Publications by authors named "Li-Yun Chang"

29 Publications

  • Page 1 of 1

Serotonin Signals Modulate Mushroom Body Output Neurons for Sustaining Water-Reward Long-Term Memory in .

Front Cell Dev Biol 2021 11;9:755574. Epub 2021 Nov 11.

Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.

Memory consolidation is a time-dependent process through which an unstable learned experience is transformed into a stable long-term memory; however, the circuit and molecular mechanisms underlying this process are poorly understood. The mushroom body (MB) is a huge brain neuropil that plays a crucial role in olfactory memory. The MB neurons can be generally classified into three subsets: γ, αβ, and α'β'. Here, we report that water-reward long-term memory (wLTM) consolidation requires activity from α'β'-related mushroom body output neurons (MBONs) in a specific time window. wLTM consolidation requires neurotransmission in MBON-γ3β'1 during the 0-2 h period after training, and neurotransmission in MBON-α'2 is required during the 2-4 h period after training. Moreover, neurotransmission in MBON-α'1α'3 is required during the 0-4 h period after training. Intriguingly, blocking neurotransmission during consolidation or inhibiting serotonin biosynthesis in serotoninergic dorsal paired medial (DPM) neurons also disrupted the wLTM, suggesting that wLTM consolidation requires serotonin signals from DPM neurons. The GFP Reconstitution Across Synaptic Partners (GRASP) data showed the connectivity between DPM neurons and MBON-γ3β'1, MBON-α'2, and MBON-α'1α'3, and RNAi-mediated silencing of serotonin receptors in MBON-γ3β'1, MBON-α'2, or MBON-α'1α'3 disrupted wLTM. Taken together, our results suggest that serotonin released from DPM neurons modulates neuronal activity in MBON-γ3β'1, MBON-α'2, and MBON-α'1α'3 at specific time windows, which is critical for the consolidation of wLTM in .
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http://dx.doi.org/10.3389/fcell.2021.755574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8631865PMC
November 2021

Effect of natural garlic essential oil on chickens with artificially infected Eimeria tenella.

Vet Parasitol 2021 Dec 3;300:109614. Epub 2021 Nov 3.

College of Animal Science and Technology, Hebei Agricultural University, Baoding, Hebei 071001, China. Electronic address:

Chicken coccidiosis is a kind of parasitic protozoosis caused by Eimeria parasitizing in the chicken intestinal epithelial cells. Eimeria tenella is considered as a significantly virulent and harmful parasite. At present, drug resistance remains a major problem and a large number of drug residues have been found to be produced in the treatment of the disease. Hence, novel strategies are needed to avoid the harmful effects caused by the generation of various chemical drug residues to the human body and also reduce the economic loss caused by coccidiosis to the chicken industry. In this study, natural garlic essential oil was used to control Eimeria tenella infection. The anticoccidial index (ACI) was calculated according to the clinical symptoms, body weight gain, oocyst excretion and cecal lesions. The immune organ index and serum biochemical indexes were measured to verify the possible anticoccidial effects. The results showed that: compared with the infected group, continuous feeding of different doses of natural garlic essential oil could significantly reduce the clinical symptoms, cecal lesions, the number of oocysts, but increase the weight of sick chickens, and effectively improve the intestinal functions. Moreover, compared with diclazuril control group, 0.06 mL/L garlic essential oil exhibited similar anticoccidial index. The content of immune organ index, serum biochemical index IgM, IgG and IgA in 0.06 mL/L garlic essential oil group was the highest, which indicated that garlic essential oil had a significant tendency to improve the immune function of the chickens. This study also showed that the natural garlic essential oil exhibited the same beneficial effects as that of diclazuril on chicken coccidiosis, and the anti-coccidiosis index of 0.06 mL/L garlic essential oil was favorable. Thus based on the above evidences and its relatively low cost, garlic essential oil can be potentially be used as an efficient anti parasitic drug.
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http://dx.doi.org/10.1016/j.vetpar.2021.109614DOI Listing
December 2021

Development and validation of a Chinese pseudo-character/non-character producing system.

Behav Res Methods 2021 Aug 2. Epub 2021 Aug 2.

Department of Educational Psychology and Counseling, National Taiwan Normal University, Taipei, Taiwan.

This study developed and validated a Chinese pseudo-character/non-character producing system (CPN system) that can assist researchers in creating experimental materials using Chinese characters. Based on a large-scale dataset of 6097 characters, the CPN system provides researchers with precise Chinese orthographic information (structures and positions, radical frequency, number of strokes, number of radical-sharing neighbors, and position-based regularity) to create three types of experimental stimuli: pseudo-characters, semi non-characters, and whole non-characters. Featuring the position-based regularity of 446 radicals, the CPN system helps researchers to manipulate, or to control for, orthographic characteristics of radicals to study Chinese lexical processing. In two empirical validations for stimuli created by the system, Chinese-as-second-language learners (n = 79) and first-language users (n = 41), respectively, participated in a Chinese orthographic choice task in which participants compared two artificial characters and chose the one that more closely resembled a real Chinese character. Both validations demonstrate that highly proficient Chinese readers are better able to identify pseudo-characters, suggesting that the radical's position-based information impacts Chinese character identification to different extents. With the empirical support for the created stimuli, the system further affords researchers auto-generated outcomes with downloadable images and Excel sheets for creating customized stimuli, making material selection easy, efficient, and effective. This CPN system is the first large-scale, data-driven tool free for researchers who are interested in studies of written Chinese. CPN should benefit the field of Chinese orthographic processing, Chinese instruction, and cross-linguistic comparisons, providing a useful tool for studying Chinese lexical processing.
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http://dx.doi.org/10.3758/s13428-021-01611-8DOI Listing
August 2021

Melatonin regulates chicken granulosa cell proliferation and apoptosis by activating the mTOR signaling pathway via its receptors.

Poult Sci 2020 Nov 26;99(11):6147-6162. Epub 2020 Aug 26.

College of Animal Science and Technology, Hebei Agricultural University, Baoding Hebei 071001, China.

Melatonin is a key regulator of follicle granular cell maturation and ovulation. The mammalian target of rapamycin (mTOR) pathway plays an important role in cell growth regulation. Therefore, our aim was to investigate whether the mTOR signaling pathway is involved in the regulation of melatonin-mediated proliferation and apoptotic mechanisms in granulosa cells. Chicken follicle granular cells were cultured with melatonin (0, 2, 20, or 200 μmol/L) for 48 h. The results showed that melatonin treatment enhanced proliferation and suppressed apoptosis in granular cells at 20 μmol/L and 200 μmol/L (P < 0.05) by upregulation of cyclin D1 (P < 0.01) and Bcl-2 (P < 0.01) and downregulation of P21, caspase-3, Beclin1, and LC3-II (P < 0.01). The effects resulted in the activation of the mTOR signaling pathway by increasing the expression of avTOR, PKC, 4E-BP1, S6K (P < 0.05), p-mTOR, and p-S6K. We added an mTOR activator and inhibitor to the cells and identified the optimal dose (10 μmol/L MHY1485 and 100 nmol/L rapamycin) for subsequent experiments. The combination of 20 μmol/L melatonin and 10 μmol/L MHY1485 significantly enhanced granulosa cell proliferation (P < 0.05), while 100 nmol/L rapamycin significantly inhibited proliferation and enhanced apoptosis (P < 0.05), but this action was reversed in the 20-μmol/L melatonin and 100-nmol/L rapamycin cotreatment groups (P < 0.05). This was confirmed by mRNA and protein expression that was associated with proliferation, apoptosis, and autophagy (P < 0.05). The combination of 20 μmol/L melatonin and 10 μmol/L MHY1485 also activated the mTOR pathway upstream genes PI3K, AKT1, and AKT2 and downstream genes PKC, 4E-BP1, and S6K (P < 0.05), as well as protein expression of p-mTOR and p-S6K. Rapamycin significantly inhibited the mTOR pathway-related genes mRNA levels (P < 0.05). In addition, activation of the mTOR pathway increased melatonin receptor mRNA levels (P < 0.05). In conclusion, these findings demonstrate that melatonin regulates chicken granulosa cell proliferation and apoptosis by activating the mTOR signaling pathway via its receptor.
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http://dx.doi.org/10.1016/j.psj.2020.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647829PMC
November 2020

Mushroom body subsets encode CREB2-dependent water-reward long-term memory in Drosophila.

PLoS Genet 2020 08 11;16(8):e1008963. Epub 2020 Aug 11.

Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taiwan.

Long-term memory (LTM) formation depends on the conversed cAMP response element-binding protein (CREB)-dependent gene transcription followed by de novo protein synthesis. Thirsty fruit flies can be trained to associate an odor with water reward to form water-reward LTM (wLTM), which can last for over 24 hours without a significant decline. The role of de novo protein synthesis and CREB-regulated gene expression changes in neural circuits that contribute to wLTM remains unclear. Here, we show that acute inhibition of protein synthesis in the mushroom body (MB) αβ or γ neurons during memory formation using a cold-sensitive ribosome-inactivating toxin disrupts wLTM. Furthermore, adult stage-specific expression of dCREB2b in αβ or γ neurons also disrupts wLTM. The MB αβ and γ neurons can be further classified into five different neuronal subsets including αβ core, αβ surface, αβ posterior, γ main, and γ dorsal. We observed that the neurotransmission from αβ surface and γ dorsal neuron subsets is required for wLTM retrieval, whereas the αβ core, αβ posterior, and γ main are dispensable. Adult stage-specific expression of dCREB2b in αβ surface and γ dorsal neurons inhibits wLTM formation. In vivo calcium imaging revealed that αβ surface and γ dorsal neurons form wLTM traces with different dynamic properties, and these memory traces are abolished by dCREB2b expression. Our results suggest that a small population of neurons within the MB circuits support long-term storage of water-reward memory in Drosophila.
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http://dx.doi.org/10.1371/journal.pgen.1008963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418956PMC
August 2020

ARC 118925XX stimulates cation influx in bEND.3 endothelial cells.

Fundam Clin Pharmacol 2019 Dec 4;33(6):604-611. Epub 2019 Jul 4.

Graduate Institute of Biomedical Sciences, China Medical University, 91 Hsuehshi Road, Taichung, 40402, Taiwan.

In a previous publication when we studied the purinergic receptor with which ATP interacted in mouse brain bEND.3 endothelial cells, we observed addition of 3 μm ARC 118925XX (ARC; selective P2Y antagonist) strongly suppressed ATP-triggered Ca release, suggesting the response was mediated via P2Y receptors. We here report ARC unexpectedly promoted substantial Ca influx even when ATP-triggered Ca release was largely inhibited. Since this large Ca influx may have important pharmacological significance, we proceeded to investigate its mechanism. ARC did not trigger intracellular Ca release thus suggesting Ca influx triggered by ARC was not store-operated. ARC-triggered Ca influx could be blocked by 1 mm Ni , a general Ca channel blocker, but not by SK&F 96365, a nonselective TRP channel blocker. Unexpectedly, ARC promoted influx of Na and La , but not Mn . This is a surprising finding, since Mn is conventionally used as a Ca surrogate ion (as it permeates Ca channel), and La is classically used as a potent Ca channel antagonist. Electrophysiological examination showed ARC did not stimulate any cation currents. Therefore, ARC opened, rather than a cation channel pore, an unidentified Ca influx pathway which was Na - and La -permeable but Mn -impermeable.
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http://dx.doi.org/10.1111/fcp.12491DOI Listing
December 2019

Reading Pinyin activates sublexcial character orthography for skilled Chinese readers.

Lang Cogn Neurosci 2019 12;34(6):736-746. Epub 2019 Feb 12.

Learning Research and Development Center, University of Pittsburgh, 3939 O'Hara Street, Pittsburgh, PA 15260, USA.

How do skilled Chinese readers, accustomed to characters, process Pinyin, a phonemic transcription of Chinese? Does the orthography of Chinese characters become activated? In four experiments, native speakers first made a meaning judgment on a two-syllable word written in Pinyin. Immediately following, they responded to a character whose orthography sometimes was related to the character corresponding to the Pinyin. In Experiments 1 and 3, participant named the color of the presented characters; there was an interference effect when the presented characters included phonetic radicals that were part of the character corresponding to the Pinyin. In Experiments 2 and 4, participants named the character; naming times were affected if either the semantic or phonetic radical was shared with the character corresponding to the Pinyin. The results indicate that access to lexical representations in Chinese is centered on the orthographic character, even when the input is Pinyin.
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http://dx.doi.org/10.1080/23273798.2019.1578891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531182PMC
February 2019

GraphCom: A multidimensional measure of graphic complexity applied to 131 written languages.

Behav Res Methods 2018 02;50(1):427-449

Learning Research and Development Center, University of Pittsburgh, 3939 O'Hara Street, Room 833, Pittsburgh, Pennsylvania, 15260, USA.

We report a new multidimensional measure of visual complexity (GraphCom) that captures variability in the complexity of graphs within and across writing systems. We applied the measure to 131 written languages, allowing comparisons of complexity and providing a basis for empirical testing of GraphCom. The measure includes four dimensions whose value in capturing the different visual properties of graphs had been demonstrated in prior reading research-(1) perimetric complexity, sensitive to the ratio of a written form to its surrounding white space (Pelli, Burns, Farell, & Moore-Page, 2006); (2) number of disconnected components, sensitive to discontinuity (Gibson, 1969); (3) number of connected points, sensitive to continuity (Lanthier, Risko, Stolz, & Besner, 2009); and (4) number of simple features, sensitive to the strokes that compose graphs (Wu, Zhou, & Shu, 1999). In our analysis of the complexity of 21,550 graphs, we (a) determined the complexity variation across writing systems along each dimension, (b) examined the relationships among complexity patterns within and across writing systems, and (c) compared the dimensions in their abilities to differentiate the graphs from different writing systems, in order to predict human perceptual judgments (n = 180) of graphs with varying complexity. The results from the computational and experimental comparisons showed that GraphCom provides a measure of graphic complexity that exceeds previous measures in its empirical validation. The measure can be universally applied across writing systems, providing a research tool for studies of reading and writing.
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http://dx.doi.org/10.3758/s13428-017-0881-yDOI Listing
February 2018

Carbon Nanodots with Sub-Nanosecond Spontaneous Emission Lifetime.

Chemphyschem 2017 Jan 16;18(1):42-46. Epub 2016 Nov 16.

Department of Physics, Chung Yuan Christian University, Taoyuan, Taiwan.

Compared with most mature cadmium-containing quantum dots (QDs), carbon nanodots (CNDs) are a new class of colloidal nanomaterials that exhibit unique photoluminescence (PL) properties while being nontoxic and easily manufactured using low-cost precursor materials. However, solid-state CNDs exhibit poor PL quantum yields (PL-QYs) and inefficient radiative transition, which significantly hinders their practical use in optoelectronic devices. To address this issue, plasmonic nanoantennas consisting of Au nanorods (Au-NRs) deposited on a flat Au film with inserted dielectric layers were used to enhance the spontaneous emission of solid-state CNDs with broad spectral linewidth. Using steady-state, time-resolved, and spatial-resolved PL measurements, we found that after coupling to plasmonic nanogaps (PNGs), the PL emission was significantly enhanced, accompanied by a PL lifetime shortening to the sub-nanosecond range (≈140 ps). According to the experimental data, the radiative transition is strongly accelerated and can thus overcome the metal loss, leading to a large PL enhancement. Our demonstration can pave the way to the design of eco-friendly nanoemitters with sub-nanosecond PL lifetime for promising applications in light-emitting devices.
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http://dx.doi.org/10.1002/cphc.201600858DOI Listing
January 2017

Synthesis of vibroarthrographic signals in knee osteoarthritis diagnosis training.

BMC Res Notes 2016 Jul 19;9:352. Epub 2016 Jul 19.

Medical Physics and Informatics Laboratory of Electronics Engineering, National Kaohsiung University of Applied Sciences, 415, Chien Kung Road, San-Min District, Kaohsiung, 807, Taiwan, ROC.

Background: Vibroarthrographic (VAG) signals are used as useful indicators of knee osteoarthritis (OA) status. The objective was to build a template database of knee crepitus sounds. Internships can practice in the template database to shorten the time of training for diagnosis of OA.

Methods: A knee sound signal was obtained using an innovative stethoscope device with a goniometer. Each knee sound signal was recorded with a Kellgren-Lawrence (KL) grade. The sound signal was segmented according to the goniometer data. The signal was Fourier transformed on the correlated frequency segment. An inverse Fourier transform was performed to obtain the time-domain signal. Haar wavelet transform was then done. The median and mean of the wavelet coefficients were chosen to inverse transform the synthesized signal in each KL category. The quality of the synthesized signal was assessed by a clinician.

Results: The sample signals were evaluated using different algorithms (median and mean). The accuracy rate of the median coefficient algorithm (93 %) was better than the mean coefficient algorithm (88 %) for cross-validation by a clinician using synthesis of VAG.

Conclusions: The artificial signal we synthesized has the potential to build a learning system for medical students, internships and para-medical personnel for the diagnosis of OA. Therefore, our method provides a feasible way to evaluate crepitus sounds that may assist in the diagnosis of knee OA.
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http://dx.doi.org/10.1186/s13104-016-2156-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4950531PMC
July 2016

The Major Prognostic Features of Nuclear Receptor NR5A2 in Infiltrating Ductal Breast Carcinomas.

Int J Genomics 2015 23;2015:403576. Epub 2015 Aug 23.

Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei 100, Taiwan ; Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei 100, Taiwan.

Background. Gene expression profiles of 181 breast cancer samples were analyzed to identify prognostic features of nuclear receptors NR5A1 and NR5A2 based upon their associated transcriptional networks. Methods. A supervised network analysis approach was used to build the NR5A-mediated transcriptional regulatory network. Other bioinformatic tools and statistical methods were utilized to confirm and extend results from the network analysis methodology. Results. NR5A2 expression is a negative factor in breast cancer prognosis in both ER(-) and ER(-)/ER(+) mixed cohorts. The clinical and cohort significance of NR5A2-mediated transcriptional activities indicates that it may have a significant role in attenuating grade development and cancer related signal transduction pathways. NR5A2 signature that conditions poor prognosis was identified based upon results from 15 distinct probes. Alternatively, the expression of NR5A1 predicts favorable prognosis when concurrent NR5A2 expression is low. A favorable signature of eight transcription factors mediated by NR5A1 was also identified. Conclusions. Correlation of poor prognosis and NR5A2 activity is identified by NR5A2-mediated 15-gene signature. NR5A2 may be a potential drug target for treating a subset of breast cancer tumors across breast cancer subtypes, especially ER(-) breast tumors. The favorable prognostic feature of NR5A1 is predicted by NR5A1-mediated 8-gene signature.
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http://dx.doi.org/10.1155/2015/403576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4561099PMC
September 2015

Pregnancy-associated breast cancer in Taiwanese women: potential treatment delay and impact on survival.

PLoS One 2014 21;9(11):e111934. Epub 2014 Nov 21.

Department of Surgery, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 10051, Taiwan.

This study investigated the clinicopathologic characteristics and survival of women diagnosed with pregnancy-associated breast cancer (PABC) in Taiwan. PABC is defined as breast cancer diagnosed during pregnancy or within 1 year after obstetric delivery. Our sample of PABC patients (N = 26) included all patients diagnosed at a major medical center in northern Taiwan from 1984 through 2009. Among these patients, 15 were diagnosed during pregnancy and 11 were diagnosed within 1 year after delivery. The comparison group included 104 patients within the same age range as the PABC patients and diagnosed with breast cancer not associated with pregnancy from 2004 through 2009 at the same hospital. Patients' initiating treatment delayed, 5-year and 10-year overall survival were delineated by stratified Kaplan-Meier estimates. Patients' characteristics were associated with initiating treatment delayed was evaluated with multivariate proportional hazards modeling. Antepartum PABC patients were younger and had longer time between diagnosis and treatment initiation than postpartum PABC patients. The predictor of treatment delayed was including birth parity, cancer stage, and pregnancy. The PABC group had larger tumors, more advanced cancer stage, and tumors with less progesterone receptor than the comparison group. The antepartum PABC patients had higher mortality than postpartum PABC and comparison groups within 5 years after diagnosis. Based on these results, we confirmed that pregnant women with breast cancer were more likely to delay treatment. Therefore, we recommend that breast cancer screening should be integrated into the prenatal and postnatal routine visits for early detection of the women's breast problems.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0111934PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240543PMC
July 2015

Correction to: Prognostic Features of Signal Transducer and Activator of Transcription 3 in an ER(+) Breast Cancer Model System.

Cancer Inform 2014 2;13:125-9. Epub 2014 Nov 2.

Department of Obstetrics and Gynecology, National Taiwan University, Taipei, Taiwan. ; Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan.

[This corrects the article on p. 21 in vol. 13, PMID: 24526833.].
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http://dx.doi.org/10.4137/CIN.S20237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4218890PMC
March 2015

A supervised network analysis on gene expression profiles of breast tumors predicts a 41-gene prognostic signature of the transcription factor MYB across molecular subtypes.

Comput Math Methods Med 2014 3;2014:813067. Epub 2014 Feb 3.

Department of Obstetrics and Gynecology, College of Medicine, National Taiwan University, Taipei 100, Taiwan ; Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei 100, Taiwan.

Background: MYB is predicted to be a favorable prognostic predictor in a breast cancer population. We proposed to find the inferred mechanism(s) relevant to the prognostic features of MYB via a supervised network analysis.

Methods: Both coefficient of intrinsic dependence (CID) and Galton Pierson's correlation coefficient (GPCC) were combined and designated as CIDUGPCC. It is for the univariate network analysis. Multivariate CID is for the multivariate network analysis. Other analyses using bioinformatic tools and statistical methods are included.

Results: ARNT2 is predicted to be the essential gene partner of MYB. We classified four prognostic relevant gene subpools in three breast cancer cohorts as feature types I-IV. Only the probes in feature type II are the potential prognostic feature of MYB. Moreover, we further validated 41 prognosis relevant probes to be the favorable prognostic signature. Surprisingly, two additional family members of MYB are elevated to promote poor prognosis when both levels of MYB and ARNT2 decline. Both MYBL1 and MYBL2 may partially decrease the tumor suppressive activities that are predicted to be up-regulated by MYB and ARNT2.

Conclusions: The major prognostic feature of MYB is predicted to be determined by the MYB subnetwork (41 probes) that is relevant across subtypes.
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http://dx.doi.org/10.1155/2014/813067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930188PMC
January 2015

Prognostic features of signal transducer and activator of transcription 3 in an ER(+) breast cancer model system.

Cancer Inform 2014 21;13:21-45. Epub 2014 Jan 21.

Department of Obstetrics and Gynecology, National Taiwan University, Taipei, Taiwan. ; Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan.

The aberrantly expressed signal transducer and activator of transcription 3 (STAT3) predicts poor prognosis, primarily in estrogen receptor positive (ER(+)) breast cancers. Activated STAT3 is overexpressed in luminal A subtype cells. The mechanisms contributing to the prognosis and/or subtype relevant features of STAT3 in ER(+) breast cancers are through multiple interacting regulatory pathways, including STAT3-MYC, STAT3-ERα, and STAT3-MYC-ERα interactions, as well as the direct action of activated STAT3. These data predict malignant events, treatment responses and a novel enhancer of tamoxifen resistance. The inferred crosstalk between ERα and STAT3 in regulating their shared target gene-METAP2 is partially validated in the luminal B breast cancer cell line-MCF7. Taken together, we identify a poor prognosis relevant gene set within the STAT3 network and a robust one in a subset of patients. VEGFA, ABL1, LYN, IGF2R and STAT3 are suggested therapeutic targets for further study based upon the degree of differential expression in our model.
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http://dx.doi.org/10.4137/CIN.S12493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3921136PMC
February 2014

In Silico Prediction for Regulation of Transcription Factors onTheir Shared Target Genes Indicates Relevant Clinical Implications in a Breast Cancer Population.

Cancer Inform 2012 19;11:113-37. Epub 2012 Apr 19.

Department of Agronomy, Biometry Division, National Taiwan University, Taipei, Taiwan.

Aberrant transcriptional activities have been documented in breast cancers. Studies often find some transcription factors to be inappropriately regulated and enriched in certain pathological states. The promoter regions of most target genes have binding sites for their transcription factors. An ample of evidence supports their combinatorial effect on their shared target gene expressions. Here, we used a new statistic method, bivariate CID, to predict combinatorial interaction activity between ERα and a transcription factor (E2F1or GATA3 or ERRα) in regulating target gene expression via four regulatory mechanisms. We identified gene sets in three signal transduction pathways perturbed in breast tumors: cell cycle, VEGF, and PDGFRB. Bivariate network analysis revealed several target genes previously implicated in tumor angiogenesis are among the predicted shared targets, including VEGFA, PDGFRB. In summary, our analysis suggests the importance for the multivariate space of an inferred ERα transcriptional regulatory network in breast cancer diagnostic and therapeutic development.
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http://dx.doi.org/10.4137/CIN.S8470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3337786PMC
August 2012

Major Functional Transcriptome of an Inferred Center Regulator of an ER(-) Breast Cancer Model System.

Cancer Inform 2012 19;11:87-111. Epub 2012 Apr 19.

Department of Agronomy, Biometry Division, National Taiwan University, Taipei, Taiwan.

We aimed to find clinically relevant gene activities ruled by the signal transducer and activator of transcription 3 (STAT3) proteins in an ER(-) breast cancer population via network approach. STAT3 is negatively associated with both lymph nodal category and stage. MYC is a component of STAT3 network. MYC and STAT3 may co-regulate gene expressions for Warburg effect, stem cell like phenotype, cell proliferation and angiogenesis. We identified a STAT3 network in silico showing its ability in predicting its target gene expressions primarily for specific tumor subtype, tumor progression, treatment options and prognostic features. The aberrant expressions of MYC and STAT3 are enriched in triple negatives (TN). They promote histological grade, vascularity, metastasis and tumor anti-apoptotic activities. VEGFA, STAT3, FOXM1 and METAP2 are druggable targets. High levels of METAP2, MMP7, IGF2 and IGF2R are unfavorable prognostic factors. STAT3 is an inferred center regulator at early cancer development predominantly in TN.
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http://dx.doi.org/10.4137/CIN.S8633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3337785PMC
August 2012

Identification of prognostic genes for recurrent risk prediction in triple negative breast cancer patients in Taiwan.

PLoS One 2011 29;6(11):e28222. Epub 2011 Nov 29.

Bioinformatics and Biostatistics Core, Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan.

Discrepancies in the prognosis of triple negative breast cancer exist between Caucasian and Asian populations. Yet, the gene signature of triple negative breast cancer specifically for Asians has not become available. Therefore, the purpose of this study is to construct a prediction model for recurrence of triple negative breast cancer in Taiwanese patients. Whole genome expression profiling of breast cancers from 185 patients in Taiwan from 1995 to 2008 was performed, and the results were compared to the previously published literature to detect differences between Asian and Western patients. Pathway analysis and Cox proportional hazard models were applied to construct a prediction model for the recurrence of triple negative breast cancer. Hierarchical cluster analysis showed that triple negative breast cancers from different races were in separate sub-clusters but grouped in a bigger cluster. Two pathways, cAMP-mediated signaling and ephrin receptor signaling, were significantly associated with the recurrence of triple negative breast cancer. After using stepwise model selection from the combination of the initial filtered genes, we developed a prediction model based on the genes SLC22A23, PRKAG3, DPEP3, MORC2, GRB7, and FAM43A. The model had 91.7% accuracy, 81.8% sensitivity, and 94.6% specificity under leave-one-out support vector regression. In this study, we identified pathways related to triple negative breast cancer and developed a model to predict its recurrence. These results could be used for assisting with clinical prognosis and warrant further investigation into the possibility of targeted therapy of triple negative breast cancer in Taiwanese patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0028222PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3226667PMC
April 2012

Voltage-gated K+ channels play a role in cAMP-stimulated neuritogenesis in mouse neuroblastoma N2A cells.

J Cell Physiol 2011 Apr;226(4):1090-8

Graduate Institute of Neural and Cognitive Sciences, China Medical University, Taichung, Taiwan.

Neuritogenesis is essential in establishing the neuronal circuitry. An important intracellular signal causing neuritogenesis is cAMP. In this report, we showed that an increase in intracellular cAMP stimulated neuritogenesis in neuroblastoma N2A cells via a PKA-dependent pathway. Two voltage-gated K(+) (Kv) channel blockers, 4-aminopyridine (4-AP) and tetraethylammonium (TEA), inhibited cAMP-stimulated neuritogenesis in N2A cells in a concentration-dependent manner that remarkably matched their ability to inhibit Kv currents in these cells. Consistently, siRNA knock down of Kv1.1, Kv1.4, and Kv2.1 expression reduced Kv currents and inhibited cAMP-stimulated neuritogenesis. Kv1.1, Kv1.4, and Kv2.1 channels were expressed in the cell bodies and neurites as shown by immunohistochemistry. Microfluorimetric imaging of intracellular [K(+)] demonstrated that [K(+)] in neurites was lower than that in the cell body. We also showed that cAMP-stimulated neuritogenesis may not involve voltage-gated Ca(2+) or Na(+) channels. Taken together, the results suggest a role of Kv channels and enhanced K(+) efflux in cAMP/PKA-stimulated neuritogenesis in N2A cells.
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http://dx.doi.org/10.1002/jcp.22430DOI Listing
April 2011

EGCG protects against oxidized LDL-induced endothelial dysfunction by inhibiting LOX-1-mediated signaling.

J Appl Physiol (1985) 2010 Jun 4;108(6):1745-56. Epub 2010 Mar 4.

Department of Physical Therapy, Graduate Institute of Rehabilitation Science, China Medical University, and Department of Obstetrics and Gynecology, China Medical University Hospital, 91 Hsueh-Shih Road, Taichung 40202, Taiwan.

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), originally identified as the major receptor for oxidized low-density lipoprotein (oxLDL) in endothelial cells, plays a major role in the pathology of vascular diseases. Green tea consumption is associated with reduced cardiovascular mortality in some epidemiological studies. In the present study, we hypothesized that the most abundant polyphenolic compound in tea, epigallocatechin-3-gallate (EGCG), can downregulate parameters of endothelial dysfunction by modulating LOX-1-regulated cell signaling. In cultured human umbilical vein endothelial cells (HUVECs), exposure to oxLDL (130 microg/ml), which led to an increase in LOX-1 expression at the RNA and protein levels, was abrogated by addition of EGCG or DPI, a well-known inhibitor of flavoproteins, suggesting the involvement of NADPH oxidase. Furthermore, oxLDL rapidly activated the membrane translocation of Rac-1 and p47phox and the subsequent induction of ROS generation, which was suppressed markedly by pretreatment with EGCG or anti-LOX-1 monoclonal antibody. OxLDL also increased p38 MAPK phosphorylation and decreased phosphorylation of the amino-terminal region of Akt, with maximal induction at about 30 min, and NF-kappaB phosphorylation within 1 h, resulting in redox-sensitive signaling. In addition, oxLDL diminished the expression of endothelial nitric oxide synthase (eNOS), enhanced the expression of endothelin-1 and adhesion molecules (ICAM, E-selectin, and monocyte chemoattractant protein-1), and increased the adherence of monocytic THP-1 cells to HUVECs. Pretreatment with EGCG, however, exerted significant cytoprotective effects in all events. These data suggest that EGCG inhibits the oxLDL-induced LOX-1-mediated signaling pathway, at least in part, by inhibiting NADPH oxidase and consequent ROS-enhanced LOX-1 expression, which contributes to further ROS generation and the subsequent activation of NF-kappaB via the p38 MAPK pathway. Results from this study may provide insight into a possible molecular mechanism by which EGCG suppresses oxLDL-mediated vascular endothelial dysfunction.
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http://dx.doi.org/10.1152/japplphysiol.00879.2009DOI Listing
June 2010

Dependence of 6beta-acetoxy-7alpha-hydroxyroyleanone block of Kv1.2 channels on C-type inactivation.

Cell Mol Life Sci 2010 Jan 29;67(1):147-56. Epub 2009 Oct 29.

Graduate Institute of Neural and Cognitive Sciences, China Medical University, Taichung, 40402, Taiwan.

Voltage-gated K(+) (Kv) channels exhibit slow or C-type inactivation during continuous depolarization. A selective pharmacological agent targeting C-type inactivation is hitherto lacking. Here, we report that 6beta-acetoxy-7alpha-hydroxyroyleanone (AHR), a diterpenoid compound isolated from Taiwania cryptomerioides, can selectively modify C-type inactivation of Kv1.2 channels. Extracellular, but not intracellular, AHR (50 muM) dramatically accelerated the slow decay of Kv currents and left-shifted the steady-state inactivation curve. AHR blocked Kv currents with an IC(50) of 17.7 muM. AHR did not affect the kinetics and voltage-dependence of Kv1.2 channel activation. Channel block by AHR was independent of intracellular K(+) concentration. In addition, effect of AHR was much attenuated in a Kv1.2 V370G mutant defective in C-type inactivation. Therefore, block of Kv1.2 channels by AHR did not appear to involve direct occlusion of the outer pore but depended on C-type inactivation. AHR could thus be a probe targeting Kv channel C-type inactivation gate.
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http://dx.doi.org/10.1007/s00018-009-0178-0DOI Listing
January 2010

Statistical identification of gene association by CID in application of constructing ER regulatory network.

BMC Bioinformatics 2009 Mar 17;10:85. Epub 2009 Mar 17.

Department of Agronomy, Biometry Division, National Taiwan University, Taipei, Taiwan.

Background: A variety of high-throughput techniques are now available for constructing comprehensive gene regulatory networks in systems biology. In this study, we report a new statistical approach for facilitating in silico inference of regulatory network structure. The new measure of association, coefficient of intrinsic dependence (CID), is model-free and can be applied to both continuous and categorical distributions. When given two variables X and Y, CID answers whether Y is dependent on X by examining the conditional distribution of Y given X. In this paper, we apply CID to analyze the regulatory relationships between transcription factors (TFs) (X) and their downstream genes (Y) based on clinical data. More specifically, we use estrogen receptor alpha (ERalpha) as the variable X, and the analyses are based on 48 clinical breast cancer gene expression arrays (48A).

Results: The analytical utility of CID was evaluated in comparison with four commonly used statistical methods, Galton-Pearson's correlation coefficient (GPCC), Student's t-test (STT), coefficient of determination (CoD), and mutual information (MI). When being compared to GPCC, CoD, and MI, CID reveals its preferential ability to discover the regulatory association where distribution of the mRNA expression levels on X and Y does not fit linear models. On the other hand, when CID is used to measure the association of a continuous variable (Y) against a discrete variable (X), it shows similar performance as compared to STT, and appears to outperform CoD and MI. In addition, this study established a two-layer transcriptional regulatory network to exemplify the usage of CID, in combination with GPCC, in deciphering gene networks based on gene expression profiles from patient arrays.

Conclusion: CID is shown to provide useful information for identifying associations between genes and transcription factors of interest in patient arrays. When coupled with the relationships detected by GPCC, the association predicted by CID are applicable to the construction of transcriptional regulatory networks. This study shows how information from different data sources and learning algorithms can be integrated to investigate whether relevant regulatory mechanisms identified in cell models can also be partially re-identified in clinical samples of breast cancers.

Availability: the implementation of CID in R codes can be freely downloaded from (http://homepage.ntu.edu.tw/~lyliu/BC/).
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http://dx.doi.org/10.1186/1471-2105-10-85DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2679734PMC
March 2009

Gene expression variation increase in trisomy 21 tissues.

Mamm Genome 2008 Jun 2;19(6):398-405. Epub 2008 Jul 2.

Department of Obstetrics and Gynecology, Cathay General Hospital, Taipei, Taiwan.

Congenital development disorders with variable severity occur in trisomy 21. However, how these phenotypic abnormalities develop with variations remains elusive. We hypothesize that the differences in euploid gene expression variation among trisomy 21 tissues are caused by the presence of an extra copy of chromosome 21 and may contribute to the phenotypic variations in Down syndrome. We used DNA microarray to measure the differences in gene expression variance between four human trisomy 21 and six euploid amniocytes. The three publicly available data sets of fetal brains, adult brains, and fetal hearts were also analyzed. The numbers of euploid genes with greater variance were significantly higher in all four kinds of trisomy 21 tissues (p<0.01) than in the corresponding euploid tissues. Seventeen euploid genes with significantly different variance between trisomy 21 and euploid amniocytes were found using the F test. In summary, there is a set of euploid genes that shows greater variance of expression in human trisomy 21 tissues than in euploid tissues. This change may contribute to producing the variable phenotypic abnormalities observed in Down syndrome.
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http://dx.doi.org/10.1007/s00335-008-9121-1DOI Listing
June 2008

Vascularity change and tumor response to neoadjuvant chemotherapy for advanced breast cancer.

Ultrasound Med Biol 2008 Jun 28;34(6):857-66. Epub 2008 Mar 28.

Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.

For advanced breast cancer with severe local disease (ABC) (stage III/IV), neoadjuvant chemotherapy improves local control and surgical outcome. However, about approximately 20 to 30% of advanced cancers show either no or poor response to chemotherapy. To prevent unnecessary treatment, a capability of predicting clinical response to neoadjuvant chemotherapy of ABC is highly desirable. Vascularity index (VI) of breast cancers was derived from the quantification results in 30 ABC patients by using power Doppler sonography. Power Doppler sonography evaluation was performed every one to two weeks during chemotherapy. The overall response rate for 30 advanced patients tested was 70%, when 50% or more reduction in tumor size was the objective clinical response. Chemotherapy response was unrelated to the original tumor size (p = 0.563) or chemotherapy agents used (p = 0.657). The median VI for all 30 patients was 4.99%. The response rates for hypervascular tumors vs. hypovascular tumors, based on initial median value, were 86.7% and 53.3%, respectively (p = 0.109). The average VIs in responders and nonresponders were 7.67 +/- 4.77% and 4.01 +/- 3.82% (p = 0.052). There was a tendency for responders who have a relatively high initial vascularity. The VI change in responder group shows a pattern of initial increasing in vascularity followed by decreasing in vascularity. All patients (17/17) with a VI increment of >5% during chemotherapy had good chemotherapy response, whereas in patients with a VI increment of <5%, the response rate was 30.8% (4/13) (p < 0.001). For patients with a peak VI of >10% during chemotherapy, the response rate was 94.1% (16/17). However, in patients with a peak VI of <10%, the response rate was 38.5% (5/13) (p = 0.001). This prediction was made mostly within one month (25.47 +/- 12.96 d for VI increments >5% and 25.44 +/- 12.41 d for VI increased to >10%). In the meantime, the differences in size reduction shown in B-mode sonography were insignificant between responders and nonresponders (patient group with VI increment >5%, p = 0.308; patient group with peak VI >10%, p = 0.396). In conclusion, we propose that VI as determined by using power Doppler sonography is a good and inexpensive clinical tool for monitoring vascularity changes during neoadjuvant chemotherapy in ABC patients. Two parameters--VI increment >5% and peak VI >10%--are potential early predictors for good responses to neoadjuvant chemotherapy within one month in patients with ABC.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2007.11.011DOI Listing
June 2008

Prediction of breast cancer and lymph node metastatic status with tumour markers using logistic regression models.

J Eval Clin Pract 2008 Apr 18;14(2):275-80. Epub 2008 Feb 18.

Department of Obstetrics and Gynecology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.

Aims: Early detection of breast cancer can improve disease mortality. The aim of this study was to evaluate the effectiveness of serum biomarkers in the detection of primary breast cancer and lymph node metastatic status.

Methods: Serum samples were obtained from 55 female patients with breast cancer and 39 women without breast cancer. For these subjects, clinicopathological data were collected and serum levels of carcinoembryonic antigen, breast cancer-specific cancer antigen 15.3 (CA15-3), tissue polypeptide-specific antigen (TPS), soluble interleukin-2 receptor (sIL-2R) and insulin-like growth factor binding protein-3 (IGFBP-3) were assayed. Univariate and multivariate logistic regression were performed to evaluate the association between biomarkers and breast cancer, as well as lymph node metastatic status.

Results: For breast cancer prediction, the serum level of TPS had the best predictive value, with a sensitivity of 80% at an optimal cut-off value of 69.1 U L(-1). The combination of TPS, CA15-3 and IGFBP-3 with logistic regression model increased the sensitivity to 85%. For lymph node metastasis prediction, the serum level of sIL-2R had the best predictive value, with a sensitivity of 66% at an optimal cut-off value of 286 U mL(-1). The combination of sIL-2R and TPS with logistic regression model increased the sensitivity to 69%.

Conclusion: TPS may be useful in the detection of primary breast cancer, while sIL-2R may be useful in lymph node metastasis prediction. The combination of more than one biomarker with logistic regression model can improve the predictive sensitivity.
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http://dx.doi.org/10.1111/j.1365-2753.2007.00849.xDOI Listing
April 2008

The interactions between GPR30 and the major biomarkers in infiltrating ductal carcinoma of the breast in an Asian population.

Taiwan J Obstet Gynecol 2007 Jun;46(2):135-45

Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.

Objective: G-protein-coupled receptor 30 (GPR30) has been reported to be a novel estrogen receptor alpha (ERalpha) in vitro. Therefore, the interactions among GPR30, ERalpha, progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2/neu), and their prognostic utilities in the infiltrating ductal carcinoma (IDC) of the breast were evaluated.

Materials And Methods: Messenger RNA (mRNA) levels of GPR30, ERalpha, PR and HER-2/neu in the tumor samples of 118 Taiwanese IDC patients and 27 non-tumor mammary tissues were measured via quantitative polymerase chain reaction analyses. The correlations of GPR30 mRNA levels with clinical parameters, i.e. tumor/non-tumor, ERalpha, PR, HER-2/neu, age, lymph node metastasis, lymph-vascular invasion, grade, stage and patient survival, were assessed by using appropriate statistical analyses.

Results: GPR30 expression was observed to be lower in IDC (p < 0.001) than in non-tumor mammary tissues. Importantly, GPR30 mRNA level was positively correlated with that of ERalpha (p = 0.001) and PR (p = 0.001) but not correlated with that of HER-2/neu when they were analyzed as continuous variables. However, lower GPR30 was noticed in tumors with HER-2/neu protein overexpression. GPR30 expression was not correlated with age, lymph node metastasis, lymph-vascular invasion, grade and stage in IDC. GPR30 expression was not an independent prognostic factor for patient survival.

Conclusion: GPR30 expression is downregulated in IDC. GPR30 is preferentially co-expressed with ER and/or PR but is lowly expressed in HER-2/neu(+) tumors. The correlation of GPR30 expression with clinical parameters, including patient survival, was not evident in this cohort.
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http://dx.doi.org/10.1016/S1028-4559(07)60007-2DOI Listing
June 2007

Gonococcal lipooligosaccharide suppresses HIV infection in human primary macrophages through induction of innate immunity.

J Infect Dis 2006 Sep 8;194(6):751-9. Epub 2006 Aug 8.

Division of Infectious Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.

Gonorrhea often occurs as a coinfection with human immunodeficiency virus (HIV). Lipooligosaccharide (LOS) is a component of the gonococcal outer membrane that induces innate immunity through engagement of Toll-like receptor 4 (TLR4). We investigated the effects that LOS from 5 different strains of Neisseria gonorrhoeae have on HIV infection and on HIV provirus in primary human macrophages. LOS-treated human primary macrophages developed resistance to new HIV infection as well as to HIV provirus. Gonococcal LOS from the 5 strains and lipopolysaccharide (LPS) from Escherichia coli showed no significant difference in their anti-HIV activities. Suppression of HIV provirus resulted from the induction of interferon (IFN)-beta and subsequent activation of signal transducer and activator of transcription 1. Neutralization of IFN-beta , but not IFN-alpha , via antibody significantly reduced the anti-HIV activity induced by LOS and LPS. We conclude that LOS expressed by various strains of N. gonorrhoeae induce specific innate immune responses through TLR4 signaling, resulting in anti-HIV activity in human primary macrophages in vitro.
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http://dx.doi.org/10.1086/506360DOI Listing
September 2006

[The discovery and genetic analysis of dwarf mutation 99CDAM in Brassica napus L].

Yi Chuan 2006 Jul;28(7):851-7

Oil Crops Research Institute of CAAS, National Center for Oil Crops Improvement, Wuhan 430062, China.

The plant height of rapeseed varieties has increased more than 20 cm due to wide application of heterosis, which leads to high risk of lodging at late stages of rapeseed development. Using dwarf genes to decrease plant height is an effective approach to resolve the lodging problem. A dwarf mutation 99CDAM with plant height of about 85 cm was discovered from a Brassica napus line which had selfed for many years. The mutation 99CDAM has good characters of early flowering and rich branches, as well as better yield and quality traits, which can be stably inherited, so 99CDAM has important value in Brassica napus breeding. Genetic analysis on reciprocal crosses between 99CDAM with high-stalk lines 2091, 7045 and 7350, and the F2BC1 and F2:3 populations derived from the cross between 2091 with 99CDAM indicated that the genetic model of dwarf genes in 99CDAM was obviously different from what had been reported before. The mutation 99CDAM was controlled by three pairs of recessive dwarf genes and showed a maternal effect..
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July 2006

Determination of matrine and oxymatrine in Sophora subprostata by CE.

J Pharm Biomed Anal 2002 Jun;28(5):1005-10

Department of Health, National Laboratories of Foods and Drugs, Executive Yuan 161-2, Kuen-Yang Street, Nankang, Taipei, Taiwan, ROC.

Shan-dou-gen is the dried roots of Sophora subprostata (Leguminosae) and a commonly used Chinese herbal drug in Taiwan. It possesses antipyretic, anti-inflammatory, analgesic effects and is used to treat sore throat and acute pharyngolaryngeal infections. To evaluate the quality of S. subprostata, a simple, rapid and accurate high-performance capillary electrophoresis (HPCE) method was developed for the assay of two alkaloids: matrine and oxymatrine. The electrolyte was a buffer solution containing 75% 130 mM phosphate buffer (NaH2PO4/H3PO4, pH 3.5) and 25% acetonitrile. Applied voltage was 10 kV and temperature was 30 degrees C. 2-(4-Hydroxyphenyl)ethylammonium chloride was used as an internal standard and detector set at 200 nm. The contents of matrine and oxymatrine of S. subprostata in several different samples of crude drugs and commercial concentrated preparation have also been determined.
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http://dx.doi.org/10.1016/s0731-7085(02)00050-xDOI Listing
June 2002
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