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Chin-Hsien Tsai, Sheue-Fen Tzeng, Shih-Chuan Hsieh, Chia-Jui Tsai, Yu-Chih Yang, Mong-Hsun Tsai and Pei-Wen Hsiao A Standardized Wedelia chinensis Extract Overcomes the Feedback Activation of HER2/3 Signaling upon Androgen-Ablation in Prostate Cancer. Frontiers in Pharmacology 2017 Oct; 8:721
pwh Androgen receptor (AR)-mediated signaling play an essential role in prostate cancer for survival, growth, and invasion. Crosstalk between the AR and other signaling pathways in prostate cancer (PCa) severely affects the therapeutic outcome of hormonal therapy. Although anti-androgen therapy prolongs overall survival in PCa patients, resistance rapidly develops and is often associated with increased AR expression and upregulation of the HER2/3-AKT signaling pathway. However, single-agent therapy targeting AR, HER2/3 or AKT usually fails due to the reciprocal feedback loop. Here, we demonstrated that a standardized herbal extract, named WCE, effectively disrupted the AR, HER2/3, and AKT signaling networks and therefore enhanced the therapeutic efficacy of androgen ablation in PCa. Furthermore, WCE remained effective in suppressing AR and HER2/3 signaling in an in vivo adapted castration-resistant PCa cells that were insensitive to androgen withdrawal and a second-line antiandrogen, enzalutamide. This study provides preclinical evidence that the use of a defined, single plant-derived extract can augment the therapeutic efficacy of castration with significantly prolonged progression-free survival. These data also establish a solid basis for using WCE as a candidate agent in clinical studies.
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Chin-Hsien Tsai, Sheue-Fen Tzeng, Shih-Chuan Hsieh, Yu-Chih Yang, Yi-Wen Hsiao, Mong-Hsun Tsai, and Pei-Wen Hsiao (2017) A standardized herbal extract mitigates tumor inflammation and augments chemotherapy effect of docetaxel in prostate cancer. Scientific Reports 2017 Nov; 7: 15624
pwh Docetaxel remains the standard treatment for castration-resistant prostate cancer by improving overall survival but having severe adverse toxicity. Inflammatory cytokines in the tumor microenvironment promote docetaxel resistance through activation of IKKα/β-NFκB pathways. To tackle such chemotherapy-elicited adverse effects, this study demonstrates the standardized Wedelia chinensis herbal extract effectively inhibited the production of tumor-promoting cytokines, therefore inhibiting angiogenesis, tumor growth, and metastasis. Transcriptomic analysis of tumors revealed that WCE modulates inflammatory tumor microenvironment by suppressing the expression of HIF1α, IKKα/β phosphorylation and the downstream cytokines/chemokines, e.g., IL6, CXCL1, and CXCL8, thus reduced tumor-elicited chemotaxis and infiltration of MDSCs, TAMs, and endothelial cells into the tumors. Furthermore, WCE suppresses the expansion and activity of MDSCs by downregulating STAT3 activity and also prevents the differentiation of macrophages toward tumor-promoting M2 phenotype. On the other hand, co-treatment of docetaxel with this botanical preparation caused significant enhancement of the docetaxel-mediated therapeutic efficacy, while prevented the drug resistance and toxicity.
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Jeng-Yuan Shiau, Kyoko Nakagawa-Goto, Kuo-Hsiung Lee, and Lie-Fen Shyur* (2017) Phytoagent deoxyelephantopin derivative inhibits triple negative breast cancer cell activity by inducing oxidative stress-mediated paraptosis-like cell death. Oncotarget, 2017, 8:56942-56958
lfs Triple negative breast cancer (TNBC) is a highly metastatic cancer among the breast cancer subgroups. A thorny issue for clinical therapy of TNBC is lack of an efficient targeted therapeutic strategy. We previously created a novel sesquiterpene lactone analog (named DETD-35) derived from plant deoxyelephantopin (DET) which exhibits potent effects against human TNBC MDA-MB-231 tumor growth in a xenograft mouse model. Here we studied the mechanisms of both DET and DETD-35 against MDA-MB-231 cells. DETD-35 (3-fold decreased in IC50) exhibited better anti-TNBC cell activity than DET as observed through induction of reactive oxygen species production (within 2 h treatment) and damage to the ER structures, resulting in ER-derived cytoplasmic vacuolation and ubiquitinated protein accumulation in the treated cells. Intriguingly, the effects of both compounds were blockaded by pretreatment with ROS scavengers, N-acetylcysteine and reduced glutathione, and protein synthesis inhibitor, cycloheximide. Further, knockdown of MEK upstream regulator RAF1 and autophagosomal marker LC3, and co-treatment with JNK or ERK1/2 inhibitor resulted in the most significant attenuation of DETD-35{induced morphological and molecular or biochemical changes in cancer cells, while the inhibitory effect of DET was not influenced by MAPK inhibitor treatment. Therefore, DETD-35 exerted both ER stress-mediated paraptosis and apoptosis, which may explain its superior activity to DET against TNBC cells. Although the chemotherapeutic drug paclitaxel induced vacuole-like structures in MDA-MB-231 cells, no paraptotic cell death features were detected. This study provides a strategy for combating TNBC through sesquiterpene lactone analogs by induction of oxidative and ER stresses that cause paraptosis-like cell death.
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Cheng-Hsun Ho* and Wolf B. Frommer (2016) Design and Functional Analysis of Fluorescent Nitrate and Peptide Transporter Acativity Sensors in Yeast Cultures Bio-protocol, vol 6, iss 3
何承訓 This protocol describes the methods used to engineer and deploy genetically encoded fluorescence activity reporters for nitrate and peptide transporter activity in yeast cells. Fusion of the dual-affinity nitrate transceptor CHL1/AtNRT1.1/AtNPF6.3 or four different peptide transporters (AtPTR1, 2, 4, and 5) from Arabidopsis to a pair of fluorescent proteins with different spectral properties, enabled us to engineer the NiTracs (nitrate transporter activity tracking sensors) and the PepTracs (peptide transporter activity tracking sensors), ratiometric fluorescence activity sensors that monitor the activity of the plasma membrane nitrate transceptor or the peptide transporters in vivo (Ho et al., 2014). The NiTrac1 sensor responds specifically and reversibly to the addition of nitrate, while the PepTracs respond to addition of dipeptides, either by a reduction in donor and acceptor emission, while acceptor-excited emission remains unaltered, or by a change in ratio of the fluorophore emission. All sensors are suitable for ratiometric imaging. The similarity of the biphasic kinetics of the NiTrac1 sensor response [from µM to mM (Liu and Tsay, 2003)] and the nitrate transport kinetics of the native nitrate transceptor, intimates that NiTrac1 provides information on conformational rearrangements during the transport cycle, thereby reporting transporter activity over a wide range of external nitrate concentrations. Several variants of NiTrac have been engineered, which differ with respect to their affinity for nitrate (NiTrac1: CHL1; NiTracT101A: CHL1T101A). NiTrac also recognizes chlorate. Here we describe a simple method for the design, implementation, and detection of nitrate transceptor activity in yeast cells using a spectrofluorimeter.
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Cindy Ast, Jessica Foret, Luke M. Oltrogge, Roberto De Michele, Thomas J. Kleist, Cheng-Hsun Ho & Wolf B. Frommer(2017) Ratiometric Matryoshka biosensors from a nested cassette of green- and orange-emitting fluorescent proteins.Nature Communications(2017), doi:10.1038/s41467-017-00400-2
何承訓 Sensitivity, dynamic and detection range as well as exclusion of expression and instrumental artifacts are critical for the quantitation of data obtained with fluorescent protein (FP)-based biosensors in vivo. Current biosensors designs are, in general, unable to simultaneously meet all these criteria. Here, we describe a generalizable platform to create dual-FP biosensors with large dynamic ranges by employing a single FP-cassette, named GO-(Green-Orange) Matryoshka. The cassette nests a stable reference FP (large Stokes shift LSSmOrange) within a reporter FP (circularly permuted green FP). GO- Matryoshka yields green and orange fluorescence upon blue excitation. As proof of concept, we converted existing, single-emission biosensors into a series of ratiometric calcium sensors (MatryoshCaMP6s) and ammonium transport activity sensors (AmTryoshka1;3). We additionally identified the internal acid-base equilibrium as a key determinant of the GCaMP dynamic range. Matryoshka technology promises flexibility in the design of a wide spectrum of ratiometric biosensors and expanded in vivo applications.
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Ji-Rong Yang, Chieh-Yu Cheng, Chih-Yuan Chen, Chao-Hua Lin, Chuan-Yi Kuo, Hsiang-Yi Huang, Fu-Ting Wu, Yu-Chih Yang, Chia-Ying Wu, Ming-Tsan Liu*, and Pei-Wen Hsiao* (2017) A virus-like particle vaccination strategy expands its tolerance to H3N2 antigenic drift by enhancing neutralizing antibodies against hemagglutinin stalk. Antiviral Research, 2017, 140: 62-75
pwh Seasonal influenza viruses impact public health annually due to their continual evolution. However, the current inactivated seasonal vaccines provide poor protection against antigenically drifted viruses and require periodical reformulation through hit-and-miss predictions about which strains will circulate during the next season. To reduce the impact caused by vaccine mismatch, we investigated the drift-tolerance of virus-like particles (VLP) as an improved vaccine candidate. The cross-protective humoral immunity elicited by the H3N2-VLP vaccine constructed for the 2011-2012 season was examined against viruses isolated from 2010 to 2015 in Taiwan evolving chronologically through clades 1, 4, 5, 3B and 3C, as well as viruses that were circulating globally in 2005, 2007 and 2009. Mouse immunization results demonstrated that H3N2-VLP vaccine elicited superior immunological breadth in comparison with the cognate conventional whole-inactivated virus (WIV) vaccine. Titers of neutralizing antibodies against heterologous strains representing each epidemic period in the VLP group were significantly higher than in the WIV group, indicating the antibody repertoire induced by the H3N2-VLPs was insensitive to viral antigenic drift over a span of at least 10 years. Noticeably, H3N2-VLP elicited higher levels of anti-stalk antibodies than H3N2-WIV, which offset the ineffectiveness caused by antigenic drift. This advantageous effect was attributed to the uncleaved precursor of their HA proteins. These results suggest a mechanism through which VLP-induced humoral immunity may better tolerate the evolutionary dynamics of influenza viruses and point to the possible use of a VLP vaccine as a method by which the requirement for annual updates of seasonal influenza vaccines may be diminished.
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Yu-Yi Wu, Bo-Han Hou, Wen-Chi Lee, Shin-Hua Lu, Chen-Jui Yang, Hervé Vaucheret and Ho-Ming Chen (2017) DCL2- and RDR6-dependent transitive silencing of SMXL4 and SMXL5 in Arabidopsis dcl4 mutants causes defective phloem transport and carbohydrate over-accumulation. The Plant Journal, 2017, 90(6):1064-1078

homing Dicer-Like (DCL) enzymes are able to process double-stranded RNA into small RNAs. Arabidopsis DCL4 and DCL2 each allow the post-transcriptional gene silencing (PTGS) of viruses and transgenes, but DCL2 activity is mostly obscured by DCL4. This hierarchy likely prevents DCL2 having any detrimental effects on endogenous genes. Indeed, dcl4 mutants exhibit leaf pigmentation under regular growth conditions. Here we report that the purple phenotype of dcl4 leaves correlates with carbohydrate over-accumulation and defective phloem transport, and depends on the activity of DCL2 and two enzymes, Suppressor of Gene Silencing 3 (SGS3) and RNA-Dependent RNA Polymerase 6 (RDR6), involved in double-stranded RNA synthesis. Further, this phenotype correlates with the down-regulation of two genes expressed in the apex and the vasculature, SMAX1-Like 4 (SMXL4) and SMXL5, and the accumulation of DCL2- and RDR6-dependent small interfering RNAs derived from these two genes. Supporting a causal effect, smxl4 smxl5 double mutants exhibit leaf pigmentation, enhanced starch accumulation and defective phloem transport, similar to dcl4 plants. Overall, this study elucidates the detrimental action of DCL2 when DCL4 is absent, and indicates that DCL4 outcompeting DCL2 in wild-type plants is crucial to prevent the degradation of endogenous transcripts by DCL2- and RDR6-dependent transitive PTGS.
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Yang S-Y, Huang T-K, Kuo H-F, Chiou T-J (2017) Role of vacuoles in phosphorus storage and remobilization Journal of Experimental Botany: erw481
TJC Vacuoles play a fundamental role in storage and remobilization of various nutrients, including phosphorus (P), an essential element for cell growth and development. Cells acquire P primarily in the form of inorganic orthophosphate (Pi). However, the form of P stored in vacuoles varies by organism and tissue. Algae and yeast store polyphosphates (polyPs), whereas plants store Pi and inositol phosphates (InsPs) in vegetative tissues and seeds, respectively. In this review, we summarize how vacuolar P molecules are stored and reallocated and how these processes are regulated and co-ordinated. The roles of SYG1/PHO81/XPR1 (SPX)-domain-containing membrane proteins in allocating vacuolar P are outlined. We also highlight the importance of vacuolar P in buffering the cytoplasmic Pi concentration to maintain cellular homeostasis when the external P supply fluctuates, and present additional roles for vacuolar polyP and InsP besides being a P reserve. Furthermore, we discuss the possibility of alternative pathways to recycle Pi from other P metabolites in vacuoles. Finally, future perspectives for researching this topic and its potential application in agriculture are proposed.
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Yao-Pin Lin, Meng-Chen Wu, and Yee-yung Charng* (2016) Identification of Chlorophyll Dephytylase Involved in Chlorophyll Turnover.The Plant Cell, 2016, 28, 2974-2990
YYChanrng In photosynthesis, chlorophylls absorb light energy, which is transformed into chemical energy by the multi-protein-pigment complex called photosystem. The photosystem, composing of chlorophylls and proteins, tends to be damaged during the process of photosynthesis. The plant cells must repair the damaged photosystem to maintain the photosynthetic efficiency, causing the bound chlorophylls to turnover. Previous studies suggest that chlorophylls in damaged photosystem would be salvaged by two successive steps: 1. Dephytylation of chlorophylls; 2. Rephytylation of the dephytylated chlorophylls (or chlorophyllides). The latter is catalyzed by chlorophyll synthase, but the enzyme involved in the first reaction has been enigmatic. More than a century, chlorophyllase has been the only enzyme known to hydrolyze chlorophyll into chlorophyllide in vitro. However, the role of chlorophyllase in chlorophyll catabolism remains controversial. In an effort in cloning the mutant gene responsible for a heat sensitive phenotype in Arabidopsis, we identified a novel chloroplast protein capable of hydrolyzing chlorophylls and named it chlorophyll dephytylase1 (CLD1). The results from genetic and biochemical experiments suggested that CLD1 is involved in the first step of the chlorophyll salvage cycle. Plants lacking CLD1 significantly reduced the photosynthetic efficiency and viability under prolonged heat stress, underscoring the importance of the chlorophyll salvage cycle for plant thermotolerance. The discovery of CLD1 fills the gap in chlorophyll metabolism and facilitates further studies in the understanding of photosystem repair and its regulation.
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Choun-Sea Lin, Jeremy JW Chen, Chi-Chou Chiu, Han C.W. Hsiao, Chen-Jui Yang, Xiao-Hua Jin, James Leebens-Mack, Claude W. dePamphilis ,Yao-Ting Huang, Ling-Hung Yang, Wan-Jung Chang, Ling Kui, Gane Ka-Shu Wong, Jer-Ming Hu, Wen Wang, Ming-Che Shih (2017) Concomitant loss of NDH complex-related genes within chloroplast and nuclear genomes in some orchids. The Plant Journal. DOI: 10.1111/tpj.13525
cslin Chloroplast NAD(P)H dehydrogenase-like (NDH) complex consists of ~30 subunits from both the nuclear and chloroplast genomes and is ubiquitous across most land plants. In some orchids, such as Phalaenopsis equestris, Dendrobium officinale and D. catenatum, most of the 11 chloroplast genome encoded ndh genes (cp-ndh) have been lost. Here we investigated whether functional cp-ndh genes have been completely lost in these orchids or whether they have been transferred and retained in the nuclear genomes. Further, we assessed whether both cp-ndh genes and nucleus-encoded NDH-related genes can be lost resulting in the absence of the NDH complex. Comparative analyses of the genome of Apostasia odorata, an orchid species with a complete complement of cp-ndh genes which represents the sister lineage to all other orchids, and three published orchid genome sequences for Phalaenopsis equestris, D. officinale and D. catenatum which are all missing cp-ndh genes, indicated that copies of cp-ndh genes are not present in any of these four nuclear genomes. This observation suggests that the NDH complex is not necessary for some plants. Comparative genomic/transcriptomic analyses of currently available plastid genome sequences and nuclear transcriptome data showed that 47 out of 660 photoautotrophic plants and all the heterotrophic plants are missing plastid encoded cp-ndh genes and exhibit no evidence for maintenance of a functional NDH complex. Our data indicate that the NDH complex can be lost in photoautotrophic plant species. Further, the loss of the NDH complex may increase the probability of transition from a photoautotrophic to a heterotrophic life history.
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*2017/12/18 10:30 AM
Dr. Anudep Rungsipipat (Associate Professor, Companion Animal Cancer Research Unit, Department of Veterinary Pathology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand)
Chemopreventive Effects of Thai Herbs on Mice Induced Colorectal Carcinogenesis
Auditorium A134, Agricultural Technology Building, Agricultural Biotechnology Research Center

*2017/12/22 10:30 AM
Hen-Hong Chang (Dean, School of Chinese Medicine, Distinguished Professor, China Medical University, Taiwan)
Herb, food and constitution in Traditional Chinese Medicine
Auditorium A134, Agricultural Technology Building, Agricultural Biotechnology Research Center

*2017/12/25 10:30 AM
Dr. Tsong-Long Hwang (Dean/Distinguished Professor, College of Human Ecology, Chang Gung University of Science and Technology, Taiwan)
Research on traditional herbal medicines for neutrophilic inflammatory diseases
Auditorium A134, Agricultural Technology Building, Agricultural Biotechnology Research Center

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