Publications by authors named "Yung-Jen Chuang"

63 Publications

Influence of Prednisolone and Alendronate on the Mineralization of Zebrafish Caudal Fin.

JBMR Plus 2021 Feb 5;5(2):e10435. Epub 2020 Dec 5.

Department of Materials Science and Engineering National Tsing Hua University Hsinchu Taiwan.

Dysregulated balance between bone resorption and formation mediates the onset and progression of osteoporosis. The administration of prednisolone is known to induce osteoporosis, whereas alendronate is commonly used to reverse the process. However, the assessment of the effects of such medicines on the nanostructure of bone remodeling and mechanical properties remains a major technical challenge. The aim of this study was to apply various analytical approaches to evaluate the compositional, morphological, and mechanical properties of regenerative zebrafish caudal fin bony rays affected by prednisolone and alendronate. Adult wild-type AB strain zebrafish were first exposed to 125μM of prednisolone for 14 days to develop glucocorticoid-induced osteoporosis. Fish fins were then amputated and let to regenerate for 21 days in tank water containing 30μM of alendronate or no alendronate. The lepidotrichia in the proximal and distal regions were evaluated separately using confocal microscope, scanning electron microscope, electron-dispersive spectroscopy, Raman spectroscopy, atomic force microscopy, and a triboindenter. As expected, prednisolone led to significant osteoporotic phenotypes. A decrease of Ca/P ratio was observed in the osteoporotic subjects (1.46 ± 0.04) as compared to the controls (1.74 ± 0.10). Subsequent treatment of alendronate overmineralized the bony rays during regeneration. Enhanced phosphate deposition was detected in the proximal part with alendronate treatment. Moreover, prednisolone attenuated the reduced elastic modulus and hardness levels (5.60 ± 5.04 GPa and 0.12 ± 0.17 GPa, respectively), whereas alendronate recovered them to the pre-amputation condition (8.68 ± 8.74 GPa and 0.34 ± 0.47 GPa, respectively). As an emerging model of osteoporosis, regrowth of zebrafish caudal fin was shown to be a reliable assay system to investigate the various effects of medicines in the mineralization process. © 2020 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872341PMC
February 2021

Systems Approach to Pathogenic Mechanism of Type 2 Diabetes and Drug Discovery Design Based on Deep Learning and Drug Design Specifications.

Int J Mol Sci 2020 Dec 26;22(1). Epub 2020 Dec 26.

Laboratory of Automatic Control, Signal Processing and Systems Biology, Department of Electrical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan.

In this study, we proposed a systems biology approach to investigate the pathogenic mechanism for identifying significant biomarkers as drug targets and a systematic drug discovery strategy to design a potential multiple-molecule targeting drug for type 2 diabetes (T2D) treatment. We first integrated databases to construct the genome-wide genetic and epigenetic networks (GWGENs), which consist of protein-protein interaction networks (PPINs) and gene regulatory networks (GRNs) for T2D and non-T2D (health), respectively. Second, the relevant "real GWGENs" are identified by system identification and system order detection methods performed on the T2D and non-T2D RNA-seq data. To simplify network analysis, principal network projection (PNP) was thereby exploited to extract core GWGENs from real GWGENs. Then, with the help of KEGG pathway annotation, core signaling pathways were constructed to identify significant biomarkers. Furthermore, in order to discover potential drugs for the selected pathogenic biomarkers (i.e., drug targets) from the core signaling pathways, not only did we train a deep neural network (DNN)-based drug-target interaction (DTI) model to predict candidate drug's binding with the identified biomarkers but also considered a set of design specifications, including drug regulation ability, toxicity, sensitivity, and side effects to sieve out promising drugs suitable for T2D.
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http://dx.doi.org/10.3390/ijms22010166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795239PMC
December 2020

Suitability of boric acid as a boron drug for boron neutron capture therapy for hepatoma.

Appl Radiat Isot 2020 Oct 30;164:109254. Epub 2020 May 30.

Institute of Nuclear Engineering and Science, National Tsing Hua University, Hsinchu, Taiwan; Nuclear Science and Technology Development Center, National Tsing Hua University, Hsinchu, Taiwan. Electronic address:

Hepatoma is the second leading cause of cancer death worldwide. Due to the poor outcomes of patients with late diagnosis, newer treatments for hepatoma are still needed. As an emerging therapy, boron neutron capture therapy (BNCT) may be an effective solution in hepatoma management. In this study, boric acid (BA) was used as the boron drug for in vivo analysis of action mechanism. The N1S1 single liver tumor-bearing rat and the VX2 multifocal liver tumor-bearing rabbit models were used to investigate the retention status of BA in the tumor regions during BNCT. The autoradiographic examination showed BA can localize specifically not only in the hepatoma cells but also in tumor blood vessels. Our findings indicate that superior hepatoma targeting could be achieved in BA-mediated BNCT, which supports BA to be a suitable boron drug for BNCT for hepatoma.
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http://dx.doi.org/10.1016/j.apradiso.2020.109254DOI Listing
October 2020

Exposure to the AhR agonist cyprodinil impacts the cardiac development and function of zebrafish larvae.

Ecotoxicol Environ Saf 2020 Sep 6;201:110808. Epub 2020 Jun 6.

State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361005, China; State Key Laboratory of Marine Environmental Science, Xiamen University, Xiamen, Fujian, 361005, China. Electronic address:

Cyprodinil is a broad-spectrum pyrimidine amine fungicide that has been reportedly used worldwide. However, toxicity studies of cyprodinil on aquatic organisms, specifically zebrafish (Danio rerio), are lacking. In our present study, we predicted cyprodinil binding to the aryl hydrocarbon receptor (AhR) by using molecular docking simulation. Then, we used recombinant HepG2 cells and Tg(cyp1a1-12DRE:egfp) transgenic zebrafish to further assess the AhR agonistic activity of cyprodinil. Besides, the significant upregulation of cyp1a1 further verified that statement. Moreover, we found that zebrafish exposure to cyprodinil induced developmental toxicity in the larvae, particularly during cardiac development. The expression levels of cardiac development-related genes, namely tbx5, nkx2.5, gata4, and tnnt2, were markedly altered, which might cause the adverse effects of cyprodinil on cardiac function and development. In summary, we found that cyprodinil, as an AhR agonist, induced development toxicity in zebrafish larvae, especially on cardiac. Data here can assess the potential effects on organisms in the aquatic environment and promote the regulation and safe use of cyprodinil.
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http://dx.doi.org/10.1016/j.ecoenv.2020.110808DOI Listing
September 2020

The Phenoxyphenol Compound 4-HPPP Selectively Induces Antiproliferation Effects and Apoptosis in Human Lung Cancer Cells through Aneupolyploidization and ATR DNA Repair Signaling.

Oxid Med Cell Longev 2020 7;2020:5167292. Epub 2020 Jan 7.

Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan.

Lung cancer is a leading cause of cancer death worldwide, and non-small-cell lung cancer (NSCLC) accounts for 85% of lung cancer, which is highly metastatic, leading to the poor survival rate of patients. We recently reported that 4-[4-(4-hydroxyphenoxy)phenoxy]phenol (4-HPPP), a phenoxyphenol, exerts antihepatoma effects by inducing apoptosis and autophagy. In this study, we further examined the effect of 4-HPPP and its analogs on NSCLC cells. Colony formation assays showed that 4-HPPP exerts selective cytotoxicity against NSCLC H1299 cells; furthermore, the inhibitory effect of 4-HPPP on the proliferation and migration of NSCLC cells was validated using an zebrafish-based tumor xenograft assay. The flow cytometry-based dichlorofluorescein diacetate (DCF-DA) assays indicated that 4-HPPP caused an increase in reactive oxygen species (ROS) in NSCLC cells, and Western blot assays showed that the major ROS scavenging enzymes superoxide dismutases- (SODs-) 1/2 were upregulated, whereas peroxidase (PRX) was downregulated. Furthermore, 4-HPPP caused both aneuploidization and the accumulation of H2AX, a sensor of DNA damage, as well as the activation of double-strand break (DSB) markers, especially Ataxia-telangiectasia-mutated and Rad3-related (ATR) in NSCLC cells. Our present work suggests that the antiproliferative effects of 4-HPPP on lung cancer cells could be due to its phenoxyphenol structure, and 4-HPPP could be a candidate molecule for treating NSCLC by modulating ROS levels and lowering the threshold of polyploidy-specific cell death in the future.
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http://dx.doi.org/10.1155/2020/5167292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024103PMC
September 2020

Analysis of DNA Damage Responses After Boric Acid-mediated Boron Neutron Capture Therapy in Hepatocellular Carcinoma.

Anticancer Res 2019 Dec;39(12):6661-6671

Department of Medical Science and Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan, R.O.C.

Background: Boron neutron capture therapy (BNCT) selectively kills tumor cells while sparing adjacent normal cells. Boric acid (BA)-mediated BNCT showed therapeutic efficacy in treating hepatocellular carcinoma (HCC) in vivo. However, DNA damage and corresponding responses induced by BA-mediated BNCT remained unclear. This study aimed to investigate whether BA-mediated BNCT induced DNA double-strand breaks (DSBs) and to explore DNA damage responses in vitro.

Materials And Methods: Huh7 Human HCC cells were treated with BA and irradiated with neutrons during BA-BNCT. Cell survival and DNA DSBs were examined by clonogenic assay and expression of phosphorylated H2A histone family member X (γH2AX), respectively. The DNA damage response was explored by determining the expression levels of DNA repair- and apoptosis-associated proteins and conducting a cell-cycle analysis.

Results: DNA DSBs induced by BA-mediated BNCT were primarily repaired through the homologous recombination pathway. BA-mediated BNCT induced G/M arrest and apoptosis in HCC.

Conclusion: Our findings may enable the identification of radiosensitizers or adjuvant drugs for potentiating the therapeutic effectiveness of BA-mediated BNCT for HCC.
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http://dx.doi.org/10.21873/anticanres.13881DOI Listing
December 2019

Therapeutic Efficacy and Radiobiological Effects of Boric Acid-mediated BNCT in a VX2 Multifocal Liver Tumor-bearing Rabbit Model.

Anticancer Res 2019 Oct;39(10):5495-5504

Institute of Nuclear Engineering and Science, National Tsing Hua University, Hsinchu, Taiwan, R.O.C.

Background/aim: Most patients with hepatocellular carcinoma (HCC) cannot be treated using traditional therapies. Boron neutron capture therapy (BNCT) may provide a new treatment for HCC. In this study, the therapeutic efficacy and radiobiological effects of boric acid (BA)-mediated BNCT in a VX2 multifocal liver tumor-bearing rabbit model are investigated.

Materials And Methods: Rabbits were irradiated with neutrons at the Tsing Hua Open Pool Reactor 35 min following an intravenous injection of BA (50 mg B/kg BW). The tumor size following BNCT treatment was determined by ultrasonography. The radiobiological effects were identified by histopathological examination.

Results: A total of 92.85% of the tumors became undetectable in the rabbits after two fractions of BNCT treatment. The tumor cells were selectively eliminated and the tumor vasculature was collapsed and destroyed after two fractions of BA-mediated BNCT, and no injury to the hepatocytes or blood vessels was observed in the adjacent normal liver regions.

Conclusion: Liver tumors can be cured by BA-mediated BNCT in the rabbit model of a VX2 multifocal liver tumor. BA-mediated BNCT may be a breakthrough therapy for hepatocellular carcinoma.
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http://dx.doi.org/10.21873/anticanres.13742DOI Listing
October 2019

Cordycepin Suppresses Endothelial Cell Proliferation, Migration, Angiogenesis, and Tumor Growth by Regulating Focal Adhesion Kinase and p53.

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

Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 350, Taiwan.

Focal adhesion kinase (FAK) plays an important role in vascular development, including the regulation of endothelial cell (EC) adhesion, migration, proliferation, and survival. 3'-deoxyadenosine (cordycepin) is known to suppress FAK expression, cell migration, and the epithelial⁻mesenchymal transition in hepatocellular carcinoma (HCC). However, whether cordycepin affects FAK expression and cellular functions in ECs and the specific molecular mechanism remain unclear. In this study, we found that cordycepin suppressed FAK expression and the phosphorylation of FAK (p-FAK) at Tyr397 in ECs. Cordycepin inhibited the proliferation, wound healing, transwell migration, and tube formation of ECs. Confocal microscopy revealed that cordycepin significantly reduced FAK expression and decreased focal adhesion number of ECs. The suppressed expression of FAK was accompanied by induced p53 and p21 expression in ECs. Finally, we demonstrated that cordycepin suppressed angiogenesis in an in vivo angiogenesis assay and reduced HCC tumor growth in a xenograft nude mice model. Our study indicated that cordycepin could attenuate cell proliferation and migration and may result in the impairment of the angiogenesis process and tumor growth via downregulation of FAK and induction of p53 and p21 in ECs. Therefore, cordycepin may be used as a potential adjuvant for cancer therapy.
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http://dx.doi.org/10.3390/cancers11020168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406613PMC
February 2019

Generation of a Tg(cyp1a-12DRE:EGFP) transgenic zebrafish line as a rapid in vivo model for detecting dioxin-like compounds.

Aquat Toxicol 2018 Dec 30;205:174-181. Epub 2018 Oct 30.

State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian 361005, China; State Key Laboratory of Marine Environmental Science, Xiamen University, Xiamen, Fujian 361102, China. Electronic address:

Dioxin-like compounds (DLCs) are extremely stable toxic organic compounds and can cause serious health risks. To develop a convenient biomonitoring tool for the detection of DLCs in the environment, we generated a transgenic line-Tg(cyp1a-12DRE:EGFP)-with a zebrafish cyp1a promoter recombined with multiple dioxin-responsive elements (DREs) that drive EGFP expression. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)-induced EGFP expression was observed in the head cartilage (most sensitive), gut, otic vesicle, pectoral fin bud and eye of larvae. The lowest observed effect concentration of TCDD was estimated to be approximately 1 ng/L. Compared with existing zebrafish lines, our transgenic fish displayed comparable or even higher detection sensitivity to DLCs and could serve as an improved and rapid assay in an in vivo context. The Tg(cyp1a-12DRE:EGFP) transgenic zebrafish line also had higher stability for inducing EGFP expression (nearly 100% of our zebrafish induced EGFP at approximately 1 ng/L TCDD) than other lines. In addition, Tg(cyp1a-12DRE:EGFP) zebrafish could serve as a convenient and straightforward tool to assess potential cranial malformations and related health effects.
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http://dx.doi.org/10.1016/j.aquatox.2018.10.022DOI Listing
December 2018

Development of a rapid and economic in vivo electrocardiogram platform for cardiovascular drug assay and electrophysiology research in adult zebrafish.

Sci Rep 2018 10 30;8(1):15986. Epub 2018 Oct 30.

Department of Medical Science & Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, 30013, Taiwan.

Zebrafish is a popular and favorable model organism for cardiovascular research, with an increasing number of studies implementing functional assays in the adult stage. For example, the application of electrocardiography (ECG) in adult zebrafish has emerged as an important tool for cardiac pathophysiology, toxicity, and chemical screen studies. However, few laboratories are able to perform such functional analyses due to the high cost and limited availability of a convenient in vivo ECG recording system. In this study, an inexpensive ECG recording platform and operation protocol that has been optimized for adult zebrafish ECG research was developed. The core hardware includes integration of a ready-to-use portable ECG kit with a set of custom-made needle electrode probes. A combined anesthetic formula of MS-222 and isoflurane was first tested to determine the optimal assay conditions to minimize the interference to zebrafish cardiac physiology under sedation. For demonstration, we treated wild-type zebrafish with different pharmacological agents known to affect cardiac rhythms in humans. Conserved electrophysiological responses to these drugs were induced in adult zebrafish and recorded in real time. This economic ECG platform has the potential to facilitate teaching and training in cardiac electrophysiology with adult zebrafish and to promote future translational applications in cardiovascular medicine.
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http://dx.doi.org/10.1038/s41598-018-33577-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207748PMC
October 2018

Extension of C. elegans lifespan using the ·NO-delivery dinitrosyl iron complexes.

J Biol Inorg Chem 2018 07 1;23(5):775-784. Epub 2018 Jun 1.

Department of Chemistry, National Tsing Hua University, Hsinchu, 30013, Taiwan.

The ubiquitous and emerging physiology function of endogenous nitric oxide in vascular, myocardial, immune, and neuronal systems prompts chemists to develop a prodrug for the controlled delivery of ·NO in vivo and for the translational biomedical application. Inspired by the discovery of natural [Fe(NO)] motif, herein, we develop the synthetic dinitrosyl iron complexes (DNICs) [Fe(μ-SR)(NO)] (1) as a universal platform for the O-triggered release of ·NO, for the regulation of ·NO-release kinetics (half-life = 0.6-27.4 h), and for the activation of physiological function of ·NO. Using C. elegans as a model organism, the ·NO-delivery DNIC 1 regulates IIS signaling pathway, AMPK signaling pathway, and mitochondrial function pathway to extend the lifespan and to delay the aging process based on the lifespan analysis, SA-βgal activity assay, and next-generation RNA sequencing analysis. This study unveils the anti-aging effect of ·NO and develops DNICs as a chemical biology probe for the continued discovery of unprecedented NO physiology.
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http://dx.doi.org/10.1007/s00775-018-1569-1DOI Listing
July 2018

Zebrafish as a model to study bone maturation: Nanoscale structural and mechanical characterization of age-related changes in the zebrafish vertebral column.

J Mech Behav Biomed Mater 2018 08 3;84:54-63. Epub 2018 May 3.

Department of Mechanical, Materials and Aerospace Engineering, School of Engineering, University of Liverpool, The Quadrangle, Brownlow Hill, Liverpool L69 3GH, UK. Electronic address:

Zebrafish (Danio rerio) is a useful model for understanding biomedical properties of bone and are widely employed in developmental and genetics studies. Here, we have studied the development of zebrafish vertebral bone at the nanoscale from adolescence (6 months), early adulthood (10 months) to mid-life (14 months). Characterization of the bone was conducted using energy-dispersive X-ray spectroscopy (EDX), scanning electron microscopy (SEM) and PeakForce QNM atomic force microscopy (AFM) techniques. SEM and AFM revealed a lamellar structure with mineralized collagen fibrils. There was a significant increase in the wall thickness from 6 to 10 months (76%) and 10 months to 14 months (26%), which is positively correlated with nanomechanical behavior. An increase in the Ca/P ratio was found which was also positively correlated with nanomechanical properties. The change in mechanical properties and Ca/P are similar to those expected in humans when transitioning from adolescence to mid-life. We suggest that zebrafish serve as a suitable model for further studies on age-related changes in bone ultrastructure.
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http://dx.doi.org/10.1016/j.jmbbm.2018.05.004DOI Listing
August 2018

Proteomic investigating the cooperative lethal effect of EGFR and MDM2 inhibitors on ovarian carcinoma.

Arch Biochem Biophys 2018 Jun 12;647:10-32. Epub 2018 Apr 12.

Institute of Bioinformatics and Structural Biology and Department of Medical Science, National Tsing Hua University, Hsinchu, Taiwan. Electronic address:

With the concept of precision medicine, combining multiple molecular-targeting therapies has brought new approaches to current cancer treatments. Malfunction of the tumor suppressor protein, p53 is a universal hallmark in human cancers. Under normal conditions, p53 is degraded through an ubiquitin-proteosome pathway regulated by its negative regulator, MDM2. In contrast, cellular stress such as DNA damage will activate p53 to carry out DNA repair, cell cycle arrest, and apoptosis. In this study, we focused on ovarian carcinoma with high EGFR and MDM2 overexpression rate. We assessed the effects of combined inhibition by MDM2 (JNJ-26854165) and EGFR (gefitinib) inhibitors on various ovarian cell lines to determine the importance of these two molecular targets on cell proliferation. We then used a proteomic strategy to investigate the relationship between MDM2 and EGFR inhibition to explore the underlying mechanisms of how their combined signaling blockades work together to exert cooperative inhibition. Our results demonstrated that all four cell lines were sensitive to both individual and combined, MDM2 and EGFR inhibition. The proteomic analysis also showed that gefitinib/JNJ-treated CAOV3 cells exhibited downregulation of proteins involved in nucleotide biosynthesis such as nucleoside diphosphate kinase B (NME2). In conclusion, our study showed that the combined treatment with JNJ and gefitinib exerted synergistic inhibition on cell proliferation, thereby suggesting the potential application of combining MDM2 inhibitors with EGFR inhibitors for enhancing efficacy in ovarian cancer treatment.
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http://dx.doi.org/10.1016/j.abb.2018.04.004DOI Listing
June 2018

Uncovering the regeneration strategies of zebrafish organs: a comprehensive systems biology study on heart, cerebellum, fin, and retina regeneration.

BMC Syst Biol 2018 03 19;12(Suppl 2):29. Epub 2018 Mar 19.

Department of Electrical Engineering, National Tsing Hua University, Hsinchu, 30013, Taiwan.

Background: Regeneration is an important biological process for the restoration of organ mass, structure, and function after damage, and involves complex bio-physiological mechanisms including cell differentiation and immune responses. We constructed four regenerative protein-protein interaction (PPI) networks using dynamic models and AIC (Akaike's Information Criterion), based on time-course microarray data from the regeneration of four zebrafish organs: heart, cerebellum, fin, and retina. We extracted core and organ-specific proteins, and proposed a recalled-blastema-like formation model to uncover regeneration strategies in zebrafish.

Results: It was observed that the core proteins were involved in TGF-β signaling for each step in the recalled-blastema-like formation model and TGF-β signaling may be vital for regeneration. Integrins, FGF, and PDGF accelerate hemostasis during heart injury, while Bdnf shields retinal neurons from secondary damage and augments survival during the injury response. Wnt signaling mediates the growth and differentiation of cerebellum and fin neural stem cells, potentially providing a signal to trigger differentiation.

Conclusion: Through our analysis of all four zebrafish regenerative PPI networks, we provide insights that uncover the underlying strategies of zebrafish organ regeneration.
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http://dx.doi.org/10.1186/s12918-018-0544-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5861487PMC
March 2018

Effect of Tumor Microenvironment on Selective Uptake of Boric Acid in HepG2 Human Hepatoma Cells.

Anticancer Res 2017 11;37(11):6347-6353

Department of Medical Science, National Tsing Hua University, Hsinchu, Taiwan, R.O.C.

Background: Feasibility and efficacy of boric acid (BA)-mediated boron neutron capture therapy (BNCT) was first demonstrated by eliminating hepatocellular carcinoma (HCC) in a rat model. Furthermore, selective uptake of BA by liver tumor cells was shown in a rabbit model. To gain further insight, this study aimed to investigate the mechanisms of transportation and selective uptake of BA in HepG2 liver tumor cells.

Materials And Methods: Transportation of BA in HepG2 cells was analyzed by time-course assays and by analyzing the rate of diffusion versus the concentration of BA. The effect of different tumor conditions on BA uptake was studied by treating HepG2 cells with 25 μg B/ml BA under different concentrations of glucose, at different pH and in the presence of water-soluble cholesterol.

Results: HepG2 cells mainly uptake BA by simple diffusion. Cell membrane permeability may also contribute to tumor-specific uptake of BA.

Conclusion: The selective uptake of BA was achieved primarily by diffusion, while other factors, such as low pH and increased membrane fluidity, which are hallmarks of HCC, might further enhance BA uptake.
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http://dx.doi.org/10.21873/anticanres.12087DOI Listing
November 2017

Effects of an injectable functionalized self-assembling nanopeptide hydrogel on angiogenesis and neurogenesis for regeneration of the central nervous system.

Nanoscale 2017 Nov;9(42):16281-16292

Department of Materials Science and Engineering, National Tsing Hua University, Hsinchu, Taiwan.

Brain injury is a devastating medical condition and represents a major health problem. Tissue and organ reconstruction have been regarded as promising therapeutic strategies. Here, we propose a regenerative methodology focusing on the provision of functionalized nanopeptide scaffolds to facilitate angiogenesis and neurogenesis at the brain injury site. The peptide RADA16-SVVYGLR undergoes self-assembly to construct an interconnected network with intertwining nanofibers, and can be controlled to display various physicochemical properties by the adjustment of microenvironmental factors such as pH and ion concentration. Such scaffolds can support endothelial cells to form tube-like structures and neural stem cells to survive and proliferate. In an in vivo zebrafish brain injury model, sprouting angiogenesis and developmental neurogenesis were achieved, and functional recovery of the severed optic tectum was enhanced in RADA16-SVVYGLR hydrogel-implanted zebrafish. This nanopeptide hydrogel was non-toxic to zebrafish embryos during early developmental stages. This angiogenic self-assembling peptide hydrogel had programmable physical properties, good biocompatibility, and regenerative ability for functional recovery in the injured brain. We suggest that functionalized self-assembling peptides encapsulated with neural stem cells or used alone could be an attractive and effective therapeutic modality for brain injury and diseases (e.g., trauma, stroke, tumor, degenerative neurological disorders, etc.).
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http://dx.doi.org/10.1039/c7nr06528kDOI Listing
November 2017

NEAP/DUSP26 suppresses receptor tyrosine kinases and regulates neuronal development in zebrafish.

Sci Rep 2017 07 12;7(1):5241. Epub 2017 Jul 12.

Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, 350, Taiwan.

Expression of neuroendocrine-associated phosphatase (NEAP, also named as dual specificity phosphatase 26, [DUSP26]) is restricted to neuroendocrine tissues. We found that NEAP, but not its phosphatase-defective mutant, suppressed nerve growth factor (NGF) receptor TrkA and fibroblast growth factor receptor 1 (FGFR1) activation in PC12 cells upon NGF stimulation. Conversely, suppressing NEAP expression by RNA interference enhanced TrkA and FGFR1 phosphorylation. NEAP was capable of de-phosphorylating TrkA and FGFR1 directly in vitro. NEAP-orthologous gene existed in zebrafish. Morpholino (MO) suppression of NEAP in zebrafish resulted in hyper-phosphorylation of TrkA and FGFR1 as well as abnormal body postures and small eyes. Differentiation of retina in zebrafishes with NEAP MO treatment was severely defective, so were cranial motor neurons. Taken together, our data indicated that NEAP/DUSP26 have a critical role in regulating TrkA and FGFR1 signaling as well as proper development of retina and neuronal system in zebrafish.
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http://dx.doi.org/10.1038/s41598-017-05584-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5507855PMC
July 2017

PI3K inhibitor enhances the cytotoxic response to etoposide and cisplatin in a newly established neuroendocrine cervical carcinoma cell line.

Oncotarget 2017 Jul;8(28):45323-45334

Department of Obstetrics and Gynecology, Hsinchu MacKay Memorial Hospital, Hsinchu, 30071, Taiwan (R.O.C.).

Background: Neuroendocrine cervical carcinoma (NECC) is a rare and aggressive subtype of cervical cancer. To date, no NECC cell-based model is available, which hinders the development of new therapeutic strategies for NECC. In this study, we derived a new NECC cell line from an ex vivo biopsy and used it to explore novel drug combination approach for NECC.

Results: The stable HM-1 cell line displayed high expression levels of the neuroendocrine marker, synaptophysin. HM-1 cell transplantation could induce tumor growth in nude mice. As expected, the combination of etoposide and cisplatin synergistically inhibited HM-1 cell proliferation. Strikingly, when etoposide and cisplatin were combined with PI3K inhibitor BEZ235, the growth of HM-1 cells was significantly reduced. Taken together, the data implied the combination of etoposide and cisplatin with BEZ235 not only inhibited HM-1 cell proliferation but also increased cell apoptosis.

Materials And Methods: A NECC tissue sample from a 75-year-old female patient was processed to derive a primary cell line annotated as HM-1. The features of HM-1 were analyzed to establish its characteristic profile. Next, HM-1 was treated with PI3K inhibitors, BKM120 and/or BEZ235, in combination with two well-known genotoxic drugs, etoposide and/or cisplatin, to evaluate which combination could serve as a more effective treatment approach. Their inhibiting effects on HM-1 were evaluated by cell viability, apoptosis, and target kinase expression.

Conclusions: The newly established NECC cell line HM-1 could serve as a cell-based model for NECC research. The synergistic drug combination of PI3K inhibitor with genotoxic drugs might become a potential new treatment strategy against NECC.
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http://dx.doi.org/10.18632/oncotarget.17335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542189PMC
July 2017

Motor neuron-derived Thsd7a is essential for zebrafish vascular development via the Notch-dll4 signaling pathway.

J Biomed Sci 2016 Aug 2;23(1):59. Epub 2016 Aug 2.

Department of Medical Science & Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, 30013, Taiwan.

Background: Development of neural and vascular systems displays astonishing similarities among vertebrates. This parallelism is under a precise control of complex guidance signals and neurovascular interactions. Previously, our group identified a highly conserved neural protein called thrombospondin type I domain containing 7A (THSD7A). Soluble THSD7A promoted and guided endothelial cell migration, tube formation and sprouting. In addition, we showed that thsd7a could be detected in the nervous system and was required for intersegmental vessels (ISV) patterning during zebrafish development. However, the exact origin of THSD7A and its effect on neurovascular interaction remains unclear.

Results: In this study, we discovered that zebrafish thsd7a was expressed in the primary motor neurons. Knockdown of Thsd7a disrupted normal primary motor neuron formation and ISV sprouting in the Tg(kdr:EGFP/mnx1:TagRFP) double transgenic zebrafish. Interestingly, we found that Thsd7a morphants displayed distinct phenotypes that are very similar to the loss of Notch-delta like 4 (dll4) signaling. Transcript profiling further revealed that expression levels of notch1b and its downstream targets, vegfr2/3 and nrarpb, were down-regulated in the Thsd7a morphants. These data supported that zebrafish Thsd7a could regulate angiogenic sprouting via Notch-dll4 signaling during development.

Conclusions: Our results suggested that motor neuron-derived Thsd7a plays a significant role in neurovascular interactions. Thsd7a could regulate ISV angiogenesis via Notch-dll4 signaling. Thus, Thsd7a is a potent angioneurin involved in the development of both neural and vascular systems.
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http://dx.doi.org/10.1186/s12929-016-0277-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971630PMC
August 2016

A Sketch of the Taiwan Zebrafish Core Facility.

Zebrafish 2016 07 6;13 Suppl 1:S24-9. Epub 2016 Jun 6.

3 Institute of Cellular and Organismic Biology , Academia Sinica, Taipei, Taiwan .

In the past three decades, the number of zebrafish laboratories has significantly increased in Taiwan. The Taiwan Zebrafish Core Facility (TZCF), a government-funded core facility, was launched to serve this growing community. The Core Facility was built on two sites, one located at the National Health Research Institutes (NHRI, called Taiwan Zebrafish Core Facility at NHRI or TZeNH) and the other is located at the Academia Sinica (Taiwan Zebrafish Core Facility at AS a.k.a. TZCAS). The total surface area of the TZCF is about 180 m(2) encompassing 2880 fish tanks. Each site has a separate quarantine room and centralized water recirculating systems, monitoring key water parameters. To prevent diseases, three main strategies have been implemented: (1) imported fish must be quarantined; (2) only bleached embryos are introduced into the main facilities; and (3) working practices were implemented to minimize pathogen transfer between stocks and facilities. Currently, there is no health program in place; however, a fourth measure for the health program, specific regular pathogen tests, is being planned. In March 2015, the TZCF at NHRI has been AAALAC accredited. It is our goal to ensure that we provide "disease-free" fish and embryos to the Taiwanese research community.
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http://dx.doi.org/10.1089/zeb.2015.1208DOI Listing
July 2016

Zebrafish model of photochemical thrombosis for translational research and thrombolytic screening in vivo.

J Biophotonics 2017 Apr 13;10(4):494-502. Epub 2016 May 13.

Department of Applied Chemistry and Institute of Molecular Science, National Chiao Tung University, Hsinchu, 300, Taiwan.

Acute thromboembolic diseases remain the major global cause of death or disability. Although an array of thrombolytic and antithrombotic drugs has been approved to treat or prevent thromboembolic diseases, many more drugs that target specific clotting mechanisms are under development. Here a novel zebrafish model of photochemical thrombosis is reported and its prospective application for the screening and preclinical testing of thrombolytic agents in vivo is demonstrated. Through photochemical excitation, a thrombus was induced to form at a selected section of the dorsal aorta of larval zebrafish, which had been injected with photosensitizers. Such photochemical thrombosis can be consistently controlled to occlude partially or completely the targeted blood vessel. Detailed mechanistic tests indicate that the zebrafish model of photochemical thrombosis exhibits essential features of classical coagulation and a thrombolytic pathway. For demonstration, tissue plasminogen activator (tPA), a clinically feasible thrombolytic agent, was shown to effectively dissolve photochemically induced blood clots. In light of the numerous unique advantages of zebrafish as a model organism, our approach is expected to benefit not only the development of novel thrombolytic and antithrombotic strategies but also the fundamental or translational research targeting hereditary thrombotic or coagulation disorders.
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http://dx.doi.org/10.1002/jbio.201500287DOI Listing
April 2017

Direct-growth carbon nanotubes on 3D structural microelectrodes for electrophysiological recording.

Analyst 2016 Jan 20;141(1):279-84. Epub 2015 Nov 20.

Department of Materials Science and Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan.

A novel 3D carbon nanotube (CNT) microelectrode was developed through direct growth of CNTs on a gold pin-shaped 3D microelectrode at a low temperature (400 °C) for applications in neural and cardiac recording. With an electroplated Ni catalyst layer covering the entire surface of the pin-shaped structure, CNTs were synthesized on a 3D microelectrode by catalytic thermal chemical vapor deposition (CVD). According to the analyses by electrochemical impedance spectroscopy, the impedance of 3D microelectrodes after CNT growth and UV/O3 treatment decreased from 9.3 Ω mm(-2) to 1.2 Ω mm(-2) and the capacitance increased largely from 2.2 mF cm(-2) to 73.3 mF cm(-2). The existence of UVO3-treated CNT led to a large improvement of interfacial capacitance, contributing to the decrease of impedance. The electrophysiological detection capability of this 3D CNT microelectrode was demonstrated by the distinguished P waves, QRS complex and T waves in the electrocardiogram of the zebrafish heart and the action potential recorded from individual rat hippocampal neurons. The compatibility of integration with ICs, high resolution in space, electrophysiological signals, and non-invasive long-term recording suggest that the 3D CNT microelectrode exhibits promising potential for applications in electrophysiological research and clinical trials.
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http://dx.doi.org/10.1039/c5an01750eDOI Listing
January 2016

A Heparan Sulfate-Binding Cell Penetrating Peptide for Tumor Targeting and Migration Inhibition.

Biomed Res Int 2015 3;2015:237969. Epub 2015 May 3.

Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu 30013, Taiwan ; Department of Medical Science, National Tsing Hua University, Hsinchu 30013, Taiwan.

As heparan sulfate proteoglycans (HSPGs) are known as co-receptors to interact with numerous growth factors and then modulate downstream biological activities, overexpression of HS/HSPG on cell surface acts as an increasingly reliable prognostic factor in tumor progression. Cell penetrating peptides (CPPs) are short-chain peptides developed as functionalized vectors for delivery approaches of impermeable agents. On cell surface negatively charged HS provides the initial attachment of basic CPPs by electrostatic interaction, leading to multiple cellular effects. Here a functional peptide (CPPecp) has been identified from critical HS binding region in hRNase3, a unique RNase family member with in vitro antitumor activity. In this study we analyze a set of HS-binding CPPs derived from natural proteins including CPPecp. In addition to cellular binding and internalization, CPPecp demonstrated multiple functions including strong binding activity to tumor cell surface with higher HS expression, significant inhibitory effects on cancer cell migration, and suppression of angiogenesis in vitro and in vivo. Moreover, different from conventional highly basic CPPs, CPPecp facilitated magnetic nanoparticle to selectively target tumor site in vivo. Therefore, CPPecp could engage its capacity to be developed as biomaterials for diagnostic imaging agent, therapeutic supplement, or functionalized vector for drug delivery.
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http://dx.doi.org/10.1155/2015/237969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433633PMC
March 2016

Robustness analysis on interspecies interaction network for iron and glucose competition between Candida albicans and zebrafish during infection.

BMC Syst Biol 2014 12;8 Suppl 5:S6. Epub 2014 Dec 12.

Candida albicans has emerged as an important model organism for the study of infectious disease. Using high-throughput simultaneously quantified time-course transcriptomics, this study constructed host-pathogen interspecies interaction networks between C. albicans and zebrafish during the adhesion, invasion, and damage stages. Given that iron and glucose have been identified as crucial resources required during the infection process between C. albicans and zebrafish, we focused on the construction of the interspecies networks associated with them. Furthermore, a randomization technique was proposed to identify differentially regulated proteins that are statistically eminent for the three infection stages. The behaviors of the highly connected or differentially regulated proteins identified from the resulting networks were further investigated. “Robustness” is an important system property that measures the ability of the system tolerating the intrinsic perturbations in a dynamic network. This characteristic provides a systematic and quantitative view to elucidate the dynamics of iron and glucose competition in terms of the interspecies interaction networks. Here, we further estimated the robustness of our constructed interspecies interaction networks for the three infection stages. The constructed networks and robustness analysis provided significant insight into dynamic interactions related to iron and glucose competition during infection and enabled us to quantify the system’s intrinsic perturbation tolerance ability during iron and glucose competition throughout the three infection stages. Moreover, the networks also assist in elucidating the offensive and defensive mechanisms of C. albicans and zebrafish during their competition for iron and glucose. Our proposed method can be easily extended to identify other such networks involved in the competition for essential resources during infection.
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http://dx.doi.org/10.1186/1752-0509-8-S5-S6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4305985PMC
September 2015

The role of TGF-β signaling and apoptosis in innate and adaptive immunity in zebrafish: a systems biology approach.

BMC Syst Biol 2014 Oct 24;8:116. Epub 2014 Oct 24.

Background: The immune system is a key biological system present in vertebrates. Exposure to pathogens elicits various defensive immune mechanisms that protect the host from potential threats and harmful substances derived from pathogens such as parasites, bacteria, and viruses. The complex immune system of humans and many other vertebrates can be divided into two major categories: the innate and the adaptive immune systems. At present, analysis of the complex interactions between the two subsystems that regulate host defense and inflammatory responses remains challenging.

Results: Based on time-course microarray data following primary and secondary infection of zebrafish by Candida albicans, we constructed two intracellular protein-protein interaction (PPI) networks for primary and secondary responses of the host. 57 proteins and 341 PPIs were identified for primary infection while 90 proteins and 385 PPIs were identified for secondary infection. There were 20 proteins in common while 37 and 70 proteins specific to primary and secondary infection. By inspecting the hub proteins of each network and comparing significant changes in the number of linkages between the two PPI networks, we identified TGF-β signaling and apoptosis as two of the main functional modules involved in primary and secondary infection.

Conclusions: Our initial in silico analyses pave the way for further investigation into the interesting roles played by the TGF-β signaling pathway and apoptosis in innate and adaptive immunity in zebrafish. Such insights could lead to therapeutic advances and improved drug design in the continual battle against infectious diseases.
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http://dx.doi.org/10.1186/s12918-014-0116-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224695PMC
October 2014

On the crucial cerebellar wound healing-related pathways and their cross-talks after traumatic brain injury in Danio rerio.

PLoS One 2014 13;9(6):e97902. Epub 2014 Jun 13.

Deptartment of Electrical Engineering, National Tsing Hua University, Hsinchu, Taiwan.

Upon injury, the direct damage and the subsequent secondary injury in the brain often result in chronic neurological disorders. Due to multifactorial nature of secondary injury and subsequent complex cellular responses, much of the underlying mechanisms are unclear. This study used an adult zebrafish cerebellum injury model to investigate the phenotypes and the secondary injury responses for recovery mechanisms of injured brain. Using the time course microarray analysis, a candidate protein-protein interaction (PPI) network was refined as cerebellar wound healing PPI network by dynamic modeling and big data mining. Pathway enrichment and ontological analysis were incorporated into the refined network to highlight the main molecular scheme of cerebellar wound healing. Several significant pathways, including chemokine, Phosphatidylinositide 3-kinases, and axon guidance signaling pathway and their cross-talks through PI3K, PAK2, and PLXNA3 were identified to coordinate for neurogenesis and angiogenesis, which are essential for the restoration of the injured brain. Our finding provides an insight into the molecular restoration mechanisms after traumatic brain injury, and open up new opportunity to devise the treatment for traumatic brain injury in human.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0097902PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057083PMC
October 2015

Essential functional modules for pathogenic and defensive mechanisms in Candida albicans infections.

Biomed Res Int 2014 18;2014:136130. Epub 2014 Mar 18.

Laboratory of Control and Systems Biology, Department of Electrical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan.

The clinical and biological significance of the study of fungal pathogen Candida albicans (C. albicans) has markedly increased. However, the explicit pathogenic and invasive mechanisms of such host-pathogen interactions have not yet been fully elucidated. Therefore, the essential functional modules involved in C. albicans-zebrafish interactions were investigated in this study. Adopting a systems biology approach, the early-stage and late-stage protein-protein interaction (PPI) networks for both C. albicans and zebrafish were constructed. By comparing PPI networks at the early and late stages of the infection process, several critical functional modules were identified in both pathogenic and defensive mechanisms. Functional modules in C. albicans, like those involved in hyphal morphogenesis, ion and small molecule transport, protein secretion, and shifts in carbon utilization, were seen to play important roles in pathogen invasion and damage caused to host cells. Moreover, the functional modules in zebrafish, such as those involved in immune response, apoptosis mechanisms, ion transport, protein secretion, and hemostasis-related processes, were found to be significant as defensive mechanisms during C. albicans infection. The essential functional modules thus determined could provide insights into the molecular mechanisms of host-pathogen interactions during the infection process and thereby devise potential therapeutic strategies to treat C. albicans infection.
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http://dx.doi.org/10.1155/2014/136130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3976935PMC
January 2015

Biomarker discovery for neuroendocrine cervical cancer.

Electrophoresis 2014 Jul 5;35(14):2039-45. Epub 2014 Jun 5.

Department of Medical Sciences, Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan.

Neuroendocrine cervical cancer is an aggressive but rare form of cervical cancer. The majority of neuroendocrine cervical cancer patients present with advanced-stage diseases. However, the limited numbers of neuroendocrine tumor markers are insufficient for clinical purposes. Thus, we used a proteomic approach combining lysine labeling 2D-DIGE and MALDI-TOF MS to investigate the biomarkers for neuroendocrine cervical cancer. By analyzing the global proteome alteration between the neuroendocrine cervical cancer line (HM-1) and non-neuroendocrine cervical cancer lines (CaSki cells, ME-180 cells, and Hela cells), we identified 82 proteins exhibiting marked changes between HM-1 and CaSki cells, and between ME-180 and Hela cells. Several proteins involved in protein folding, cytoskeleton, transcription control, signal transduction, glycolysis, and redox regulation exhibited significant changes in abundance. Proteomic and immunoblot analyses indicated respective 49.88-fold and 25-fold increased levels of transgelin in HM-1 cells compared with that in other non-neuroendocrine cervical cancer cell lines, implying that transgelin is a biomarker for neuroendocrine cervical cancer. In summary, we used a comprehensive neuroendocrine/non-neuroendocrine cervical cancer model based proteomic approach for identifying neuroendocrine cervical cancer markers, which might contribute to the prognosis and diagnosis of neuroendocrine cervical cancer.
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http://dx.doi.org/10.1002/elps.201400014DOI Listing
July 2014

Synthesis and evaluation of a photoactive probe with a multivalent carbohydrate for capturing carbohydrate-lectin interactions.

Bioconjug Chem 2013 Nov 6;24(11):1895-906. Epub 2013 Nov 6.

Department of Chemistry and.

Lectins are ubiquitous carbohydrate-binding proteins of nonimmune origin that are characterized by their specific recognition of defined monosaccharide or oligosaccharide structures. However, the use of carbohydrates to study lectin has been restricted by the weak binding affinity and noncovalent character of the interaction between carbohydrates and lectin. In this report, we designed and synthesized a multifunctional photoaffinity reagent composed of a trialkyne chain, a masked latent amine group, and a photoreactive 3-trifluoromethyl-3-phenyl-diazirine group in high overall yield. Two well-defined chemistries, Huisgen-Sharpless click chemistry and amide bond coupling, were the key steps for installing the multivalent character and tag in our designed photoaffinity probe. The photolabeling results demonstrated that the designed probe selectively labeled the target lectin, RCA120 ( Ricinus communis Agglutinin), in an E. coli lysate and an asialoglycoprotein receptor (ASGP-R) on intact HepG2 cell membranes. Moreover, the probe also enabled the detection of weak protein-protein interactions between RCA120 and ovalbumin (OVA).
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http://dx.doi.org/10.1021/bc400306gDOI Listing
November 2013

Dynamic transcript profiling of Candida albicans infection in zebrafish: a pathogen-host interaction study.

PLoS One 2013 3;8(9):e72483. Epub 2013 Sep 3.

Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan, R.O.C.

Candida albicans is responsible for a number of life-threatening infections and causes considerable morbidity and mortality in immunocompromised patients. Previous studies of C. albicans pathogenesis have suggested several steps must occur before virulent infection, including early adhesion, invasion, and late tissue damage. However, the mechanism that triggers C. albicans transformation from yeast to hyphae form during infection has yet to be fully elucidated. This study used a systems biology approach to investigate C. albicans infection in zebrafish. The surviving fish were sampled at different post-infection time points to obtain time-lapsed, genome-wide transcriptomic data from both organisms, which were accompanied with in sync histological analyses. Principal component analysis (PCA) was used to analyze the dynamic gene expression profiles of significant variations in both C. albicans and zebrafish. The results categorized C. albicans infection into three progressing phases: adhesion, invasion, and damage. Such findings were highly supported by the corresponding histological analysis. Furthermore, the dynamic interspecies transcript profiling revealed that C. albicans activated its filamentous formation during invasion and the iron scavenging functions during the damage phases, whereas zebrafish ceased its iron homeostasis function following massive hemorrhage during the later stages of infection. Most of the immune related genes were expressed as the infection progressed from invasion to the damage phase. Such global, inter-species evidence of virulence-immune and iron competition dynamics during C. albicans infection could be crucial in understanding control fungal pathogenesis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0072483PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3760836PMC
May 2014