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The Covalent Binding of Genistein to the Non-prosthetic-heme-moiety of Bovine Lactoperoxidase Leads to Enzymatic Inactivation

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Biomedical and Environmental Sciences 2011年第3期24卷 284-290页

作者： Hebron C. CHANG Daniel R. DOERGE ChengHong HSIEH LIN YingJu FuuJen TSAI Department of Biotechnology Asia University Taichung 41354 Taiwan China Division of Biochemical Toxieology national center for toxicological research FDA Jeffkrson AR 72079 USA Department of Health and Nutritional Biotechnology Asia University Taichung 41354 Taiwan China Genetic center China Medical University Taichung 40402 Taiwan China

Objective Genistein, a major soy isoflavone metabolite （SIF）, inactivates oxidation activity of bovine lactoperoxidase （LPO）. Modification of the heme moiety of LPO by nitrogen-containing compounds has been shown to inactivate LPO. In contrast, SIF mediated inactivation of LPO does not involve a heme modification and the mechanism of SIF inhibition is poorly understood. Methods After inactivation of LPO by genistein in the presence of H202, trypsin-digested LPO peptide fragments were collected and analyzed by MALDI-TOF-MS to characterize the chemical binding of genistein（s） to LPO. Results The heme moiety of LPO was not modified by genistein. A covalent binding study showed that 3H-genistein bound to LPO with a ratio of ~12 to 1. After HPLC analysis and peak collection, trypsin-digested peptide fragments were analyzed by MALDI-TOF-MS. The 3H-genistein co-eluted peptide fragments （RT=24 min） were putatively identified as 1991VGYLDEEGVLDQNR214 with two bound genistein molecules or a genistein dimer （2 259 Da）, 486TPDNIDIWlGGNAEPMVER504 with two bound genistein molecules or a genistein dimer （2 663 Da）, and 161ARWLPAEYEDGLALPFGWTQR182 with three bound genistein molecules or a genistein trimer （3 060 Da）. The fragment with a mass of 2 792 Da （RT=36 min） was identified as 132CDENSPYR139 with three genistein molecules or a genistein trimer. Conclusions The results suggest that LPO was inactivated by irreversible covalent binding of genistein or genistein polymers to particular peptide fragments constituting regions of the outward domain. No genistein interaction with the prosthetic heme moiety of LPO was observed.

关键词： Lactoperoxidase Genistein Modification of heme Covalent binding Peptide fragments

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Pitfall of genome-wide association studies: Sources of inconsistency in genotypes and their effects

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Journal of Biomedical Science and Engineering 2012年第10期5卷 557-573页

作者： Huixiao Hong Lei Xu Zhenqiang Su Jie Liu Weigong Ge Jie Shen Hong Fang Roger Perkins Leming Shi Weida Tong Bioinformatics Graduate Program University of Arkansas at Little Rock/University of Arkansas for Medical Sciences Little Rock AR 72079 USA Division of Bioinformatics and Biostatistics National Center for Toxicological Research US Food and Drug Administration Jefferson AR 72079 USA icf international at national center for toxicological research US Food and Drug Administration Jefferson AR 72079 USA School of Materials Science and Engineering Chang’an University Xi’an China

Personalized medicine will improve heath outcomes and patient satisfaction. However, implementing personalized medicine based on individuals’ biological information is far from simple, requiring genetic biomarkers that are mainly developed and used by the pharmaceutical companies for selecting those patients who benefit more, or have less risk of adverse drug reactions, from a particular drug. Genome-wide Association Studies (GWAS) aim to identify genetic variants across the human genome that might be utilized as genetic biomarkers for diagnosis and prognosis. During the last several years, high-density genotyping SNP arrays have facilitated GWAS that successfully identified common genetic variants associated with a variety of phenotypes. However, each of the identified genetic variants only explains a very small fraction of the underlying genetic contribution to the studied phenotypic trait. The replication studies demonstrated that only a small portion of associated loci in the initial GWAS can be replicated, even within the same populations. Given the complexity of GWAS, multiple sources of Type I (false positive) and Type II (false negative) errors exist. The inconsistency in genotypes that caused either by the genotypeing experiment or by genotype calling process is a major source of the false GWAS findings. Accurate and reproducible genotypes are paramount as inconsistency in genotypes can lead to an inflation of false associations. This article will review the sources of inconsistency in genotypes and discuss its effect in GWAS findings.

关键词： Genotype Association Reproducibility Inconsistency Batch Effect Genotyping Platform

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Genotoxic and tumorigenic pyrrolizidine alkaloids in Chinese herbal plants

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Journal of Nanjing Medical University 2005年第1期19卷 1-9页

作者： P.P. Fu Q. Xia M.W. Chou G. Lin national center for toxicological research Jefferson AR 72079 USA.National Center for Toxicological Research Jefferson AR 72079 USA. National Center for Toxicological Research Jefferson AR 72079 USA.Department of Pharmacology the Chinese University of Hong Kong Shatin Hong Kong Special Administrative Region.

Pyrrolizidine alkaloids are a class of hepatotoxic and tumorigenic compounds detected in Chinese herbal plants, contaminated foods, and dietary supplements. In this review, the sources, toxicity, genotoxicity, tumorigenicity, and the metabolic pathways, particular the activation pathways leading to hepatotoxicity and tumorigenicity, of pyrrolizidine alkaloids are briefly discussed, with a focus on the most recent important findings concerning the genotoxic mechanism by which riddelliine liver tumors. This mechanism involves the formation of 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts and may be general to most carcinogenic pyrrolizidine alkaloids.

关键词： hepatotoxicity tumorigenicity pyrrolizidine alkaloids Chinese herbal

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Biogenic Amines as Biomarkers for Neurotoxicity

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Biomedical and Environmental Sciences 1991年第1期4卷 207-216页

作者： SYED F.ALI LOUIS W.CHANG WILLIAM SLIKKER JR Division of Reproductive and Developmental Toxicology National Center for Toxicological Research JeffersonDepartment of Pharmacology and Toxicology Department of Biochemistry and Molecular BiologyDivision of Reproductive and Developmental Toxicology National Center for Toxicological Research JeffersonDivision of Reproductive and Developmental Toxicology National Center for Toxicological Research Jefferson Arkansas 72079-9502 Department of Pharmacology and Toxicology Department of Biochemistry and Molecular BiologyDepartment of Pharmacology University of Arkansas for Medical Sciences Little Rock Arkansas 72205Arkansas 72079-9502 Department of Pharmacology and Toxicology Department of Pediatrics Universtiy of Arkansas for Medical Sciences and Arkansas Children's Hospital Little Rock Arkansas 72205 Arkansas 72079-9502 Department of Pharmacology and Toxicology Department of Pediatrics Universtiy of Arkansas for Medical Sciences and Arkansas Children's Hospital Little Rock Arkansas 72205

There has been a surge of interest over the past several years in the use of neurochemical endpoints to contribute to our understanding of the mechanism of action of neurotoxicants. In our present presentation, two biogenic amine systems were selected as examples of biomarkers for neurotoxicity. To investigate these neurochemical endpoints, two prototype neurotoxicants were evaluated in experimental animals. One agent, reserpine, was used to assess developmental neurotoxicity and administered prenatally, while the other, MDMA, was used in the adult animal. The neurochemical biomarkers measured were dopamine, serotonin, and their metabolite (DOPAC and 5-HIAA) concentrations by HPLC/EC and dopamine receptor binding by radioligand receptor techniques. A review of the background, experimental design, and results are presented in this article. Our findings indicate that components of the biogenic amine systems can be used as sensitive neurochemical biomarkers of neurotoxicity. These neurochemical biomarkers can be correlated with neuropathological and behavioral biomarkers to aid in the understanding of mechanisms of neurotoxicity.

关键词： MDMA Biogenic Amines as Biomarkers for Neurotoxicity oral DOPAC

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Thiolated arsenicals in arsenic metabolism: Occurrence,formation, and biological implications

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Journal of Environmental Sciences 2016年第11期28卷 59-73页

作者： Yuzhen Sun Guangliang Liu Yong Cai Institute of Environment and Health Jianghan University Department of Chemistry and Biochemistry&Southeast Environmental research center Florida International University

Arsenic（As） is a notoriously toxic pollutant of health concern worldwide with potential risk of cancer induction, but meanwhile it is used as medicines for the treatment of different conditions including hematological cancers. Arsenic can undergo extensive metabolism in biological systems, and both toxicological and therapeutic effects of arsenic compounds are closely related to their metabolism. Recent studies have identified methylated thioarsenicals as a new class of arsenic metabolites in biological systems after exposure of inorganic and organic arsenicals, including arsenite, dimethylarsinic acid（DMAV）, dimethylarsinous glutathione（DMAIIIGS）, and arsenosugars. The increasing detection of thiolated arsenicals,including monomethylmonothioarsonic acid（MMMTAV）, dimethylmonothioarsinic acid（DMMTAV） and its glutathione conjugate（DMMTAVGS）, and dimethyldithioarsinic acid（DMDTAV） suggests that thioarsenicals may be important metabolites and play important roles in arsenic toxicity and therapeutic effects. Here we summarized the reported occurrence of thioarsenicals in biological systems, the possible formation pathways of thioarsenicals, and their toxicity, and discussed the biological implications of thioarsenicals on arsenic metabolism, toxicity, and therapeutic effects.

关键词： Arsenic Thioarsenicals Occurrence Formation pathways Toxicity

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S Phase Cell Percentage Normalized BrdU Incorporation Rate, a New Parameter for Determining S Arrest

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Biomedical and Environmental Sciences 2014年第3期27卷 215-219页

作者： ZHAO Peng FU Juan Ling YAO Bi Yun JIA Yong Rui ZHOU Zong Can Department of Toxicology Peking University Health Science Center Beijing Key Laboratory of toxicological research and Risk Assessment for Food Safety Peking University Health Science Center Medical and Healthy Analytical center Peking University Health Science Center

In this study, a new parameter, S phase cell percentage （S fraction） normalized BrdU （SFN-BrdU） incorporation rate, was introduced to detect $ arrest. The results showed a positive linear correlation between the BrdU incorporation rate and the S fraction in unperturbed 16HBE cells. Theoretical analysis indicated that only S arrest could result in a decrease in the SFN-BrdU incorporation rate. Additionally, the decrease in SFN-BrdU incorporation rate and the activation of DNA damage checkpoints further demonstrated that S arrest was induced by diethyl sulfate treatment of 16HBE cells. In conclusion, $FN-BrdU incorporation rate can be used to detecting S arrest.

关键词： BrdU rate S Phase Cell Percentage Normalized BrdU Incorporation Rate a New Parameter for Determining S Arrest

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不相交主成分分析(PCA)和遗传算法(GA)用于差异表达基因的识别

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高等学校化学学报 2007年第9期28卷 1640-1644页

作者：苏振强 HONG Hui—Xiao TONG Wei-Da PERKINS Roger 邵学广蔡文生中国科学技术大学化学系合肥230026 Division of Bioinformatics Z-Tech at FDA＇s National Center for Toxicological Research Jefferson AR 72079 USA center for Toxicoinformatics National Center for Toxicological Research（NCTR） US Food and Drug Administration（FDA） Jefferson AR 72079 USA 南开大学化学系天津300071

建立了一种基于不相交主成分分析(Disjoint PCA)和遗传算法(GA)的特征变量选择方法,并用于从基因表达谱(Gene expression profiles)数据中识别差异表达的基因.在该方法中,用不相交主成分分析评估基因组在区分两类不同样品时的区分能力;... 详细信息

建立了一种基于不相交主成分分析(Disjoint PCA)和遗传算法(GA)的特征变量选择方法,并用于从基因表达谱(Gene expression profiles)数据中识别差异表达的基因.在该方法中,用不相交主成分分析评估基因组在区分两类不同样品时的区分能力;用GA寻找区分能力最强的基因组;所识别基因的偶然相关性用统计方法评估.由于该方法考虑了基因间的协同作用更接近于基因的生物过程,从而使所识别的基因具有更好的差异表达能力.将该方法应用于肝细胞癌(HCC)样品的基因芯片数据分析,结果表明,所识别的基因具有较强的区分能力,优于常用的基因芯片显著性分析(Significance analysis of microarrays,SAM)方法.

关键词：基因芯片主成分分析(PCA) 遗传算法(GA) 基因芯片显著性分析(SAM) 偶然相关

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Retrieval and Amplification of DNA from Unstained Histopathological Sections

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Biomedical and Environmental Sciences 1993年第3期6卷 211-216页

作者： DONNAC.MONTAGUE BEVERLYD.LYN-COOK PARIMALCHOWDHURY LOUISW.CHANG University NationalUniversityUniversity of Arkansas for Medical SciencesDeparments of Pharmacology/ToxicologyCenter for Toxicological ResearchJeffersonAR72079USAof Arkansas for Medical SciencesDepartments of Pharmacology/ToxicologyPhysiologyof Arkansas for Medical SciencesDepartments of Pharmacology/ToxicologyNational Center for ToxicologicalResearchJeffersonAR 72079USA

Testing of compounds for carcinogenic potential in vivo involves various experimental designs. A few of these techniques are directed to demonstrate the genotoxicity and mutagenicity of the compound by histopathology. These changes shown by histochemical means include monoclonal antibody directed cellular markers. Development of the polymerase chain reaction technique (PCR) for amplification of DNA has facilitated the investigation of molecular events related to the formation of malignant neoplasms. We describe here a method for screening tissues for mutations of the H-ras gene using monoclonal antibodies directed toward normal and mutant p21 proteins. Formalin-fixed, paraffin-embedded tissue sections are used to subsequently confirm the gene mutation by PCR amplification of the H-ras gene. The results indicated a successful application of this technique to demonstrate the presence of p21 oncoprotein in the tissues tested.

关键词： Retrieval and Amplification of DNA from Unstained Histopathological Sections DNA

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A reduction scheme of PAPR in CO-OFDM system using time-delay neural networks

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Optoelectronics Letters 2025年

作者： TONG Zhengrong LIU Zhihong WANG Hao ZHANG Weihua ZHANG Tianhao JIA Qiqi Tianjin Key Laboratory of Thin Film Electronics and Communication Devices， Engineering research center for Optoelectronic Devices and Communication Technology of the Ministry of Education， School of Integrated Circuit Science and Engineering， Tianjin University of Technology

An iterative partial transmission sequence （IPTS） cascading time-delay neural network （TDNN） scheme is proposed to reduce peak-to-average power ratio （PAPR） in the coherent optical orthogonal frequency division multiplexing （CO-OFDM） systems. The IPTS algorithm further reduces computational complexity based on the partial transmission sequence （PTS） algorithm. TDNN is trained by the iterative clipping filtering （icf） method. Simulation results show that the proposed scheme achieves a PAPR reduction of 5.84 dB when complementary cumulative distribution function （CCDF） is 10-4and an extra transmission distance of 200 km for 10-3bit error rate （BER） compared to the original signals.

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World Impact of 3D Cell Models and Microphysiological Systems on Drug and Chemical Safety Assessment

World Impact of 3D Cell Models and Microphysiological System...

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中国毒理学会第七次全国毒理学大会暨第八届湖北科技论坛

作者： William Slikker Jr. national center for toxicological research U.S.Food and Drug Administration

Recent advances in biomedical research have offered a broad range of approaches and tools that enhance our capability to practice evidence-based medicine and evidence-based regulation and thereby to improve human health."Human-on-a-chip" and "human organ construct"micropHysiological systems are a new,emerging technology that has the potential to correlate in vivo with in vitro and simulate human organ *** human-on-a-chip technology basically uses in vitro human organ constructs in which the various cells *** chips and constructs are designed to reflect biological activity similar to the in vivo *** organ-on-a-chip can then be used to determine if drugs and chemicals can elicit in vitro the physiological activity of a human organ observed in *** microphysiological systems have the potential to be used to assess basic biology and physiology,as well as the pharmacology and toxicology of drugs and chemicals,to study organ-organ interactions,and/or to be used as a human disease model.

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