multivariable linear regressions to investigate each of the fatty acids that were suggestively correlated with some of the phthalates in PCA. There were 994 participants (51.91% women). As for men, after adjustments for potential confounding factors, MECPP, MEHHP, and ∑DEHP were all positively correlated with gamma-linolenic, myristoleic, and myristic acids; both MEHHP and ∑DEHP were positively correlated with stearic acid; MMP was positively correlated with docosahexaenoic acid. As for women, MMP was negatively correlated with docosanoic, lignoceric, and arachidic acids; MBzP was negatively correlated with docosahexaenoic acid; both MEHP and MCPP were negatively correlated with docosatetraenoic acid; MEHP was negatively correlated with arachidonic acid, and MCPP was negatively correlated with docosapentaenoic-6 acid. Our findings support that phthalates may be correlated with circulating fatty acids.
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http://dx.doi.org/10.1016/j.envpol.2020.114714DOI Listing
October 2020

New classification may assist the development of targeted therapies for treatment-refractory castration-resistant prostate cancer.

Transl Androl Urol 2020 Apr;9(2):837-839

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

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http://dx.doi.org/10.21037/tau.2020.03.24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215030PMC
April 2020

ROR2 suppresses metastasis of prostate cancer via regulation of miR-199a-5p-PIAS3-AKT2 signaling axis.

Cell Death Dis 2020 05 15;11(5):376. Epub 2020 May 15.

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

Bones are the most common metastatic sites for prostate cancer (PCa). Receptor tyrosine kinase-like orphan receptor 2 (ROR2), a noncanonical Wnt receptor, plays crucial roles in skeletal morphogenesis, osteoblast differentiation, and bone formation. The role of ROR2 in PCa metastasis is unclear. We analyzed online datasets from Oncomine as well as using IHC staining on tissue array to determine the relationship between ROR2 expression level and disease outcome of PCa. To investigate how ROR2 regulates migration and invasion of PCa cells, we performed transwell assay and orthotopic xenograft model in nude mice. We then applied the Micro-Western Array (MWA), a high-throughput western blotting platform to analyze the downstream signaling pathways being regulated by ROR2. Compared with nonmalignant PZ-HPV-7 and RWPE-1 cells, PCa cell lines express lower level of ROR2 protein. Constitutive expression of ROR2 in PC-3, DU-145, or C4-2B PCa cells significantly suppressed the cell migration, invasion, and epithelial-mesenchymal transition (EMT) proteins. MWA, western blotting, and microRNA analysis showed that elevation of ROR2 suppressed the expression of miR-199a-5p, which in turn increased the expression of PIAS3. The upregulation of PIAS3 then decreased AKT2 and the phosphorylation of AKT, resulting in the inhibition of migration and invasion of PCa cells both in vitro and in orthotopic xenograft mice model. IHC staining of tissue array and Oncomine datasets analysis indicated that the gene and protein level of ROR2 is much lower in metastatic prostate tumors as compared with primary tumors or adjacent normal prostate tissues. Low level of ROR2 correlated to poor survival and high recurrent frequency in PCa patients. In conclusion, we discovered that ROR2 suppresses PCa metastasis via regulation of PIAS3-PI3K-AKT2 signaling axis.
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http://dx.doi.org/10.1038/s41419-020-2587-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228945PMC
May 2020

Group A NAD-Glycohydrolase Inhibits Caveolin 1-Mediated Internalization Into Human Epithelial Cells.

Front Cell Infect Microbiol 2019 28;9:398. Epub 2019 Nov 28.

Department of Microbiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Group A (GAS) invades epithelial cells causing persistent infection. GAS has a variety of effector proteins that modulate host systems to affect their survival in host environments. The main effector proteins of GAS are NAD-glycohydrolase (Nga) and streptolysin O (SLO). Although Nga has NADase activity and shows SLO-dependent cytotoxicity, some clinical isolates harbor NADase-inactive subtypes of Nga, and the function of NADase-inactive Nga is still unclear. In this study, we found that deletion of enhanced the internalization of GAS into HeLa and Ca9-22 cells. Amino acid substitution of Nga R289K/G330D (NADase-inactive) does not enhance GAS invasion, suggesting that Nga may inhibit the internalization of GAS into host cells in an NADase-independent manner. Moreover, double deletion of and showed similar invasion percentages compared with wild-type GAS, indicating the important role of SLO in the inhibition of GAS invasion by Nga. Furthermore, enhanced internalization of the deletion mutant was not observed in -knockout HeLa cells. Altogether, these findings demonstrate an unrecognized NADase-independent function of Nga as a negative regulator of CAV1-mediated internalization into epithelial cells.
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http://dx.doi.org/10.3389/fcimb.2019.00398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893971PMC
August 2020

Brain lipid profiles in the spontaneously hypertensive rat after subchronic real-world exposure to ambient fine particulate matter.

Sci Total Environ 2020 Mar 18;707:135603. Epub 2019 Nov 18.

Institute of Environmental Health, College of Public Health, National Taiwan University, Taiwan; Department of Public Health, National Taiwan University, Taiwan. Electronic address:

Recent studies have illustrated an association between ambient fine particulate matter (PM) exposure and neuronal toxicity in epidemiological studies and animal models. However, the possible molecular effects on brains under real-world exposure to PM remain unclear. In this pilot study, male spontaneously hypertensive rats were whole-bodily exposed to ambient air from the outdoor environment of Taipei City for 3 months, while the control rats inhaled HEPA-filtered air. The PM-induced phosphatidylcholine and sphingomyelin profiles in the hippocampus, cortex, medulla, cerebellum, and olfactory bulb were assessed by mass spectrometry (MS)-based lipidomics. Partial least squares discriminant analysis (PLS-DA) and the Wilcoxon rank sum test were used to examine the lipid changes between the exposed and control groups. The PLS-DA models showed that phosphatidylcholine and sphingomyelin profiles of the PM exposure group were different from those of the control group in each brain region except the cortex. More lipid changes were found in the hippocampus, while fewer lipid changes were observed in the olfactory bulb. The lipid alteration in the hippocampus may strengthen membrane integrity, modulate signaling pathways, and avoid accumulation of lipofuscin to counter the PM-induced stress. The lipid changes in the cortex and medulla may respond to PM-induced injury and inflammation; while the lipid changes in the cerebellum were associated with neuron protection. This study suggests that the MS-based lipidomics is a powerful approach to discriminate the brain lipid profiles even at the environmental level of ambient PM and has the potential to suggest possible adverse health effects in long-term PM exposure studies.
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http://dx.doi.org/10.1016/j.scitotenv.2019.135603DOI Listing
March 2020

Histone Demethylase KDM4C Stimulates the Proliferation of Prostate Cancer Cells via Activation of AKT and c-Myc.

Cancers (Basel) 2019 Nov 13;11(11). Epub 2019 Nov 13.

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

Our three-dimensional organotypic culture revealed that human histone demethylase (KDM) 4C, a histone lysine demethylase, hindered the acini morphogenesis of RWPE-1 prostate cells, suggesting its potential oncogenic role. Knockdown (KD) of KDM4C suppressed cell proliferation, soft agar colony formation, and androgen receptor (AR) transcriptional activity in PCa cells as well as reduced tumor growth of human PCa cells in zebrafish xenotransplantation assay. Micro-Western array (MWA) analysis indicated that KD of KDM4C protein decreased the phosphorylation of AKT, c-Myc, AR, mTOR, PDK1, phospho-PDK1 S241, KDM8, and proteins involved in cell cycle regulators, while it increased the expression of PTEN. Fluorescent microscopy revealed that KDM4C co-localized with AR and c-Myc in the nuclei of PCa cells. Overexpression of either AKT or c-Myc rescued the suppressive effect of KDM4C KD on PCa cell proliferation. Echoing the above findings, the mRNA and protein expression of KDM4C was higher in human prostate tumor tissues as compared to adjacent normal prostate tissues, and higher KDM4C protein expression in prostate tumors correlated to higher protein expression level of AKT and c-Myc. In conclusion, KDM4C promotes the proliferation of PCa cells via activation of c-Myc and AKT.
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http://dx.doi.org/10.3390/cancers11111785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896035PMC
November 2019

Metabolomic Analysis of Platelets of Patients With Aspirin Non-Response.

Front Pharmacol 2019 10;10:1107. Epub 2019 Oct 10.

Cardiovascular Center and Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.

Aspirin is the most commonly used antiplatelet agent for the prevention of cardiovascular diseases. However, a certain proportion of patients do not respond to aspirin therapy. The mechanisms of aspirin non-response remain unknown. The unique metabolomes in platelets of patients with coronary artery disease (CAD) with aspirin non-response may be one of the causes of aspirin resistance. We enrolled 29 patients with CAD who were aspirin non-responders, defined as a study subject who were taking aspirin with a platelet aggregation time less than 193 s by PFA-100, and 31 age- and sex-matched patients with CAD who were responders. All subjects had been taking 100 mg of aspirin per day for more than 1 month. Hydrophilic metabolites from the platelet samples were extracted and analyzed by nuclear magnetic resonance (NMR). Both 1D H and 2D J-resolved NMR spectra were obtained followed by spectral processing and multivariate statistical analysis, such as partial least squares discriminant analysis (PLS-DA). Eleven metabolites were identified. The PLS-DA model could not distinguish aspirin non-responders from responders. Those with low serum glycine level had significantly shorter platelet aggregation time (mean, 175.0 s) compared with those with high serum glycine level (259.5 s). However, this association became non-significant after correction for multiple tests. The hydrophilic metabolic profile of platelets was not different between aspirin non-responders and responders. An association between lower glycine levels and higher platelet activity in patients younger than 65 years suggests an important role of glycine in the pathophysiology of aspirin non-response.
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http://dx.doi.org/10.3389/fphar.2019.01107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797853PMC
October 2019

Caffeic acid phenethyl ester suppresses androgen receptor signaling and stability via inhibition of phosphorylation on Ser81 and Ser213.

Cell Commun Signal 2019 08 20;17(1):100. Epub 2019 Aug 20.

Institute of Cellular and System Medicine, National Health Research Institutes, Room R2-2021, 35, Keyan Road, Zhunan Town, Miaoli County, 35053, Taiwan.

Background: Androgen receptor (AR) plays important role in the development, progression, and metastasis of prostate cancer (PCa). Caffeic acid phenethyl ester (CAPE) is the main component of honey bee propolis. We determined if CAPE affects the signaling and stability of AR in PCa cells.

Methods: Effects of CAPE on AR transcriptional activity and localization were determined by reporter gene assay and immunofluorescent microscopy. Western blotting, fluorescent polarization, computer simulation, and animal experiment were performed to investigate the molecular mechanism how CAPE reduces the stability of AR.

Results: CAPE treatment dose-dependently suppressed the transcriptional activity of AR as well as the protein levels of AR and its target gene PSA. Cyclohexamide treatment revealed that androgen stabilized AR protein, but AR stability was diminished by CAPE. Fluorescence microscopy demonstrated that androgen promoted the nucleus translocation of AR in PCa cells, while treatment with CAPE reduced protein level of AR in both nucleus and cytoplasm. CAPE treatment suppressed the phosphorylation of Ser81 and Ser213 on AR, which regulates the stability of AR. CDK1 and AKT are the kinases phosphorylating Ser81 and Ser213 on AR, respectively. CAPE treatment significantly reduced the protein level and activity of CDK1 and AKT in PCa cells. Overexpression of CDK1 or AKT rescued the AR protein level under CAPE treatment.

Conclusions: Our results suggested that CAPE treatment reduced AR stability and AR transcriptional activity in PCa cells, implying the possibility of using CAPE as a treatment for advanced PCa.
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http://dx.doi.org/10.1186/s12964-019-0404-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700801PMC
August 2019

Rooibos suppresses proliferation of castration-resistant prostate cancer cells via inhibition of Akt signaling.

Phytomedicine 2019 Nov 8;64:153068. Epub 2019 Aug 8.

Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli County 35053, Taiwan; PhD Program for Aging and Graduate Institute of Basic Medical Science, China Medical University, Taichung City 40402, Taiwan; Biotechnology Center, National Chung Hsing University, Taichung City 40227, Taiwan. Electronic address:

Background: Androgen ablation therapy is the primary treatment for metastatic prostate cancer (PCa). However, the majority of PCa patients receiving the androgen deprivation therapy develop recurrent castration-resistant prostate cancer (CRPC) within two years. Chemotherapies show little effect on prolonging survival of CRPC patients and new treatments are needed. Previous studies reported that the extracts from rooibos (Aspalathus linearis) exhibit chemopreventive properties in some cancer models, including skin, liver and oesophagus cancers in animals. We therefore investigate if extracts from rooibos can suppress the proliferation of CRPC cells.

Purpose: We investigated whether an aspalathin-rich green rooibos extract (GRT™; 12.78 g aspalathin/100 g extract) demonstrates anti-cancer activity against CRPC cells.

Methods: High performance liquid chromatography (HPLC) was used to profile the major flavonoids in GRT. Hoechst-dye proliferation assay, 3,4,5-dimethylthiazol-2-yl)-2-5-diphenyltetrazolium bromide (MTT) viability assay and flow cytometry assay were used to explore the effects of GRT on the proliferation and cell cycle progression of CRPC cells. Comet assay was used to survey whether GRT induces apoptosis in CRPC cells. LNCaP 104-R1 xenograft nude mice model was used to determine the inhibitory effect of GRT on CRPC tumors in vivo. Micro-Western Array (MWA) and Western blot analysis were carried out to unravel the underlying molecular mechanism.

Results: GRT contained aspalathin as the most abundant flavonoid. GRT suppressed the proliferation and survival of LNCaP 104-R1, LNCaP FGC and PC-3 PCa cells. Flow cytometry analysis showed that GRT decreased the population of PCa cells in S phase but increased the cell population in G2/M phase. Comet assay confirmed that GRT induced apoptosis in LNCaP 104-R1 cells. Gavage of 400 mg/kg GRT suppressed LNCaP 104-R1 xenografts in castrated nude mice. MWA and Western blot analysis indicated that GRT treatment suppressed Akt1, phospho-Akt Ser473, Cdc2, Bcl-2, TRAF4 and Aven, but increased activated Caspase 3, cytochrome c, and p27. Overexpression of Akt rescued the suppressive effects of GRT on CRPC cells. Co-treatment of GRT with Bcl-2 inhibitor ABT-737, PI3K inhibitor LY294002 and Akt inhibitor GSK 690693 exhibited additive inhibitory effect on proliferation of CRPC cells.

Conclusions: GRT suppresses the proliferation of CRPC cells via inhibition of Akt signaling.
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http://dx.doi.org/10.1016/j.phymed.2019.153068DOI Listing
November 2019

Metabolic adaptation to feed restriction on the green sturgeon (Acipenser medirostris) fingerlings.

Sci Total Environ 2019 Sep 11;684:78-88. Epub 2019 May 11.

Department of Animal Science, University of California, Davis 95616, USA.

Food restriction may cause severe biological effects on wildlife and lead to population decline and extinction. The objective of the current study was to examine the metabolic effects on green sturgeon in response to feed restriction. Green sturgeon fingerlings were fed for two weeks at 12.5, 25, 50 and 100% of the optimum feeding rate (OFR), which corresponded to 0.25, 0.50, 1.00, and 2.00% body weight per day. We characterized the changes in hydrophilic and hydrophobic metabolites from extracts of muscle, liver, and kidney using nuclear magnetic resonance spectroscopy followed by multivariate statistical analysis. The results of principal component analysis (PCA) score plots from the analyses of hydrophilic metabolites showed that they exhibited a greater response to feed restriction than hydrophobic metabolites. In general, the hydrophilic metabolites in tissues from fish fed ≦25% of the OFR were separated from those fed 100% of the OFR in the PCA score plots. Among the three types of tissues examined, the overall metabolite changes showed a greater response to feed restriction in kidney tissue than in liver or muscle tissues. Numerous glucogenic amino acids in muscle and most amino acids in the kidney were decreased under feed restriction conditions. A significant decrease in ketone bodies (3-hydroxyisobutyrate) was observed in the muscle. Most fatty acids except for glycerol, phospholipid and cholesterol in the liver and kidney tissues were decreased under feed restriction conditions. Creatine phosphate, taurine and glycine were also significantly increased in tissues under feed restriction conditions. In conclusion, this study suggests that the manipulation of feed restriction under the current conditions perturbed metabolites related to energy metabolism, osmolality regulation, and antioxidation capacity in the sturgeon.
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http://dx.doi.org/10.1016/j.scitotenv.2019.05.044DOI Listing
September 2019

Low Levels of IgM and IgA Recognizing Acetylated C1-Inhibitor Peptides Are Associated with Systemic Lupus Erythematosus in Taiwanese Women.

Molecules 2019 Apr 26;24(9). Epub 2019 Apr 26.

School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan.

The objective of this study was to identify novel acetylation (Ac) modifications of the C1-inhibitor (C1-INH) and explain the association of the levels of autoantibodies against acetylated C1-INH peptides with the risk of developing systemic lupus erythematosus (SLE). Ac modifications of the C1-INH were identified and validated through in-gel digestion, nano-liquid chromatography-tandem mass spectrometry, immunoprecipitation, and Western blotting by using serum protein samples obtained from patients with SLE and age-matched healthy controls (HCs). In addition, the levels of serum C1-INH, Ac-protein adducts, and autoantibodies against unmodified and acetylated C1-INH peptides were measured. C1-INH levels in patients with SLE were significantly lower than those in HCs by 1.53-fold ( = 0.0008); however, Ac-protein adduct concentrations in patients with SLE were significantly higher than those in HCs by 1.35-fold ( = 0.0009). Moreover, immunoglobulin M (IgM) anti-C1-INH Ac and IgA anti-C1-INH Ac levels in patients with SLE were significantly lower than those in HCs. The low levels of IgM anti-C1-INH (odds ratio [OR] = 4.725, < 0.001), IgM anti-C1-INH Ac (OR = 4.089, = 0.001), and IgA anti-C1-INH Ac (OR = 5.566, < 0.001) indicated increased risks for the development of SLE compared with HCs.
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http://dx.doi.org/10.3390/molecules24091645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539680PMC
April 2019

CD44 Promotes Migration and Invasion of Docetaxel-Resistant Prostate Cancer Cells Likely via Induction of Hippo-Yap Signaling.

Cells 2019 03 30;8(4). Epub 2019 Mar 30.

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

Patients receiving docetaxel developed a drug resistance within a few months. We generated docetaxel-resistant PC/DX25 and DU/DX50 CRPC cells from PC-3 and DU-145 PCa cells, respectively. We investigated the mechanism behind why PC/DX25 and DU/DX50 cells exhibited higher migration and invasion ability. Transwell assays were used to measure the migration and invasion of PCa cell. Fluorescence activated cell sorter (FACS) analysis was used to determine the population of cancer stem cell (CSC)-like cell. Micro-Western Array (MWA) was used to study the changes of the protein profile. FACS analysis revealed that PC/DX25 cells and DU/DX50 cells contain higher CD44+ population. MWA and Western blotting assay revealed that protein expression of CD44, YAP, CYR61, CTGF, phospho-ERK1/2 T202/Y204, ERK and vimentin was elevated in PC/DX25 cells. Knockdown of CD44 or YAP suppressed migration and invasion of PC/DX25 and DU/DX50 cells. Knockdown of CD44 decreased expression of YAP, CTGF and CYR61 but increased phosphorylation of S127 on YAP. CD44 knockdown also suppressed protein level of AKT, phospho-AKT T308, phospho-ERK1/2 T202/Y204 and vimentin. CD44 promotes migration and invasion of docetaxel-resistant PCa cells probably via induction of Hippo-Yap signaling pathway and CD44/YAP pathway may be a therapeutic target for docetaxel-resistant PCa.
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http://dx.doi.org/10.3390/cells8040295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6523775PMC
March 2019

Corrigendum to "Isotypes of autoantibodies against differentially expressed novel malondialdehyde-modifiedpeptide adducts in serum of Taiwanese women with rheumatoid arthritis" [J Proteomics 170: (2018) 141-150].

J Proteomics 2019 Mar 13;194:226. Epub 2018 Dec 13.

Department of Biotechnology and Animal Science, National Ilan University, Ilan 26047, Taiwan; School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan. Electronic address:

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http://dx.doi.org/10.1016/j.jprot.2018.11.017DOI Listing
March 2019

Lipidomics as a diagnostic tool of the metabolic and physiological state of managed whales: A correlation study of systemic metabolism.

Zoo Biol 2018 Nov 20;37(6):440-451. Epub 2018 Nov 20.

Department of Biology, National Museum of Marine Biology and Aquarium, Pingtung, Taiwan.

Integrating multifactor blood analysis is a key step toward a precise diagnosis of the health status of marine mammals. Variations in the circulating lipid profile reflect changes in the metabolism and physiology of an individual. To demonstrate the practicability of lipid profiling for physiological assessment, the phosphorylcholine-containing lipids in the plasma of long-term managed beluga whales (Delphinapterus leucas) were profiled using a lipidomics methodology. Using a multivariate analysis, the mean corpuscular volume, cholesterol, potassium, and γ-glutamyltranspeptidase levels were well modeled with the lipid profile of the female whales. In the models, the correlated lipids provided information about blood parameter-related metabolism and physiological regulation, in particular relating to cholesterol and inflammation. In the males, the levels of cholesterol, triglycerides, blood urea nitrogen, creatinine, plasma iron, and segmented neutrophil were well modeled with the lipid profile. In addition to providing information about the related metabolism and regulation, through a cross-linked analysis of the blood parameters, the correlated lipids indicated a parallel regulation involved in the energy metabolism of the male whales. Lipidomics as a method for revealing the context of physiological change shows practical potential for the health care of managed whales.
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http://dx.doi.org/10.1002/zoo.21452DOI Listing
November 2018

Photoacoustic imaging for monitoring periodontal health: A first human study.

Photoacoustics 2018 Dec 1;12:67-74. Epub 2018 Nov 1.

Department of NanoEngineering, University of California, San Diego, 9500 Gilman Drive. La Jolla, CA, 92092, USA.

The gold-standard periodontal probe is an aging tool that can detect periodontitis and monitor gingival health but is highly error-prone, does not fully characterize the periodontal pocket, and causes pain. Photoacoustic imaging is a noninvasive technique that can address these limitations. Here, a range of ultrasound frequencies between 16-40 MHz were used to image the periodontium and a contrast medium based on cuttlefish ink was used to label the pockets. A 40 MHz ultrasound frequency could spatially resolve the periodontal anatomy, including tooth, gum, gingival margin, and gingival thickness of tooth numbers 7-10 and 22-27. The photoacoustic-ultrasound measurements were more precise (0.01 mm) than those taken with physical probes by a dental hygienist. Furthermore, the full geometry of the pockets could be visualized with relative standard deviations of 10% (n = 5). This study shows the potential for non-invasive monitoring of periodontal health with photoacoustic-ultrasound imaging in the dental clinic.
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http://dx.doi.org/10.1016/j.pacs.2018.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226559PMC
December 2018

LAMTOR2/LAMTOR1 complex is required for TAX1BP1-mediated xenophagy.

Cell Microbiol 2019 04 21;21(4):e12981. Epub 2019 Jan 21.

Department of Microbiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Xenophagy, also known as antibacterial autophagy, plays a role in host defence against invading pathogens such as Group A Streptococcus (GAS) and Salmonella. In xenophagy, autophagy receptors are used in the recognition of invading pathogens and in autophagosome maturation and autolysosome formation. However, the mechanism by which autophagy receptors are regulated during bacterial infection remains poorly elucidated. In this study, we identified LAMTOR2 and LAMTOR1, also named p14 and p18, respectively, as previously unrecognised xenophagy regulators that modulate the autophagy receptor TAX1BP1 in response to GAS and Salmonella invasion. LAMTOR1 was localized to bacterium-containing endosomes, and LAMTOR2 was recruited to bacterium-containing damaged endosomes in a LAMTOR1-dependent manner. LAMTOR2 was dispensable for the formation of autophagosomes targeting damaged membrane debris surrounding cytosolic bacteria, but it was critical for autolysosome formation, and LAMTOR2 interacted with the autophagy receptors NBR1, TAX1BP1, and p62 and was necessary for TAX1BP1 recruitment to pathogen-containing autophagosomes. Notably, knockout of TAX1BP1 caused a reduction in autolysosome formation and subsequent bacterial degradation. Collectively, our findings demonstrated that the LAMTOR1/2 complex is required for recruiting TAX1BP1 to autophagosomes and thereby facilitating autolysosome formation during bacterial infection.
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http://dx.doi.org/10.1111/cmi.12981DOI Listing
April 2019

Correction: ASPM promotes prostate cancer stemness and progression by augmenting Wnt-Dvl-3-β-catenin signaling.

Oncogene 2019 02;38(8):1354

Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei City, 11031, Taiwan.

In the published version of this paper the author Shu-Pin Huang's surname was incorrectly given as Hwang instead of Huang. This has now been corrected in the HTML and PDF versions of the paper.
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http://dx.doi.org/10.1038/s41388-018-0561-0DOI Listing
February 2019

Using lipidomic methodology to characterize coral response to herbicide contamination and develop an early biomonitoring model.

Sci Total Environ 2019 Jan 23;648:1275-1283. Epub 2018 Aug 23.

National Museum of Marine Biology and Aquarium, 2 Hou-Wan Rd., Checheng, Pingtung 944, Taiwan; Department of Marine Biotechnology and Resources, Asia-Pacific Ocean Research Center, National Sun Yat-sen University, 70 Lien-Hai Rd., Kaohsiung 804, Taiwan. Electronic address:

The use of omics technologies to profile an organism's systemic response to environmental changes can improve the effectiveness of biomonitoring. In cell physiology, the dynamic characteristics of membranes can be used to identify lipid profiles that detect environmental threats and assess the health problems associated with them. The efficacy of this approach was demonstrated by profiling glycerophosphocholines (GPCs, a major membrane lipid class) in the coral Seriatopora caliendrum after exposure to Irgarol 1051. A quantitative biomonitoring model for this photosystem II herbicide was developed by correlating variations in coral lipid profile with herbicide exposure levels and degree of photoinhibition. After 4 days of exposure, the predominant changes correlated with photoinhibition were an increase in lyso-GPCs and saturated GPCs and a decrease in phosphatidylcholines with unsaturated C18 chains or a polyunsaturated C22 chain. A time-course experiment showed that most of these lipid changes occurred opposite to the initial response and that the persistent changes can be attributed to photosynthetic shortages and the membrane accommodation of photoinhibition-induced oxidative conditions. These changes can help predict risk factors leading to coral bleaching. In this study, the application of a lipidomic methodology to characterize the adaptation of coral to ambient contamination serves as a basis for advancing environmental monitoring and assessment.
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http://dx.doi.org/10.1016/j.scitotenv.2018.08.296DOI Listing
January 2019

Mass spectrometry-based lipidomics to explore the biochemical effects of naphthalene toxicity or tolerance in a mouse model.

PLoS One 2018 1;13(10):e0204829. Epub 2018 Oct 1.

Institute of Environmental Health, College of Public Health, National Taiwan University, Taipei, Taiwan.

Naphthalene causes mouse airway epithelial injury. However, repeated exposures of naphthalene result in mouse airway tolerance. Previous results showed that toxicity or tolerance was correlated with changes of phosphorylcholine-containing lipids. In this study, a mass spectrometry-based lipidomic approach was applied to examine the effects of naphthalene-induced injury or tolerance in the male ICR mice. The injury model was vehicle x 7 plus 300 mg/kg naphthalene while the tolerant one was 200 mg/kg daily x 7 followed by 300 mg/kg naphthalene on day 8. The lung, liver, kidney, and serum samples were collected for profiles of phosphorylcholine-containing lipids including phosphatidylcholines (PCs) and sphingomyelins (SMs). A partial least-square-discriminate analysis model showed different lung phosphorylcholine-containing lipid profiles from the injured, tolerant, and control groups. Perturbation of diacyl-PCs and plasmenylcholines may be associated with enhanced membrane flexibility and anti-oxidative mechanisms in the lungs of tolerant mice. Additionally, alterations of lyso-PCs and SMs may be responsible for pulmonary dysfunction and inflammation in the lungs of injured mice. Moreover, serum PC(16:0/18:1) has potential to reflect naphthalene-induced airway injuries. Few phosphorylcholine-containing lipid alterations were found in the mouse livers and kidneys across different treatments. This study revealed the changes in lipid profiles associated with the perturbations caused by naphthalene tolerance and toxicity; examination of lipids in serum may assist biomarker development with the potential for application in the human population.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0204829PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166967PMC
March 2019

ASPM promotes prostate cancer stemness and progression by augmenting Wnt-Dvl-3-β-catenin signaling.

Oncogene 2019 02 28;38(8):1340-1353. Epub 2018 Sep 28.

Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei City, 11031, Taiwan.

Recurrent and hormone-refractory prostate cancer (PCA) exhibits aggressive behaviors while current therapeutic approaches show little effect of prolonging the survival of patients with PCA. Thus, a deeper understanding of the patho-molecular mechanisms underlying the disease progression in PCA is crucial to identify novel diagnostic and/or therapeutic targets to improve the outcome of patients. Recent evidence suggests that activation of Wnt signaling in cancer stem cells (CSCs) contributes to cancer progression in malignant tumors. Here, we report that a novel Wnt co-activator ASPM (abnormal spindle-like microcephaly associated) maintains the prostate CSC subpopulation by augmenting the Wnt-β-catenin signaling in PCA. ASPM expression is incrementally upregulated in primary and metastatic PCA, implicating its potential role in PCA progression. Consistently, downregulation of ASPM expression pronouncedly attenuated the proliferation, colony formation, and the invasive behavior of PCA cells, and dramatically reduced the number of ALDH CSCs and inhibited cancer stemness and tumorigenicity. Mechanistically, ASPM interacts with disheveled-3 (Dvl-3), a cardinal upstream regulator of canonical Wnt signaling, and inhibits its proteasome-dependent degradation, thereby increasing its protein stability and enabling the Wnt-induced β-catenin transcriptional activity in PCA cells. In keeping with the role of ASPM as a CSC-regulator, ASPM co-localizes with ALDH in PCA tissues and its expression exhibits high intra-tumoral heterogeneity. The proportion of high-ASPM-expressing cells in the tumor inversely correlates with the relapse-free survival of PCA patients. Collectively, our data points to ASPM as a novel oncoprotein and an essential regulator of Wnt signaling and cancer stemness in PCA, which has important clinical and therapeutic significance.
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http://dx.doi.org/10.1038/s41388-018-0497-4DOI Listing
February 2019

Elevation of androgen receptor promotes prostate cancer metastasis by induction of epithelial-mesenchymal transition and reduction of KAT5.

Cancer Sci 2018 Nov 25;109(11):3564-3574. Epub 2018 Sep 25.

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

Androgen receptor (AR), an androgen-activated transcription factor, belongs to the nuclear receptor superfamily. AR plays an important role in the development and progression of prostate cancer (PCa). However, the role of AR in PCa metastasis is not fully understood. To investigate the role of AR in PCa metastasis, we examined AR expression level in primary and metastatic PCa by analyzing gene array data of 378 primary prostate tumors and 120 metastatic prostate tumors from Oncomine, as well as carrying out immunohistochemical (IHC) staining of 56 prostate cancer samples. Expression of mRNA and protein of AR as well as its target gene prostate-specific antigen (PSA) was much higher in metastatic prostate tumors than in primary prostate tumors. Knockdown of AR with siRNA or treating with anti-androgen Casodex reduced migration and invasion ability of C4-2B PCa cells. Knockdown of AR increased protein expression of E-cadherin and AR coregulator KAT5 but reduced expression of epithelial-mesenchymal transition (EMT) marker proteins Slug, Snail, MMP-2, vimentin, and β-catenin. Knockdown of KAT5 increased migration of C4-2B cells, whereas overexpression of KAT5 suppressed cell migration. KAT5 knockdown rescues the suppressive effect of AR knockdown on migration of C4-2B cells. Gene expression level of AR and KAT5 showed a negative correlation. PCa patients with higher AR expression or lower KAT5 expression correlated with shorter recurrence-free survival. Our study suggested that elevation of AR expression and AR signaling in prostate tumors promotes PCa metastasis by induction of EMT and reduction of KAT5.
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http://dx.doi.org/10.1111/cas.13776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215884PMC
November 2018

Elevated IgM against Nε-(Carboxyethyl)lysine-modified Apolipoprotein A1 peptide 141-147 in Taiwanese with Alzheimer's disease.

Clin Biochem 2018 Jun 20;56:75-82. Epub 2018 Apr 20.

School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan; Ph.D. Program in Medical Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan. Electronic address:

Objective: Advanced glycation end products (AGEs) are involved in the pathogenesis of Alzheimer's disease (AD). Specific AGEs and related autoantibodies may be early AD markers. Apolipoprotein A1 (ApoA1) and its post-translational modifications (PTMs) are associated with neurodegeneration and thus selected to test the hypothesis.

Methods: Serum samples from totally 64 AD or health control (HC) Taiwanese were analyzed. ApoA1 was isolated from the serum and examined through LC-MS/MS and PTM analyses. A specific AGE and its autoantibodies were determined using Western blotting or ELISA.

Results: Nε-(Carboxyethyl)lysine (CEL) modification, a kind of AGEs, was identified on ApoA1 peptide -QKVEPLR- (ApoA1) from AD serum. Total CEL adducts and autoantibodies against CEL on ApoA1 were significantly increased in AD samples. The area under the receiver operating characteristic curve was 0.965 for anti-CEL-ApoA1 IgM. Mini Mental State Examination scores of the AD patients were positively correlated with anti-CEL-ApoA1 IgM, suggesting that the IgM level is high in early AD pathology and decreased with disease progression.

Conclusion: CEL modification was increased on AD serum proteins including ApoA1, leading to an elevated anti-CEL IgM in early disease state. Both CEL and anti-CEL IgM may serve as AD biomarkers.
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http://dx.doi.org/10.1016/j.clinbiochem.2018.04.009DOI Listing
June 2018

Serum ApoA4 levels predicted the progression of renal impairment in T2DM.

Eur J Clin Invest 2018 Jun 13;48(6):e12937. Epub 2018 May 13.

Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.

Background: Among multiple causes, diabetic nephropathy (DN) is the major underlying renal disease that leads to end-stage renal disease (ESRD), and early diagnosis can effectively prevent or delay the progression to ESRD. Therefore, the current study aimed to develop noninvasive, accurate detection markers.

Materials & Methods: For this study, 62 diabetes mellitus (DM) patients, 59 DN patients and 21 healthy controls (HCs) were recruited. All participants' serum samples were subjected to concavanalin (Con) A affinity chromatography, which utilizes glycoproteins to discover potential markers.

Results: From nano LC-MS and Western blot analysis, apolipoprotein A-IV (ApoA4) was selected which featured a gradual, almost twofold increase in the order of HC, DM and DN. In the Con A-based ELISA, the DM group was 1.91-fold higher than the HC group, while the DN group was 2.56-fold higher than the HCs and 1.33-fold higher than the DM group. In addition, significant positive correlations were observed between ApoA4 and blood urea nitrogen levels and between ApoA4 and creatine levels, while significant negative correlations were seen between serum protein levels and between serum albumin levels in comparisons of DM and DN samples.

Conclusions: Serum Con A-bound ApoA4 levels were higher in the DM group than in HCs, and further increased in the DN group. Levels of ApoA4 were positively correlated with blood urea nitrogen and creatine, but negatively correlated with serum protein and albumin. This evidence supports serum Con A-bound ApoA4 as a circulating marker for predicting the progression of renal impairment in DM patients.
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http://dx.doi.org/10.1111/eci.12937DOI Listing
June 2018
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