T-2 Toxin—The Most Toxic Trichothecene Mycotoxin: Metabolism,Toxicity, and Decontamination Strategies

Among trichothecenes, T-2 toxin is the most toxic fungal secondary metabolite produced by different Fusarium species. Moreover, T-2 is the most common cause of poisoning that results from the consumption of contaminated cereal-based food and feed reported among humans and animals. The food and feed most contaminated with T-2 toxin is made from wheat, barley, rye, oats, and maize. After exposition or ingestion, T-2 is immediately absorbed from the alimentary tract or through the respiratory mucosal membranes and transported to the liver as a primary organ responsible for toxin''s metabolism. Depending on the age, way of exposure, and dosage, intoxication manifests by vomiting, feed refusal, stomach necrosis, and skin irritation, which is rarely observed in case of mycotoxins intoxication. In order to eliminate T-2 toxin, various decontamination techniques have been found to mitigate the concentration of T-2 toxin in agricultural commodities. However, it is believed that 100% degradation of this toxin could be not possible. In this review, T-2 toxin toxicity, metabolism, and decontamination strategies are presented and discussed.     

Advances in Research on Bioactivity,Toxicity, Metabolism,and Pharmacokinetics of Usnic Acid In Vitro and In Vivo

Lichens are among the most widely distributed plants on earth and have the longest growth cycle. Usnic acid is an abundant characteristic secondary metabolite of lichens and the earliest lichen compound used commercially. It has diverse pharmacological activities, such as anti-inflammatory, antibacterial, antiviral, anticancer, antioxidant, and photoprotective effects, and promotes wound healing. It is widely used in dietary supplements, daily chemical products (fodder, dyes, food, perfumery, and cosmetics), and medicine. However, some studies have found that usnic acid can cause allergic dermatitis and drug-induced liver injury. In this paper, the bioactivity, toxicity, in vivo and in vitro metabolism, and pharmacokinetics of usnic acid were summarized. The aims were to develop and utilize usnic acid and provide reference for its future research.     

Androstenedione (a Natural Steroid and a Drug Supplement): A Comprehensive Review of Its Consumption,Metabolism, Health Effects,and Toxicity with Sex Differences

Androstenedione is a steroidal hormone produced in male and female gonads, as well as in the adrenal glands, and it is known for its key role in the production of estrogen and testosterone. Androstenedione is also sold as an oral supplement, that is being utilized to increase testosterone levels. Simply known as “andro” by athletes, it is commonly touted as a natural alternative to anabolic steroids. By boosting testosterone levels, it is thought to be an enhancer for athletic performance, build body muscles, reduce fats, increase energy, maintain healthy RBCs, and increase sexual performance. Nevertheless, several of these effects are not yet scientifically proven. Though commonly used as a supplement for body building, it is listed among performance-enhancing drugs (PEDs) which is banned by the World Anti-Doping Agency, as well as the International Olympic Committee. This review focuses on the action mechanism behind androstenedione’s health effects, and further side effects including clinical features, populations at risk, pharmacokinetics, metabolism, and toxicokinetics. A review of androstenedione regulation in drug doping is also presented.     

Garlic Root Biomass as Novel Biosorbents for Malachite Green Removal: Parameter Optimization,Process Kinetics and Toxicity Test

The potential of the agricultural waste garlic root to remove malachite green(MG) from aqueous solutions was evaluated. The adsorption of this dye onto garlic root was confirmed by means of Fourier transform infrared analysis(FTIR) and scanning electron microscopy(SEM). The equilibrium data fitted well into the Langmuir mo- del(R²>0.99), and the adsorption kinetics followed the pseudo-second-order equation(R²>0.99). The maximum adsorption capacities of MG onto the adsorbent were 172.41 and 232.56 mg/g with the addition of 1 and 2 g/L garlic root, respectively. The optimal conditions for MG removal were established on the basis of orthogonal experiments(OA₁₆ matrix). The concentrations of both MG and garlic root significantly affected the removal efficiency. The acute toxicity test indicated that the treated MG solutions were less toxic than the parent solutions. These results suggest that garlic root is a potential low-cost adsorbent for removing dye from industrial wastewater.     

QSAR for Acetylcholinesterase Inhibition and Toxicity of Two Classes of Phosphoramidothioates

Abstract

Methamidophos (Met) is a weak inhibitor of housefly head AChE but at the same time it is highly toxic to the common housefly. The lethality of Met is believed to be due to AChE inhibition. An extensive QSAR study may help in determining the mode of action of Met in vivo and in vitro and provide a rational for its high insecticidal toxicity. Acephate (Ace), like Met, is a poor inhibitor of AChE in vitro and has a comparable to Met insect toxicity in vivo. Contrary to Met, though, Ace has much lower mammalian toxicity. Understanding the structural properties which make insecticides toxic to insects but not to mammals is of great importance, since mammals (including humans) are inadvertently exposed to these compounds.

Our results were consistent with the model in which both the in vitro and in vivo toxicity of Met depends on the inhibition of the active center of AChE by the unchanged Met. An optimal susceptibility to hydrolysis is needed for Met and its analogs to have high insecticidal activity since in order to phosphorylate AChE they need to be hydrolyzed and at the same time their stability is of great importance in vivo for accumulating at the site of action. The insecticidal activity of Ace analogs may be due to direct interaction with the active center of the AChE. The mammalian toxicity of Ace analogs may be due to interaction with an 'allosteric' reaction center in the AChE.     

蛋白质相互作用预测、设计与调控

蛋白质相互作用是生命活动在分子水平上的基本事件. 蛋白质相互作用的三维图像可以给出关键生命活动过程的分子细节. 了解蛋白质相互作用的原理有助于揭示生命活动的机制, 并在此基础上开展有重要价值的蛋白质设计. 本文对于蛋白质相互作用预测、设计和调控研究的近期进展进行了总结归纳, 介绍了作者实验室在相关领域的研究进展, 并对今后的研究方向进行了展望. 主要包括: (1) 蛋白质相互作用网络、蛋白质相互作用机制和蛋白质复合物结构计算分析; (2) 基于序列、结合位点以及复合物结构的蛋白质相互作用预测; (3)蛋白质相互作用设计方法; (4) 利用化学分子调控蛋白质相互作用的方法; (5) 针对蛋白质相互作用的蛋白质药物设计方法.     

Triazine Dendrimers for Drug Delivery: Evaluation of Solubilization Properties,Activity in Cell Culture,and In Vivo Toxicity of a Candidate Vehicle

Three criteria are evaluated to assess the potential of a dendrimer based on triazines, 1, for use as a vehicle for drug delivery. These criteria are: (1) its ability to solubilize small hydrophobic guests as measured spectrophotometrically; (2) its ability to deliver a drug in vitro as evaluated using a gene reporter assay; and (3) its in vivo toxicity in mice as determined by autopsy and screens of liver and kidney function. Vehicle 1 solubilizes pyrene to a similar extent to dendrimers based on poly(arylether)s, 4, encapsulating approximately 0.2 molecules of pyrene per dendrimer. This activity is approximately 10-fold greater than that of the more polar poly(propyleneimine) and poly(amidoamine) dendrimers, 2 and 3. Gas-phase computational models reveal that both 1 and 4 have cores that are accessible to solvent, suggesting that these dendrimers can occupy much greater volumes than 2 and 3 whose cores are confined toward the interior of the structure. Electrostatic potential maps can be used to rationalize differences in solubilization between 1 and 4. Precipitation results from mixing cationic 1 with the anionic indomethacin, but not with methotrexate, suggesting that the composition of the drug may dictate the scope of delivery applications. Dendrimer 1 solubilizes 10-hydroxycamptothecin and a novel bisindolemethane; approximately four and five molecules of drug per dendrimer are solubilized, respectively. In cell-culture experiments using a luciferase reporter gene assay, the dendrimer:bisindolemethane conjugate shows comparable activity to the bisindolemethane delivered in aqueous DMSO, suggesting that the dendrimer does not preclude delivery of the molecule to an intracellular target. Preliminary toxicology studies of 1 in mice show that this molecule has no adverse toxicity to the kidneys or the liver in single doses delivered intraperitoneally up to 10?mg/kg.     

Advances in Star‐Shaped π‐Conjugated Systems: Properties and Applications

Until recently π‐conjugated organic materials are based mainly on linear systems. Recent years, however, have brought about increasing interest in molecules boasting a dendritic, branched, or star‐shaped architecture. This tendency is a direct result of the ongoing search for materials with progressively better properties. Such compounds, featuring novel, 3D architectures, exhibit a multitude of interesting qualities, making them stand out from well‐known materials. The direction of star‐shaped compound application is determined by whether they are able to form aggregates, π‐stacks. This feature is a source of some astounding properties, coveted in numerous applications. Among this class of compounds high charge mobility, high fluorescence efficiency, and good charge separation are all found. Depending on the structure of the core, the molecule may adopt various types of symmetry. Similarly, the conjugation of orbitals may extend over the whole structure or be interrupted at chosen segments. The number of papers pertaining to star‐shaped oligomers and polymers is ascending with each year, evidencing a growing interest in them. Consequently, this Review focuses particularly on the most recent reports concerning modification of the structure and properties of the aforementioned type of compounds, as well as on the development of devices based on them.

     

Globally Approved EGFR Inhibitors: Insights into Their Syntheses,Target Kinases,Biological Activities,Receptor Interactions,and Metabolism

Targeting the EGFR with small-molecule inhibitors is a confirmed valid strategy in cancer therapy. Since the FDA approval of the first EGFR-TKI, erlotinib, great efforts have been devoted to the discovery of new potent inhibitors. Until now, fourteen EGFR small-molecule inhibitors have been globally approved for the treatment of different types of cancers. Although these drugs showed high efficacy in cancer therapy, EGFR mutations have emerged as a big challenge for these drugs. In this review, we focus on the EGFR small-molecule inhibitors that have been approved for clinical uses in cancer therapy. These drugs are classified based on their chemical structures, target kinases, and pharmacological uses. The synthetic routes of these drugs are also discussed. The crystal structures of these drugs with their target kinases are also summarized and their bonding modes and interactions are visualized. Based on their binding interactions with the EGFR, these drugs are also classified into reversible and irreversible inhibitors. The cytotoxicity of these drugs against different types of cancer cell lines is also summarized. In addition, the proposed metabolic pathways and metabolites of the fourteen drugs are discussed, with a primary focus on the active and reactive metabolites. Taken together, this review highlights the syntheses, target kinases, crystal structures, binding interactions, cytotoxicity, and metabolism of the fourteen globally approved EGFR inhibitors. These data should greatly help in the design of new EGFR inhibitors.     

APTox: 化学混合物毒性评估与预测

真实环境中化学混合物的存在是普遍规律. 化学混合物联合效应具有与单个组分不同的变化规律, 目前缺少有效方法学与可靠基础数据. 近年来, 我们试图探索建立化学混合物毒性评估与预测(APTox)的方法体系. 发展了微板毒性分析法(MTA)以提高测试数据精密度, 创建了直接均分射线(EquRay)与均匀设计射线(UD-Ray)法来有效表征混合物浓度组成, 建立了支持向量回归(SVR)技术拟合不同形状浓度-效应曲线, 提出了将实验混合物整体剂量-效应曲线(CRC)与加和参考模型预测CRC比较以评价混合物毒性相互作用的方法, 集成多种技术设计开发了化学混合物毒性评估与预测的应用程序.     

硝酸盐型卤水体系的综合热力学模型与多温相图预测

硝酸盐型卤水是盐湖卤水、 硝酸盐工业、 废水处理中普遍遇到的电解质溶液体系. 硝酸盐具有极高的溶解度, 实现硝酸盐型复杂电解质体系物性和相平衡的精准热力学表达依然具有挑战性. 以煤化工废水的典型体系Na⁺//NO₃^- , Cl^-, SO₄^{2 -} -H₂O为对象, 以改进的eNRTL模型为基础, 由活度系数模型、 溶液物性模型、 物种热力学模型和固液相平衡模型构成了电解质体系的综合热力学模型. 利用二元体系的冰点、 饱和蒸汽压、 等压摩尔热容、 活度系数和渗透压系数等物性数据和三元体系等温相平衡数据, 采用多目标优化方法, 获得了表达研究体系的多温特性的12组液相特征参数和7个固相物种的热力学参数. 据此完成了3个二元体系、 3个三元体系等温相平衡的准确计算和三元、 四元完整相图的预测, 适用温度达到实验所及的全部温度范围(254.65~543.15 K); 适用浓度达到饱和程度, 其中NaNO₃的浓度高达226.88 mol/kg. 三元、 四元体系的多温相图预测结果与实验数据相吻合, 并给出了9个三元、 5个四元体系零变点的完整信息.     

Enantioselectivity in Drug Pharmacokinetics and Toxicity: Pharmacological Relevance and Analytical Methods

Enzymes, receptors, and other binding molecules in biological processes can recognize enantiomers as different molecular entities, due to their different dissociation constants, leading to diverse responses in biological processes. Enantioselectivity can be observed in drugs pharmacodynamics and in pharmacokinetic (absorption, distribution, metabolism, and excretion), especially in metabolic profile and in toxicity mechanisms. The stereoisomers of a drug can undergo to different metabolic pathways due to different enzyme systems, resulting in different types and/or number of metabolites. The configuration of enantiomers can cause unexpected effects, related to changes as unidirectional or bidirectional inversion that can occur during pharmacokinetic processes. The choice of models for pharmacokinetic studies as well as the subsequent data interpretation must also be aware of genetic factors (such as polymorphic metabolic enzymes), sex, patient age, hepatic diseases, and drug interactions. Therefore, the pharmacokinetics and toxicity of a racemate or an enantiomerically pure drug are not equal and need to be studied. Enantioselective analytical methods are crucial to monitor pharmacokinetic events and for acquisition of accurate data to better understand the role of the stereochemistry in pharmacokinetics and toxicity. The complexity of merging the best enantioseparation conditions with the selected sample matrix and the intended goal of the analysis is a challenge task. The data gathered in this review intend to reinforce the importance of the enantioselectivity in pharmacokinetic processes and reunite innovative enantioselective analytical methods applied in pharmacokinetic studies. An assorted variety of methods are herein briefly discussed.     

Comparative Metabolism of Mequindox in Liver Microsomes,Hepatocytes, and Intestinal Microflora of Chicken

Drug metabolism studies in vitro were carried out inexpensively and readily to serve as an adequate mechanism to characterize drug metabolites, elucidate their pathways, and make suggestions for further testing in vivo. In this work, the comparative metabolism of mequindox (MEQ) was investigated in vitro by incubation with chicken liver microsomes, hepatocytes, and intestinal microflora, followed by analysis using ultra-performance liquid chromatography coupled with electrospray ionization hybrid quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) for structure identification. There were 12 metabolites detected when MEQ was incubated with liver microsomes, 6 metabolites with the hepatocytes and 4 metabolites with intestinal microflora, respectively. The major metabolites in liver microsomes were bideoxymequindox and 2-isoethanol-N1-deoxymequindox, and that in hepatocytes were 2-isoethanol mequindox and 2-isoethanol-N1-deoxymequindox, but in intestinal incubations, N1-deoxymequindox and bideoxymequindox were the major metabolites. The results indicated that the metabolism of MEQ was active in vitro; meanwhile, revealed the main metabolic pathways of MEQ were N→O group reduction, carbonyl reduction and hydroxylation reaction. The information regarding in vitro metabolism of MEQ provided a better understanding of the role of the liver and intestinal tract in the disposition of MEQ.     

Raman Microspectroscopic Evidence for the Metabolism of a Tyrosine Kinase Inhibitor,Neratinib, in Cancer Cells

Tyrosine kinase receptors are one of the main targets in cancer therapy. They play an essential role in the modulation of growth factor signaling and thereby inducing cell proliferation and growth. Tyrosine kinase inhibitors such as neratinib bind to EGFR and HER2 receptors and exhibit antitumor activity. However, little is known about their detailed cellular uptake and metabolism. Here, we report for the first time the intracellular spatial distribution and metabolism of neratinib in different cancer cells using label‐free Raman imaging. Two new neratinib metabolites were detected and fluorescence imaging of the same cells indicate that neratinib accumulates in lysosomes. The results also suggest that both EGFR and HER2 follow the classical endosome lysosomal pathway for degradation. A combination of Raman microscopy, DFT calculations, and LC‐MS was used to identify the chemical structure of neratinib metabolites. These results show the potential of Raman microscopy to study drug pharmacokinetics.     

Molecular Modification of Benzophenone Derivatives for Lower Bioenrichment and Toxicity Through the Pharmacophore Model

In this study, we used the improved extreme-difference normalization method to calculate the comprehensive evaluation values of bioenrichment and toxicity of benzophenone UV light absor-bers(BPs). Based on this parameter, a 3D-QSAR(QSAR=quantitative structure activity relationship) pharmacophore model was constructed using Discovery Studio software and applied to the mole-cular modification of BPs. With three commonly used ingredients in sunscreen 2-hydroxy-4-methoxybenzophenone(BP-3), 2,2'-dihydroxy-4,4'-dimethoxybenzophenone(BP-6) and 2,2'-dihydroxy-4-methoxybenzophenone(BP-8) as target molecules, we performed BPs substitution reaction based on the binding positions of characteristic elements of the pharmacophore model and designed BP derivatives with reduced bioenrichment and toxicity. Stability and function evaluation showed that while the stability of 6 BP derivatives was enhanced, the light absorption capacity was also significantly enhanced(from 9.16% to 43.16%). Molecular dynamics simulation results showed that the binding ability of BP-609 molecule with serum albumin was reduced by 16.37% compared with BP-6, and the binding with collagen could not occur spontaneously, which could be used as an explanation for the simultaneous reduction of its bioenrichment and toxicity. Besides, through the simulation of human metabolism, it was found that the liver metabolites of BP-609 were less toxic, which reduced the potential risk of human metabolism. It proved that the molecular modification scheme of BPs was environment-friendly.     

Development,Characterization and Application of Predictive-Toxicology Models

Abstract

The adoption of SAR techniques for risk assessment purposes requires that the predictive performance of models be characterized and optimized. The development of such methods with respect to CASE/MULTICASE are described. Moreover the effects of size, informational content, ratio of actives/inactives in the model on predictivity must be determined.

Characterized models can provide mechanistic insights: nature of toxicophore, reactivity, receptor binding. Comparison of toxicophores among SAR models allows a determination of mechanistic overlaps (e.g., mutagenicity, toxicity, inhibition of gap junctional intercellular communication vs. carcinogenicity).

Methods have been developed to combine SAR submodels and thereby improve predictive performance.

Now that predictive toxicology methods are gaining acceptance, the development of Good Laboratory Practices is a further priority, as is the development of graduate programs in Computational Toxicology to adequately train the needed professional.     

Analysis of Fatty Acid, and Lipoprotein, Metabolism by GC and HPLC: Effect of Low-Density Lipoprotein Apheresis

 Blood samples from 5 hyperlipidemic patients on chronic treatment with low-density lipoprotein (LDL) – apheresis were analysed for lipids and fatty acids in serum, lipoprotein fractions and erythrocyte membrane by capillary gas chromatography (GC), reversed-phase high-performance liquid chromatography (LC), spectrofluorometry and spectrophotometry. LDL-apheresis has been associated with significant changes of fatty acids metabolism in relation to triglyceride-rich lipoproteins. Oleic acid may exert its hypotriglyceridemic effect via VLDL, IDL, LDL and HDL fractions. Polyunsaturated fatty acids, associated with triglyceride metabolism via IDL or VLDL, are linoleic, gamma-linolenic and docosahexaenoic fatty acids. Received November 25, 1999. Revision September 5, 2000.     

Computational Design of High Energy RDX-Based Derivatives: Property Prediction,Intermolecular Interactions,and Decomposition Mechanisms

A series of new high-energy insensitive compounds were designed based on 1,3,5-trinitro-1,3,5-triazinane (RDX) skeleton through incorporating -N(NO₂)-CH₂-N(NO₂)-, -N(NH₂)-, -N(NO₂)-, and -O- linkages. Then, their electronic structures, heats of formation, detonation properties, and impact sensitivities were analyzed and predicted using DFT. The types of intermolecular interactions between their bimolecular assemble were analyzed. The thermal decomposition of one compound with excellent performance was studied through ab initio molecular dynamics simulations. All the designed compounds exhibit excellent detonation properties superior to 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane (CL-20), and lower impact sensitivity than CL-20. Thus, they may be viewed as promising candidates for high energy density compounds. Overall, our design strategy that the construction of bicyclic or cage compounds based on the RDX framework through incorporating the intermolecular linkages is very beneficial for developing novel energetic compounds with excellent detonation performance and low sensitivity.