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登革熱抑制劑快速篩選系統之建構
(2003)
楊進木
;
Jinn-Moon, Yang
;
國立交通大學生物科技研究所
登革病毒(Dengue virus)屬於黃質病毒科( Flaviviridae )中黃質病毒屬( Flavivirus)內的登革病毒亞屬，目前世界上尚無穩定、安全的疫苗可供防治登革熱，亦無有效的治療藥物。登革病毒基因體(genome)為單一正股RNA鏈(single-stranded RNA，+ strand )，約含10700個鹼基。其RNA經轉譯後，所得的單一多蛋白聚合鏈(single polyprotein chain)將被宿主細胞或病毒的酵素切割出10個蛋白質，包括3個結構性蛋白(structural protein)和7個非結構性蛋白(non-structural protein)。結構性蛋白主要功能是構成病毒的外殼，而非結構性蛋白則與病毒RNA分子的複製有關。 10種蛋白質中，已知其立體結構及功能的有二：套膜蛋白Ｅ(major envelope protein E，PDB code:1K4R)以及非結構性蛋白NS3 (PDB code:1BEF)。套膜蛋白E為構成病毒外殼的主要蛋白，是主要的抗原決定部位，宿主的免疫系統即針對此蛋白質產生抗體。目前研究顯示，virus-　antibody complex進入細胞的能力遠高於單獨存在的病毒，這亦是不同血清型登革熱交叉感染後會引發登革出血熱的可能機制之一。NS3為一蛋白質水解?(protease)，與胰蛋白?(trypsin)同屬絲胺酸催化蛋白?(serine protease)，負責切割RNA轉譯後所得的單一多蛋白鏈，以產生其他非結構性蛋白。此兩種蛋白質結構已知，且為登革病毒感染與成熟過程中不可缺少的重要環節，因此若能利用我們已發展完成的軟體並配合現有的藥物資料庫，針對此二蛋白質的結構，搜尋可與其嵌合的化學物質，即有可能從中揀選出具備藥物潛力的化合物分子。本計畫將提出一個能辨識藥物、預測藥物副作用以及毒性的雛形系統，暫稱為DockGEM，此系統可與傳統的藥物開發方式互補，組合成一個更完善的藥物開發體系，並極有可能大大壓縮臨床實驗所需的時間與經費。此系統包含三個主要元素: Docking知識庫、工具庫及發現藥物之系統步驟(drug discovery roadmap)。Docking知識庫包含藥物資料庫(drug database)、活性區域知識庫(binding-site information database)、蛋白質與其副作用及毒性的關聯資料庫；而工具庫則以演化式方法(evolutionary approaches)及類神經網路(neural networks)為基礎，可自動整合ligand-protein docking及ligand-protein inverse docking運算程式，並具備資料庫搜索(database search)功能，以自動化流程揀選出具有藥物潛力的小分子化學物質；發現藥物的系統步驟包含rapid ligand docking, flexible ligand docking與ligand optimization，並希望達到下列目標: 1. 建立能自動整合ligand-protein docking 及 ligand-protein inverse docking的系統，此系統能辨識潛在藥物，同時也可預測這些藥物的副作用以及毒性。 2. 開發登革熱已知蛋白質抑制劑之專屬快速篩選系統。 3. 建立藥物庫、活性區域知識庫、蛋白質與其副作用及毒性的整合性關聯資料庫。 4. 整合知識為基及物理為基的方法，建立更準確的scoring functions及更有效率的ligand-protein docking及ligand-protein inverse docking的程式，以提高系統準確度。過去幾年我們在整合演化式方法、結構生物、及protein docking上已獲得一些成果，我們認為以知識為基礎的演化式計算是以自然的演化方式解決生物資訊問題，我們希望此系統能應用於預防登革熱之相關藥物開發上。
Discrepancies between different response parameters in batch and continuous algal toxicity tests
(2001-03-30)
Chao, MR
;
Chen, CY
;
環境工程研究所
;
Institute of Environmental Engineering
The test sensitivities and reproducibilities based on different response endpoints (cell density and total cell volume) were compared using both bath and continuous algal toxicity tests. Parameters related to algal cell density are found to be more sensitive and reproducible than total cell volume which bears a direct correlation to algal biomass or dry weight. The magnitude of differences in the median effective concentration values could be upto six folds. The main cause for the above discrepancies is because the cell density and total cell volume are two response endpoints reflecting the degree of inhibition on the binary fission mechanism and overall photosynthesis, respectively. At low toxicant concentrations, the inhibitory effect is primarily on the cell division rather than on the cellular photosynthesis. Thus, more severe toxic effects are expected to be observed based on the cell density than the total cell volume. The results of this study clearly demonstrate that sensitivity and reproducibility can be significantly improved if response parameters are calculated based on the cell density. Traditionally, cell density data are often converted into biomass before assessing the effects of toxicants. This procedure may not be necessary and may reduce the test sensitivity. (C) 2001 Elsevier Science B.V. All rights reserved.
A novel algal toxicity testing technique for assessing the toxicity of both metallic and organic toxicants
(2005-05-01)
Lin, JH
;
Kao, WC
;
Tsai, KP
;
Chen, CY
;
環境工程研究所
This study presents a closed-system algal toxicity test technique that is capable of detecting the effects of both organic and metallic toxicants. Toxicity testing was conducted by transferring adequate amounts of algal suspension, dilution water (with culture growth medium), and toxicants into 300-mL BOD bottles. The BOD bottles were completely filled up with no head-space left. The initial cell density and the exposure time were 15,000 cells/mL and 48 h, respectively. The performance of the above test method was evaluated using three heavy metals and six organic toxicants based on three different test endpoints, i.e., dissolved oxygen production, algal growth rate, and cell density. The proposed test revealed excellent test sensitivity and reproducibility. Currently, none of the existing algal toxicity test protocols is adequate for assessing the toxicity of organic chemicals. The closed-system algal toxicity tests developed by previous researchers also may not be ideal because the enlarged headspace and/or enriched bicarbonate buffer may result in either underestimations of the exposure concentrations or insensitive responses to both heavy metals and organic toxicants. Compared to the aforementioned algal toxicity test methods, the proposed technique in the present study has a more general applicability under conditions such as effluent samples containing both metals and organic toxicants or samples with unknown compositions. (c) 2005 Elsevier Ltd. All rights reserved.
Toxicity assessment of pesticides to Pseudokirchneriella subcapitata under air-tight test environment
(2006-04-17)
Yeh, HJ
;
Chen, CY
;
環境工程研究所
;
Institute of Environmental Engineering
This paper presents the toxicity data of seven pesticides including atrazine, parathion, dichlorvos, malathion, fenthion, 2-methyl-4-chiorophenoxyacetic acid, and pentachlorophenol on Pseudokirchneriella subcapitata based on a new algal toxicity testing technique conducted under air-tight environment. The dissolved oxygen production and the cell density were adopted as the response endpoints. Median effective concentrations (EC50) range from 0.0035 to 3.40 mg/L (DO production) and from 0.0067 to 3.12 mg/L (cell density). No-observed-effect concentration (NOEC) was determined using the Dunnett's test. NOEC values are with in the range of 0.001-1.20 mg/L. In general, the two test endpoints revealed similar sensitivities. From comparisons of literature data also based on Pseudokirchneriella subcapitata, it is clear that conventional batch tests tend to underestimate the toxicity of pesticides due to their open test environment. Closed-system tests, i.e., microplate test, respirometer test, and our BOD-bottle test, generally provide better assessment to the effects of pesticides. Data based on our test method reveals much higher toxicity (3-100 times) than that from the conventional batch tests. Furthermore, for organophosphorus insecticides, results from the present study show that Pseudokirchneriella subcapitata is less sensitive than Daphnia magna and rainbow trout, but is more susceptible than fathead minnow. The closed-system test applied in this study provides more adequate assessment for the toxicity of pesticides than the conventional batch tests. (c) 2005 Elsevier B.V. All rights reserved.
The combined toxic effects of nonpolar narcotic chemicals to Pseudokirchneriella subcapitata
(2006-06-01)
Hsieh, SH
;
Tsai, KP
;
Chen, CY
;
環境工程研究所
;
Institute of Environmental Engineering
This paper presents the toxicity data of 10 nonpolar narcotic chemicals on Pseudokirchneriella subcapitata (green algae) assessed by a new algal toxicity testing technique conducted under air-tight environment. Based on DO production, median effective concentration (EC50) varies from 1.73mg/L (1-octanol) to8040 mg/L (2-propanol). The endpoint of algal growth rate reveals similar sensitivity as that from DO production. Compared to literature data, Pseudokirchneriella subcapitata and Nitrosomonas are apparently more sensitive to nonpolar narcotics than other organisms such as minnow, daphnia, and Tetrahymena pyriformis. Furthermore, good correlations between toxic effects observed from Pseudokirchneriella subcapitata and other aquatic organisms were found. Hence, algal toxicity test can be considered as a surrogate test for estimating the toxicity of nonpolar chemicals to fathead minnow, Microtox, activated sludge, Daphina magna, and Tetrohymena pyriformis. The combined effects of 13 binary mixtures of nonpolar chemicals were investigated using both additive-index method and isobologram analysis. overall speaking, the joint actions between these chemicals are strictly additive. Model analyses indicate that these compounds act on identical reaction sites or receptors, which verify that these chemicals are of the same toxicity mechanism (narcosis). (c) 2006 Elsevier Ltd. All rights reserved.
Metal toxicity to Chlorella pyrenoidosa assessed by a short-term continuous test
(2007-04-02)
Lin, Kuo-Ching
;
Lee, Yu-Long
;
Chen, Chung-Yuan
;
環境工程研究所
;
Institute of Environmental Engineering
This study presents the metal toxicity as revealed by Chlorella pyrenoidosa using a short-term continuous test and the conventional batch test. Toxicity tests were conducted in a chemostat with a test duration of I day. Toxicity data of five different metals (Cd, Ph, Co, Ni, and Zn) derived from the continuous test were compared against results from the conventional batch tests. The batch test is characterized by its saturated nutrient status for algal growth and, on the other hand, the continuous test is conducted at a nutrient-limiting condition simulating more closely to the aquatic field environment. The continuous test consistently yielded smaller EC50 values, which indicated that alga in the chemostat is approximately four to six times more sensitive than those from the batch culture. Similar phenomena between the two types of tests were observed based on the NOEC values. Compared to literature data (US EPA ECOTOX Database) from the same species of alga, differences in test sensitivity between the batch tests and chemostat technique varied from 9.25 to 160 times. Such distinct differences indicate that current toxicity database may not adequately reflect the impact of various metal toxicants on C. pyrenoidosa. The continuous test method presented herein is a sensitive and rapid assessment technique and, therefore, has a potential for more general applications such as routine checkup for regulatory purposes. (c) 2006 Published by Elsevier B.V.
Toxicity of substituted anilines to Pseudokirchneriella subcapitata and quantitative structure-activity relationship analysis for polar narcotics
(2007-06-01)
Chen, Chung-Yuan
;
Ko, Chia-Wen
;
Lee, Po-I
;
環境工程研究所
;
Institute of Environmental Engineering
This study evaluated the toxic effects of substituted anilines on Pseudokirchneriella subcapitata with the use of a closed algal toxicity testing technique with no headspace. Two response endpoints (i.e., dissolved oxygen production [DO] and algal growth rate) were used to evaluate the toxicity of anilines. Both DO and growth rate endpoints revealed similar sensitivity to the effects of anilines. However, trichloroanilines showed stronger inhibitory effects on microalgal photosynthetic reactions than that on algal growth. For various aquatic organisms, the relative sensitivity relationship for anilines is Daphnia magna > luminescent bacteria (Microtox) >= Pocelia reticulata >= PseudDkirchneriella subcapitata >= fathead minnow > Tetrahymena pyriformis. The susceptibility of P. subcapitata to anilines is similar to fish, but P. subcapitata is apparently less sensitive than the water flea. The lack of correlation between the toxicity revealed by different aquatic organisms (microalgae, D. magna, luminescent bacteria, and P. reticulata) suggests that anilines might have different metabolic routes in these organisms. Both hydrogen bonding donor capacity (the lowest unoccupied molecular orbital energy, E-lumo) and hydrophobicity (1-octanol:water partition coefficient, K-OW) were found to provide satisfactory descriptions for the toxicity of polar narcotics (substituted anilines and chlorophenols). Quantitative structure-activity relationships (QSARs) based on E-lumo, log K-OW, or both values were established with r(2) values varying from 0.75 to 0.92. The predictive power for the QSAR models were found to be satisfactory through leave-one-out cross-validation. Such relationships could provide useful information for the estimation of toxicity for other polar narcotic compounds.
Toxicity and quantitative structure-activity relationships of nitriles based on Pseudokirchneriella subcapitata
(2007-07-01)
Huang, Chun-Pin
;
Wang, Yun-Ju
;
Chen, Chung-Yuan
;
環境工程研究所
;
Institute of Environmental Engineering
This study presents the toxicity data of various nitriles to Pseudokirchneriella subcapitata using a closed algal toxicity testing technique with no headspace. Two different response endpoints, i.e., dissolved oxygen (DO) production and algal growth rate, were used to evaluate the toxicity of nitriles. In general, the DO endpoint revealed higher inhibitory effects than that from algal growth rate. Furthermore, halo.-en-substituted nitriles were found to be extremely toxic to P. subcapitata. With increasing numbers of the halogen atoms, stronger toxicity was observed. The bromine substitutent also seems to be more toxic than chlorine substitutent. Quantitative structure-activity relationships (QSARs) were established based on the chemicals' Elumo values and hydrophobicity (log K-ow). Such relationships may thus be useful in predicting the toxicity of other compounds of the same mode of toxic action. Furthermore, for various aquatic organisms, the relative sensitivity relationship is: Pimephales promelas >= P. subcapitata > Tetrahymena Pyriformis > Daphnia magna > luminescent bacteria (Microtox). The alga, P. subcapitata, was found to be quite sensitive to nitrites compared to other organisms. (C) 2006 Elsevier Inc. All rights reserved.
An algal toxicity database of organic toxicants derived by a closed-system technique
(2007-09-01)
Tsai, Kuo-Pet
;
Chen, Chung-Yuan
;
環境工程研究所
;
Institute of Environmental Engineering
The current study presents the toxicity data of 90 organic compounds with various modes of actions to Pserldokirch-neriella subcapitata. The assessment was conducted using a closed-system technique, and a biomass-type end point based on the cell density was employed. The above toxicity data were compared with test results from ciliate (Tetrahymena pyriformis), water flea (Daphnia magna). fish (Pintephales promelas), and luminescent bacteria (Photobacterium phosphoreum). Satisfactory correlation relationships between toxicity data from algae and other aquatic organisms were found (r(2) = 0.66-0.82). Pseudokirchneriella subcapitata revealed considerably higher sensitivity to organic toxicants compared with other organisms. Benzenes, aldehydes, and alkanes also were highly selective to the test alga. In addition, the results show that conventional alga] batch tests tend to underestimate the toxicity of organic compounds, except in the case of 4-chlorophenol. Toxicity observed from the closed-system test is approximately 2- to 380-fold higher than that estimated by conventional batch tests. Such a phenomenon can be found in nearly all organic compounds. regardless of the chemical's Henry's law constant. In the risk assessment of chemicals, following the European Union's practice. approximately 30% (7 of 23) of the cases may result in a more strict classification when the batch test is replaced by the closed-system test. More effort therefore is needed to revise the algal toxicity database using the closed-system test method.

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