Authors:Vibha Shukla; Somya Asthana; Parul Gupta; Premendra D. Dwivedi; Anurag Tripathi; Mukul Das Pages: 1 - 50 Abstract: Publication date: 2017 Source:Advances in Molecular Toxicology, Volume 11 Author(s): Vibha Shukla, Somya Asthana, Parul Gupta, Premendra D. Dwivedi, Anurag Tripathi, Mukul Das Among the vast array of secondary metabolites produced by plants, anthraquinones (AQs) are the group of compounds produced by different plants of various families such as Polygonaceae, Rhamnaceae, Rubiaceae, Fabaceae, Xanthorrhoeaceae, Leguminosae, and Liliacae. Owing to their biological and chemical diversity, AQs have wide industrial applications in food, pharmaceutical, and paper industries. Despite their diverse application, anthraquinones have been reported to be toxic to experimental animals. However, very little is known about their toxicity on the human population. In this chapter, the metabolic routes for the biosynthesis of AQs in plants have been described. Efforts have been focused on the profile of AQs present in different plant species and their toxic effects on the various animal models and in humans.
Authors:Yan Jiang; Yufei Dai; Tao Chen Pages: 51 - 79 Abstract: Publication date: 2017 Source:Advances in Molecular Toxicology, Volume 11 Author(s): Yan Jiang, Yufei Dai, Tao Chen Trichloroethylene (TCE) is a widely used industrial solvent and a common environmental contaminant. It has been reported that TCE exposure is associated with a wide range of diseases, including cancer, immune system diseases, and congenital heart defect. TCE is metabolized in vivo through two main pathways, Cytochrome P450-dependent oxidation and glutathione conjugation. The adverse effects of TCE in different target tissues may be partly due to specific reactive metabolites. In this review, we will evaluate the evidence on carcinogenicity, immunotoxicity, and cardiac developmental toxicity of TCE and will discuss the potential underlying molecule mechanisms.
Authors:Kandatege Wimalasena Pages: 81 - 122 Abstract: Publication date: 2017 Source:Advances in Molecular Toxicology, Volume 11 Author(s): Kandatege Wimalasena Among Parkinson's disease (PD) toxin models, MPTP/MPP+ has been the most popular, extensively characterized, and widely used to identify the cellular mechanisms associated with the selective degeneration of dopaminergic neurons in PD. A number of recent studies have found some gaps and weaknesses in the generally accepted mechanism especially with regard to the selective dopaminergic toxicity of the model. Accumulating evidence suggests that the inherent physiological predisposition of dopaminergic neurons to generate high oxidative stress, especially when exposed to various environmental and genetic factors and their inability to cope with these conditions effectively, could contribute to their selective destruction. However, the current models for the selective dopaminergic toxicity of MPTP/MPP+ have not taken into account the unique susceptibilities of these neurons. The focus of this chapter is to discuss the discovery, current status, gaps, and weaknesses of the mechanism of the specific dopaminergic toxicity of the MPTP/MPP+ model.
Authors:Audronė V. Kalvelytė; Aušra Imbrasaitė; Natalija Krestnikova; Aurimas Stulpinas Pages: 123 - 202 Abstract: Publication date: 2017 Source:Advances in Molecular Toxicology, Volume 11 Author(s): Audronė V. Kalvelytė, Aušra Imbrasaitė, Natalija Krestnikova, Aurimas Stulpinas This chapter first describes the potential of stem cells in diverse biopharmaceutical applications, such as replacement therapy, disease modeling, and drug development. On the other hand, stem cells can become the targets of various potential toxicities in the body. In this context, an overview of stem cells as objects in toxicology as well as various experimental approaches to analyze the effects of toxic substances including anticancer drugs is presented, single-cell methods and natural microenvironment-mimicking models among them. Further, anticancer drugs (both conventional and targeted) and their molecular targets are described, with advances and challenges in their use as well as current directions in their combination and development. Then, recent knowledge about adult stem cell response to anticancer therapy is presented, paying attention to the molecular mechanisms of cell death induction and resistance, and uncovering the possible role of stem cell differentiation state during the anticancer treatment. Finally, various ideas, suggestions, and experimental data to protect adult stem cells during cancer therapy are presented.
Authors:Matthew B. Murphy; Susan L. Mercer; Joseph E. Deweese Pages: 203 - 240 Abstract: Publication date: 2017 Source:Advances in Molecular Toxicology, Volume 11 Author(s): Matthew B. Murphy, Susan L. Mercer, Joseph E. Deweese Topoisomerases are critical cellular enzymes involved in the regulation of DNA topology. These enzymes generate transient single- (type I) and double-strand (type II) DNA breaks in order to relieve topological strain due to replication, transcription, and chromosome segregation. Disruption of topoisomerase activity has been used as a target of antineoplastic therapy for several decades. While some agents have been used for over 30 years, many new compounds continue to be explored. This chapter will focus on reviewing the function, mechanism, and targeting of mammalian type II topoisomerases. In particular, we will highlight newer compounds that are under examination and explore new strategies for targeting topoisomerase II in humans that may provide alternatives to existing therapies.
Authors:Ye Tian; Jiang Zheng Pages: 241 - 272 Abstract: Publication date: 2017 Source:Advances in Molecular Toxicology, Volume 11 Author(s): Ye Tian, Jiang Zheng This chapter introduces the bioactivation and toxicity of bis-benzylisoquinoline alkaloid, particularly their pulmonary toxicity. It starts with a brief description of pharmacological activities of bis-benzylisoquinoline alkaloids, followed by mechanisms of metabolic activation of para-methylene phenol containing compounds and the interactions of reactive metabolites of isoquinoline alkaloids with proteins. A total of four bis-benzylisoquinoline alkaloids, i.e., dauricine, tetrandrine, neferine, and berbamine are discussed as examples. The chapter covers (1) the natural source and pharmacological activities of the bis-benzylisoquinoline alkaloids; (2) identification of reactive metabolites and major cytochromes P450 involved in the metabolic activation of the para-methylene phenol containing compounds; and (3) protein modifications induced by the reactive metabolites of the isoquinoline alkaloids. It also describes a newly developed approach to screen potentially harmful para-methylene phenol containing compounds from complicated mixtures.
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