Linking gene expression to mechanisms of toxicity

Stevens, James; Liu, Hong; Halleck, Margaretann M.; Bowes, Russell C.; Chen, Qin Mary; Water, Bob van de

doi:10.1016/s0378-4274(99)00200-3

Cited by 24 publications

(21 citation statements)

References 33 publications

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“…The most important members of the Hsp70 family are the constitutive cytosolic Hsc70 (Hsp73), the inducible cytosolic Hsp70 (Hsp72), the Bip (Grp78) localized in the endoplasmic reticulum, the mHsp70 (Grp75, mortalin [24]) localized in the mitochondria, and the several bacterial homologues such as DnaK (in E. coli). By using ATP, and working in concert with other chaperones and co-chaperones, the members of the Hsp70-family take part in nearly all of the typical intracellular chaperone functions, including protein folding [21,22,30,38], refolding of damaged proteins [68], inhibition of aggregation [30,38], resolubilization of aggregated proteins [73], the transport of several proteins [30,38], and the control of several signal transduction pathways [9,60], including the induction of senescence [24]. Furthermore, Hsp70 proteins are also involved in many processes outside the cell, including cytoprotection [36,37,41], cytokine-releasing effects, and the modulation of various immune functions [39,51,53,54,64,65,72,76,84].…”

Section: Members Of the Hsp70 Molecular Chaperone Familymentioning

confidence: 99%

“…antibodies) and the surrounding cells, leading to tissue damage. Hsp70 may play a crucial role in defending these important molecules and tissues under these conditions by increasing the resistance of the cells against extracellular toxins [41], and decreasing the apoptotic and necrotic liability of the cells [36], and also because of its protein repair character (refolding ability) [68], the prevention of protein aggregation [30,38], and resolubilization of such aggregates [73].…”

Section: The Possible Defense Functions Of Salivary Hsp70 In Mucosal mentioning

confidence: 99%

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Potential immunological functions of salivary Hsp70 in mucosal and periodontal defense mechanisms

Fábían

Fejérdy

Nguyen

et al. 2007

Arch. Immunol. Ther. Exp.

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Molecular chaperones were considered to be intracellular, but there is increasing evidence demonstrating their cytoprotective and immune modulator properties outside the cell. The major extracellular chaperone (Hsp70) was also found in saliva, indicating a possible effect of Hsp70 on mucosal surfaces. Here we summarize the immune-modulatory role of the 70-kDa stress protein family, with special attention on the potential impact of salivary Hsp70 on oral defense mechanisms. There are three major facets of Hsp70-induced immune activation: 1) the appearance of Hsp70 on the surface of certain tumor cells or virally infected cells, leading to their phagocytosis and subsequent lysis; 2) the role of extracellular uncomplexed Hsp70 as a danger signal, leading to the secretion of proinflammatory cytokines from antigen-presenting cells and T lymphocytes and of nitric oxide from macrophages as well as to complement activation; 3) receptor-mediated uptake of peptide-loaded Hsp70 to antigen-presenting cells and cross-presentation of the Hsp70-peptide complex as an antigen to cytotoxic T cells and natural killer lymphocytes. The immune-activating effect of salivary Hsp70 may also be highly important in oral defense, especially in areas where molecular and cellular participants of the immune response appear on the surface of the oral cavity (i.e. several lesions of the mucosa and the periodontal tissues).

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Section: Members Of the Hsp70 Molecular Chaperone Familymentioning

confidence: 99%

Section: The Possible Defense Functions Of Salivary Hsp70 In Mucosal mentioning

confidence: 99%

Potential immunological functions of salivary Hsp70 in mucosal and periodontal defense mechanisms

Fábían

Fejérdy

Nguyen

et al. 2007

Arch. Immunol. Ther. Exp.

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“…Substantial oxidation of protein thiols is also observed, and exposure to the reducing agent DTT reverses iodoacetamide-induced protein oxidation and cytotoxicity (Chen and Stevens 1991;Liu et al 1996). Thus, depletion of GSH leading to protein oxidation has been proposed as the MoA for this reagent (Stevens et al 2000). Other alkylating agents, however, have different affinities for GSH versus GAPDH.…”

Section: Iodoacetamidementioning

confidence: 99%

SEURAT-1 liver gold reference compounds: a mechanism-based review

et al. 2014

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There is an urgent need for the development of alternative methods to replace animal testing for the prediction of repeat dose chemical toxicity. To address this need, the European Commission and Cosmetics Europe have jointly funded a research program for 'Safety Evaluation Ultimately Replacing Animal Testing.' The goal of this program was the development of in vitro cellular systems and associated computational capabilities for the prediction of hepatic, cardiac, renal, neuronal, muscle, and skin toxicities. An essential component of this effort is the choice of appropriate reference compounds that can be used in the development and validation of assays. In this review, we focus on the selection of reference compounds for liver pathologies in the broad categories of cytotoxicity and lipid disorders. Mitochondrial impairment, oxidative stress, and apoptosis are considered under the category of cytotoxicity, while steatosis, cholestasis, and phospholipidosis are considered under the category of lipid dysregulation. We focused on four compound classes capable of initiating such events, i.e., chemically reactive compounds, compounds with specific cellular targets, compounds that modulate lipid regulatory networks, and compounds that disrupt the plasma membrane. We describe the molecular mechanisms of these compounds and the cellular response networks which they elicit. This information will be helpful to both improve our understanding of mode of action and help in the selection of appropriate mechanistic biomarkers, allowing us to progress the development of animal-free models with improved predictivity to the human situation.

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“…Advances in gene expression technology provide the means to profile expression of thousands of messenger RNAs simultaneously, and similarly, the expression of proteins within a cell (66)(67)(68). Toxicology will benefit enormously from the application of genomics (transcriptomics, proteomics, metabolomics) to analyze chemically induced alterations in gene expression.…”

Section: Experimental Studies and Upcoming Technologiesmentioning

confidence: 99%

“…Once validated, the use of combined transcriptomics, proteomics, and metabolomics will make it possible to map early toxicity-related alterations in cells, tissues, or animals exposed to chemicals, and thus will lead to insight in numerous toxicologically relevant cellular processes simultaneously. Clearly, validation studies are crucial, and indeed, some have been performed (66,70,71). However, many more will have to follow to understand the strengths and limitations of this new very promising technology (72).…”

Section: Experimental Studies and Upcoming Technologiesmentioning

confidence: 99%